%0 journal article %@ 2222-1751 %A Zhang, B.,Xu, X.,Song, X.,Wen, Y.,Zhu, Z.,Lv, J.,Xie, X.,Chen, L.,Tang, Y.-W.,Du, H. %D 2022 %J Emerging Microbes & Infections %N 1 %P 2735-2745 %R doi:10.1080/22221751.2022.2140609 %T Emerging and re-emerging KPC-producing hypervirulent Pseudomonas aeruginosa ST697 and ST463 between 2010 and 2021 %U https://doi.org/10.1080/22221751.2022.2140609 1 %X Carbapenem-resistant Pseudomonas aeruginosa (CRPA) has been a major threat to human health due to its increased morbidity and mortality in clinical settings. Carbapenemase genes are less frequently found in CRPA compared with carbapenem-resistant Enterobacterales, of which carbapenemase producers are common. In this study, we identified 11 blaKPC-2-harbouring P. aeruginosa isolates from 139 carbapenemase-insensitive P. aeruginosa isolates collected between 2010 and 2021 in a tertiary hospital in China. Nine isolates belonged to ST697, while the other two were ST463. The antibiotic susceptibility testing showed that all the isolates were multidrug resistant, including resistance to imipenem, meropenem, ceftazidime, and tigecycline. Patients with Klebsiella pneumoniae carbapenemase-2 (KPC-2)-producing P. aeruginosa infections were mostly associated with complicated diseases and prolonged hospital stay, with 30% deterioration. The whole-genome sequencing analysis showed that these isolates carried multiple antibiotic resistance genes and virulence genes, and the KPC-2 genetic elements were highly related in ST697 isolates. The complete sequencing of ST697 isolate SE5416 showed that the harbouring of blaKPC-2 resulted from complex transposition and homologous recombination of an IncpRBL16 plasmid and other mobile elements. The Galleria mellonella infection model experiment showed that these KPC-2-producing P. aeruginosa–infected larvae had low survival rates and high virulence. The present study revealed the shifting of CRPA from ST697 to ST463 in East China; ST463 had higher drug resistance, posing greater challenges for clinical management. %0 journal article %@ 2352-4928 %A Mazurek-Budzyńska, M.,Behl, M.,Neumann, R.,Lendlein, A. %D 2022 %J Materials Today Communications %N %P 102966 %R doi:10.1016/j.mtcomm.2021.102966 %T 4D-actuators by 3D-printing combined with water-based curing %U https://doi.org/10.1016/j.mtcomm.2021.102966 %X The shape and the actuation capability of state of the art robotic devices typically relies on multimaterial systems from a combination of geometry determining materials and actuation components. Here, we present multifunctional 4D-actuators processable by 3D-printing, in which the actuator functionality is integrated into the shaped body. The materials are based on crosslinked poly(carbonate-urea-urethane) networks (PCUU), synthesized in an integrated process, applying reactive extrusion and subsequent water-based curing. Actuation capability could be added to the PCUU, prepared from aliphatic oligocarbonate diol, isophorone diisocyanate (IPDI) and water, in a thermomechanical programming process. When programmed with a strain of εprog = 1400% the PCUU networks exhibited actuation apparent by reversible elongation ε'rev of up to 22%. In a gripper a reversible bending ε'rev(bend) in the range of 37–60% was achieved when the actuation temperature (Thigh) was varied between 45 °C and 49 °C. The integration of actuation and shape formation could be impressively demonstrated in two PCUU-based reversible fastening systems, which were able to hold weights of up to 1.1 kg. In this way, the multifunctional materials are interesting candidate materials for robotic applications where a freedom in shape design and actuation is required as well as for sustainable fastening systems. %0 journal article %@ 2329-0501 %A Peter, L.,Wendering, D.J.,Schlickeiser, S.,Hoffmann, H.,Noster, R.,Wagner, D.L.,Zarrinrad, G.,Münch, S.,Picht, S.,Schulenberg, S.,Moradian, H.,Mashreghi, M.-F.,Klein, O.,Gossen, M.,Roch, T.,Babel, N.,Reinke, P.,Volk, H.-D.,Amini, L.,Schmueck-Henneresse, M. %D 2022 %J Molecular Therapy. Methods & Clinical Development %N %P 52-73 %R doi:10.1016/j.omtm.2022.02.012 %T Tacrolimus-resistant SARS-CoV-2-specific T cell products to prevent and treat severe COVID-19 in immunosuppressed patients %U https://doi.org/10.1016/j.omtm.2022.02.012 %X Solid organ transplant (SOT) recipients receive therapeutic immunosuppression that compromises their immune response to infections and vaccines. For this reason, SOT patients have a high risk of developing severe coronavirus disease 2019 (COVID-19) and an increased risk of death from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Moreover, the efficiency of immunotherapies and vaccines is reduced due to the constant immunosuppression in this patient group. Here, we propose adoptive transfer of SARS-CoV-2-specific T cells made resistant to a common immunosuppressant, tacrolimus, for optimized performance in the immunosuppressed patient. Using a ribonucleoprotein approach of CRISPR-Cas9 technology, we have generated tacrolimus-resistant SARS-CoV-2-specific T cell products from convalescent donors and demonstrate their specificity and function through characterizations at the single-cell level, including flow cytometry, single-cell RNA (scRNA) Cellular Indexing of Transcriptomes and Epitopes (CITE), and T cell receptor (TCR) sequencing analyses. Based on the promising results, we aim for clinical validation of this approach in transplant recipients. Additionally, we propose a combinatory approach with tacrolimus, to prevent an overshooting immune response manifested as bystander T cell activation in the setting of severe COVID-19 immunopathology, and tacrolimus-resistant SARS-CoV-2-specific T cell products, allowing for efficient clearance of viral infection. Our strategy has the potential to prevent severe COVID-19 courses in SOT or autoimmunity settings and to prevent immunopathology while providing viral clearance in severe non-transplant COVID-19 cases. %0 journal article %@ 2470-1343 %A Herrera, K.,Morales, L.F.,Tarazona, N.A.,Aguado, R.,Saldarriaga, J.F. %D 2022 %J ACS Omega %N 9 %P 7625-7637 %R doi:10.1021/acsomega.1c06147 %T Use of Biochar from Rice Husk Pyrolysis: Part A: Recovery as an Adsorbent in the Removal of Emerging Compounds %U https://doi.org/10.1021/acsomega.1c06147 9 %X One of the main products of pyrolysis is char. For the better performance and improvement of its physicochemical properties, it is necessary to make temperature changes. In this study, different temperatures have been tested for the pyrolysis of rice husk, and the biochar obtained from the process went through an evaluation to test its yield in the removal of emerging compounds such as azithromycin (AZT) and erythromycin (ERY). For this, pyrolysis of rice husk has been carried out at temperatures of 450, 500, 550, and 600 °C, and the biochars have been characterized by ultimate analysis and proximate analysis, as well as specific surface area tests. Then, different adsorption tests have been carried out with a 200 mg L–1 drug (AZT and ERY) solution prepared in the laboratory. All biochars have been found to present removal percentages higher than 95%. Therefore, obtaining biochar from rice husk at any temperature and using it in the removal of high-molecular-weight compounds are quite suitable. %0 journal article %@ 1932-6254 %A Rasińska, J.,Klein, C.,Stahn, L.,Maidhof, F.,Pfeffer, A.,Schreyer, S.,Gossen, M.,Kurtz, A.,Steiner, B.,Hemmati-Sadeghi, S. %D 2022 %J Journal of Tissue Engineering and Regenerative Medicine %N 6 %P 515-529 %R doi:10.1002/term.3296 %T Transposon-mediated glial cell line-derived neurotrophic factor overexpression in human adipose tissue-derived mesenchymal stromal cells: A potential approach for neuroregenerative medicine? %U https://doi.org/10.1002/term.3296 6 %X Glial cell line-derived neurotrophic factor (GDNF) has neuroprotective effects and may be a promising candidate for regenerative strategies focusing on neurodegenerative diseases. As GDNF cannot cross the blood–brain barrier to potentially regenerate damaged brain areas, continuous in situ delivery with host cells is desired. Here, a non-viral Sleeping Beauty transposon was used to achieve continuous in vitro overexpression of GDNF in immune-privileged human adipose tissue-derived mesenchymal stromal cells (GDNF-tASCs). In addition, in vivo survival, tolerance, and effectiveness of transfected cells were tested in a very mild 6-hydroxydopamine (6-OHDA)-induced dopamine depletion rat model by means of intrastriatal injection on a sample basis up to 6 months after treatment. GDNF-tASCs showed vast in vitro gene overexpression up to 13 weeks post-transfection. In vivo, GDNF was detectable 4 days following transplantation, but no longer after 1 month, although adipose tissue-derived mesenchymal stromal cells (ASCs) could be visualized histologically even after 6 months. Despite successful long-term in vitro GDNF overexpression and its in vivo detection shortly after cell transplantation, the 6-OHDA model was too mild to enable sufficient evaluation of in vivo disease improvement. Still, in vivo immunocompatibility could be further examined. ASCs initially induced a pronounced microglial accumulation at transplantation site, particularly prominent in GDNF-tASCs. However, 6-OHDA-induced pro-inflammatory immune response was attenuated by ASCs, although delayed in the GDNF-tASCs group. To further test the therapeutic potential of the generated GDNF-overexpressing cells in a disease-related context, a follow-up study using a more appropriate 6-OHDA model is needed. %0 journal article %@ 2047-9980 %A Beyhoff, N.,Zhu, M.,Zanders, L.,Leistner, D.M.,Nobles, A.,Schroeder, M.,Barbieri, F.,Landmesser, U.,Reinthaler, M. %D 2022 %J Journal of the American Heart Association %N 4 %P e023757 %R doi:10.1161/JAHA.121.023757 %T Teleproctoring for Training in Structural Heart Interventions: Initial Real‐World Experience During the COVID‐19 Pandemic %U https://doi.org/10.1161/JAHA.121.023757 4 %X Background,Proctoring represents a cornerstone in the acquisition of state‐of‐the‐art cardiovascular interventions. Yet, travel restrictions and containment measures during the COVID‐19 pandemic limited on‐site proctoring for training and expert support in interventional cardiology.,Methods and Results,We established a teleproctoring setup for training in a novel patent foramen ovale closure device system (NobleStitch EL, HeartStitch Inc, Fountain Valley, CA) at our institution using web‐based real‐time bidirectional audiovisual communication. A total of 6 patients with prior paradoxical embolic stroke and a right‐to‐left shunt of grade 2 or 3 were treated under remote proctorship after 3 cases were performed successfully under on‐site proctorship. No major device/procedure‐related adverse events occurred, and none of the patients had a residual right‐to‐left shunt of grade 1 or higher after the procedure. Additionally, we sought to provide an overview of current evidence available for teleproctoring in interventional cardiology. Literature review was performed identifying 6 previous reports on teleproctoring for cardiovascular interventions, most of which were related to the current COVID‐19 pandemic. In all reports, teleproctoring was carried out in similar settings with comparable setups; no major adverse events were reported.,Conclusions,Teleproctoring may represent a feasible and safe tool for location‐independent and cost‐effective training in a novel patent foramen ovale closure device system. Future prospective trials comparing teleproctoring with traditional on‐site proctoring are warranted. %0 journal article %@ 0884-2914 %A Hoffmann, F.,Machatschek, R.,Lendlein, A. %D 2022 %J Journal of Materials Research %N %P 1093-1101 %R doi:10.1557/s43578-022-00495-4 %T Analytical model and Monte Carlo simulations of polymer degradation with improved chain cut statistics %U https://doi.org/10.1557/s43578-022-00495-4 %X The degradation of polymers is described by mathematical models based on bond cleavage statistics including the decreasing probability of chain cuts with decreasing average chain length. We derive equations for the degradation of chains under a random chain cut and a chain end cut mechanism, which are compared to existing models. The results are used to predict the influence of internal molecular parameters. It is shown that both chain cut mechanisms lead to a similar shape of the mass or molecular mass loss curve. A characteristic time is derived, which can be used to extract the maximum length of soluble fragments l of the polymer. We show that the complete description is needed to extract the degradation rate constant k from the molecular mass loss curve and that l can be used to design polymers that lose less mechanical stability before entering the mass loss phase. %0 journal article %@ 2159-6859 %A Moradian, H.,Gossen, M.,Lendlein, A. %D 2022 %J MRS Communications %N %P 145-153 %R doi:10.1557/s43579-021-00128-7 %T Co-delivery of genes can be confounded by bicistronic vector design %U https://doi.org/10.1557/s43579-021-00128-7 %X Maximizing the efficiency of nanocarrier-mediated co-delivery of genes for co-expression in the same cell is critical for many applications. Strategies to maximize co-delivery of nucleic acids (NA) focused largely on carrier systems, with little attention towards payload composition itself. Here, we investigated the effects of different payload designs: co-delivery of two individual “monocistronic” NAs versus a single bicistronic NA comprising two genes separated by a 2A self-cleavage site. Unexpectedly, co-delivery via the monocistronic design resulted in a higher percentage of co-expressing cells, while predictive co-expression via the bicistronic design remained elusive. Our results will aid the application-dependent selection of the optimal methodology for co-delivery of genes. %0 journal article %@ 2059-8521 %A Zhang, S.,Liu, Y.,Machatschek, R.,Lendlein, A. %D 2022 %J MRS Advances %N 4 %P 56-62 %R doi:10.1557/s43580-021-00160-8 %T Ultrathin collagen type I films formed at the air-water interface %U https://doi.org/10.1557/s43580-021-00160-8 4 %X Collagen-based biomaterials with oriented fibrils have shown great application potential in medicine. However, it is still challenging to control the type I collagen fibrillogenesis in ultrathin films. Here, we report an approach to produce cohesive and well-organized type I collagen ultrathin films of about 10 nm thickness using the Langmuir-Blodgett technique. Ellipsometry, rheology, and Brewster angle microscopy are applied to investigate in situ how the molecules behave at the air-water interface, both at room temperature and 37 °C. The interfacial storage modulus observed at room temperature vanishes upon heating, indicating the existence and disappearance of the network structure in the protein nanosheet. The films were spanning over holes as large as 1 mm diameter when transferred at room temperature, proving the strong cohesive interactions. A highly aligned and fibrillar structure was observed by atomic force microscopy (AFM) and optical microscopy. %0 journal article %@ 2329-2237 %A Tarazona, N.,Machatschek, R.,Balcucho, J.,Castro-Mayorga, J.,Saldarriaga, J.,Lendlein, A. %D 2022 %J MRS Energy & Sustainability %N %P 28-34 %R doi:10.1557/s43581-021-00015-7 %T Opportunities and challenges for integrating the development of sustainable polymer materials within an international circular (bio)economy concept %U https://doi.org/10.1557/s43581-021-00015-7 %X Leading-edge polymer-based materials for consumer and advanced applications are necessary to achieve sustainable development at a global scale. It is essential to understand how sustainability can be incorporated in these materials via green chemistry, the integration of bio-based building blocks from biorefineries, circular bioeconomy strategies, and combined smart and functional capabilities. %0 journal article %@ 2196-7350 %A Tartivel, L.,Blocki, A.,Braune, S.,Jung, F.,Behl, M.,Lendlein, A. %D 2022 %J Advanced Materials Interfaces %N 6 %P 2101588 %R doi:10.1002/admi.202101588 %T An Inverse Shape-Memory Hydrogel Scaffold Switching Upon Cooling in a Tissue-Tolerated Temperature Range %U https://doi.org/10.1002/admi.202101588 6 %X Tissue reconstruction has an unmet need for soft active scaffolds that enable gentle loading with regeneration-directing bioactive components by soaking up but also provide macroscopic dimensional stability. Here microporous hydrogels capable of an inverse shape-memory effect (iSME) are described, which in contrast to classical shape-memory polymers (SMPs) recover their permanent shape upon cooling. These hydrogels are designed as covalently photo cross-linked polymer networks with oligo(ethylene glycol)-oligo(propylene glycol)-oligo(ethylene glycol) (OEG-OPG-OEG) segments. When heated after deformation, the OEG-OPG-OEG segments form micelles fixing the temporary shape. Upon cooling, the micelles dissociate again, the deformation is reversed and the permanent shape is obtained. Applicability of this iSME is demonstrated by the gentle loading of platelet-rich plasma (PRP) without causing any platelet activation during this process. PRP is highly bioactive and is widely acknowledged for its regenerative effects. Hence, the microporous inverse shape-memory hydrogel (iSMH) with a cooling induced pore-size effect represents a promising candidate scaffold for tissue regeneration for potential usage in minimally invasive surgery applications. %0 journal article %@ 2399-7532 %A Mazzolai, B.,Mondini, A.,Del Dottore, E.,Margheri, L.,Carpi, F.,Suzumori, K.,Cianchetti, M.,Speck, T.,Smoukov, S.K.,Burgert, I.,Keplinger, T.,Siqueira, G.D.F.,Vanneste, F.,Goury, O.,Duriez, C.,Nanayakkara, T.,Vanderborght, B.,Brancart, J.,Terryn, S.,Rich, S.I.,Liu, R.,Fukuda, K.,Someya, T.,Calisti, M.,Laschi, C.,Sun, W.,Wang, G.,Wen, L.,Baines, R.,Patiballa, S.K.,Kramer-Bottiglio, R.,Rus, D.,Fischer, P.,Simmel, F.C.,Lendlein, A. %D 2022 %J Multifunctional Materials %N 3 %P 032001 %R doi:10.1088/2399-7532/ac4c95 %T Roadmap on soft robotics: multifunctionality, adaptability and growth without borders %U https://doi.org/10.1088/2399-7532/ac4c95 3 %X Soft robotics aims at creating systems with improved performance of movement and adaptability in unknown, challenging, environments and with higher level of safety during interactions with humans. This Roadmap on Soft Robotics covers selected aspects for the design of soft robots significantly linked to the area of multifunctional materials, as these are considered a fundamental component in the design of soft robots for an improvement of their peculiar abilities, such as morphing, adaptivity and growth. The roadmap includes different approaches for components and systems design, bioinspired materials, methodologies for building soft robots, strategies for the implementation and control of their functionalities and behaviour, and examples of soft-bodied systems showing abilities across different environments. For each covered topic, the author(s) describe the current status and research directions, current and future challenges, and perspective advances in science and technology to meet the challenges. %0 journal article %@ 1022-1336 %A Baudis, S.,Behl, M. %D 2022 %J Macromolecular Rapid Communications %N 12 %P 2100400 %R doi:10.1002/marc.202100400 %T High-Throughput and Combinatorial Approaches for the Development of Multifunctional Polymers %U https://doi.org/10.1002/marc.202100400 12 %X High-throughput (HT) development of new multifunctional polymers is accomplished by the combination of different HT tools established in polymer sciences in the last decade. Important advances are robotic/HT synthesis of polymer libraries, the HT characterization of polymers, and the application of spatially resolved polymer library formats, explicitly microarray and gradient libraries. HT polymer synthesis enables the generation of material libraries with combinatorial design motifs. Polymer composition, molecular weight, macromolecular architecture, etc. may be varied in a systematic, fine-graded manner to obtain libraries with high chemical diversity and sufficient compositional resolution as model systems for the screening of these materials for the functions aimed. HT characterization allows a fast assessment of complementary properties, which are employed to decipher quantitative structure–properties relationships. Moreover, these methods facilitate the HT determination of important surface parameters by spatially resolved characterization methods, including time-of-flight secondary ion mass spectrometry and X-ray photoelectron spectroscopy. Here current methods for the high-throughput robotic synthesis of multifunctional polymers as well as their characterization are presented and advantages as well as present limitations are discussed. %0 journal article %@ 0930-9225 %A Stamm, C. %D 2022 %J Zeitschrift für Herz-, Thorax- und Gefässchirurgie %N %P 107-114 %R doi:10.1007/s00398-021-00476-5 %T Kardiale Zelltherapie - „lost in translation?“ : Cardiac cell therapy - Lost in translation? %U https://doi.org/10.1007/s00398-021-00476-5 %X Die kardiale Zelltherapie hat über zwei Dekaden bewegter Geschichte hinter sich, in denen sich die Wahrnehmung des Herzens als Organ, bestehend aus einer fixierten Zahl terminal differenzierter Kardiomyozyten, fundamental geändert hat. Plötzlich galt bzw. gilt das Myokard als regenerierbar – durch intrinsische Vorläuferzellen, induzierbare Proliferation, aber v. a. durch exogene, transplantierte Zellen. Während die klinische Translation echter Kardiomyozyten, gewonnen durch zelluläre Reprogrammierung, nur langsam vorankommt, wurde eine Vielzahl klinischer Studien mit Zellprodukten somatischen Ursprungs durchgeführt. Diese beruhten zumeist auf Annahmen bzw. experimentell erhobenen Daten bezüglich der Plastizität adulter Vorläuferzellen, die sich im Nachhinein als nichthaltbar erwiesen haben. Dementsprechend waren auch der Ergebnisse der klinischen Studien bei genauer Betrachtung wenig überzeugend, wurden jedoch trotzdem oft ausgesprochen optimistisch dargestellt. Mittlerweile gilt die kardiale Zelltherapie mit Zellen somatischen Ursprungs als gescheitert. Die Etappen dieser Ära zu rekapitulieren, kann helfen, derartige Fehlentwicklungen in Zukunft frühzeitig zu erkennen und zu verhindern. %0 journal article %@ 1932-6203 %A Xu, Z.,Neuber, S.,Nazari-Shafti, T.,Liu, Z.,Dong, F.,Stamm, C. %D 2022 %J PLoS One %N 1 %P e0261462 %R doi:10.1371/journal.pone.0261462 %T Impact of procedural variability and study design quality on the efficacy of cell-based therapies for heart failure - a meta-analysis %U https://doi.org/10.1371/journal.pone.0261462 1 %X Background,Cell-based therapy has long been considered a promising strategy for the treatment of heart failure (HF). However, its effectiveness in the clinical setting is now doubted. Because previous meta-analyses provided conflicting results, we sought to review all available data focusing on cell type and trial design.,Methods and findings,The electronic databases PubMed, Cochrane library, ClinicalTrials.gov, and EudraCT were searched for randomized controlled trials (RCTs) utilizing cell therapy for HF patients from January 1, 2000 to December 31, 2020. Forty-three RCTs with 2855 participants were identified. The quality of the reported study design was assessed by evaluating the risk-of-bias (ROB). Primary outcomes were defined as mortality rate and left ventricular ejection fraction (LVEF) change from baseline. Secondary outcomes included both heart function data and clinical symptoms/events. Between-study heterogeneity was assessed using the I2 index. Subgroup analysis was performed based on HF type, cell source, cell origin, cell type, cell processing, type of surgical intervention, cell delivery routes, cell dose, and follow-up duration. Only 10 of the 43 studies had a low ROB for all method- and outcome parameters. A higher ROB was associated with a greater increase in LVEF. Overall, there was no impact on mortality for up to 12 months follow-up, and a clinically irrelevant average LVEF increase by LVEF (2.4%, 95% CI = 0.75−4.05, p = 0.004). Freshly isolated, primary cells tended to produce better outcomes than cultured cell products, but there was no clear impact of the cell source tissue, bone marrow cell phenotype or cell chricdose (raw or normalized for CD34+ cells). A meaningful increase in LVEF was only observed when cell therapy was combined with myocardial revascularization.,Conclusions,The published results suggest a small increase in LVEF following cell therapy for heart failure, but publication bias and methodologic shortcomings need to be taken into account. Given that cardiac cell therapy has now been pursued for 20 years without real progress, further efforts should not be made. %0 journal article %@ 2162-2531 %A Moradian, H.,Roch, T.,Anthofer, L.,Lendlein, A.,Gossen, M. %D 2022 %J Molecular Therapy Nucleic Acids %N %P 854-869 %R doi:10.1016/j.omtn.2022.01.004 %T Chemical modification of uridine modulates mRNA-mediated proinflammatory and antiviral response in primary human macrophages %U https://doi.org/10.1016/j.omtn.2022.01.004 %X In vitro transcribed (IVT)-mRNA has been accepted as a promising therapeutic modality. Advances in facile and rapid production technologies make IVT-mRNA an appealing alternative to protein- or virus-based medicines. Robust expression levels, lack of genotoxicity and their manageable immunogenicity benefit its clinical applicability. We postulated that innate immune responses of therapeutically relevant human cells can be tailored or abrogated by combinations of 5’-end and internal IVT-mRNA modifications. Using primary human macrophages as targets, our data show the particular importance of uridine modifications for IVT-mRNA performance. Among five nucleotide modification schemes tested, 5-methoxy-uridine outperformed other modifications up to 4-fold increased transgene expression, triggering moderate proinflammatory and non-detectable antiviral responses. Macrophage responses against IVT-mRNAs exhibiting high immunogenicity (e.g., pseudouridine) could be minimized upon HPLC purification. Conversely, 5’-end modifications, had only modest effects on mRNA expression and immune responses. Our results revealed how the uptake of chemically modified IVT-mRNA impacts human macrophages, responding with distinct patterns of innate immune responses concomitant with increased transient transgene expression. We anticipate our findings are instrumental to predictively address specific cell responses required for wide range of therapeutic applications from eliciting controlled immunogenicity in mRNA vaccines to, e.g., completely abrogating cell activation in protein replacement therapies. %0 journal article %@ 0884-2914 %A Machatschek, R.,Heuchel, M.,Lendlein, A. %D 2022 %J Journal of Materials Research %N 1 %P 67-76 %R doi:10.1557/s43578-021-00339-7 %T Thin-layer studies on surface functionalization of polyetherimide: Hydrolysis versus amidation %U https://doi.org/10.1557/s43578-021-00339-7 1 %X Among the high-performance and engineering polymers, polyimides and the closely related polyetherimide (PEI) stand out by their capability to react with nucleophiles under relatively mild conditions. By targeting the phthalimide groups in the chain backbone, post-functionalization offers a pathway to adjust surface properties such as hydrophilicity, solvent resistance, and porosity. Here, we use ultrathin PEI films on a Langmuir trough as a model system to investigate the surface functionalization with ethylene diamine and tetrakis(4-aminophenyl)porphyrin as multivalent nucleophiles. By means of AFM, Raman spectroscopy, and interfacial rheology, we show that hydrolysis enhances the chemical and mechanical stability of ultrathin films and allows for the formation of EDC/NHS-activated esters. Direct amidation of PEI was achieved in the presence of a Lewis acid catalyst, resulting in free amine groups rather than cross-linking. When comparing amidation with hydrolysis, we find a greater influence of the latter on material properties. %0 journal article %@ 1613-6810 %A Liu, Y.,Gould, O.,Kratz, K.,Lendlein, A. %D 2022 %J Small %N 5 %P 2104621 %R doi:10.1002/smll.202104621 %T On Demand Sequential Release of (Sub)Micron Particles Controlled by Size and Temperature %U https://doi.org/10.1002/smll.202104621 5 %X Polymeric devices capable of releasing submicron particles (subMP) on demand are highly desirable for controlled release systems, sensors, and smart surfaces. Here, a temperature-memory polymer sheet with a programmable smooth surface served as matrix to embed and release polystyrene subMP controlled by particle size and temperature. subMPs embedding at 80 °C can be released sequentially according to their size (diameter D of 200 nm, 500 nm, 1 µm) when heated. The differences in their embedding extent are determined by the various subMPs sizes and result in their distinct release temperatures. Microparticles of the same size (D ≈ 1 µm) incorporated in films at different programming temperatures Tp (50, 65, and 80 °C) lead to a sequential release based on the temperature-memory effect. The change of apparent height over the film surface is quantified using atomic force microscopy and the realization of sequential release is proven by confocal laser scanning microscopy. The demonstration and quantification of on demand subMP release are of technological impact for assembly, particle sorting, and release technologies in microtechnology, catalysis, and controlled release. %0 journal article %@ 2194-4296 %A Schwarze, M.,Thiel, T.,Tasbihi, M.,Schroeter, M.,Menezes, P.,Walter, C.,Driess, M.,Schomäcker, R. %D 2022 %J Energy Technology %N 1 %P 2100525 %R doi:10.1002/ente.202100525 %T Use of Cellulose for the Production of Photocatalytic Films for Hydrogen Evolution Along the Lines of Paper Production %U https://doi.org/10.1002/ente.202100525 1 %X Following the example of photovoltaics, one approach to large-scale photocatalytic hydrogen production is the irradiation of a correspondingly large catalyst area. Paper production is a process in which large areas can already be produced based on the main component: cellulose. Herein, the TiO2 photocatalyst modification PC500, which also uses platinum nanoparticles as a cocatalyst, is supported in two different ways using cellulose. On the one hand, the catalyst is fixed to the surface of a commercial filter paper and, on the other hand, a photocatalytic paper is produced. For comparison, the catalyst is immobilized by means of drop coating using Nafion and measured as a suspension. The cellulose-stabilized films are active and hydrogen production is comparable with the activity obtained from the drop-coating method. The experiments show that the aggregation behavior of cellulose can be used to produce photocatalytically active films. The preparation is easy and can be applied to different kinds of (photo)catalysts. Although the films are very active, their stability during reaction due to swelling and hydrogen production must be further improved. %0 journal article %@ 1386-0291 %A Ullah, I.,Wang, W.,Ma, N.,Lendlein, A. %D 2022 %J Clinical Hemorheology and Microcirculation %N 3 %P 327-341 %R doi:10.3233/CH-211264 %T Multiblock copolymers type PDC- a family of multifunctional biomaterials for regenerative medicine %U https://doi.org/10.3233/CH-211264 3 %X Multiblock copolymers type PDC are polyetheresterurethanes composed of poly(ɛ-caprolactone) and poly(p-dioxanone) segments. They were designed as degradadable shape-memory polymers for medical devices, which can be implanted minimally-invasively. While providing structural support in the initial phase after implantation, they are capable to modulate soft tissue regeneration while degradation. In this perspective, we elucidate cell-material interactions, compatibility both in-vitro and in-vivo and biofunctionality of PDC, which represents a promising candidate biomaterial family especially for cardiovascular applications. %0 journal article %@ 2666-0849 %A Rroku, A.,Barbieri, F.,Landmesser, U.,Skurk, C.,Kasner, M.,Reinthaler, M. %D 2022 %J JACC: Case Reports %N 8 %P 481-485 %R doi:10.1016/j.jaccas.2022.02.014 %T Transcatheter Caval Valve Implantation for Tricuspid Regurgitation After Single Leaflet Device Attachment %U https://doi.org/10.1016/j.jaccas.2022.02.014 8 %X An 86-year-old patient experienced progressive heart failure symptoms. Echocardiographic evaluation revealed severe tricuspid regurgitation, which was treated by transcatheter edge-to-edge repair. During the procedure, single leaflet device attachment occurred. On the basis of a prohibitive surgical risk, caval valve implantation was performed, with no notable complications. (Level of Difficulty: Advanced.) %0 journal article %@ 1386-0291 %A Lau, S.,Gossen, M.,Lendlein, A.,Jung, F. %D 2022 %J Clinical Hemorheology and Microcirculation %N 3 %P 191-203 %R doi:10.3233/CH-211294 %T Differential sensitivity of assays for determining vein endothelial cell senescence %U https://doi.org/10.3233/CH-211294 3 %X In vivo endothelialization of polymer-based cardiovascular implant materials is a promising strategy to reduce the risk of platelet adherence and the subsequent thrombus formation and implant failure. However, endothelial cells from elderly patients are likely to exhibit a senescent phenotype that may counteract endothelialization. The senescence status of cells should therefore be investigated prior to implantation of devices designed to be integrated in the blood vessel wall. Here, human umbilical vein endothelial cells (HUVEC) were cultivated up to passage (P) 4, 10 and 26/27 to determine the population doubling time and the senescence status by four different methods. Determination of the senescence-associated β-galactosidase activity (SA-β-Gal) was carried out by colorimetric staining and microscopy (i), as well as by photometric quantification (ii), and the expression of senescence-associated nuclear proteins p16 and p21 as well as the proliferation marker Ki67 was assessed by immunostaining (iii), and by flow cytometry (iv). The population doubling time of P27-cells was remarkably greater (103±65 h) compared to P4-cells (24±3 h) and P10-cell (37±15 h). Among the four different methods tested, the photometric SA-β-Gal activity assay and the flow cytometric determination of p16 and Ki67 were most effective in discriminating P27-cells from P4- and P10-cells. These methods combined with functional endothelial cell analyses might aid predictions on the performance of implant endothelialization in vivo. %0 journal article %@ 1616-301X %A Tung, W.T.,Maring, J.A.,Xu, X.,Liu, Y.,Becker, M.,Somesh, D.B.,Klose, K.,Wang, W.,Sun, X.,Ullah, I.,Kratz, K.,Neffe, A.T.,Stamm, C.,Ma, N.,Lendlein, A. %D 2022 %J Advanced Functional Materials %N 31 %P 2110179 %R doi:10.1002/adfm.202110179 %T In Vivo Performance of a Cell and Factor Free Multifunctional Fiber Mesh Modulating Postinfarct Myocardial Remodeling %U https://doi.org/10.1002/adfm.202110179 31 %X Guidance of postinfarct myocardial remodeling processes by an epicardial patch system may alleviate the consequences of ischemic heart disease. As macrophages are highly relevant in balancing immune response and regenerative processes their suitable instruction would ensure therapeutic success. A polymeric mesh capable of attracting and instructing monocytes by purely physical cues and accelerating implant degradation at the cell/implant interface is designed. In a murine model for myocardial infarction the meshes are compared to those either coated with extracellular matrix or loaded with induced cardiomyocyte progenitor cells. All implants promote macrophage infiltration and polarization in the epicardium, which is verified by in vitro experiments. 6 weeks post-MI, especially the implantation of the mesh attenuates left ventricular adverse remodeling processes as shown by reduced infarct size (14.7% vs 28–32%) and increased wall thickness (854 µm vs 400–600 µm), enhanced angiogenesis/arteriogenesis (more than 50% increase compared to controls and other groups), and improved heart function (ejection fraction = 36.8% compared to 12.7–31.3%). Upscaling as well as process controls is comprehensively considered in the presented mesh fabrication scheme to warrant further progression from bench to bedside. %0 journal article %@ 2637-6105 %A Liu, Y.,Liang, F. %D 2022 %J ACS Applied Polymer Materials %N 9 %P 6440-6448 %R doi:10.1021/acsapm.2c00865 %T Reconfigurable and Actuating Microbowls with Variable Steps %U https://doi.org/10.1021/acsapm.2c00865 9 %X Polymeric microdevices with bioinspired multifunctional features like defined geometrical actuation or spatially segregated surface properties are attractive with potential applications in sensors, microfluidic systems, on-demand carriers, and biomedical devices. In this regard, here, we aim at enhancing the programability of multi-shape memory micro-objects using atomic force microscopy (AFM) to achieve a sequential shape reconfiguration or actuation at different geometrical levels on demand. Temperature-memory polymer-based microcuboids were designed and fabricated as a model system. The first step in the programing of the microcuboids was achieved by compression between glass slides with external force at selected programing temperatures Tp. Then, microbowls were generated by AFM nanoindentation using a spherical tip on the surface of the microcuboids to create temporary nanocavities at different Tp,inds. The geometry and surface structure of the microcuboids was analyzed by AFM height images. By varying Tp/Tp,inds and the sequence of the procedure, multiple nanocavities can be generated on the same microbowl to achieve sequential full recovery and actuations of 2–6%. In addition, a demonstration of microbowl trapping and sequential elevating submicron particles was performed to prove the concept of the on-demand carrier and release system. The technology presented in this work can inspire future design of multifunctional micro-objects in order to fulfill complex tasks with shape reconfiguration or actuation functions on micro-/nanolevel. %0 journal article %@ 1999-4923 %A Altabal, O.,Wischke, C.,Lendlein, A. %D 2022 %J Pharmaceutics %N 12 %P 2611 %R doi:10.3390/pharmaceutics14122611 %T Design of Reservoirs Enabling Stress-Induced Sequential Release Systems %U https://doi.org/10.3390/pharmaceutics14122611 12 %X Mechanical stress is recognized as a principle for opening enclosed compartments through compression, stretching, or shear, eventually resulting in the onset of a diffusion-controlled release. Here, we hypothesized that the geometrical design of cavities (cut-outs) introduced as containers in elastic polymer substrates and sealed with a brittle coating layer would enable a pre-defined release of different compounds by stress concentration phenomena. Design criteria such as cut-out shapes, orientations, and depths were initially assessed for suitably different stress concentrations in computational models. In substrates fabricated from polydimethylsiloxane by photolithographic techniques, the local strains at horizontal rectangular, circular, and vertical rhombus-shaped cut-outs systematically increased under horizontal stretching as proposed. When filled with model compounds and coated with poly(n-butyl cyanoacrylate), a pre-defined induced breakage of the coating and compound release was confirmed upon continuous uniaxial stretching. This proof of concept demonstrates how device design and functions interlink and may motivate further exploration in technology and medicine for deformation-induced on-demand dosage applications. %0 journal article %@ 2073-4360 %A Altabal, O.,Wischke, C. %D 2022 %J Polymers %N 22 %P 4863 %R doi:10.3390/polym14224863 %T Analyzing the Mechanical Properties of Free-Standing PACA Thin Films Using Microindentation Technique %U https://doi.org/10.3390/polym14224863 22 %X Assessing the mechanical properties of materials is of fundamental relevance for their rational usage, but can be challenging with standard tensile testing for highly brittle polymers used, e.g., as coatings. Here, a procedure for the mechanical analysis of free-standing poly(alkyl cyanoacrylate) (PACA) films using microindentation has been explored. Rigid and transparent films from PACA with various side chain compositions were formed on top of square polymer frames by in situ polymerization. Under microscopic control, the free-standing films were analyzed using a microelectromechanical sensing system. By this procedure, decreasing Young’s moduli E for increasing PACA side chain length and flexibility were determined with strain at break εB between 0.36% for poly(ethyl cyanoacrylate) and 4.6% for poly(methoxyethyl cyanoacrylate). Based on this successful application, the applied methodology may be relevant for characterizing various coating materials, which are otherwise hard to form as thin free-standing films, and using the data, e.g., in computationally assisted design and evaluation of hybrid material devices. %0 journal article %@ 2667-1093 %A Tarazona, N.,Wei, R.,Brott, S.,Pfaff, L.,Bornscheuer, U.,Lendlein, A.,Machatschek, R. %D 2022 %J Chem Catalysis %N 12 %P 3573-3589 %R doi:10.1016/j.checat.2022.11.004 %T Rapid depolymerization of poly(ethylene terephthalate) thin films by a dual-enzyme system and its impact on material properties %U https://doi.org/10.1016/j.checat.2022.11.004 12 %X Enzymatic hydrolysis holds great promise for plastic waste recycling and upcycling. The interfacial catalysis mode, and the variability of polymer specimen properties under different degradation conditions, add to the complexity and difficulty of understanding polymer cleavage and engineering better biocatalysts. We present a systemic approach to studying the enzyme-catalyzed surface erosion of poly(ethylene terephthalate) (PET) while monitoring/controlling operating conditions in real time with simultaneous detection of mass loss and changes in viscoelastic behavior. PET nanofilms placed on water showed a porous morphology and a thickness-dependent glass transition temperature (Tg) between 40°C and 44°C, which is >20°C lower than the Tg of bulk amorphous PET. Hydrolysis by a dual-enzyme system containing thermostabilized variants of Ideonella sakaiensis PETase and MHETase resulted in a maximum depolymerization of 70% in 1 h at 50°C. We demonstrate that increased accessible surface area, amorphization, and Tg reduction speed up PET degradation while simultaneously lowering the threshold for degradation-induced crystallization. %0 journal article %@ 2046-2069 %A Thiel, T.,Zhang, X.,Radhakrishnan, B.,van de Krol, R.,Abdi, F.,Schroeter, M.,Schomäcker, R.,Schwarze, M. %D 2022 %J RSC Advances %N 48 %P 30860-30870 %R doi:10.1039/D2RA05507D %T Kinetic investigation of para-nitrophenol reduction with photodeposited platinum nanoparticles onto tunicate cellulose %U https://doi.org/10.1039/D2RA05507D 48 %X Photodeposition is a specific method for depositing metallic co-catalysts onto photocatalysts and was applied for immobilizing platinum nanoparticles onto cellulose, a photocatalytically inactive biopolymer. The obtained Pt@cellulose catalysts show narrow and well-dispersed nanoparticles with average sizes between 2 and 5 nm, whereby loading, size and distribution depend on the preparation conditions. The catalysts were investigated for the hydrogenation of para-nitrophenol via transfer hydrogenation using sodium borohydride as the hydrogen source, and the reaction rate constant was determined using the pseudo-first-order reaction rate law. The Pt@cellulose catalysts are catalytically active with rate constant values k from 0.09 × 10−3 to 0.43 × 10−3 min−1, which were higher than the rate constant of a commercial Pt@Al2O3 catalyst (k = 0.09 × 10−3 min−1). Additionally, the Pt@cellulose catalyst can be used for electrochemical hydrogenation of para-nitrophenol where the hydrogen is electrocatalytically formed. The electrochemical hydrogenation is faster compared to the transfer hydrogenation (k = 0.11 min−1). %0 journal article %@ 1999-4923 %A Tuncaboylu, D.C.,Wischke, C. %D 2022 %J Pharmaceutics %N 11 %P 2331 %R doi:10.3390/pharmaceutics14112331 %T Opportunities and Challenges of Switchable Materials for Pharmaceutical Use %U https://doi.org/10.3390/pharmaceutics14112331 11 %X Switchable polymeric materials, which can respond to triggering signals through changes in their properties, have become a major research focus for parenteral controlled delivery systems. They may enable externally induced drug release or delivery that is adaptive to in vivo stimuli. Despite the promise of new functionalities using switchable materials, several of these concepts may need to face challenges associated with clinical use. Accordingly, this review provides an overview of various types of switchable polymers responsive to different types of stimuli and addresses opportunities and challenges that may arise from their application in biomedicine. %0 journal article %@ 2730-6151 %A Díaz Rodríguez, C.,Díaz-García, L.,Bunk, B.,Spröer, C.,Herrera, K.,Tarazona, N.,Rodriguez-R, L.,Overmann, J.,Jiménez, D. %D 2022 %J ISME Communications %N %P 89 %R doi:10.1038/s43705-022-00176-7 %T Novel bacterial taxa in a minimal lignocellulolytic consortium and their potential for lignin and plastics transformation %U https://doi.org/10.1038/s43705-022-00176-7 %X The understanding and manipulation of microbial communities toward the conversion of lignocellulose and plastics are topics of interest in microbial ecology and biotechnology. In this study, the polymer-degrading capability of a minimal lignocellulolytic microbial consortium (MELMC) was explored by genome-resolved metagenomics. The MELMC was mostly composed (>90%) of three bacterial members (Pseudomonas protegens; Pristimantibacillus lignocellulolyticus gen. nov., sp. nov; and Ochrobactrum gambitense sp. nov) recognized by their high-quality metagenome-assembled genomes (MAGs). Functional annotation of these MAGs revealed that Pr. lignocellulolyticus could be involved in cellulose and xylan deconstruction, whereas Ps. protegens could catabolize lignin-derived chemical compounds. The capacity of the MELMC to transform synthetic plastics was assessed by two strategies: (i) annotation of MAGs against databases containing plastic-transforming enzymes; and (ii) predicting enzymatic activity based on chemical structural similarities between lignin- and plastics-derived chemical compounds, using Simplified Molecular-Input Line-Entry System and Tanimoto coefficients. Enzymes involved in the depolymerization of polyurethane and polybutylene adipate terephthalate were found to be encoded by Ps. protegens, which could catabolize phthalates and terephthalic acid. The axenic culture of Ps. protegens grew on polyhydroxyalkanoate (PHA) nanoparticles and might be a suitable species for the industrial production of PHAs in the context of lignin and plastic upcycling. %0 journal article %@ 2297-055X %A Vellguth, K.,Barbieri, F.,Reinthaler, M.,Kasner, M.,Landmesser, U.,Kuehne, T.,Hennemuth, A.,Walczak, L.,Goubergrits, L. %D 2022 %J Frontiers in Cardiovascular Medicine %N %P 915074 %R doi:10.3389/fcvm.2022.915074 %T Effect of transcatheter edge-to-edge repair device position on diastolic hemodynamic parameters: An echocardiography-based simulation study %U https://doi.org/10.3389/fcvm.2022.915074 %X Background: Transcatheter edge-to-edge repair (TEER) has developed from innovative technology to an established treatment strategy of mitral regurgitation (MR). The risk of iatrogenic mitral stenosis after TEER is, however, a critical factor in the conflict of interest between maximal reduction of MR and minimal impairment of left ventricular filling. We aim to investigate systematically the impact of device position on the post treatment hemodynamic outcome by involving the patient-specific segmentation of the diseased mitral valve.,Materials and methods: Transesophageal echocardiographic image data of ten patients with severe MR (age: 57 ± 8 years, 20% female) were segmented and virtually treated with TEER at three positions by using a position based dynamics approach. Pre- and post-interventional patient geometries were preprocessed for computational fluid dynamics (CFD) and simulated at peak-diastole with patient-specific blood flow boundary conditions. Simulations were performed with boundary conditions mimicking rest and stress. The simulation results were compared with clinical data acquired for a cohort of 21 symptomatic MR patients (age: 79 ± 6 years, 43% female) treated with TEER.,Results: Virtual TEER reduces the mitral valve area (MVA) from 7.5 ± 1.6 to 2.6 ± 0.6 cm2. Central device positioning resulted in a 14% smaller MVA than eccentric device positions. Furthermore, residual MVA is better predictable for central than for eccentric device positions (R2 = 0.81 vs. R2 = 0.49). The MVA reduction led to significantly higher maximal diastolic velocities (pre: 0.9 ± 0.2 m/s, post: 2.0 ± 0.5 m/s) and pressure gradients (pre: 1.5 ± 0.6 mmHg, post: 16.3 ± 9 mmHg) in spite of a mean flow rate reduction by 23% due to reduced MR after the treatment. On average, velocities were 12% and pressure gradients were 25% higher with devices in central compared to lateral or medial positions.,Conclusion: Virtual TEER treatment combined with CFD is a promising tool for predicting individual morphometric and hemodynamic outcomes. Such a tool can potentially be used to support clinical decision making, procedure planning, and risk estimation to prevent post-procedural iatrogenic mitral stenosis. %0 journal article %@ 2073-4360 %A Wischke, C.,Hofmann, D. %D 2022 %J Polymers %N 18 %P 3762 %R doi:10.3390/polym14183762 %T Predictive Shapes of Ellipsoid PPDL-PTHF Copolymer Particles Prepared by the Phantom Stretching Technique %U https://doi.org/10.3390/polym14183762 18 %X Ellipsoidal polymer particles can be prepared from spheres by unidirectional stretching at elevated temperatures, while the particles’ aspect ratios (AR) that result from this phantom stretching methodology are often not precisely predictable. Here, an elastic deformation model was exemplarily evaluated for ~50 µm spherical microparticles from PPDL-PTHF block copolymers. The prolate ellipsoidal particles, obtained by stretching in polyvinyl alcohol phantoms, differed in dimensions at identical relative phantoms elongations up to 150%, depending on the relative polymer composition and their systematically altered mechanical properties. Importantly, the resulting particle shapes within the studied range of AR up to ~4 matched the predictions of the elastic deformation model, which includes information of the elastic moduli of phantom and particle materials. These data suggest that the model may be applicable to predict the conditions needed to precisely prepare ellipsoids of desired AR and may be applicable to various deformable particle materials. %0 journal article %@ 2073-4360 %A Zhou, L.,Yang, H.,Zhang, Z.,Liu, Y.,Epaarachchi, J.,Fang, Z.,Fang, L.,Lu, C.,Xu, Z. %D 2022 %J Polymers %N 10 %P 2098 %R doi:10.3390/polym14102098 %T Effects of Ligands in Rare Earth Complex on Properties, Functions, and Intelligent Behaviors of Polyurea–Urethane Composites %U https://doi.org/10.3390/polym14102098 10 %X There is a need to create next-generation polymer composites having high property, unique function, and intelligent behaviors, such as shape memory effect (SME) and self-healing (SH) capability. Rare earth complexes can provide luminescence for polymers, and their dispersion is highly affected by ligand structures. Here, we created three different REOCs with different ligands before studying the effects of ligands on REOC dispersion in polyurea–urethane (PUU) with disulfide bonds in main chains. In addition, the effects of different REOCs on mechanical properties, luminescent functions, and intelligent behaviors of PUU composites were studied. The results showed that REOC I (Sm(TTA)3phen: TTA, thenoyltrifluoroacetone; phen, 1,10-phenanthroline) has incompatible ligands with the PUU matrix. REOC I and REOC III (Sm(BUBA)3phen: BUBA, 4-benzylurea-benzoic acid) with amine and urea groups facilitate their dispersion. It was REOC III that helped the maintenance of mechanical properties of PUU composites due to the good dispersion and the needle-like morphologies. Due to more organic ligands of REOC III, the fluorescence intensity of composite materials is reduced. The shape recovery ratio of the composite was not as good as that of pure PUU when a large amount of fillers was added. Besides, REOC I reduced the self-healing efficiency of PUU composites due to poor dispersion, and the other two REOCs increased the self-healing efficiency. The results showed that ligands in REOCs are important for their dispersion in the PUU matrix. The poor dispersion of REOC I is unbeneficial for mechanical properties and intelligent behavior. The high miscibility of REOC II (Sm(PABA)3phen: PABA, 4-aminobenzoic acid) decreases mechanical properties as well but ensures the good shape recovery ratio and self-healing efficiency. The mediate miscibility and needle-like morphology of REOC III are good for mechanical properties. The shape recovery ratio, however, was decreased. %0 journal article %@ 0009-3084 %A Sęk, A.,Perczyk, P.,Szcześ, A.,Machatschek, R.,Wydro, P. %D 2022 %J Chemistry and Physics of Lipids %N %P 105236 %R doi:10.1016/j.chemphyslip.2022.105236 %T Studies on the interactions of tiny amounts of common ionic surfactants with unsaturated phosphocholine lipid model membranes %U https://doi.org/10.1016/j.chemphyslip.2022.105236 %X In order to provide the fundamental information about the interactions of common anionic surfactants with the basic unsaturated phospholipids the influence of three cationic (dodecyltrimethylammonium bromide, DTAB; tetradecyltrimethylammonium bromide, TTAB and hexadecyltrimethylamonium bromide, CTAB) and one anionic (sodium dodecylsulfate, SDS) surfactants on the properties of the 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) layers was investigated. The studies proved that a tiny amount of the ionic surfactant added to the already synthesized liposome suspension is sufficient to change the zeta potential of the POPC and DOPC liposomes significantly. This impact increases with the surfactant concentration, the alkyl chain length of the surfactant and the degree of lipid saturation. Moreover, this effect is greater for the anionic surfactant than for the cationic one of the same alkyl chain length. The observed findings were confirmed in the course of the research carried out with the use of the corresponding Langmuir monolayers where the surface pressure – mean area isotherms, the compressibility modulus – surface pressure dependences, the monolayer penetration tests, the surface potential – mean molecular area isotherms and Brewster angle microscopy were discussed. It was found that the presence of the surfactants shifts the isotherms towards larger molecular area, to the higher extent for the SDS than DTAB. This effect increases with the increasing surfactant concentration in the subphase. Moreover, the investigated surfactants remain in the monolayer even at high surface pressure. Nevertheless, no effect on the morphology of the POPC and DOPC monolayers was detected from the BAM images. The surface potential and surface charge of the liposomes calculated on the basis of the zeta potential results reflected the interactions between the surfactant and the lipid layers. %0 journal article %@ 2059-8521 %A Zhou, S.,Xu, X.,Ma, N.,Jung, F.,Lendlein, A. %D 2022 %J MRS Advances %N %P 354-359 %R doi:10.1557/s43580-021-00132-y %T Prediction of the epichlorohydrin derived cytotoxic substances from the eluent of poly(glycerol glycidyl ether) films %U https://doi.org/10.1557/s43580-021-00132-y %X Glycerol-based epoxy networks have great potential for surface functionalization, providing anti-microbial and protein repellant function. However, the synthesis of glycerol glycidyl ether (GGE) monomer often requires excessive epichlorohydrin (ECH). ECH derived organochloride containing byproducts from monomer production maybe present in the eluent of the polymer networks prepared by cationic ring-opening polymerization. Here, the cytotoxicity analysis revealed cell damages in contact with the polyGGE eluent. The occurrence of organochlorides, which was predicted based on the data from high-performance liquid chromatography/electrospray ionization mass spectrometry, as confirmed by a constant chloride level in GGE and polyGGE, and by a specific peak of C–Cl in infrared spectra of GGE. The resulting polyGGE was densely crosslinked, which possibly contribute to the trapping of organochlorides. These results provide a valuable information for exploring the toxins leaching from polyGGE and propose a feasible strategy for minimizing the cytotoxicity via reducing their crosslink density. %0 journal article %@ 1438-7492 %A Ndiripo, A.,Lamola, H.,Ndlovu, P.,Lederer, A.,Pasch, H.,van Reenen, A. %D 2022 %J Macromolecular Materials and Engineering %N 9 %P 2200149 %R doi:10.1002/mame.202200149 %T Reverse Engineering of Chemically Similar Bimodal High Density Polyethylenes: A Comprehensive Study Using Advanced Chromatographic Techniques %U https://doi.org/10.1002/mame.202200149 9 %X Bimodal high-density polyethylene (bHDPE) is a complex, multicomponent polyethylene (PE) material whose synthesis in a multistage process can be challenging. Three bHDPEs with good and bad end-use properties are reverse engineered using advanced analytical techniques. Average chemical composition is determined using 13C NMR and 1-butene is identified as the comonomer for the good resin (bHDPE 1) while 1-hexene is the comonomer in bHDPE 2 and 3. The presence of comonomer in the high molar mass fractions of the samples is shown using high-temperature triple-detection size exclusion chromatography (HT-SEC-d3). Chemical composition separation using high-temperature interaction chromatography (HT-IC) is achieved using porous graphitic carbon (PGC) and silica stationary phases. Some problems in temperature gradient interaction chromatography (TGIC) on PGC are overcome by using a non-adsorptive stationary phase, enabling better separation and visualization of homopolymer and copolymer components. Coupling HT-SEC in 2D liquid chromatography (2D-LC) analyses at high temperatures reveals the presence of a larger copolymer component in bHDPE 1 at high elution volume. In contrast, bHDPE 2 and bHDPE 3 have copolymer components at low elution volumes, indicating poor comonomer distribution in the copolymer component which ultimately explains the poor mechanical properties at similar comonomer contents. %0 journal article %@ 0964-1726 %A Yang, H.,Liu, Y.,Sun, K.,Fang, L.,Lu, C.,Xu, Z. %D 2022 %J Smart Materials and Structures %N 9 %P 095041 %R doi:10.1088/1361-665X/ac7fc9 %T Precise prediction of photothermally induced irreversible bending deformation based on non-uniform thermal expansion of layer-structure films %U https://doi.org/10.1088/1361-665X/ac7fc9 9 %X Although photothermally induced self-bending films based on nonuniform thermal expansion are created, heat transfer and shape-deformation procedures are not investigated very well, limiting the understanding of such complicated behavior and the achievement of precise shape control. Here, thermally expanded microspheres (TEMs) were added into polydimethylsiloxane (PDMS) to create active layers as PDMS-TEM single-layer films that were attached onto pure PDMS passive layer to create PDMS/PDMS-TEM bi-layer films subsequently. After heating, TEMs in the film undergo phase transition and present irreversible thermal expansion, driving deformation of films. Combined with steady-state (uniform heating) deformation simulations and experiments, a deformation model was established before a non-steady state (light irradiation) heat transfer model was set up to simulate the heat transfer process of films under light irradiation. Then the temperature distribution was coupled with the deformation model to simulate the photothermally induced deformation of the samples. The PDMS-TEM single-layer films also presented bending deformation under illumination due to the non-uniform thermal expansion caused by temperature gradient. For bi-layer films, different degrees of thermal expansion between two layers lead to bending deformation. The films with TEM concentration of 30 wt% can achieve great deformation, and the bending curvature was 0.07 mm−1. The geometric parameters including thickness, layer thickness ratio and aspect ratio had little effect on deformation degrees of the films. Deformation mode was varied with aspect ratio. A long side bending and diagonal bending were achieved in bi-layer films at aspect ratios of 7:1 and 1:1. In combination with experimental results, the heat transfer model and deformation model were constructed to demonstrate the complex deformation process, which provides guidance for the structural design of the photothermally induced shape-changing films in practical applications. %0 journal article %@ 2227-9059 %A Rief, M.,Raggam, R.,Rief, P.,Metnitz, P.,Stojakovic, T.,Reinthaler, M.,Brodmann, M.,März, W.,Scharnagl, H.,Silbernagel, G. %D 2022 %J Biomedicines %N 7 %P 1766 %R doi:10.3390/biomedicines10071766 %T Comparison of Two Nuclear Magnetic Resonance Spectroscopy Methods for the Measurement of Lipoprotein Particle Concentrations %U https://doi.org/10.3390/biomedicines10071766 7 %X Background: Measuring lipoprotein particle concentrations may help to improve cardiovascular risk stratification. Both the lipofit (Numares) and lipoprofile (LabCorp) NMR methods are widely used for the quantification of lipoprotein particle concentrations. Objective: The aim of the present work was to perform a method comparison between the lipofit and lipoprofile NMR methods. In addition, there was the objective to compare lipofit and lipoprofile measurements of standard lipids with clinical chemistry-based results. Methods: Total, LDL, and HDL cholesterol and triglycerides were measured with ß-quantification in serum samples from 150 individuals. NMR measurements of standard lipids and lipoprotein particle concentrations were performed by Numares and LabCorp. Results: For both NMR methods, differences of mean concentrations compared to ß-quantification-derived measurements were ≤5.5% for all standard lipids. There was a strong correlation between ß-quantification- and NMR-derived measurements of total and LDL cholesterol and triglycerides (all r > 0.93). For both, the lipofit (r = 0.81) and lipoprofile (r = 0.84) methods, correlation coefficients were lower for HDL cholesterol. There was a reasonable correlation between LDL and HDL lipoprotein particle concentrations measured with both NMR methods (both r > 0.9). However, mean concentrations of major and subclass lipoprotein particle concentrations were not as strong. Conclusions: The present analysis suggests that reliable measurement of standard lipids is possible with these two NMR methods. Harmonization efforts would be needed for better comparability of particle concentration data. %0 journal article %@ 2161-5063 %A Duran, A.,Schwestka, M.,Nazari-Shafti, T.,Neuber, S.,Stamm, C.,Gossen, M. %D 2022 %J ACS Synthetic Biology %N 8 %P 2623-2635 %R doi:10.1021/acssynbio.2c00036 %T Limiting Transactivator Amounts Contribute to Transgene Mosaicism in Tet-On All-in-One Systems %U https://doi.org/10.1021/acssynbio.2c00036 8 %X MicroRNAs play an essential role in cell homeostasis and have been proposed as therapeutic agents. One strategy to deliver microRNAs is to genetically engineer target cells to express microRNAs of interest. However, to control dosage and timing, as well as to limit potential side-effects, microRNAs’ expression should ideally be under exogenous, inducible control. Conditional expression of miRNA-based short hairpin RNAs (shRNAmirs) via gene regulatory circuits such as the Tet-system is therefore a promising strategy to control shRNAmirs’ expression in research and therapy. Single vector approaches like Tet-On all-in-one designs are more compatible with potential clinical applications by providing the Tet-On system components in a single round of genetic engineering. However, all-in-one systems often come at the expense of heterogeneous and unstable expression. In this study, we aimed to understand the causes that lead to such erratic transgene expression. By using a reporter cell, we found that the degree of heterogeneity mostly correlated with reverse tetracycline transactivator (rtTA) expression levels. Moreover, the targeted integration of a potent rtTA expression cassette into a genomic safe harbor locus functionally rescued previously silenced rtTA-responsive transcription units. Overall, our results suggest that ensuring homogenous and stable rtTA expression is essential for the robust and reliable performance of future Tet-On all-in-one designs. %0 journal article %@ 2227-9059 %A Silbernagel, G.,Scharnagl, H.,Saely, C.H.,Reinthaler, M.,Rief, M.,Kleber, M.E.,Larcher, B.,Chapman, J.,Schaefer, J.R.,Drexel, H.,März, W. %D 2022 %J Biomedicines %N 6 %P 1302 %R doi:10.3390/biomedicines10061302 %T The LDL Apolipoprotein B-to-LDL Cholesterol Ratio: Association with Cardiovascular Mortality and a Biomarker of Small, Dense LDLs %U https://doi.org/10.3390/biomedicines10061302 6 %X Background and Objective: Small, dense low-density lipoproteins (LDLs) are considered more atherogenic than normal size LDLs. However, the measurement of small, dense LDLs requires sophisticated laboratory methods, such as ultracentrifugation, gradient gel electrophoresis, or nuclear magnetic resonance. We aimed to analyze whether the LDL apolipoprotein B (LDLapoB)-to-LDL cholesterol (LDLC) ratio is associated with cardiovascular mortality and whether this ratio represents a biomarker for small, dense LDLs. Methods: LDLC and LDLapoB were measured (beta-quantification) and calculated (according to Friedewald and Baca, respectively) for 3291 participants of the LURIC Study, with a median (inter-quartile range) follow-up for cardiovascular mortality of 9.9 (8.7–10.7) years. An independent replication cohort included 1660 participants. Associations of the LDLapoB/LDLC ratio with LDL subclass particle concentrations (ultracentrifugation) were tested for 282 participants. Results: In the LURIC Study, the mean (standard deviation) LDLC and LDLapoB concentrations were 117 (34) and 85 (22) mg/dL, respectively; 621 cardiovascular deaths occurred. Elevated LDLapoB/LDLC (calculated and measured) ratios were significantly and independently associated with increased cardiovascular mortality in the entire cohort (fourth vs. first quartile: hazard ratio (95% confidence interval) = 2.07 (1.53–2.79)) and in statin-naïve patients. The association between calculated LDLapoB/LDLC ratio and cardiovascular mortality was replicated in an independent cohort. High LDLapoB/LDLC ratios were associated with higher LDL5 and LDL6 concentrations (both p < 0.001), but not with concentrations of larger LDLs. Conclusions: Elevated measured and calculated LDLapoB/LDLC ratios are associated with increased cardiovascular mortality. Use of LDLapoB/LDLC ratios allows estimation of the atherogenic risk conferred by small, dense LDLs. %0 journal article %@ 1422-0067 %A Rolińska, K.,Mazurek-Budzyńska, M.,Parzuchowski, P.G.,Wołosz, D.,Balk, M.,Gorący, K.,El Fray, M.,Polanowski, P.,Sikorski, A. %D 2022 %J International Journal of Molecular Sciences %N 13 %P 7064 %R doi:10.3390/ijms23137064 %T Synthesis of Shape-Memory Polyurethanes: Combined Experimental and Simulation Studies %U https://doi.org/10.3390/ijms23137064 13 %X The presented research focuses on the synthesis and structure–properties relationship of poly(carbonate-urea-urethane) (PCUU) systems including investigations on shape-memory effect capability. Furthermore, we approached the topic from a broader perspective by conducting extensive analysis of the relationship between the synthesized compounds and the results of computer simulations by means of the Monte Carlo method. For the first time, by using a unique simulation tool, the dynamic lattice liquid model (DLL), all steps of multi-step synthesis of these materials were covered by the simulations. Furthermore, broad thermal, mechanical, and thermomechanical characterization of synthesized PCUUs was performed, as well as determining the shape-memory properties. PCUUs exhibited good mechanical properties with a tensile strength above 20 MPa, elongation at break around 800%, and an exhibited shape-memory effect with shape fixity and shape recovery ratios above 94% and 99%, respectively. The dynamic lattice liquid model was employed to show the products and their molar mass distribution, as well as monomer conversion or the dispersity index for individual reaction steps. The results obtained in the following manuscript allow the planning of syntheses for the PCUUs of various structures, including crosslinked and soluble systems, which can provide a broad variety of applications of these materials, as well as a better understanding of the composition–properties relationship. %0 journal article %@ 2352-9407 %A Sauter, T.,Kratz, K.,Farhan, M.,Heuchel, M.,Lendlein, A. %D 2022 %J Applied Materials Today %N %P 101562 %R doi:10.1016/j.apmt.2022.101562 %T Design and fabrication of fiber mesh actuators %U https://doi.org/10.1016/j.apmt.2022.101562 %X Soft actuator performance can be tuned by chemistry or mechanical manipulation, but this adjustability is limited especially in view of their growing technological relevance. Inspired from textile engineering, we designed and fabricated fiber mesh actuators and introduced new features like anisotropic behavior and soft-tissue like elastic deformability. Design criteria for the meshes are the formation of fiber bundles, the angle between fiber bundles in different stacked layers and covalent crosslinks forming within and between fibers at their interfacial contact areas. Through crosslinking the interfiber bond strength increased from a bond transmitting neither axial nor rotational loads (pin joint) to a bond strength capable of both (welded joint). For non-linear elastic stiffening, stacked fiber bundles with four embracing fibers were created forming microstructural rhombus shapes. Loading the rhombus diagonally allowed generation of “soft tissue”-like mechanics. By adjustment of stacking angles, the point of strong increase in stress is tuned. While the highest stresses are observed in aligned and crosslinked fiber mats along the direction of the fiber, the strongest shape-memory actuation behavior is found in randomly oriented fiber mats. Fiber mesh actuators controlled by temperature are of high significance as soft robot skins and as for active patches supporting tissue regeneration. %0 journal article %@ 0099-2240 %A Jiménez, D.,Öztürk, B.,Wei, R.,Bugg, T.,Gomez, C.,Galan, F.,Castro-Mayorga, J.,Saldarriaga, J.,Tarazona, N. %D 2022 %J Applied and Environmental Microbiology %N 14 %P %R doi:10.1128/aem.00721-22 %T Merging Plastics, Microbes, and Enzymes: Highlights from an International Workshop %U https://doi.org/10.1128/aem.00721-22 14 %X In the Anthropocene, plastic pollution is a worldwide concern that must be tackled from different viewpoints, bringing together different areas of science. Microbial transformation of polymers is a broad-spectrum research topic that has become a keystone in the circular economy of fossil-based and biobased plastics. To have an open discussion about these themes, experts in the synthesis of polymers and biodegradation of lignocellulose and plastics convened within the framework of The Transnational Network for Research and Innovation in Microbial Biodiversity, Enzymes Technology and Polymer Science (MENZYPOL-NET), which was recently created by early-stage scientists from Colombia and Germany. In this context, the international workshop “Microbial Synthesis and Degradation of Polymers: Toward a Sustainable Bioeconomy” was held on 27 September 2021 via Zoom. The workshop was divided into two sections, and questions were raised for discussion with panelists and expert guests. Several key points and relevant perspectives were delivered, mainly related to (i) the microbial evolution driven by plastic pollution; (ii) the relevance of and interplay between polymer structure/composition, enzymatic mechanisms, and assessment methods in plastic biodegradation; (iii) the recycling and valorization of plastic waste; (iv) engineered plastic-degrading enzymes; (v) the impact of (micro)plastics on environmental microbiomes; (vi) the isolation of plastic-degrading (PD) microbes and design of PD microbial consortia; and (vii) the synthesis and applications of biobased plastics. Finally, research priorities from these key points were identified within the microbial, enzyme, and polymer sciences. %0 journal article %@ 1525-7797 %A Folikumah, M.,Behl, M.,Lendlein, A. %D 2021 %J Biomacromolecules %N 5 %P 1875-1884 %R doi:10.1021/acs.biomac.0c01690 %T Thiol–Thioester Exchange Reactions in Precursors Enable pH-Triggered Hydrogel Formation %U https://doi.org/10.1021/acs.biomac.0c01690 5 %X Bio-interactive hydrogel formation in situ requires sensory capabilities toward physiologically relevant stimuli. Here, we report on pH-controlled in situ hydrogel formation relying on latent cross-linkers, which transform from pH sensors to reactive molecules. In particular, thiopeptolide/thio-depsipeptides were capable of pH-sensitive thiol–thioester exchange reactions to yield α,ω-dithiols, which react with maleimide-functionalized multi-arm polyethylene glycol to polymer networks. Their water solubility and diffusibility qualify thiol/thioester-containing peptide mimetics as sensory precursors to drive in situ localized hydrogel formation with potential applications in tissue regeneration such as treatment of inflamed tissues of the urinary tract. %0 journal article %@ 1422-0067 %A Neffe, A.,Löwenberg, C.,Julich-Gruner, K.,Behl, M.,Lendlein, A. %D 2021 %J International Journal of Molecular Sciences %N 11 %P 5892 %R doi:10.3390/ijms22115892 %T Thermally-Induced Shape-Memory Behavior of Degradable Gelatin-Based Networks %U https://doi.org/10.3390/ijms22115892 11 %X Shape-memory hydrogels (SMH) are multifunctional, actively-moving polymers of interest in biomedicine. In loosely crosslinked polymer networks, gelatin chains may form triple helices, which can act as temporary net points in SMH, depending on the presence of salts. Here, we show programming and initiation of the shape-memory effect of such networks based on a thermomechanical process compatible with the physiological environment. The SMH were synthesized by reaction of glycidylmethacrylated gelatin with oligo(ethylene glycol) (OEG) α,ω-dithiols of varying crosslinker length and amount. Triple helicalization of gelatin chains is shown directly by wide-angle X-ray scattering and indirectly via the mechanical behavior at different temperatures. The ability to form triple helices increased with the molar mass of the crosslinker. Hydrogels had storage moduli of 0.27–23 kPa and Young’s moduli of 215–360 kPa at 4 °C. The hydrogels were hydrolytically degradable, with full degradation to water-soluble products within one week at 37 °C and pH = 7.4. A thermally-induced shape-memory effect is demonstrated in bending as well as in compression tests, in which shape recovery with excellent shape-recovery rates Rr close to 100% were observed. In the future, the material presented here could be applied, e.g., as self-anchoring devices mechanically resembling the extracellular matrix. %0 journal article %@ 2059-8521 %A Neffe, A.,Zhang, Q.,Hommes-Schattmann, P.,Lendlein, A. %D 2021 %J MRS Advances %N 33 %P 786-789 %R doi:10.1557/s43580-021-00058-5 %T Ethylene oxide sterilization of electrospun poly(l-lactide)/poly(d-lactide) core/shell nanofibers %U https://doi.org/10.1557/s43580-021-00058-5 33 %X The application of polymers in medicine requires sterilization while retaining material structure and properties. This demands detailed analysis, which we show exemplarily for the sterilization of PLLA/PDLA core–shell nanofibers with ethylene oxide (EtO). The electrospun patch was exposed to EtO gas (6 vol% in CO2, 1.7 bar) for 3 h at 45 °C and 75% rel. humidity, followed by degassing under pressure/vacuum cycles for 12 h. GC–MS analysis showed that no residual EtO was retained. Fiber diameters (~ 520 ± 130 nm) of the patches remained constant as observed by electron microscopy. Young’s modulus slightly increased and the elongation at break slightly decreased, determined at 37 °C. No changes were detected in 1H-NMR spectra, in molar mass distribution (GPC) or in crystallinity measured for annealed samples with comparable thermal history (Wide Angle X-Ray Scattering). Altogether, EtO emerged as suitable sterilization method for polylactide nanofibers with core–shell morphology. %0 journal article %@ 2045-2322 %A Reinthaler, M.,Großhauser, J.,Schmidt, T.,Unger, J.,Morgan, R.,Zimmermann, F.,Hartung, J.,Seppelt, C.,Meteva, D.,Haider, W.,Landmesser, U.,Skurk, C. %D 2021 %J Scientific Reports %N 1 %P 2988 %R doi:10.1038/s41598-021-82359-1 %T Preclinical assessment of a modified Occlutech left atrial appendage closure device in a porcine model %U https://doi.org/10.1038/s41598-021-82359-1 1 %X Left atrial appendage (LAA) closure is being developed as an alternative for stroke prevention in patients with atrial fibrillation that cannot tolerate long-term oral anticoagulation. To assess the feasibility, safety, and performance of a novel modified Occlutech LAA closure device in a preclinical porcine model, the modified Occlutech modified Occlutech Plus LAA closure device was implanted in 12 female pigs (25–39 kg body weight) under fluoroscopic and transesophageal echocardiography (TEE) guidance. Procedural and technical success, as well as safety of LAA closure, were evaluated peri-procedurally and after 4, 8, and 12 weeks. Moreover, after 4, 8 and, 12 weeks animals were sacrificed for pathological analysis (e.g., thrombus formation, device ingrowth, endothelialization, and inflammation). All LAA closure devices were successfully implanted. On follow-up, no serious adverse events such as device-associated thrombus or translocalization/embolization were observed. A clinically non-significant pericarditis was observed in 4 animals at the time of autopsy. Endothelialization of the device was visible after 4 weeks, advanced after 8 weeks and completed after 12 weeks. Immunohistochemistry showed low amounts of inflammatory infiltration on the edges of the device. The results of this study indicate that implantation of a modified Occlutech LAA closure device is feasible with rapid endothelialization and low inflammatory infiltration in a porcine model. Human data are needed to further characterize safety and efficacy. %0 journal article %@ 1944-8244 %A Deng, Z.,Wang, W.,Xu, X.,Nie, Y.,Liu, Y.,Gould, O.,Ma, N.,Lendlein, A. %D 2021 %J ACS Applied Materials and Interfaces %N 9 %P 10748-10759 %R doi:10.1021/acsami.0c22565 %T Biofunction of Polydopamine Coating in Stem Cell Culture %U https://doi.org/10.1021/acsami.0c22565 9 %X High levels of reactive oxygen species (ROS) during stem cell expansion often lead to replicative senescence. Here, a polydopamine (PDA)-coated substrate was used to scavenge extracellular ROS for mesenchymal stem cell (MSC) expansion. The PDA-coated substrate could reduce the oxidative stress and mitochondrial damage in replicative senescent MSCs. The expression of senescence-associated β-galactosidase of MSCs from three human donors (both bone marrow- and adipose tissue-derived) was suppressed on PDA. The MSCs on the PDA-coated substrate showed a lower level of interleukin 6 (IL-6), one of the senescence-associated inflammatory components. Cellular senescence-specific genes, such as p53 and p21, were downregulated on the PDA-coated substrate, while the stemness-related gene, OCT4, was upregulated. The PDA-coated substrate strongly promoted the proliferation rate of MSCs, while the stem cell character and differentiation potential were retained. Large-scale expansion of stem cells would greatly benefit from the PDA-coated substrate. %0 journal article %@ 2059-8521 %A Saretia, S.,Machatschek, R.,Lendlein, A. %D 2021 %J MRS Advances %N 33 %P 790-795 %R doi:10.1557/s43580-021-00067-4 %T Degradation kinetics of oligo(ε-caprolactone) ultrathin films: Influence of crystallinity %U https://doi.org/10.1557/s43580-021-00067-4 33 %X The potential of using crystallinity as morphological parameter to control polyester degradation in acidic environments is explored in ultrathin films by Langmuir technique. Films of hydroxy or methacrylate end-capped oligo(ε-caprolactone) (OCL) are prepared at the air–water interface as a function of mean molecular area (MMA). The obtained amorphous, partially crystalline or highly crystalline ultrathin films of OCL are hydrolytically degraded at pH ~ 1.2 on water surface or on silicon surface as-transferred films. A high crystallinity reduces the hydrolytic degradation rate of the films on both water and solid surfaces. Different acceleration rates of hydrolytic degradation of semi-crystalline films are achieved either by crystals complete melting, partially melting, or by heating them below their melting temperatures. Semi-crystalline OCL films transferred via water onto a solid surface retain their crystalline morphology, degrade in a controlled manner, and are of interest as thermoswitchable coatings for cell substrates and medical devices. %0 journal article %@ 2079-4991 %A Neffe, A.,Izraylit, V.,Hommes-Schattmann, P.,Lendlein, A. %D 2021 %J Nanomaterials %N 6 %P 1472 %R doi:10.3390/nano11061472 %T Soft, Formstable (Co)Polyester Blend Elastomers %U https://doi.org/10.3390/nano11061472 6 %X High crystallization rate and thermomechanical stability make polylactide stereocomplexes effective nanosized physical netpoints. Here, we address the need for soft, form-stable degradable elastomers for medical applications by designing such blends from (co)polyesters, whose mechanical properties are ruled by their nanodimensional architecture and which are applied as single components in implants. By careful controlling of the copolymer composition and sequence structure of poly[(L-lactide)-co-(ε-caprolactone)], it is possible to prepare hyperelastic polymer blends formed through stereocomplexation by adding poly(D-lactide) (PDLA). Low glass transition temperature Tg ≤ 0 °C of the mixed amorphous phase contributes to the low Young’s modulus E. The formation of stereocomplexes is shown in DSC by melting transitions Tm > 190 °C and in WAXS by distinct scattering maxima at 2θ = 12° and 21°. Tensile testing demonstrated that the blends are soft (E = 12–80 MPa) and show an excellent hyperelastic recovery Rrec = 66–85% while having high elongation at break εb up to >1000%. These properties of the blends are attained only when the copolymer has 56–62 wt% lactide content, a weight average molar mass >140 kg·mol−1, and number average lactide sequence length ≥4.8, while the blend is formed with a content of 5–10 wt% of PDLA. The devised strategy to identify a suitable copolymer for stereocomplexation and blend formation is transferable to further polymer systems and will support the development of thermoplastic elastomers suitable for medical applications. %0 journal article %@ 1742-5689 %A Bastola, A.,Soffiatti, P.,Behl, M.,Lendlein, A.,Rowe, N. %D 2021 %J Journal of the Royal Society Interface %N 178 %P 20210040 %R doi:10.1098/rsif.2021.0040 %T Structural performance of a climbing cactus: making the most of softness %U https://doi.org/10.1098/rsif.2021.0040 178 %X Climbing plants must reach supports and navigate gaps to colonize trees. This requires a structural organization ensuring the rigidity of so-called ‘searcher’ stems. Cacti have succulent stems adapted for water storage in dry habitats. We investigate how a climbing cactus Selenicereus setaceus develops its stem structure and succulent tissues for climbing. We applied a ‘wide scale’ approach combining field-based bending, tensile and swellability tests with fine-scale rheological, compression and anatomical analyses in laboratory conditions. Gap-spanning ‘searcher’ stems rely significantly on the soft cortex and outer skin of the stem for rigidity in bending (60–94%). A woody core contributes significantly to axial and radial compressive strength (80%). Rheological tests indicated that storage moduli were consistently higher than loss moduli indicating that the mucilaginous cortical tissue behaved like a viscoelastic solid with properties similar to physical or chemical hydrogels. Rheological and compression properties of the soft tissue changed from young to old stages. The hydrogel–skin composite is a multi-functional structure contributing to rigidity in searcher stems but also imparting compliance and benign failure in environmental situations when stems must fail. Soft tissue composites changing in function via changes in development and turgescence have a great potential for exploring candidate materials for technical applications. %0 journal article %@ 0884-0431 %A Rössler, U.,Hennig, A.,Stelzer, N.,Bose, S.,Kopp, J.,Søe, K.,Cyganek, L.,Zifarelli, G.,Ali, S.,von der Hagen, M.,Strässler, E.,Hahn, G.,Pusch, M.,Stauber, T.,Izsvák, Z.,Gossen, M.,Stachelscheid, H.,Kornak, U. %D 2021 %J Journal of Bone and Mineral Research %N 8 %P 1621-1635 %R doi:10.1002/jbmr.4322 %T Efficient generation of osteoclasts from human induced pluripotent stem cells and functional investigations of lethal CLCN7-related osteopetrosis %U https://doi.org/10.1002/jbmr.4322 8 %X Human induced pluripotent stem cells (hiPSCs) hold great potential for modeling human diseases and the development of innovative therapeutic approaches. Here, we report on a novel, simplified differentiation method for forming functional osteoclasts from hiPSCs. The three-step protocol starts with embryoid body formation, followed by hematopoietic specification, and finally osteoclast differentiation. We observed continuous production of monocyte-like cells over a period of up to 9 weeks, generating sufficient material for several osteoclast differentiations. The analysis of stage-specific gene and surface marker expression proved mesodermal priming, the presence of monocyte-like cells, and of terminally differentiated multinucleated osteoclasts, able to form resorption pits and trenches on bone and dentine in vitro. In comparison to peripheral blood mononuclear cell (PBMC)-derived osteoclasts hiPSC-derived osteoclasts were larger and contained a higher number of nuclei. Detailed functional studies on the resorption behavior of hiPSC-osteoclasts indicated a trend towards forming more trenches than pits and an increase in pseudoresorption. We used hiPSCs from an autosomal recessive osteopetrosis (ARO) patient (BIHi002-A, ARO hiPSCs) with compound heterozygous missense mutations p.(G292E) and p.(R403Q) in CLCN7, coding for the Cl−/H+-exchanger ClC-7, for functional investigations. The patient's leading clinical feature was a brain malformation due to defective neuronal migration. Mutant ClC-7 displayed residual expression and retained lysosomal co-localization with OSTM1, the gene coding for the osteopetrosis-associated transmembrane protein 1, but only ClC-7 harboring the mutation p.(R403Q) gave strongly reduced ion currents. An increased autophagic flux in spite of unchanged lysosomal pH was evident in undifferentiated ARO hiPSCs. ARO hiPSC-derived osteoclasts showed an increased size compared to hiPSCs of healthy donors. They were not able to resorb bone, underlining a loss-of-function effect of the mutations. In summary, we developed a highly reproducible, straightforward hiPSC-osteoclast differentiation protocol. We demonstrated that osteoclasts differentiated from ARO hiPSCs can be used as a disease model for ARO and potentially also other osteoclast-related diseases. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). %0 journal article %@ 1422-0067 %A Lau, S.,Maier, A.,Braune, S.,Gossen, M.,Lendlein, A. %D 2021 %J International Journal of Molecular Sciences %N 13 %P 7006 %R doi:10.3390/ijms22137006 %T Effect of Endothelial Culture Medium Composition on Platelet Responses to Polymeric Biomaterials %U https://doi.org/10.3390/ijms22137006 13 %X Near-physiological in vitro thrombogenicity test systems for the evaluation of blood-contacting endothelialized biomaterials requires co-cultivation with platelets (PLT). However, the addition of PLT has led to unphysiological endothelial cell (EC) detachment in such in vitro systems. A possible cause for this phenomenon may be PLT activation triggered by the applied endothelial cell medium, which typically consists of basal medium (BM) and nine different supplements. To verify this hypothesis, the influence of BM and its supplements was systematically analyzed regarding PLT responses. For this, human platelet rich plasma (PRP) was mixed with BM, BM containing one of nine supplements, or with BM containing all supplements together. PLT adherence analysis was carried out in six-channel slides with plasma-treated cyclic olefin copolymer (COC) and poly(tetrafluoro ethylene) (PTFE, as a positive control) substrates as part of the six-channel slides in the absence of EC and under static conditions. PLT activation and aggregation were analyzed using light transmission aggregometry and flow cytometry (CD62P). Medium supplements had no effect on PLT activation and aggregation. In contrast, supplements differentially affected PLT adherence, however, in a polymer- and donor-dependent manner. Thus, the use of standard endothelial growth medium (BM + all supplements) maintains functionality of PLT under EC compatible conditions without masking the differences of PLT adherence on different polymeric substrates. These findings are important prerequisites for the establishment of a near-physiological in vitro thrombogenicity test system assessing polymer-based cardiovascular implant materials in contact with EC and PLT. %0 journal article %@ 2059-8521 %A Izraylit, V.,Heuchel, M.,Kratz, K.,Lendlein, A. %D 2021 %J MRS Advances %N 33 %P 781-785 %R doi:10.1557/s43580-021-00063-8 %T Non-woven shape-memory polymer blend actuators %U https://doi.org/10.1557/s43580-021-00063-8 33 %X The hierarchical design approach provides various opportunities to adjust the structural performance of polymer materials. Electrospinning processing techniques give access to molecular orientation as a design parameter, which we consider here in view of the shape-memory actuation performance. The aim of this work is to investigate how the reversible strain ε′rev can be affected by a morphology change from a bulk material to an electrospun mesh. ε′rev could be increased from 5.5 ± 0.5% to 15 ± 1.8% for a blend from a multiblock copolymer with poly(ε-caprolactone) (PCL) and poly(L-lactide) (PLLA) segments with oligo(D-lactide) (ODLA). This study demonstrates an effective design approach for enhancing soft actuator performance, which can be broadly applied in soft robotics and medicine. %0 journal article %@ 0884-2914 %A Neffe, A.,Zhang, Q.,Hommes-Schattmann, P.,Wang, W.,Xu, X.,Ahmad, B.,Williams, G.,Lendlein, A. %D 2021 %J Journal of Materials Research %N 14 %P 2995-3009 %R doi:10.1557/s43578-021-00260-z %T Functionalizable coaxial PLLA/PDLA nanofibers with stereocomplexes at the internal interface %U https://doi.org/10.1557/s43578-021-00260-z 14 %X Multifunctionality of electrospun polylactic acid (PLA) nonwovens was generated by the morphological design of nanofibers. Coaxial fibers with a lower number average molar mass Mn PLLA core and a higher Mn PDLA shell form PDLA–PLLA stereocrystals at the interface, induced by annealing. In tensile tests under physiological conditions, the core–shell fibers with higher crystallinity (22% compared to 11–14%) had lower Young’s moduli E (9 ± 1 MPa) and lower elongation at break εb (26 ± 3%) than PDLA alone (E = 31 ± 9 MPa, εb = 80 ± 5%), which can be attributed to simultaneous crystallization and relaxation effects. Gelatin incorporated in the PDLA phase was presented on the outer surface providing a biointerface putatively favorable for cell adherence. Gelatin incorporation did not influence the crystallization behavior but slightly lowered Tg (60 → 54 °C). Employing exclusively polymers established in the clinic, multifunctionality was generated by design. %0 journal article %@ 2159-6859 %A Farhan, M.,Behl, M.,Kratz, K.,Lendlein, A. %D 2021 %J MRS Communications %N 4 %P 476-482 %R doi:10.1557/s43579-021-00058-4 %T Origami hand for soft robotics driven by thermally controlled polymeric fiber actuators %U https://doi.org/10.1557/s43579-021-00058-4 4 %X Active fibers can serve as artificial muscles in robotics or components of smart textiles. Here, we present an origami hand robot, where single fibers control the reversible movement of the fingers. A recovery/contracting force of 0.2 N with a work capacity of 0.175 kJ kg−1 was observed in crosslinked poly[ethylene-co-(vinyl acetate)] (cPEVA) fibers, which could enable the bending movement of the fingers by contraction upon heating. The reversible opening of the fingers was attributed to a combination of elastic recovery force of the origami structure and crystallization-induced elongation of the fibers upon cooling. %0 journal article %@ 2059-8521 %A Rodriguez, N.,Bastola, A.,Behl, M.,Soffiatti, P.,Rowe, N.,Lendlein, A. %D 2021 %J MRS Advances %N 25 %P 625-630 %R doi:10.1557/s43580-021-00081-6 %T Approaches of combining a 3D-printed elastic structure and a hydrogel to create models for plant-inspired actuators %U https://doi.org/10.1557/s43580-021-00081-6 25 %X Inspired by the interesting functional traits of a climbing cactus, Selenicereus setaceus, found in the forest formations of Southeastern Brazil, we formulated a hypothesis that we can directly learn from the plants to develop multi-functional artificial systems by means of a multi-disciplinary approach. In this context, our approach is to take advantage of 3D-printing techniques and shape-memory hydrogels synergistically to mimic the functional traits of the cactus. This work reports on the preliminary investigation of cactus-inspired artificial systems. First, we 3D-printed soft polymeric materials and characterized them, which defines the structure and is a passive component of a multi-material system. Second, different hydrogels were synthesized and characterized, which is an active component of a multi-material system. Finally, we investigated how the hydrogel can be integrated into the 3D-printed constructs to develop artificial functional systems. %0 journal article %@ 0014-3057 %A Liang, X.,Behl, M.,Lendlein, A. %D 2021 %J European Polymer Journal %N %P 110189 %R doi:10.1016/j.eurpolymj.2020.110189 %T Dihydroxy terminated teroligomers from morpholine-2,5-diones %U https://doi.org/10.1016/j.eurpolymj.2020.110189 %X Oligodepsipeptides (ODPs) attract increasing attention as degradable materials in controlled drug delivery or as building blocks for nano-carriers. Their strong intermolecular interactions provide high stability. Tailoring the side groups of the amino acid repeating units to achieve a strong affinity to particular drugs allows a high drug-loading capacity. Here we describe synthesis and characterization of dihydroxy terminated teroligodepsipeptides (ter-ODPs) by ring-opening copolymerization (ROP) of three different morpholine-2,5-diones (MDs) in bulk in order to provide a set of teroligomers with structural variation for drug release or transfection. Ter-ODPs with equivalent co-monomer feed ratios were prepared as well as ter-ODPs, in which the co-monomer feed ratio was varied between 9 mol% and 78 mol%. Ter-ODPs were synthesized by ROP using 1,1,10,10-tetra-n-butyl-1,10-distanna-2,9,11,18-tetraoxa-5,6,14,15-tetrasulfur-cyclodecane (tin(IV) alkoxide) that was obtained by the reaction of dibutyl tin(II) oxide with 2-hydroxyethyl disulfide. The number average molecular weight (Mn) of ter-ODPs, determined by 1H NMR and gel permeation chromatography (GPC), ranged between 4000 g·mol−1 and 8600 g·mol−1. Co-monomer compositions in ter-ODPs could be controlled by changing the feed ratio of co-monomers as observed by 1H NMR spectroscopy and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The amount of remaining monomers as determined by 1H NMR could be kept below 1 wt%. Macrocycles as main sources of byproducts as determined from MALDI-TOF-MS measurements were significantly lower as compared to polymerization by Sn(Oct)2. Glass-transition temperature (Tg) of ter-ODPs ranged between 59 °C and 70 °C. %0 journal article %@ 0264-1275 %A Bastola, A.,Rodriguez, N.,Behl, M.,Soffiatti, P.,Rowe, N.,Lendlein, A. %D 2021 %J Materials & Design %N %P 109515 %R doi:10.1016/j.matdes.2021.109515 %T Cactus-inspired design principles for soft robotics based on 3D printed hydrogel-elastomer systems %U https://doi.org/10.1016/j.matdes.2021.109515 %X Plants have evolved many capabilities to anchor, position their stems and leaves favourably, and adapt themselves to different environmental conditions by virtue of growing. Selenicereus setaceus is a cactus and is an impressive example of a climbing plant found mostly in the Atlantic forest formations of southern Brazil. This cactus displays striking changes in stem geometry along different stages of growth: older parts are circular while the younger parts are star-like in shape. Such a transformation in shape optimizes its flexural rigidity and allows the cactus to search in three-dimensionally complex environments. Its organisation offers novel schemes for the design of plant-inspired soft robotic systems. In this paper, we have created multi-material systems for soft robotics that display controlled movements as well as mimicking the cactus stem geometries from star-like to circular. The unique star-shaped geometry is 3D printed using a soft elastomer and hydrogel is used as an actuating component. Through anisotropic swelling, the hydrogel-elastomer system adjusts its configuration and shows a controlled movement. Furthermore, the isotropic swelling of the hydrogel of the artificial cactus multi-material system result in the change in shape from star-like to circular as the cactus does naturally in the tropical forest. %0 journal article %@ 1386-0291 %A Braune, S.,Bäckemo, J.,Lau, S.,Heuchel, M.,Kratz, K.,Jung, F.,Reinthaler, M.,Lendlein, A. %D 2021 %J Clinical Hemorheology and Microcirculation %N 4 %P 367-380 %R doi:10.3233/CH-201029 %T The influence of different rewetting procedures on the thrombogenicity of nanoporous poly(ether imide) microparticles %U https://doi.org/10.3233/CH-201029 4 %X Nanoporous microparticles prepared from poly(ether imide) (PEI) are discussed as candidate adsorber materials for the removal of uremic toxins during apheresis. Polymers exhibiting such porosity can induce the formation of micro-gas/air pockets when exposed to fluids. Such air presenting material surfaces are reported to induce platelet activation and thrombus formation. Physical or chemical treatments prior to implantation are discussed to reduce the formation of such gas nuclei. Here, we report about the influence of different rewetting procedures – as chemical treatments with solvents – on the thrombogenicity of hydrophobic PEI microparticles and PEI microparticles hydrophilized by covalent attachment of poly(vinyl pyrrolidone) (PVP) of two different chain lengths. Autoclaved dry PEI particles of all types with a diameter range of 200 – 250 μm and a porosity of about 84% ±2% were either rewetted directly with phosphate buffered saline (24 h) or after immersion in an ethanol-series. Thrombogenicity of the particles was studied in vitro using human sodium citrated whole blood (60 min, 5 rpm vertical rotation). Numbers of non-adherent platelets were quantified, and adhesion of blood cells was qualitatively analyzed by bright field microscopy. Platelet activation (percentage of CD62P positive platelets and amounts of soluble P-Selectin) and platelet function (PFA100 closure times) were analysed. Retention of blood platelets on the particles was similar for all particle types and both rewetting procedures. Non-adherent platelets were less activated after contact with ethanol-treated particles of all types compared to those rewetted with phosphate buffered saline as assessed by a reduced number of CD62P-positive platelets and reduced amounts of secreted P-Selectin (P < 0.05 each). Interestingly, the hydrophilic surfaces significantly increased the number of activated platelets compared to hydrophobic PEI regardless of the rewetting agent. This suggests that, apart from wettability, other material properties might be more important to regulate platelet activation. PFA100 closure times were reduced and within the reference ranges in the ethanol group, however, significantly increased in the saline group. No substantial difference was detected between the tested surface modifications. In summary, rewetting with ethanol resulted in a reduced thrombogenicity of all studied microparticles regardless of their wettability, most likely resulting from the evacuation of air from the nanoporous particles. %0 journal article %@ 1438-7492 %A Farhan, M.,Chaudhary, D.,Nöchel, U.,Behl, K.,Kratz, K.,Lendlein, A. %D 2021 %J Macromolecular Materials and Engineering %N 2 %P 2000579 %R doi:10.1002/mame.202000579 %T Electrical Actuation of Coated and Composite Fibers Based on Poly[ethylene‐co‐(vinyl acetate)] %U https://doi.org/10.1002/mame.202000579 2 %X Robots are typically controlled by electrical signals. Resistive heating is an option to electrically trigger actuation in thermosensitive polymer systems. In this study electrically triggerable poly[ethylene‐co‐(vinyl acetate)] (PEVA)‐based fiber actuators are realized as composite fibers as well as polymer fibers with conductive coatings. In the coated fibers, the core consists of crosslinked PEVA (cPEVA), while the conductive coating shell is achieved via a dip coating procedure with a coating thickness between 10 and 140 µm. The conductivity of coated fibers σ = 300–550 S m−1 is much higher than that of the composite fibers σ = 5.5 S m−1. A voltage (U) of 110 V is required to heat 30 cm of coated fiber to a targeted temperature of ≈ 65 °C for switching in less than a minute. Cyclic electrical actuation investigations reveal ε′rev = 5 ± 1% reversible change in length for coated fibers. The fabrication of such electro‐conductive polymeric actuators is suitable for upscaling so that their application potential as artificial muscles can be explored in future studies. %0 journal article %@ 0014-3057 %A Neffe, A.,Garcia Cruz, D.,Roch, T.,Lendlein, A. %D 2021 %J European Polymer Journal %N %P 110148 %R doi:10.1016/j.eurpolymj.2020.110148 %T Microparticles from glycidylmethacrylated gelatin as cell carriers prepared in an aqueous two-phase system %U https://doi.org/10.1016/j.eurpolymj.2020.110148 %X Encapsulation by polymeric biomaterials can provide mechanical protection of cells and shielding from the immune system of the host when implanted as cell therapy. At the same time, free exchange of nutrients and metabolites including bioactive molecules guiding regenerative processes is facilitated. Here, glycidylmethacrylated gelatin (GMA-gelatin) is explored as matrix material for adherent (L929 mouse fibroblasts) or non-adherent (Ramos blue) cells by an integrated process of shaping and chemical crosslinking. Microparticle formation was driven by a water-in-water-emulsion technique, which allowed simultaneous irradiation with light of 365 nm in the presence of the photosensitizer irgacure 2959. Suitable photopolymerization conditions were determined in experiments with GMA-gelatin and cells. More than 85% of the cells survived this procedure, and an encapsulation efficiency of up to 75 ± 2% was reached. Diffusivity of molecules up to a molar mass of 150 kg·mol−1 in the matrix was shown by the release of co-encapsulated FITC-labelled dextran. L929 as well as Ramos blue cells proliferated in the microparticle matrix after encapsulation and released enzymes that could be detected in the cell culture medium in an active form. L929 showed the ability to escape the particles over time. Altogether, the presented cell encapsulation system based on a material that is stable to hydrolytic degradation for several weeks is generally suitable for cell based therapy or in vitro test systems. %0 journal article %@ 1438-7492 %A Behl, M.,Balk, M.,Mansfeld, U.,Lendlein, A. %D 2021 %J Macromolecular Materials and Engineering %N 3 %P 2000672 %R doi:10.1002/mame.202000672 %T Phase Morphology of Multiblock Copolymers Differing in Sequence of Blocks %U https://doi.org/10.1002/mame.202000672 3 %X The chemical nature, the number length of integrated building blocks, as well as their sequence structure impact the phase morphology of multiblock copolymers (MBC) consisting of two non‐miscible block types. It is hypothesized that a strictly alternating sequence should impact phase segregation. A library of well‐defined MBC obtained by coupling oligo(ε‐caprolactone) (OCL) of different molecular weights (2, 4, and 8 kDa) with oligotetrahydrofuran (OTHF, 2.9 kDa) via Steglich esterification results in strictly alternating (MBCalt) or random (MBCran) MBC. The three different series has a weight average molecular weight (Mw) of 65 000, 165 000, and 168 000 g mol−1 for MBCalt and 80 500, 100 000, and 147 600 g mol−1 for MBCran. When the chain length of OCL building blocks is increased, the tendency for phase segregation is facilitated, which is attributed to the decrease in chain mobility within the MBC. Furthermore, it is found that the phase segregation disturbs the crystallization by causing heterogeneities in the semi‐crystalline alignment, which is attributed to an increase of the disorder of the OCL semi‐crystalline alignment. %0 journal article %@ 2159-6859 %A Folikumah, M.,Behl, M.,Lendlein, A. %D 2021 %J MRS Communications %N 4 %P 402-410 %R doi:10.1557/s43579-021-00041-z %T Reaction behaviour of peptide-based single thiol-thioesters exchange reaction substrate in the presence of externally added thiols %U https://doi.org/10.1557/s43579-021-00041-z 4 %X Identification of patterns in chemical reaction pathways aids in the effective design of molecules for specific applications. Here, we report on model reactions with a water-soluble single thiol-thioester exchange (TTE) reaction substrate, which was designed taking in view biological and medical applications. This substrate consists of the thio-depsipeptide, Ac-Pro-Leu-Gly-SLeu-Leu-Gly-NEtSH (TDP) and does not yield foul-smelling thiol exchange products when compared with aromatic thiol containing single TTE substrates. TDP generates an α,ω-dithiol crosslinker in situ in a ‘pseudo intramolecular’ TTE. Competitive intermolecular TTE of TDP with externally added “basic” thiols increased the crosslinker concentration whilst “acidic” thiols decreased its concentration. TDP could potentially enable in situ bioconjugation and crosslinking applications. %0 journal article %@ 1022-1352 %A Zhang, P.,Rešetic, A.,Behl, M.,Lendlein, A. %D 2021 %J Macromolecular Chemistry and Physics %N 3 %P 2000394 %R doi:10.1002/macp.202000394 %T Multifunctionality in Polymer Networks by Dynamic of Coordination Bonds %U https://doi.org/10.1002/macp.202000394 3 %X The need for multifunctional materials is driven by emerging technologies and innovations, such as in the field of soft robotics and tactile or haptic systems, where minimizing the number of operational components is not only desirable, but can also be essential for realizing such devices. This study report on designing a multifunctional soft polymer material that can address a number of operating requirements such as solvent resistance, reshaping ability, self‐healing capability, fluorescence stimuli‐responsivity, and anisotropic structural functions. The numerous functional abilities are associated to rhodium(I)–phosphine coordination bonds, which in a polymer network act with their dynamic and non‐covalently bonded nature as multifunctional crosslinks. Reversible aggregation of coordination bonds leads to changes in fluorescence emission intensity that responds to chemical or mechanical stimuli. The fast dynamics and diffusion of rhodium–phosphine ions across and through contacting areas of the material provide for reshaping and self‐healing abilities that can be further exploited for assembly of multiple pieces into complex forms, all without any loss to material‐sensing capabilities. %0 journal article %@ 0014-3057 %A Behl, M.,Balk, M.,Lützow, K.,Lendlein, A. %D 2021 %J European Polymer Journal %N %P 110207 %R doi:10.1016/j.eurpolymj.2020.110207 %T Impact of block sequence on the phase morphology of multiblock copolymers obtained by high-throughput robotic synthesis %U https://doi.org/10.1016/j.eurpolymj.2020.110207 %X The chemical nature, the number length of integrated building blocks, as well as their sequence structure impact the phase morphology of multiblock copolymers (MBC) consisting of two non-miscible block types. We hypothesized that a strictly alternating sequence should favour phase segregation and in this way the elastic properties. A library of well-defined MBCs composed of two different hydrophobic, semi-crystalline blocks providing domains with well-separated melting temperatures (Tms) were synthesized from the same type of precursor building blocks as strictly alternating (MBCsalt) or random (MBCsran) MBCs and compared. Three different series of MBCsalt or MBCsran were synthesized by high-throughput synthesis by coupling oligo(ε-caprolactone) (OCL) of different molecular weights (2, 4, and 8 kDa) with oligotetrahydrofuran (OTHF, 2.9 kDa) via Steglich esterification in which the molar ratio of the reaction partners was slightly adjusted. Maximum of weight average molecular weight (Mw) were 65,000 g∙mol−1, 165,000 g∙mol−1, and 168,000 g∙mol−1 for MBCsalt and 80,500 g∙mol−1, 100,000 g∙mol−1, and 147,600 g∙mol−1 for MBCsran. When Mw increased, a decrease of both Tms associated to the melting of the OCL and OTHF domains was observed for all MBCs. Tm (OTHF) of MBCsran was always higher than Tm (OTHF) of MBCsalt, which was attributed to a better phase segregation. In addition, the elongation at break of MBCsalt was almost half as high when compared to MBCsran. In this way this study elucidates role of the block length and sequence structure in MBCs and enables a quantitative discussion of the structure-function relationship when two semi-crystalline block segments are utilized for the design of block copolymers. %0 journal article %@ 2196-7350 %A Machatschek, R.,Saretia, S.,Lendlein, A. %D 2021 %J Advanced Materials Interfaces %N 6 %P 2001926 %R doi:10.1002/admi.202001926 %T Assessing the Influence of Temperature‐Memory Creation on the Degradation of Copolyesterurethanes in Ultrathin Films %U https://doi.org/10.1002/admi.202001926 6 %X Copolyesterurethanes (PDLCLs) based on oligo(ε‐caprolactone) (OCL) and oligo(ω‐pentadecalactone) (OPDL) segments are biodegradable thermoplastic temperature‐memory polymers. The temperature‐memory capability in these polymers with crystallizable control units is implemented by a thermomechanical programming process causing alterations in the crystallite arrangement and chain organization. These morphological changes can potentially affect degradation. Initial observations on the macroscopic level inspire the hypothesis that switching of the controlling units causes an accelerated degradation of the material, resulting in programmable degradation by sequential coupling of functions. Hence, detailed degradation studies on Langmuir films of a PDLCL with 40 wt% OPDL content are carried out under enzymatic catalysis. The temperature‐memory creation procedure is mimicked by compression at different temperatures. The evolution of the chain organization and mechanical properties during the degradation process is investigated by means of polarization‐modulated infrared reflection absorption spectroscopy, interfacial rheology and to some extend by X‐ray reflectivity. The experiments on PDLCL Langmuir films imply that degradability is not enhanced by thermal switching, as the former depends on the temperature during cold programming. Nevertheless, the thin film experiments show that the leaching of OCL segments does not induce further crystallization of the OPDL segments, which is beneficial for a controlled and predictable degradation. %0 journal article %@ 1386-0291 %A Brunacci, N.,Wischke, C.,Naolou, T.,Patzelt, A.,Lademann, J.,Neffe, A.,Lendlein, A. %D 2021 %J Clinical Hemorheology and Microcirculation %N 2 %P 201-219 %R doi:10.3233/CH-200977 %T Formulation of drug-loaded oligodepsipeptide particles with submicron size %U https://doi.org/10.3233/CH-200977 2 %X The size of particulate carriers is key to their transport and distribution in biological systems, and needs to be tailored in the higher submicron range to enable follicular uptake for dermal treatment. Oligodepsipeptides are promising nanoparticulate carrier systems as they can be designed to exhibit enhanced interaction with drug molecules. Here, a fabrication scheme for drug-loaded submicron particles from oligo[3-(S)-sec-butylmorpholine-2,5-dione]diol (OBMD) is presented based on an emulsion solvent evaporation method with cosolvent, surfactant, and polymer concentration as variable process parameters. The particle size (300–950 nm) increased with lower surfactant concentration and higher oligomer concentration. The addition of acetone increased the particle size at low surfactant concentration. Particle size remained stable upon the encapsulation of models compounds dexamethasone (DXM) and Nile red (NR), having different physicochemical properties. DXM was released faster compared to NR due to its higher water solubility. Overall, the results indicated that both drug-loading and size control of OBMD submicron particles can be achieved. When applied on porcine ear skin samples, the NR-loaded particles have been shown to allow NR penetration into the hair follicle and the depth reached with the 300 nm particles was comparable to the one reached with the cream formulation. A potential benefit of the particles compared to a cream is their sustained release profile. %0 journal article %@ 1422-0067 %A Lau, S.,Gossen, M.,Lendlein, A.,Jung, F. %D 2021 %J International Journal of Molecular Sciences %N 2 %P 978 %R doi:10.3390/ijms22020978 %T Venous and Arterial Endothelial Cells from Human Umbilical Cords: Potential Cell Sources for Cardiovascular Research %U https://doi.org/10.3390/ijms22020978 2 %X Although cardiovascular devices are mostly implanted in arteries or to replace arteries, in vitro studies on implant endothelialization are commonly performed with human umbilical cord-derived venous endothelial cells (HUVEC). In light of considerable differences, both morphologically and functionally, between arterial and venous endothelial cells, we here compare HUVEC and human umbilical cord-derived arterial endothelial cells (HUAEC) regarding their equivalence as an endothelial cell in vitro model for cardiovascular research. No differences were found in either for the tested parameters. The metabolic activity and lactate dehydrogenase, an indicator for the membrane integrity, slightly decreased over seven days of cultivation upon normalization to the cell number. The amount of secreted nitrite and nitrate, as well as prostacyclin per cell, also decreased slightly over time. Thromboxane B2 was secreted in constant amounts per cell at all time points. The Von Willebrand factor remained mainly intracellularly up to seven days of cultivation. In contrast, collagen and laminin were secreted into the extracellular space with increasing cell density. Based on these results one might argue that both cell types are equally suited for cardiovascular research. However, future studies should investigate further cell functionalities, and whether arterial endothelial cells from implantation-relevant areas, such as coronary arteries in the heart, are superior to umbilical cord-derived endothelial cells. %0 journal article %@ 2196-7350 %A Saretia, S.,Machatschek, R.,Bhuvanesh, T.,Lendlein, A. %D 2021 %J Advanced Materials Interfaces %N 7 %P 2001940 %R doi:10.1002/admi.202001940 %T Effect of Water on Crystallization and Melting of Telechelic Oligo(ε‐caprolactone)s in Ultrathin Films %U https://doi.org/10.1002/admi.202001940 7 %X The thermal behavior of ultrathin, semi‐crystalline films of oligo(ε‐caprolactone)s (OCLs) with hydroxy or methacrylate end groups, is studied by the Langmuir technique in dependence on mean molecular areas and crystallization temperatures. The films on solid substrate as obtained by Langmuir–Schaefer transfer exhibit different lamellar thicknesses, crystal number densities, and lateral sizes. The melting temperature of OCL single crystals at the water and solid surface is proportional to the inverse crystal thickness and generally lower than in bulk PCL. An influence of OCL end groups on the melting behavior is observed mainly at the air–solid interface, where methacrylate end capped OCL melts at lower temperatures than hydroxy end capped OCL. Comparing the underlying substrate, melting/recrystallization of OCL ultrathin films is achievable at lower temperatures at the air–water interface than at the air–solid interface, where recrystallization is not identifiable. Recrystallization at the air–water interface generally occurs at higher temperature than the initial crystallization temperature. The surface pressure, as an additional thermodynamic variable, seems to further affect the crystallization behavior, with crystal thickness and lateral growth rate increasing with surface pressure. The results presented here are important when designing temperature‐sensitive or active nanostructured materials or interfaces based on OCL. %0 journal article %@ 1422-0067 %A Schulz, C.,Krüger-Genge, A.,Lendlein, A.,Küpper, J.,Jung, F. %D 2021 %J International Journal of Molecular Sciences %N 3 %P 1493 %R doi:10.3390/ijms22031493 %T Potential Effects of Nonadherent on Adherent Human Umbilical Venous Endothelial Cells in Cell Culture %U https://doi.org/10.3390/ijms22031493 3 %X The adherence and shear-resistance of human umbilical venous endothelial cells (HUVEC) on polymers is determined in vitro in order to qualify cardiovascular implant materials. In these tests, variable fractions of HUVEC do not adhere to the material but remain suspended in the culture medium. Nonadherent HUVEC usually stop growing, rapidly lose their viability and can release mediators able to influence the growth and function of the adherent HUVEC. The aim of this study was the investigation of the time dependent behaviour of HUVEC under controlled nonadherent conditions, in order to gain insights into potential influences of these cells on their surrounding environment in particular adherent HUVEC in the context of in vitro biofunctionality assessment of cardiovascular implant materials. Data from adherent or nonadherent HUVEC growing on polystyrene-based cell adhesive tissue culture plates (TCP) or nonadhesive low attachment plates (LAP) allow to calculate the number of mediators released into the culture medium either from adherent or nonadherent cells. Thus, the source of the inflammatory mediators can be identified. For nonadherent HUVEC, a time-dependent aggregation without further proliferation was observed. The rate of apoptotic/dead HUVEC progressively increased over 90% within two days. Concomitant with distinct blebbing and loss of membrane integrity over time, augmented releases of prostacyclin (PGI2, up to 2.91 ± 0.62 fg/cell) and platelet-derived growth factor BB (PDGF-BB, up to 1.46 ± 0.42 fg/cell) were detected. The study revealed that nonadherent, dying HUVEC released mediators, which can influence the surrounding microenvironment and thereby the results of in vitro biofunctionality assessment of cardiovascular implant materials. Neglecting nonadherent HUVEC bears the risk for under- or overestimation of the materials endothelialization potential, which could lead to the loss of relevant candidates or to uncertainty with regard to their suitability for cardiac applications. One approach to minimize the influence from nonadherent endothelial cells could be their removal shortly after observing initial cell adhesion. However, this would require an individual adaptation of the study design, depending on the properties of the biomaterial used. %0 journal article %@ 0264-1275 %A Sauter, T.,Kratz, K.,Heuchel, M.,Lendlein, A. %D 2021 %J Materials & Design %N %P 109546 %R doi:10.1016/j.matdes.2021.109546 %T Fiber diameter as design parameter for tailoring the macroscopic shape-memory performance of electrospun meshes %U https://doi.org/10.1016/j.matdes.2021.109546 %X Fibrous shape-memory polymer (SMP) scaffolds were investigated considering the fiber as basic microstructural feature. By reduction of the fiber diameter in randomly oriented electrospun polyetherurethane (PEU) meshes from the micro- to the nano-scale, we observed changes in the molecular orientation within the fibers and its impact on the structural and shape-memory performance. It was assumed that a spatial restriction by reduction of the fiber diameter increases molecular orientation along the orientation of the fiber. The stress-strain relation of random PEU scaffolds is initially determined by the 3D arrangement of the fibers and thus is independent of the molecular orientation. Increasing the molecular orientation with decreasing single fiber diameter in scaffolds composed of randomly arranged fibers did not alter the initial stiffness and peak stress but strongly influenced the elongation at break and the stress increase above the Yield point. Reduction of the single fiber diameter also distinctly improved the shape-memory performance of the scaffolds. Fibers with nanoscale diameters (< 100 nm) possessed an almost complete shape recovery, high recovery stresses and fast relaxation kinetics, while the shape fixity was found to decrease with decreasing fiber diameter. Hence, the fiber diameter is a relevant design parameter for SMP. %0 journal article %@ 1438-7492 %A Sauter, T.,Kratz, K.,Madbouly, S.,Klein, F.,Heuchel, M.,Lendlein, A. %D 2021 %J Macromolecular Materials and Engineering %N 4 %P 2000730 %R doi:10.1002/mame.202000730 %T Anisotropy Effects in the Shape‐Memory Performance of Polymer Foams %U https://doi.org/10.1002/mame.202000730 4 %X Isotropic and anisotropic shape‐memory polymer foams are prepared by supercritical carbon dioxide foaming from a multiblock copolymer (PDLCL) consisting of poly(ω‐pentadecalactone) and poly(ε‐caprolactone) segments. Analysis by micro‐computed tomography reveals for the anisotropic PDLCL foam cells a high shape anisotropy ratio of R = 1.72 ± 0.62 with a corresponding Young's compression moduli ratio between longitudinal and transversal direction of 4.3. The experimental compression data in the linear elastic range can be well described by the anisotropic open foam model of Gibson and Ashby. A micro‐morphological analysis for single pores using scanning electron microscopy images permits the correlation between the macroscopic stress‐compression behavior and microscale structural changes. %0 journal article %@ 2059-8521 %A Saretia, S.,Machatschek, R.,Lendlein, A. %D 2021 %J MRS Advances %N 10 %P 283-290 %R doi:10.1557/s43580-021-00020-5 %T Highly crystalline PCL ultrathin films as thermally switchable biomaterial coatings %U https://doi.org/10.1557/s43580-021-00020-5 10 %X Semi-crystalline oligomers are explored as functionalized thermoswitchable coatings for modification of biomaterials surface. Highly crystalline oligo(ε-caprolactone) (OCL) films are prepared at the air–water interface by the Langmuir technique, which consist of tightly packed single crystals. Their morphology and melting temperature can be tuned by the chemical structure of the OCL end-groups (hydroxy or methacrylate) and by the crystallization temperature (12 or 21 °C) as physical parameter. This demand of high crystallite density and adjustable morphology of coatings is not met by conventional methodologies for preparing thin films, e.g., spin coating, spray coating, or solvent evaporation. The high crystallinity reduces the enzymatic degradation rate of the films on both water and solid surfaces. The high density of methacrylate end-groups at the crystal surfaces enables post-functionalization, which was demonstrated using fluorescein dimethacrylate as chemically linked label. The thermoswitching behavior (melting and recrystallization) of fluorescein functionalized, highly crystalline OCL films shows temperature-dependent distribution of the chemically linked fluorescein moieties, which are accumulated on the surfaces of crystals, and homogeneously dispersed when the crystals are molten. Thermally switchable highly crystalline films are relevant for cell substrates modulating adhesion at the biointerface or for coatings as barrier layer influencing the degradation rate. %0 journal article %@ 2059-8521 %A Tung, W.,Sun, X.,Wang, W.,Xu, X.,Ma, N.,Lendlein, A. %D 2021 %J MRS Advances %N 10 %P 276-282 %R doi:10.1557/s43580-020-00001-0 %T Structure, mechanical properties and degradation behavior of electrospun PEEU fiber meshes and films %U https://doi.org/10.1557/s43580-020-00001-0 10 %X The capability of a degradable implant to provide mechanical support depends on its degradation behavior. Hydrolytic degradation was studied for a polyesteretherurethane (PEEU70), which consists of poly(p-dioxanone) (PPDO) and poly(ε-caprolactone) (PCL) segments with a weight ratio of 70:30 linked by diurethane junction units. PEEU70 samples prepared in the form of meshes with average fiber diameters of 1.5 µm (mesh1.5) and 1.2 µm (mesh1.2), and films were sterilized and incubated in PBS at 37 °C with 5 vol% CO2 supply for 1 to 6 weeks. Degradation features, such as cracks or wrinkles, became apparent from week 4 for all samples. Mass loss was found to be 11 wt%, 6 wt%, and 4 wt% for mesh1.2, mesh1.5, and films at week 6. The elongation at break decreased to under 20% in two weeks for mesh1.2. In case of the other two samples, this level of degradation was achieved after 4 weeks. The weight average molecular weight of both PEEU70 mesh and film samples decreased to below 30 kg/mol when elongation at break dropped below 20%. The time period of sustained mechanical stability of PEEU70-based meshes depends on the fiber diameter and molecular weight. %0 journal article %@ 2159-6859 %A Xu, X.,Nie, Y.,Wang, W.,Ma, N.,Lendlein, A. %D 2021 %J MRS Communications %N 4 %P 425-431 %R doi:10.1557/s43579-021-00049-5 %T Periodic thermomechanical modulation of toll-like receptor expression and distribution in mesenchymal stromal cells %U https://doi.org/10.1557/s43579-021-00049-5 4 %X Toll-like receptor (TLR) can trigger an immune response against virus including SARS-CoV-2. TLR expression/distribution is varying in mesenchymal stromal cells (MSCs) depending on their culture environments. Here, to explore the effect of periodic thermomechanical cues on TLRs, thermally controlled shape-memory polymer sheets with programmable actuation capacity were created. The proportion of MSCs expressing SARS-CoV-2-associated TLRs was increased upon stimulation. The TLR4/7 colocalization was promoted and retained in the endoplasmic reticula. The TLR redistribution was driven by myosin-mediated F-actin assembly. These results highlight the potential of boosting the immunity for combating COVID-19 via thermomechanical preconditioning of MSCs. %0 journal article %@ 2159-6859 %A Lau, S.,Liu, Y.,Maier, A.,Braune, S.,Gossen, M.,Neffe, A.,Lendlein, A. %D 2021 %J MRS Communications %N 5 %P 559-567 %R doi:10.1557/s43579-021-00072-6 %T Establishment of an in vitro thrombogenicity test system with cyclic olefin copolymer substrate for endothelial layer formation %U https://doi.org/10.1557/s43579-021-00072-6 5 %X In vitro thrombogenicity test systems require co-cultivation of endothelial cells and platelets under blood flow-like conditions. Here, a commercially available perfusion system is explored using plasma-treated cyclic olefin copolymer (COC) as a substrate for the endothelial cell layer. COC was characterized prior to endothelialization and co-cultivation with platelets under static or flow conditions. COC exhibits a low roughness and a moderate hydrophilicity. Flow promoted endothelial cell growth and prevented platelet adherence. These findings show the suitability of COC as substrate and the importance of blood flow-like conditions for the assessment of the thrombogenic risk of drugs or cardiovascular implant materials. %0 journal article %@ 2159-6859 %A Bäckemo, J.,Liu, Y.,Lendlein, A. %D 2021 %J MRS Communications %N 4 %P 462-469 %R doi:10.1557/s43579-021-00056-6 %T Bio-inspired and computer-supported design of modulated shape changes in polymer materials %U https://doi.org/10.1557/s43579-021-00056-6 4 %X The Venus flytrap is a fascinating plant with a finely tuned mechanical bi-stable system, which can switch between mono- and bi-stability. Here, we combine geometrical design of compliant mechanics and the function of shape-memory polymers to enable switching between bi- and mono-stable states. Digital design and modelling using the Chained Beam Constraint Model forecasted two geometries, which were experimentally realized as structured films of cross-linked poly[ethylene-co-(vinyl acetate)] supported by digital manufacturing. Mechanical evaluation confirmed our predicted features. We demonstrated that a shape-memory effect could switch between bi- and mono-stability for the same construct, effectively imitating the Venus flytrap. %0 journal article %@ 2308-3425 %A Langer, C.,Barbieri, F.,Plank, F.,Beyer, C.,Baldauf, B.,Friedrich, G.,Widmann, G.,Luger, A.,Adukauskaite, A.,Reinthaler, M.,Dichtl, W.,Homma, S.,Feuchtner, G.M. %D 2021 %J Journal of Cardiovascular Development and Disease %N 11 %P 141 %R doi:10.3390/jcdd8110141 %T Coronary Artery Dimensions in Endurance Athletes by Computed Tomography Angiography: A Quantitative Analysis %U https://doi.org/10.3390/jcdd8110141 11 %X (1) Background: The athlete’s heart may develop permanent vessel enlargement. The purpose of our study was to define normal values for coronary artery dimensions of endurance athletes by coronary computed tomography angiography (CTA). (2) Methods: Ninety-eight individuals (56.2 ± 11 years) were included into this retrospective matched case-controlled-study. Endurance athletes had regular training volumes of ≥1 h per unit, ≥3–7 times per week (either cycling, running or mountain-endurance). Athletes were matched for age and gender with sedentary controls using propensity score. Quantitative CTA analysis included coronary vessel dimensions (two diameters and area) of the LM, LAD, CX and RCA for all AHA-16-segments. (3) Results: Proximal LAD area and diameter (p = 0.019); proximal/mid CX (diameter and area; p = 0.026 and p = 0.018/p = 0.008 and p = 0.009); mid RCA diameter and area; and proximal RCA diameter were significantly larger in endurance athletes (p < 0.05). The left main area (p = 0.708) and diameter (p = 0.809) as well as the mid LAD and distal segments were not different. We present the histograms and data for normal values ±1 and ± 2 SD. (4) Conclusions: Endurance athletes have larger proximal LAD, proximal/mid CX and RCA vessel dimensions, while LM and distal segments are similar. Hence, dilated coronary arteries in endurance athletes (“Athlete’s arteries”) have to be distinguished from diffuse ectatic segments developing during Kawasaki disease or multisystemic inflammation syndrome after COVID-19. %0 journal article %@ 2159-6859 %A Izraylit, V.,Liu, Y.,Tarazona, N.,Machatschek, R.,Lendlein, A. %D 2021 %J MRS Communications %N 6 %P 850-855 %R doi:10.1557/s43579-021-00107-y %T Crystallization and degradation behaviour of multiblock copolyester blends in Langmuir monolayers %U https://doi.org/10.1557/s43579-021-00107-y 6 %X Supporting the wound healing of soft tissues requires fixation devices becoming more elastic while degrading. To address this unmet need, we designed a blend of degradable multiblock copolymers, which is cross-linked by PLA stereocomplexation combining two soft segments differing substantially in their hydrolytic degradation rate. The degradation path and concomitant structural changes are predicted by Langmuir monolayer technique. The fast hydrolysis of one soft segment leads to a decrease of the total polymer mass at constant physical cross-linking density. The corresponding increase of the average spacing between the network nodes suggests the targeted increase of the blend’s flexibility. %0 journal article %@ 1744-683X %A Friess, F.,Lendlein, A.,Wischke, C. %D 2021 %J Soft Matter %N 41 %P 9326-9331 %R doi:10.1039/d1sm00947h %T Switching microobjects from low to high aspect ratios using a shape-memory effect %U https://doi.org/10.1039/d1sm00947h 41 %X Spherical particles from shape-memory polymers (SMP) can be stretched to ellipsoids with high aspect ratio (AR) and temporarily stabilized. They can switch back to low AR upon thermal stimulation. Here, the creation of an alternative shape-switching capability of particles from low to high AR is introduced, where a SMP matrix from polyvinyl alcohol (PVA) is used to create crosslinked high AR particles and to program the embedded micrometer-sized particles from a second SMP (oligo(ε-caprolactone) micronetworks, MN) with a low switching temperature Tsw. This programming proceeds through shape-recovery of the PVA matrix, from which the MN are harvested by PVA matrix dissolution. The use of a dissolvable SMP matrix may be a general strategy to efficiently create systems with complex moving capabilities. %0 journal article %@ 2059-8521 %A Neffe, A.,Löwenberg, C.,Lendlein, A. %D 2021 %J MRS Advances %N 33 %P 796-800 %R doi:10.1557/s43580-021-00136-8 %T Hydrogel networks by aliphatic dithiol Michael addition to glycidylmethacrylated gelatin %U https://doi.org/10.1557/s43580-021-00136-8 33 %X Functionalization of gelatin with glycidylmethacrylate (GMA-gelatin) enables network formation employing the double bond, so that the reaction is orthogonal to the inherent functional groups in the biomacromolecule. Here, network formation by crosslinking of GMA-gelatin with hexane 1,6-dithiol or nonane 1,9-dithiol to tailor properties and enable a shape-memory effect is shown by 1H NMR and FT-IR spectroscopy. Hydrogel swelling (460–1900 vol%) and mechanical properties (Young’s modulus E = 59–512 kPa, elongation at break εb = 44–127%) depended on the molecular composition of the networks and temperature. Increased crosslinker length, thiol:methacrylate molar ratio, and precursor concentrations led to denser networks. Change of properties with temperature suggested adoption of triple helices by gelatin chains, forming physical netpoints at lower temperatures (< 20 °C). However, the limited freedom of the gelatin chains to move allowed only a minimal extent of triple helices formation, as it became apparent from the related signal in wide-angle X-ray scattering and the thermal transition associated to triple helices in some networks by DSC. The presented strategy is likely transferable to other biomacromolecules, and the results suggest that too short crosslinkers may result in a significant amount of grafting rather than network formation. %0 journal article %@ 2308-3425 %A Barbieri, F.,Schröder, M.,Beyhoff, N.,Landmesser, U.,Reinthaler, M.,Kasner, M. %D 2021 %J Journal of Cardiovascular Development and Disease %N 9 %P 111 %R doi:10.3390/jcdd8090111 %T Percutaneous Edge-to-Edge Tricuspid Valve Repair in a Patient with Cor Triatriatum Dexter: A Case Report %U https://doi.org/10.3390/jcdd8090111 9 %X Background: Tricuspid regurgitation is gaining importance due to its high morbidity and mortality. Especially in the elderly, novel technologies in percutaneous therapies have become valuable options due to the commonly present high surgical risk. Case presentation: We report a case of a 78-year-old female suffering from massive tricuspid regurgitation with repetitive right-sided heart failure hospitalizations. As the patient was very frail and deemed as high surgical risk, we used the TriClip® system to improve her symptomatic status. During diagnostic work-up, an additional membrane separating the right atrium, consistent with the definition of a cor triatriatum dexter, was found. Although increasing the complexity of the procedure, implantation of 3 clips with reduction of tricuspid regurgitation to a mild-to-moderate degree was achieved without any notable complications. The patient was discharged with ameliorated symptoms on the fourth postoperative day. Conclusions: Our case highlights the feasibility of percutaneous edge-to-edge tricuspid valve repair in an elderly woman with cor triatriatum dexter. Accurate echocardiographic visualization is an absolute requirement to gain access to the tricuspid valve without interacting with prevailing additional membranes. %0 journal article %@ 2374-7951 %A Lendlein, A.,Heuchel, M. %D 2021 %J ACS Central Science %N 10 %P 1599-1601 %R doi:10.1021/acscentsci.1c01032 %T Shape-Memory Polymers Designed in View of Thermomechanical Energy Storage and Conversion Systems %U https://doi.org/10.1021/acscentsci.1c01032 10 %X Effective temporary shape fixation by,strain-induced formation of supramolecular nanostructures enables high energy density,one-way shape-memory polymers. %0 journal article %@ 1944-8244 %A Balk, M.,Behl, M.,Nöchel, U.,Lendlein, A. %D 2021 %J ACS Applied Materials and Interfaces %N 7 %P 8095-8101 %R doi:10.1021/acsami.1c00466 %T Enzymatically Triggered Jack-in-the-Box-like Hydrogels %U https://doi.org/10.1021/acsami.1c00466 7 %X Enzymes can support the synthesis or degradation of biomacromolecules in natural processes. Here, we demonstrate that enzymes can induce a macroscopic-directed movement of microstructured hydrogels following a mechanism that we call a “Jack-in-the-box” effect. The material’s design is based on the formation of internal stresses induced by a deformation load on an architectured microscale, which are kinetically frozen by the generation of polyester locking domains, similar to a Jack-in-the-box toy (i.e., a compressed spring stabilized by a closed box lid). To induce the controlled macroscopic movement, the locking domains are equipped with enzyme-specific cleavable bonds (i.e., a box with a lock and key system). As a result of enzymatic reaction, a transformed shape is achieved by the release of internal stresses. There is an increase in entropy in combination with a swelling-supported stretching of polymer chains within the microarchitectured hydrogel (i.e., the encased clown pops-up with a pre-stressed movement when the box is unlocked). This utilization of an enzyme as a physiological stimulus may offer new approaches to create interactive and enzyme-specific materials for different applications such as an optical indicator of the enzyme’s presence or actuators and sensors in biotechnology and in fermentation processes. %0 journal article %@ 2059-8521 %A Liang, X.,Behl, M.,Luetzow, K.,Lendlein, A. %D 2021 %J MRS Advances %N %P 764-768 %R doi:10.1557/s43580-021-00082-5 %T Cooligomers from morpholine-2,5-dione and para-dioxanone and catalyst complex SnOct2/2-hydroxyethyl sulfide %U https://doi.org/10.1557/s43580-021-00082-5 %X Complexes from catalysts and initiator can be used to insert a specific number of additional chemical functional groups in (co)polymers prepared by ring-opening polymerization (ROP) of lactones. We report on the synthesis of cooligomers from sec-butyl-morpholine-2,5-dione (SBMD) and para-dioxanone (PDX) by ROP with varied feed ratios in the bulk using the catalyst complex SnOct2/2-hydroxyethyl sulfide. Mn of the cooligomers (determined by GPC) decreased with decreasing SBMD feed ratio from 4200 ± 420 to 800 ± 80 g mol−1. When the feed ratio was reduced from 80 to 50 mol% the molar ratio of SBMD of the cooligomers (determined by 1H-NMR) remained nearly unchanged between 81 and 86 mol% and was attributed to a higher reactivity of SBMD. This assumption was confirmed by fractionation of GPC, in which an increase of SBMD with increasing molecular weight was observed. The catalyst/initiator system provides a high potential to create orthogonal building blocks by cleavage of the sulfide bond. %0 journal article %@ 2399-7532 %A Sahabudeen, H.,Machatschek, R.,Lendlein, A. %D 2021 %J Multifunctional Materials %N 4 %P 042001 %R doi:10.1088/2399-7532/ac1e7d %T Multifunctionality as design principle for contact lens materials %U https://doi.org/10.1088/2399-7532/ac1e7d 4 %X From synthesis through storage to disposal, contact lenses (CLs) interact with different system environments throughout their functional life cycle. To fulfill their therapeutic purpose, they need to exhibit a distinct behavior in each of them, which is achieved through a combination of different material functions. As such, CL materials are a showcase of highly advanced and mass-produced multifunctional biomaterials. Their great relevance and long history mean that a vast amount of work has gone into the implementation of ever more advanced functions. From understanding the approaches used to achieve multifunctionality in CLs, a lot of inspiration for the design of other multifunctional medical devices can be drawn. Therefore, here, we provide a systematic overview of the different functions that are combined in today's CL materials, together with their quantification methods, chemical design principles and fabrication techniques. We further provide an outlook on the functions that are currently under investigation for the next generation of commercial CLs. %0 journal article %@ 1420-3049 %A Durán-Aranguren, D.D.,Robledo, S.,Gomez-Restrepo, E.,Valencia, J.W.A.,Tarazona, N.A. %D 2021 %J Molecules %N 24 %P 7605 %R doi:10.3390/molecules26247605 %T Scientometric Overview of Coffee By-Products and Their Applications %U https://doi.org/10.3390/molecules26247605 24 %X As coffee consumption is on the rise, and the global coffee production creates an excess of 23 million tons of waste per year, a revolutionary transition towards a circular economy via the transformation and valorization of the main by-products from its cultivation and preparation (Coffee Husk (CH), Coffee Pulp (CP), Coffee Silverskin (CS), and Spent Coffee Grounds (SCG)) is inspiring researchers around the world. The recent growth of scholarly publications in the field and the emerging applications of coffee by-products published in these scientific papers encourages a systematic review to identify the knowledge structure, research hotspots, and to discuss the challenges and future directions. This paper displays a comprehensive scientometric analysis based on 108 articles with a high level of influence in the field of coffee by-products and their applications. According to our analysis, the research in this field shows an explosive growth since 2017, clustered in five core applications: bioactive compounds, microbial transformation, environmental applications, biofuels from thermochemical processes, and construction materials. %0 journal article %@ 1386-0291 %A Krüger-Genge, A.,Tondera, C.,Hauser, S.,Braune, S.,Görs, J.,Roch, T.,Klopfleisch, R.,Neffe, A.,Lendlein, A.,Pietzsch, J.,Jung, F. %D 2021 %J Clinical Hemorheology and Microcirculation %N 3 %P 335-350 %R doi:10.3233/CH-201028 %T Immunocompatibility and non-thrombogenicity of gelatin-based hydrogels %U https://doi.org/10.3233/CH-201028 3 %X Immunocompatibility and non-thrombogenicity are important requirements for biomedical applications such as vascular grafts. Here, gelatin-based hydrogels formed by reaction of porcine gelatin with increasing amounts of lysine diisocyanate ethyl ester were investigated in vitro in this regard. In addition, potential adverse effects of the hydrogels were determined using the “Hen’s egg test on chorioallantoic membrane” (HET-CAM) test and a mouse model. The study revealed that the hydrogels were immunocompatible, since complement activation was absent and a substantial induction of reactive oxygen species generating monocytes and neutrophils could not be observed in whole human blood. The density as well as the activation state of adherent thrombocytes was comparable to medical grade polydimethylsiloxane, which was used as reference material. The HET-CAM test confirmed the compatibility of the hydrogels with vessel functionality since no bleedings, thrombotic events, or vessel destructions were observed. Only for the samples synthesized with the highest LDI amount the number of growing blood vessels in the CAM was comparable to controls and significantly higher than for the softer materials. Implantation into mice showed the absence of adverse or toxic effects in spleen, liver, or kidney, and only a mild lymphocytic activation in the form of a follicular hyperplasia in draining lymph nodes (slightly increased after the implantation of the material prepared with the lowest LDI content). These results imply that candidate materials prepared with mid to high amounts of LDI are suitable for the coating of the blood contacting surface of cardiovascular implants. %0 journal article %@ 2373-9878 %A Krüger-Genge, A.,Hauser, S.,Neffe, A.,Liu, Y.,Lendlein, A.,Pietzsch, J.,Jung, F. %D 2021 %J ACS Biomaterials Science & Engineering %N 2 %P 527-540 %R doi:10.1021/acsbiomaterials.0c01432 %T Response of Endothelial Cells to Gelatin-Based Hydrogels %U https://doi.org/10.1021/acsbiomaterials.0c01432 2 %X The establishment of confluent endothelial cell (EC) monolayers on implanted materials has been identified as a concept to avoid thrombus formation but is a continuous challenge in cardiovascular device engineering. Here, material properties of gelatin-based hydrogels obtained by reacting gelatin with varying amounts of lysine diisocyanate ethyl ester were correlated with the functional state of hydrogel contacting venous EC (HUVEC) and HUVEC’s ability to form a monolayer on these hydrogels. The density of adherent HUVEC on the softest hydrogel at 37 °C (G’ = 1.02 kPa, E = 1.1 ± 0.3 kPa) was significantly lower (125 mm–1) than on the stiffer hydrogels (920 mm–1; G’ = 2.515 and 5.02 kPa, E = 4.8 ± 0.8 and 10.3 ± 1.2 kPa). This was accompanied by increased matrix metalloprotease activity (9 pmol·min–2 compared to 0.6 pmol·min–2) and stress fiber formation, while cell-to-cell contacts were comparable. Likewise, release of eicosanoids (e.g., prostacyclin release of 1.7 vs 0.2 pg·mL–1·cell–1) and the pro-inflammatory cytokine MCP-1 (8 vs <1.5 pg·mL–1·cell–1) was higher on the softer than on the stiffer hydrogels. The expressions of pro-inflammatory markers COX-2, COX-1, and RAGE were slightly increased on all hydrogels on day 2 (up to 200% of the control), indicating a weak inflammation; however, the levels dropped to below the control from day 6. The study revealed that hydrogels with higher moduli approached the status of a functionally confluent HUVEC monolayer. The results indicate the promising potential especially of the discussed gelatin-based hydrogels with higher G’ as biomaterials for implants foreseen for the venous system. %0 journal article %@ 1936-8798 %A Skurk, C.,Reinthaler, M.,Kasner, M.,Landmesser, U. %D 2021 %J JACC Cardiovascular Interventions %N 16 %P 1846-1847 %R doi:10.1016/j.jcin.2021.05.016 %T Large LAA - Too Big for Closure?: LAA Closure With the World’s Biggest Percutaneous Closure Device %U https://doi.org/10.1016/j.jcin.2021.05.016 16 %X %0 journal article %@ 1936-8798 %A Barbieri, F.,Abdelwahed, Y.,Landmesser, U.,Reinthaler, M.,Skurk, C. %D 2021 %J JACC Cardiovascular Interventions %N 24 %P e333-e334 %R doi:10.1016/j.jcin.2021.09.025 %T Massive Left Atrial Thrombus in a Patient With Left Atrial Appendage Closure %U https://doi.org/10.1016/j.jcin.2021.09.025 24 %X %0 journal article %@ 2514-2119 %A Barbieri, F.,Landmesser, U.,Kasner, M.,Reinthaler, M. %D 2021 %J European Heart Journal - Case Reports %N 12 %P ytab492 %R doi:10.1093/ehjcr/ytab492 %T Combined transcatheter treatment of severe mitral regurgitation and secundum atrial septal defect in an inoperable patient: a case report %U https://doi.org/10.1093/ehjcr/ytab492 12 %X Background,Chronic mitral regurgitation (MR) is one of the most common valvular heart diseases and is associated with poor outcomes. Although other structural diseases are regularly seen in such patients, concomitant atrial septal defects (ASDs) remain a rarity in the elderly.,Case summary,We report a case of an 82-year-old woman with progressive right-sided heart failure (HF) due to MR and an ASD of secundum type, despite optimal medical therapy. Combined transcatheter mitral valve repair (MVR) by utilizing a separate transseptal puncture and ASD closure was performed resulting in amelioration of symptoms.,Discussion,Procedural planning for simultaneous transcatheter therapies of coupled structural heart disease entities remains complex. Our case illustrates feasibility of percutaneous edge-to-edge MVR and consecutive closure of a large secundum ASD. Different options of accessing the left atrium should be discussed on an individual basis, while additional ASD closure may be beneficial in terms of right ventricular function and symptoms of right HF. %0 journal article %@ 1386-0291 %A Maring, J.,Becker, M.,Tung, W.,Stamm, C.,Ma, N.,Lendlein, A. %D 2021 %J Clinical Hemorheology and Microcirculation %N 1 %P 205-216 %R doi:10.3233/CH-219114 %T Cellular response of blood-borne immune cells to PEEU fiber meshes %U https://doi.org/10.3233/CH-219114 1 %X BACKGROUND:,Polymeric materials have been widely used as artificial grafts in cardiovascular applications. These polymeric implants can elicit a detrimental innate and adaptive immune response after interacting with peripheral blood. A surface modification with components from extracellular matrices (ECM) may minimize the activation of immune cells from peripheral blood. The aim of this study is to compare the cellular response of blood-born immune cells to the fiber meshes from polyesteretherurethane (PEEUm) and PEEUm with ECM coating (PEEUm + E).,MATERIALS AND METHODS:,Electrospun PEEUm were used as-is or coated with human cardiac ECM. Different immune cells were isolated form human peripheral blood. Cytokine release profile from naïve and activated monocytes was assessed. Macrophage polarization and T cell proliferation, as indication of immune response were evaluated.,RESULTS:,There was no increase in cytokine release (IL-6, TNF-α, and IL-10) from activated monocytes, macrophages and mononuclear cells on PEEUm; neither upon culturing on PEEUm + E. Naïve monocytes showed increased levels of IL-6 and TNF-α, which were not present on PEEUm + E. There was no difference on monocyte derived macrophage polarization towards pro-inflammatory M1 or anti-inflammatory M2 on PEEUm and PEEUm + E. Moreover, T cell proliferation was not increased upon interacting with PEEUm directly.,CONCLUSION:,As PEEUm only elicits a minimal response from naïve monocytes but not from monocytes, peripheral blood mononuclear cells (PBMCs) or T cells, the slight improvement in response to PEEUm + E might not justify the additional effort of coating with a human ECM. %0 journal article %@ 1422-0067 %A Lau, S.,Gossen, M.,Lendlein, A. %D 2021 %J International Journal of Molecular Sciences %N 23 %P 13120 %R doi:10.3390/ijms222313120 %T Designing Cardiovascular Implants Taking in View the Endothelial Basement Membrane %U https://doi.org/10.3390/ijms222313120 23 %X Insufficient endothelialization of cardiovascular grafts is a major hurdle in vascular surgery and regenerative medicine, bearing a risk for early graft thrombosis. Neither of the numerous strategies pursued to solve these problems were conclusive. Endothelialization is regulated by the endothelial basement membrane (EBM), a highly specialized part of the vascular extracellular matrix. Thus, a detailed understanding of the structure–function interrelations of the EBM components is fundamental for designing biomimetic materials aiming to mimic EBM functions. In this review, a detailed description of the structure and functions of the EBM are provided, including the luminal and abluminal interactions with adjacent cell types, such as vascular smooth muscle cells. Moreover, in vivo as well as in vitro strategies to build or renew EBM are summarized and critically discussed. The spectrum of methods includes vessel decellularization and implant biofunctionalization strategies as well as tissue engineering-based approaches and bioprinting. Finally, the limitations of these methods are highlighted, and future directions are suggested to help improve future design strategies for EBM-inspired materials in the cardiovascular field. %0 journal article %@ 1386-0291 %A Xu, X.,Nie, Y.,Wang, W.,Ullah, I.,Tung, W.,Ma, N.,Lendlein, A. %D 2021 %J Clinical Hemorheology and Microcirculation %N 1 %P 217-230 %R doi:10.3233/CH-219111 %T Generation of 2.5D lung bud organoids from human induced pluripotent stem cells %U https://doi.org/10.3233/CH-219111 1 %X Human induced pluripotent stem cells (hiPSCs) are a promising cell source to generate the patient-specific lung organoid given their superior differentiation potential. However, the current 3D cell culture approach is tedious and time-consuming with a low success rate and high batch-to-batch variability. Here, we explored the establishment of lung bud organoids by systematically adjusting the initial confluence levels and homogeneity of cell distribution. The efficiency of single cell seeding and clump seeding was compared. Instead of the traditional 3D culture, we established a 2.5D organoid culture to enable the direct monitoring of the internal structure via microscopy. It was found that the cell confluence and distribution prior to induction were two key parameters, which strongly affected hiPSC differentiation trajectories. Lung bud organoids with positive expression of NKX 2.1, in a single-cell seeding group with homogeneously distributed hiPSCs at 70% confluence (SC_70%_hom) or a clump seeding group with heterogeneously distributed cells at 90% confluence (CL_90%_het), can be observed as early as 9 days post induction. These results suggest that a successful lung bud organoid formation with single-cell seeding of hiPSCs requires a moderate confluence and homogeneous distribution of cells, while high confluence would be a prominent factor to promote the lung organoid formation when seeding hiPSCs as clumps. 2.5D organoids generated with defined culture conditions could become a simple, efficient, and valuable tool facilitating drug screening, disease modeling and personalized medicine. %0 journal article %@ 1386-0291 %A Zhou, S.,Di Luca, M.,Xu, X.,Ma, N.,Jung, F.,Lendlein, A. %D 2021 %J Clinical Hemorheology and Microcirculation %N 4 %P 609-623 %R doi:10.3233/CH-211250 %T Defeating antibiotic-resistant bacteria with protein-resistant polyGGE film %U https://doi.org/10.3233/CH-211250 4 %X Biofouling on medical device surfaces, which is initiated by protein adsorption and adhesion of microbes especially the antibiotic-resistant bacteria, attracts global attention for centuries due to its enduring challenges in healthcare. Here, the antifouling effect of hydrophilic poly(glycerol glycidyl ether) (polyGGE) film is explored in comparison to hemocompatible and protein-resistant control polymers. The chemical and thermomechanical stability of polyGGE in hydrated conditions at body temperature was achieved via adjusting UV curing and KOH quenching time. The polyGGE surface is inert to the plasma protein adsorption and interfered the metabolism conditions, biofilm formation and growth of both Gram negative (Gram–) and antibiotic-resistant Gram positive (Gram+) bacteria. These results indicate the potential application of polyGGE for combating the risk of hospital-acquired infections and preventing drug-resistant superbug spreading. %0 journal article %@ 2059-8521 %A Deng, Z.,Wang, W.,Xu, X.,Ma, N.,Lendlein, A. %D 2021 %J MRS Advances %N %P 739-744 %R doi:10.1557/s43580-021-00091-4 %T Polydopamine-based biofunctional substrate coating promotes mesenchymal stem cell migration %U https://doi.org/10.1557/s43580-021-00091-4 %X Rapid migration of mesenchymal stem cells (MSCs) on device surfaces could support in vivo tissue integration and might facilitate in vitro organoid formation. Here, polydopamine (PDA) is explored as a biofunctional coating to effectively promote MSC motility. It is hypothesized that PDA stimulates fibronectin deposition and in this way enhances integrin-mediated migration capability. The random and directional cell migration was investigated by time-lapse microscopy and gap closure assay respectively, and analysed with softwares as computational tools. A higher amount of deposited fibronectin was observed on PDA substrate, compared to the non-coated substrate. The integrin β1 activation and focal adhesion kinase (FAK) phosphorylation at Y397 were enhanced on PDA substrate, but the F-actin cytoskeleton was not altered, suggesting MSC migration on PDA was regulated by integrin initiated FAK signalling. This study strengthens the biofunctionality of PDA coating for regulating stem cells and offering a way of facilitating tissue integration of devices. %0 journal article %@ 0884-2914 %A Friess, F.,Lendlein, A.,Wischke, C. %D 2021 %J Journal of Materials Research %N %P 3248-3257 %R doi:10.1557/s43578-021-00295-2 %T Size control of shape switchable micronetworks by fast two-step microfluidic templating %U https://doi.org/10.1557/s43578-021-00295-2 %X Shape-memory polymer micronetworks (MN) are micrometer-sized objects that can switch their outer shape upon external command. This study aims to scale MN sizes to the low micrometer range at very narrow size distributions. In a two-step microfluidic strategy, the specific design of coaxial class capillary devices allowed stabilizing the thread of the dispersed phase to efficiently produce precursor particles in the tip-streaming regime at rates up to ~ 170 kHz and final sizes down to 4 µm. In a subsequent melt-based microfluidic photocrosslinking of the methacrylate-functionalized oligo(ɛ-caprolactone) precursor material, MN could be produced without particle aggregation. A comprehensive analysis of MN properties illustrated successful crosslinking, semi-crystalline morphology, and a shape-switching functionality for all investigated MN sizes (4, 6, 9, 12, 22 µm). Such functional micronetworks tailored to and below the dimension of cells can enable future applications in technology and medicine like controlling cell interaction. %0 journal article %@ 2059-8521 %A Nie, Y.,Wang, W.,Xu, X.,Ma, N.,Lendlein, A. %D 2021 %J MRS Advances %N %P 745-749 %R doi:10.1557/s43580-021-00110-4 %T The response of human induced pluripotent stem cells to cyclic temperature changes explored by BIO-AFM %U https://doi.org/10.1557/s43580-021-00110-4 %X Human induced pluripotent stem cells (hiPSCs) are highly sensitive to extrinsic physical and biochemical signals from their extracellular microenvironments. In this study, we analyzed the effect of cyclic temperature changes on hiPSCs behaviors, especially by means of scanning force microscopy (BIO-AFM). The alternation in cellular mechanics, as well as the secretion and pattern of deposition of extracellular matrix (ECM) protein in hiPSCs were evaluated. The arrangement of the actin cytoskeleton changed with the variation of the temperature. The rearranged cytoskeleton architecture led to the subsequent changes in cell mechanics (Young's modulus of hiPSCs). With the exposure to the cyclic cold stimuli, an increase in the average surface roughness (Ra) and roughness mean square (RMS) was detected. This observation might be at least in part due to the upregulated secretion of Laminin α5 during repeated temporary cooling. The expression of pluripotent markers, NANOG and SOX2, was not impaired in hiPSCs, when exposed to the cyclic cold stimuli for 24 h. Our findings provide an insight into the effect of temperature on the hiPSC behaviors, which may contribute to a better understanding of the application of locally controlled therapeutic hypothermia. %0 journal article %@ 1944-8244 %A Ortega-Guerrero, A.,Sahabudeen, H.,Croy, A.,Dianat, A.,Dong, R.,Feng, X.,Cuniberti, G. %D 2021 %J ACS Applied Materials and Interfaces %N 22 %P 26411-26420 %R doi:10.1021/acsami.1c05967 %T Multiscale Modeling Strategy of 2D Covalent Organic Frameworks Confined at an Air–Water Interface %U https://doi.org/10.1021/acsami.1c05967 22 %X Two-dimensional covalent organic frameworks (2D COFs) have attracted attention as versatile active materials in many applications. Recent advances have demonstrated the synthesis of monolayer 2D COF via an air–water interface. However, the interfacial 2D polymerization mechanism has been elusive. In this work, we have used a multiscale modeling strategy to study dimethylmethylene-bridged triphenylamine building blocks confined at the air–water interface to form a 2D COF via Schiff-base reaction. A synergy between the computational investigations and experiments allowed the synthesis of a 2D-COF with one of the linkers considered. Our simulations complement the experimental characterization and show the preference of the building blocks to be at the interface with a favorable orientation for the polymerization. The air–water interface is shown to be a key factor to stabilize a flat conformation when a dimer molecule is considered. The structural and electronic properties of the monolayer COFs based on the two monomers are calculated and show a semiconducting nature with direct bandgaps. Our strategy provides a first step toward the in silico polymerization of 2D COFs at air–water interfaces capturing the initial steps of the synthesis up to the prediction of electronic properties of the 2D material. %0 journal article %@ 2045-2322 %A Taieb, H.,Garske, D.,Contzen, J.,Gossen, M.,Bertinetti, L.,Robinson, T.,Cipitria, A. %D 2021 %J Scientific Reports %N 1 %P 13455 %R doi:10.1038/s41598-021-92054-w %T Osmotic pressure modulates single cell cycle dynamics inducing reversible growth arrest and reactivation of human metastatic cells %U https://doi.org/10.1038/s41598-021-92054-w 1 %X Biophysical cues such as osmotic pressure modulate proliferation and growth arrest of bacteria, yeast cells and seeds. In tissues, osmotic regulation takes place through blood and lymphatic capillaries and, at a single cell level, water and osmoregulation play a critical role. However, the effect of osmotic pressure on single cell cycle dynamics remains poorly understood. Here, we investigate the effect of osmotic pressure on single cell cycle dynamics, nuclear growth, proliferation, migration and protein expression, by quantitative time-lapse imaging of single cells genetically modified with fluorescent ubiquitination-based cell cycle indicator 2 (FUCCI2). Single cell data reveals that under hyperosmotic stress, distinct cell subpopulations emerge with impaired nuclear growth, delayed or growth arrested cell cycle and reduced migration. This state is reversible for mild hyperosmotic stress, where cells return to regular cell cycle dynamics, proliferation and migration. Thus, osmotic pressure can modulate the reversible growth arrest and reactivation of human metastatic cells. %0 journal article %@ 0884-2914 %A Machatschek, R.,Heuchel, M.,Lendlein, A. %D 2021 %J Journal of Materials Research %N 14 %P 2987-2994 %R doi:10.1557/s43578-021-00267-6 %T Hydrolytic stability of polyetherimide investigated in ultrathin films %U https://doi.org/10.1557/s43578-021-00267-6 14 %X Increasing the surface hydrophilicity of polyetherimide (PEI) through partial hydrolysis of the imide groups while maintaining the length of the main-chain was explored for adjusting its function in biomedical and membrane applications. The outcome of the polymer analogous reaction, i.e., the degree of ring opening and chain cleavage, is difficult to address in bulk and microstructured systems, as these changes only occur at the interface. Here, the reaction was studied at the air–water interface using the Langmuir technique, assisted by atomic force microscopy and vibrational spectroscopy. Slow PEI hydrolysis sets in at pH > 12. At pH = 14, the ring opening is nearly instantaneous. Reduction of the layer viscosity with time at pH = 14 suggested moderate chain cleavage. No hydrolysis was observed at pH = 1. Hydrolyzed PEI films had a much more cohesive structure, suggesting that the nanoporous morphology of PEI can be tuned via hydrolysis. %0 journal article %@ 1758-5082 %A Drzeniek, N.,Mazzocchi, A.,Schlickeiser, S.,Forsythe, S.,Moll, G.,Geißler, S.,Reinke, P.,Gossen, M.,Gorantla, V.,Volk, H.,Soker, S. %D 2021 %J Biofabrication %N %P 045002 %R doi:10.1088/1758-5090/ac0a32 %T Bio-instructive hydrogel expands the paracrine potency of mesenchymal stem cells %U https://doi.org/10.1088/1758-5090/ac0a32 %X The therapeutic efficacy of clinically applied mesenchymal stromal cells (MSCs) is limited due to their injection into harsh in vivo environments, resulting in the significant loss of their secretory function upon transplantation. A potential strategy for preserving their full therapeutic potential is encapsulation of MSCs in a specialized protective microenvironment, for example hydrogels. However, commonly used injectable hydrogels for cell delivery fail to provide the bio-instructive cues needed to sustain and stimulate cellular therapeutic functions. Here we introduce a customizable collagen I-hyaluronic acid (COL-HA)-based hydrogel platform for the encapsulation of MSCs. Cells encapsulated within COL-HA showed a significant expansion of their secretory profile compared to MSCs cultured in standard (2D) cell culture dishes or encapsulated in other hydrogels. Functionalization of the COL-HA backbone with thiol-modified glycoproteins such as laminin led to further changes in the paracrine profile of MSCs. In depth profiling of more than 250 proteins revealed an expanded secretion profile of proangiogenic, neuroprotective and immunomodulatory paracrine factors in COL-HA-encapsulated MSCs with a predicted augmented pro-angiogenic potential. This was confirmed by increased capillary network formation of endothelial cells stimulated by conditioned media from COL-HA-encapsulated MSCs. Our findings suggest that encapsulation of therapeutic cells in a protective COL-HA hydrogel layer provides the necessary bio-instructive cues to maintain and direct their therapeutic potential. Our customizable hydrogel combines bioactivity and clinically applicable properties such as injectability, on-demand polymerization and tissue-specific elasticity, all features that will support and improve the ability to successfully deliver functional MSCs into patients. %0 journal article %@ 1386-0291 %A Zhou, S.,Xu, X.,Ma, N.,Jung, F.,Lendlein, A. %D 2021 %J Clinical Hemorheology and Microcirculation %N 4 %P 597-608 %R doi:10.3233/CH-211241 %T Influence of sterilization conditions on sulfate-functionalized polyGGE %U https://doi.org/10.3233/CH-211241 4 %X Sulfated biomolecules are known to influence numerous biological processes in all living organisms. Particularly, they contribute to prevent and inhibit the hypercoagulation condition. The failure of polymeric implants and blood contacting devices is often related to hypercoagulation and microbial contamination. Here, bioactive sulfated biomacromolecules are mimicked by sulfation of poly(glycerol glycidyl ether) (polyGGE) films. Autoclaving, gamma-ray irradiation and ethylene oxide (EtO) gas sterilization techniques were applied to functionalized materials. The sulfate group density and hydrophilicity of sulfated polymers were decreased while chain mobility and thermal degradation were enhanced post autoclaving when compared to those after EtO sterilization. These results suggest that a quality control after sterilization is mandatory to ensure the amount and functionality of functionalized groups are retained. %0 journal article %@ 1525-7797 %A Löwenberg, C.,Julich-Gruner, K.,Neffe, A.,Behl, M.,Lendlein, A. %D 2020 %J Biomacromolecules %N 6 %P 2024-2031 %R doi:10.1021/acs.biomac.9b01753 %T Salt-Induced Shape-Memory Effect in Gelatin-Based Hydrogels %U https://doi.org/10.1021/acs.biomac.9b01753 6 %X Hydrophilic biopolymers display a strong tendency for self-organization into stable secondary, tertiary, and quaternary structures in aqueous environments. These structures are sensitive to changes in external conditions, such as temperature, pH or ions/salts, which may lead to molecular and/or macroscopic transitions. Here, we report on biopolymer-based stimuli-sensitive switchable matrices showing a shape-memory function as an output being alternatively switched by two different input signals, such as environmental changes in salt concentration or temperature. This was realized by implementing a shape-memory function in hydrogels based on the coil-to-helix transition of protein chains in gelatin-based networks. The hydrogels exhibited mechanical properties similar to that of soft tissue (storage modulus G′ = 1–100 kPa) and high swelling capabilities (Q = 1000–3000 vol %). In these gelatin-based networks, the covalent netpoints defined the permanent shape while after deformation helicalization of the gelatin acted as reversible stimuli-sensitive switches providing additional crosslinks capable of fixing the deformed temporary shape. By using either chaotropic salts to suppress gelatin helicalization or kosmotropic salts to support conformational changes of gelatin toward a helical orientation, these additional crosslinks could be cleaved or formed. In bending experiments, the strain fixity (Rf) and strain recovery ratios (Rr) were determined. While Rf ranged from 65 to 95% and was depending on the network composition, Rr were independent of the hydrogel composition with values about 100%. In addition, Rf and Rr were independent of the type of chaotropic salt that was used in this study, showing equal Rf and Rr values for MgCl2, NaSCN, and Mg(SCN)2. %0 journal article %@ 1525-7797 %A Izraylit, V.,Gould, O.,Rudolph, T.,Kratz, K.,Lendlein, A. %D 2020 %J Biomacromolecules %N 2 %P 338-348 %R doi:10.1021/acs.biomac.9b01279 %T Controlling Actuation Performance in Physically Cross-Linked Polylactone Blends Using Polylactide Stereocomplexation %U https://doi.org/10.1021/acs.biomac.9b01279 2 %X Within the field of shape-changing materials, synthetic chemical modification has been widely used to introduce key structural units and subsequently expand the mechanical functionality of actuator devices. The introduction of architectural elements that facilitate in situ control over mechanical properties and complete geometric reconfiguration of a device is highly desirable to increase the morphological diversity of polymeric actuator materials. The subject of the present study is a multiblock copolymer with semicrystalline poly(l-lactide) and poly(ε-caprolactone) (PLLA–PCL) segments. By harnessing the stereocomplexation of copolymer chains with a poly(d-lactide) oligomer (PDLA), we provide anchoring points for physical network formation and demonstrate how a blending process can be used to efficiently vary the mechanical properties of a shape-memory actuator. We investigate the effect of molecular structure on the actuation performance of the material in cyclic thermomechanical tests, with a maximum reversible shape change εrev′ = 13.4 ± 1.5% measured at 3.1 wt % of polylactide stereocomplex content in the multiblock copolymer matrix. The thermophysical properties, crystalline structure, and phase morphology were analyzed by DSC, WAXS and AFM respectively, elucidating the structure-to-function relationship in physically cross-linked blended materials. The work demonstrates a one-step technique for manufacturing a polymeric actuator and tuning its performance in situ. This approach should greatly improve the efficiency of physically cross-linked actuator fabrication, allowing composition and physical behavior to be precisely and easily controlled. %0 journal article %@ 1386-0291 %A Al-Hindwan, H.,Silbernagel, G.,Curio, J.,Abulgasim, K.,Schröder, M.,Wuerdemann, I.,Kasner, M.,Landmesser, U.,Reinthaler, M. %D 2020 %J Clinical Hemorheology and Microcirculation %N 4 %P 447-455 %R doi:10.3233/CH-200818 %T The impact of moderate aortic valve disease in patients undergoing MitraClip for severe MR %U https://doi.org/10.3233/CH-200818 4 %X BACKGROUND:,High surgical risk patients presenting with severe mitral valve regurgitation (MR) and concomitant aortic valve disease are frequently a challenge for the interdisciplinary heart team meeting. If open-heart surgery for severe MR is performed, aortic stenosis (AS) or regurgitation (AR) is corrected during the same procedure if at least moderate severity of AS or AR has been confirmed. In patients with prohibitive surgical risk, optimal management strategies in the light of available transcatheter interventions still needs to be established.,METHODS AND RESULTS:,In this retrospective single center Study, we aimed to investigate the impact of coincident moderate aortic valve disease on the outcome of patients undergoing MitraClip for severe MR. In 286 MitraClip procedures performed in our institution, 21 patients (7,3%) were identified to suffer from concomitant moderate AS and 28 patients had moderate AR (9,8%). Patients with AS were found to have a higher incidence of >moderate MR following the procedure when compared to patients without aortic valve disease (14,3% vs. 8,9%, p = 0.001). No differences between the groups were found regarding a combined endpoint of all cause deaths and heart failure hospitalizations after 1 year follow up (no aortic-valve disease vs. moderate AS: 19% vs 18%; p = 0,881 and no aortic valve disease vs moderate AR: 19% vs. 25%; p = 0.477). However, mortality was significantly higher in patients with coincidental moderate AR (3.8% patients without aortic valve disease, 5% in patients with AS, 17,9% in patients with AR; p = 0.006).,CONCLUSION:,According to our analysis coincidental Aortic valve stenosis may be associated with worse technical results regarding residual MR after MitraClip. Although our results regarding a combined endpoint of all-cause mortality and heart failure hospitalizations within one year of follow up were comparable between the groups, patients with moderate AR had significantly higher mortality rates. Due to the limited number of patients, our study is only hypothesis generating. Larger trials are necessary to confirm our result. %0 journal article %@ 2045-2322 %A Listek, M.,Hönow, A.,Gossen, M.,Hanack, K. %D 2020 %J Scientific Reports %N %P 1664 %R doi:10.1038/s41598-020-58571-w %T A novel selection strategy for antibody producing hybridoma cells based on a new transgenic fusion cell line %U https://doi.org/10.1038/s41598-020-58571-w %X The use of monoclonal antibodies is ubiquitous in science and biomedicine but the generation and validation process of antibodies is nevertheless complicated and time-consuming. To address these issues we developed a novel selective technology based on an artificial cell surface construct by which secreted antibodies were connected to the corresponding hybridoma cell when they possess the desired antigen-specificity. Further the system enables the selection of desired isotypes and the screening for potential cross-reactivities in the same context. For the design of the construct we combined the transmembrane domain of the EGF-receptor with a hemagglutinin epitope and a biotin acceptor peptide and performed a transposon-mediated transfection of myeloma cell lines. The stably transfected myeloma cell line was used for the generation of hybridoma cells and an antigen- and isotype-specific screening method was established. The system has been validated for globular protein antigens as well as for haptens and enables a fast and early stage selection and validation of monoclonal antibodies in one step. %0 journal article %@ 1022-1336 %A Zhang, P.,Behl, M.,Balk, M.,Peng, X.,Lendlein, A. %D 2020 %J Macromolecular Rapid Communications %N 7 %P 1900658 %R doi:10.1002/marc.201900658 %T Shape‐Programmable Architectured Hydrogels Sensitive to Ultrasound %U https://doi.org/10.1002/marc.201900658 7 %X On‐demand motion of highly swollen polymer systems can be triggered by changes in pH, ion concentrations, or by heat. Here, shape‐programmable, architectured hydrogels are introduced, which respond to ultrasonic‐cavitation‐based mechanical forces (CMF) by directed macroscopic movements. The concept is the implementation and sequential coupling of multiple functions (swellability in water, sensitivity to ultrasound, shape programmability, and shape‐memory) in a semi‐interpenetrating polymer network (s‐IPN). The semi‐IPN‐based hydrogels are designed to function through rhodium coordination (Rh‐s‐IPNH). These coordination bonds act as temporary crosslinks. The porous hydrogels with coordination bonds (degree of swelling from 300 ± 10 to 680 ± 60) exhibit tensile strength σmax up to 250 ± 60 kPa. Shape fixity ratios up to 90% and shape recovery ratios up to 94% are reached. Potential applications are switches or mechanosensors. %0 journal article %@ 2666-3864 %A Machatschek, R.,Schulz, B.,Lendlein, A. %D 2020 %J Cell reports. Physical science %N 1 %P 100009 %R doi:10.1016/j.xcrp.2019.100009 %T Quantitative Model and Thin Film Studies Relating Molecular Architecture and Degradation of Multifunctional Materials %U https://doi.org/10.1016/j.xcrp.2019.100009 1 %X A characteristic of multifunctional polymer materials is their complex molecular architecture, which creates a challenge in predicting their degradation behavior. Hence, their appropriate design demands a quantitative correlation between their molecular architecture and their molecular degradation behavior. Here, we present a method to analyze and predict the degradation of such molecules by fast and conclusive Langmuir monolayer experiments in combination with kinetic models. Important findings include the retardation of the degradation in the early stage caused by high molecular weight as well as end caps. In multiblock copolymers consisting of fast- and slow-degrading blocks, the molecular weight and the block length have little effect on degradation behavior. In semicrystalline multiblock copolymers, the degradation rate of amorphous blocks is reduced compared to completely amorphous materials. The reaction rate constants that are obtained by this method are essential for predictive models for the degradation of multifunctional devices. %0 journal article %@ 0378-5173 %A Wischke, C. %D 2020 %J International Journal of Pharmaceutics %N %P 119401 %R doi:10.1016/j.ijpharm.2020.119401 %T Concepts for efficient preparation of particulate polymer carrier systems by droplet-based microfluidics %U https://doi.org/10.1016/j.ijpharm.2020.119401 %X Droplet-based microfluidics has grown out of its infancy as technical solutions became available for a broad community of researchers aiming at highly defined structures of polymer-based drug carrier systems. While the beauty of obtained particles and the precision of their (continuous) production may be very fascinating from a scientific perspective, microfluidics is further developing towards the use in production processes. This review summarizes recent concepts and developments in droplet-based microfluidics covering theoretical aspects of the operation principle as well as approaches to increased throughput and thus to enable efficient production. The application of microfluidic templating for preparing functional polymer particles including dispersions of preformed polymers, multicompartment particles and the use of template droplets as microreactors for carrier synthesis are also included. When operated at high-throughput, in a continuous process and with excellent control over particle properties, microfluidics may become a preparation technique for particulate carriers competitive to batch emulsification not only in research but also for commercial fabrication, e.g., of individualized, patient-specific formulations. %0 journal article %@ 1616-5187 %A Löwenberg, C.,Tripodo, G.,Julich-Gruner, K.,Neffe, A.,Lendlein, A. %D 2020 %J Macromolecular Bioscience %N 10 %P 2000221 %R doi:10.1002/mabi.202000221 %T Supramolecular Gelatin Networks Based on Inclusion Complexes %U https://doi.org/10.1002/mabi.202000221 10 %X Hydrogel forming physical networks based on gelatin are an attractive approach toward multifunctional biomaterials with the option of reshaping, self‐healing, and stimuli‐sensitivity. However, it is challenging to design such gelatin‐based hydrogels to be stable at body temperature. Here, gelatin functionalized with desaminotyrosine (DAT) or desaminotyrosyl tyrosine (DATT) side chains is crosslinked with cyclodextrin (CD) dimers under formation of inclusions complexes. The supramolecular networks displayed at room temperature decreased water uptake (200–600 wt% for DAT‐based systems, 200 wt% for DATT based systems), and increased storage moduli up to 25.6 kPa determined by rheology compared to DAT(T) gelatin. The gel–sol transition temperature increased from 33 up to 42 °C. The presented system that is completely based on natural building blocks may form the basis for materials that may potentially respond by dissolution or changes of properties to changes in environmental conditions or to the presence of CD guest molecules. %0 journal article %@ 0884-2914 %A Behl, M.,Zhao, Q.,Lendlein, A. %D 2020 %J Journal of Materials Research %N 18 %P 2396-2404 %R doi:10.1557/jmr.2020.204 %T Glucose-responsive shape-memory cryogels %U https://doi.org/10.1557/jmr.2020.204 18 %X Boronic ester bonds can be reversibly formed between phenylboronic acid (PBA) and triol moieties. Here, we aim at a glucose-induced shape-memory effect by implementing such bonds as temporary netpoints, which are cleavable by glucose and by minimizing the volume change upon stimulation by a porous cryogel structure. The polymer system consisted of a semi-interpenetrating network (semi-IPN) architecture, in which the triol moieties were part of the permanent network and the PBA moieties were located in the linear polymer diffused into the semi-IPN. In an alkaline medium (pH = 10), the swelling ratio was approximately 35, independent of Cglu varied between 0 and 300 mg/dL. In bending experiments, shape fixity Rf ≈ 80% and shape recovery Rr ≈ 100% from five programming/recovery cycles could be determined. Rr was a function of Cglu in the range from 0 to 300 mg/dL, which accords with the fluctuation range of Cglu in human blood. In this way, the shape-memory hydrogels could play a role in future diabetes treatment options. %0 journal article %@ 1386-0291 %A Schulz, C.,Krüger-Genge, A.,Jung, F.,Lendlein, A. %D 2020 %J Clinical Hemorheology and Microcirculation %N 2 %P 201-217 %R doi:10.3233/CH-190775 %T Aptamer supported in vitro endothelialization of poly(ether imide) films %U https://doi.org/10.3233/CH-190775 2 %X Implantation of synthetic small-diameter vascular bypass grafts is often associated with an increased risk of failure, due to thrombotic events or late intimal hyperplasia. As one of the causes an insufficient hemocompatibility of the artificial surface is discussed. Endothelialization of synthetic grafts is reported to be a promising strategy for creating a self-renewing and regulative anti-thrombotic graft surface. However, the establishment of a shear resistant cell monolayer is still challenging. In our study, cyto- and immuno-compatible poly(ether imide) (PEI) films were explored as potential biomaterial for cardiovascular applications. Recently, we reported that the initial adherence of primary human umbilical vein endothelial cells (HUVEC) was delayed on PEI-films and about 9 days were needed to establish a confluent and almost shear resistant HUVEC monolayer. To accelerate the initial adherence of HUVEC, the PEI-film surface was functionalized with an aptamer-cRGD peptide based endothelialization supporting system. With this functionalization the initial adherence as well as the shear resistance of HUVEC on PEI-films was considerable improved compared to the unmodified polymer surface. The in vitro results confirm the general applicability of aptamers for an efficient functionalization of substrate surfaces. %0 journal article %@ 2059-8521 %A Izraylit, V.,Gould, O.,Kratz, K.,Lendlein, A. %D 2020 %J MRS Advances %N 14 - 15 %P 699-707 %R doi:10.1557/adv.2019.465 %T Investigating the Phase-Morphology of PLLA-PCL Multiblock Copolymer / PDLA Blends Cross-linked Using Stereocomplexation %U https://doi.org/10.1557/adv.2019.465 14 - 15 %X The macroscale function of multicomponent polymeric materials is dependent on their phase-morphology. Here, we investigate the morphological structure of a multiblock copolymer consisting of poly(L-lactide) and poly(ε-caprolactone) segments (PLLA-PCL), physically cross-linked by stereocomplexation with a low molecular weight poly(D-lactide) oligomer (PDLA). The effects of blend composition and PLLA-PCL molecular structure on the morphology are elucidated by AFM, TEM and SAXS. We identify the formation of a lattice pattern, composed of PLA domains within a PCL matrix, with an average domain spacing d0 = 12 – 19 nm. The size of the PLA domains were found to be proportional to the block length of the PCL segment of the copolymer and inversely proportional to the PDLA content of the blend. Changing the PLLA-PCL / PDLA ratio caused a shift in the melt transition Tm attributed to the PLA stereocomplex crystallites, indicating partial amorphous phase dilution of the PLA and PCL components within the semicrystalline material. By elucidating the phase structure and thermal character of multifunctional PLLA-PCL / PDLA blends, we illustrate how composition affects the internal structure and thermal properties of multicomponent polymeric materials. This study should facilitate the more effective incorporation of a variety of polymeric structural units capable of stimuli responsive phase transitions, where an understanding the phase-morphology of each component will enable the production of multifunctional soft-actuators with enhanced performance. %0 journal article %@ 2059-8521 %A Wischke, C.,Kersting, M.,Welle, A.,Lysyakova, L.,Braune, S.,Kratz, K.,Jung, F.,Franzreb, M.,Lendlein, A. %D 2020 %J MRS Advances %N 14 - 15 %P 773-783 %R doi:10.1557/adv.2020.218 %T Thin hydrogel coatings formation catalyzed by immobilized enzyme horseradish peroxidase %U https://doi.org/10.1557/adv.2020.218 14 - 15 %X Enzymes can be a renewable source of catalytic agents and thus be interesting for sustainable approaches to create and modify functional materials. Here, thin hydrogel layers were prepared as thin coatings on hard substrates by immobilized horseradish peroxidase. Hydrophilic 4-arm star shaped telechelics from oligo(ethylene glycol) bearing on average 55% end groups derived from aromatic amino acids served as monomers and enzymatic substrates. Shifts of the contact angle from 84° to 62° for the wetting process and of zeta potential towards the neutral range illustrated an alteration of physicochemical properties of the model surfaces by a hydrophilic shielding. Time-of-flight secondary ion mass spectrometry (ToF-SIMS), quartz crystal microbalance and atomic force microscopy (AFM) experiments enabled the qualitative and quantitative proof of hydrogel deposition at the interface with thicknesses in the medium nanometer size range. Conceptually, as the immobilized enzyme becomes entrapped in the hydrogel and the crosslinking mechanism bases on a radical reaction after enzymatic activation of the monomers with a limited diffusivity and lifetime, the formed network material can be assumed to be inhomogeneous on the molecular level. On the macroscale, however, relative homogeneity of the coating was observed via ToF-SIMS and AFM mapping. As an exemplary functional evaluation in view of bioanalytical applications, the thrombogenicity of the coating was studied in static tests with human blood from several donors. In the future, this “coating-from” approach may be explored for cell culture substrate coatings, for protein/biofilm repellence in technical applications, or in bioanalytical devices. %0 journal article %@ 2196-7350 %A Tarazona, N.,Machatschek, R.,Lendlein, A. %D 2020 %J Advanced Materials Interfaces %N 17 %P 2000872 %R doi:10.1002/admi.202000872 %T Influence of Depolymerases and Lipases on the Degradation of Polyhydroxyalkanoates Determined in Langmuir Degradation Studies %U https://doi.org/10.1002/admi.202000872 17 %X Microbially produced polyhydroxyalkanoates (PHAs) are polyesters that are degradable by naturally occurring enzymes. Albeit PHAs degrade slowly when implanted in animal models, their disintegration is faster compared to abiotic hydrolysis under simulated physiological environments. Ultrathin Langmuir‐Blodgett (LB) films are used as models for fast in vitro degradation testing, to predict enzymatically catalyzed hydrolysis of PHAs in vivo. The activity of mammalian enzymes secreted by pancreas and liver, potentially involved in biomaterials degradation, along with microbial hydrolases is tested toward LB‐films of two model PHAs, poly(3‐R‐hydroxybutyrate) (PHB) and poly[(3‐R‐hydroxyoctanoate)‐co‐(3‐R‐hydroxyhexanoate)] (PHOHHx). A specific PHA depolymerase from Streptomyces exfoliatus, used as a positive control, is shown to hydrolyze LB‐films of both polymers regardless of their side‐chain‐length and phase morphology. From amorphous PHB and PHOHHx, ≈80% is eroded in few hours, while mass loss for semicrystalline PHB is 25%. Surface potential and interfacial rheology measurements show that material dissolution is consistent with a random‐chain‐scission mechanism. Degradation‐induced crystallization of semicrystalline PHB LB‐films is also observed. Meanwhile, the surface and the mechanical properties of both LB‐films remain intact throughout the experiments with lipases and other microbial hydrolases, suggesting that non‐enzymatic hydrolysis could be the predominant factor for acceleration of PHAs degradation in vivo. %0 journal article %@ 2059-8521 %A Deng, Z.,Wang, W.,Xu, X.,Ma, N.,Lendlein, A. %D 2020 %J MRS Advances %N 46 - 47 %P 2381-2390 %R doi:10.1557/adv.2020.235 %T Modulation of Mesenchymal Stem Cell Migration using Programmable Polymer Sheet Actuators %U https://doi.org/10.1557/adv.2020.235 46 - 47 %X Recruitment of mesenchymal stem cells (MSCs) to damaged tissue is a crucial step to modulate tissue regeneration. Here, the migration of human adipose-derived stem cells (hADSCs) responding to thermal and mechanical stimuli was investigated using programmable shape-memory polymer actuator (SMPA) sheets. Changing the temperature repetitively between 10 and 37 °C, the SMPA sheets are capable of reversibly changing between two different pre-defined shapes like an artificial muscle. Compared to non-actuating sheets, the cells cultured on the programmed actuating sheets presented a higher migration velocity (0.32 ± 0.1 vs. 0.57 ± 0.2 μm/min). These results could motivate the next scientific steps, for example, to investigate the MSCs pre-loaded in organoids towards their migration potential. %0 journal article %@ 2059-8521 %A Xu, X.,Wang, W.,Nie, Y.,Kratz, K.,Ma, N.,Lendlein, A. %D 2020 %J MRS Advances %N 12 - 13 %P 643-653 %R doi:10.1557/adv.2019.446 %T Fine-tuning of Rat Mesenchymal Stem Cell Senescence via Microtopography of Polymeric Substrates %U https://doi.org/10.1557/adv.2019.446 12 - 13 %X Cellular senescence, a driver of aging and age-related diseases, is a stable state found in metabolically active cells characterized by irreversible cell growth arrest and dramatic changes in metabolism, gene expression and secretome profile. Endogenous regeneration efficacy of mesenchymal stem cells (MSCs) could be attenuated due to senescence. MSCs can be modulated by not only biochemical signals but also by physical cues such as substrate topography. To provide a cell culture substrate that can prevent MSC senescence over an extended period of in vitro cultivation, here, the cell- and immunocompatible poly(ether imide) (PEI) substrate was used. Two distinct levels of roughness were created on the bottom surfaces of PEI inserts via injection molding: Low-R (similar to the thickness of attached single MSC, Rq: 3.9 ± 0.2 µm) and High-R (larger than single MSC thickness. Rq: 22.7 ± 0.8 µm). Cell expansion, lysosomal enzymatic activity, apoptosis and paracrine effects of senescent MSCs were examined by cell counting, detection of senescence-associated β-galactosidase (SA β-gal), Caspase 3/7, and CFSE labeling. MSCs showed high cell viability and similar spindle-shaped morphology on all investigated surfaces. Cells on Low-R presented the highest expansion (80000 ± 1805 cells), as compared to cells on smooth PEI and High-R. The low apoptosis level (0.08 vs 0.12 from smooth PEI) and senescence ratio (35% vs. 54% from smooth PEI) were observed in MSCs cultured on Low-R. The secretome from Low-R effectively prevents senescence and supports the proliferation of neighboring cells (1.5-fold faster) as compared to the smooth PEI secretome. In summary, the Low-R PEI provided a superior surface environment for MSCs, which promoted proliferation, inhibited apoptosis and senescence, and effectively influenced the proliferation of neighboring cells via their paracrine effect. Such microroughness can be considered as a key parameter for improving the therapeutic potential of endogenous regeneration, anti-organismal aging and anti-age-related pathologies via directly promoting cell growth and modulating paracrine effects of the senescence associated secretome. %0 journal article %@ 1386-0291 %A Tung, W.,Zou, J.,Sun, X.,Wang, W.,Gould, O.,Kratz, K.,Ma, N.,Lendlein, A. %D 2020 %J Clinical Hemorheology and Microcirculation %N 1 %P 53-66 %R doi:10.3233/CH-199235 %T Coaxial electrospinning of PEEU/gelatin to fiber meshes with enhanced mesenchymal stem cell attachment and proliferation %U https://doi.org/10.3233/CH-199235 1 %X Microfibers with a core-shell structure can be produced by co-axial electrospinning, allowing for the functionalization of the outer layer with bioactive molecules. In this study, a thermoplastic, degradable polyesteretherurethane (PEEU), consisting of poly(p-dioxanone) (PPDO) and poly(ɛ-caprolactone) (PCL) segments with different PPDO to PCL weight ratios, were processed into fiber meshes by co-axial electrospinning with gelatin. The prepared PEEU fibers have a diameter of 1.3±0.5 μm and an elastic modulus of around 5.1±1.0 MPa as measured by tensile testing in a dry state at 37°C, while the PEEU/Gelatin core-shell fibers with a gelatin content of 12±6 wt% and a diameter of 1.5±0.5 μm possess an elastic modulus of 15.0±1.1 MPa in a dry state at 37 °C but as low as 0.7±0.7 MPa when hydrated at 37 °C. Co-axial electrospinning allowed for the homogeneous distribution of the gelatin shell along the whole microfiber. Gelatin with conjugated Fluorescein (FITC) remained stable on the PEEU fibers after 7 days incubation in Phosphate-buffered saline (PBS) at 37 °C. The gelatin coating on PEEU fibers lead to enhanced human adipose tissue derived mesenchymal stem cell (hADSC) attachment and a proliferation rate 81.7±34.1 % higher in cell number in PEEU50/Gelatin fibers after 7 days of cell culture when compared to PEEU fibers without coating. In this work, we demonstrate that water-soluble gelatin can be incorporated as the outer shell of a polymer fiber via molecular entanglement, with a sustained presence and role in enhancing stem cell attachment and proliferation. %0 journal article %@ 1525-7797 %A Seppälä, J.,van Bochove, B.,Lendlein, A. %D 2020 %J Biomacromolecules %N 2 %P 273-275 %R doi:10.1021/acs.biomac.9b01701 %T Developing Advanced Functional Polymers for Biomedical Applications %U https://doi.org/10.1021/acs.biomac.9b01701 2 %X %0 journal article %@ 1525-7797 %A Tarazona, N.,Machatschek, R.,Lendlein, A. %D 2020 %J Biomacromolecules %N 2 %P 761-771 %R doi:10.1021/acs.biomac.9b01458 %T Unraveling the Interplay between Abiotic Hydrolytic Degradation and Crystallization of Bacterial Polyesters Comprising Short and Medium Side-Chain-Length Polyhydroxyalkanoates %U https://doi.org/10.1021/acs.biomac.9b01458 2 %X Polyhydroxyalkanoates (PHAs) have attracted attention as degradable (co)polyesters which can be produced by microorganisms with variations in the side chain. This structural variation influences not only the thermomechanical properties of the material but also its degradation behavior. Here, we used Langmuir monolayers at the air–water (A–W) interface as suitable models for evaluating the abiotic degradation of two PHAs with different side-chain lengths and crystallinity. By controlling the polymer state (semicrystalline, amorphous), the packing density, the pH, and the degradation mechanism, we could draw several significant conclusions. (i) The maximum degree of crystallinity for a PHA film to be efficiently degraded up to pH = 12.3 is 40%. (ii) PHA made of repeating units with shorter side-chain length are more easily hydrolyzed under alkaline conditions. The efficiency of alkaline hydrolysis decreased by about 65% when the polymer was 40% crystalline. (iii) In PHA films with a relatively high initial crystallinity, abiotic degradation initiated a chemi-crystallization phenomenon, detected as an increase in the storage modulus (E′). This could translate into an increase in brittleness and reduction in the material degradability. Finally, we demonstrate the stability of the measurement system for long-term experiments, which allows degradation conditions for polymers that could closely simulate real-time degradation. %0 journal article %@ 2045-2322 %A Moradian, H.,Roch, T.,Lendlein, A.,Gossen, M. %D 2020 %J Scientific Reports %N %P 4181 %R doi:10.1038/s41598-020-60506-4 %T mRNA Transfection-Induced Activation of Primary Human Monocytes and Macrophages: Dependence on Carrier System and Nucleotide Modification %U https://doi.org/10.1038/s41598-020-60506-4 %X Monocytes and macrophages are key players in maintaining immune homeostasis. Identifying strategies to manipulate their functions via gene delivery is thus of great interest for immunological research and biomedical applications. We set out to establish conditions for mRNA transfection in hard-to-transfect primary human monocytes and monocyte-derived macrophages due to the great potential of gene expression from in vitro transcribed mRNA for modulating cell phenotypes. mRNA doses, nucleotide modifications, and different carriers were systematically explored in order to optimize high mRNA transfer rates while minimizing cell stress and immune activation. We selected three commercially available mRNA transfection reagents including liposome and polymer-based formulations, covering different application spectra. Our results demonstrate that liposomal reagents can particularly combine high gene transfer rates with only moderate immune cell activation. For the latter, use of specific nucleotide modifications proved essential. In addition to improving efficacy of gene transfer, our findings address discrete aspects of innate immune activation using cytokine and surface marker expression, as well as cell viability as key readouts to judge overall transfection efficiency. The impact of this study goes beyond optimizing transfection conditions for immune cells, by providing a framework for assessing new gene carrier systems for monocyte and macrophage, tailored to specific applications. %0 journal article %@ 2059-8521 %A Bhuvanesh, T.,Machatschek, R.,Liu, Y.,Ma, N.,Lendlein, A. %D 2020 %J MRS Advances %N 12 - 13 %P 609-620 %R doi:10.1557/adv.2019.401 %T Self-stabilized fibronectin films at the air/water interface %U https://doi.org/10.1557/adv.2019.401 12 - 13 %X Fibronectin (FN) is a mediator molecule, which can connect cell receptors to the extracellular matrix (ECM) in tissues. This function is highly desirable for biomaterial surfaces in order to support cell adhesion. Controlling the fibronectin adsorption profile on substrates is challenging because of possible conformational changes after deposition, or due to displacement by secondary proteins from the culture medium. Here, we aim to develop a method to realize self-stabilized ECM glycoprotein layers with preserved native secondary structure on substrates. Our concept is the assembly of FN layers at the air-water (A-W) interface by spreading FN solution as droplets on the interface and transfer of the layer by the Langmuir-Schäfer (LS) method onto a substrate. It is hypothesized that 2D confinement and high local concentration at A-W interface supports FN self-interlinking to form cohesive films. Rising surface pressure with time, plateauing at 10.5 mN·m-1 (after 10 hrs), indicated that FN was self-assembling at the A-W interface. In situ polarization-modulation infrared reflection absorption spectroscopy of the layer revealed that FN maintained its native anti-parallel β-sheet structure after adsorption at the A-W interface. FN self-interlinking and elasticity was shown by the increase in elastic modulus and loss modulus with time using interfacial rheology. A network-like structure of FN films formed at the A-W interface was confirmed by atomic force microscopy after LS transfer onto Si-wafer. FN films consisted of native, globular FN molecules self-stabilized by intermolecular interactions at the A-W interface. Therefore, the facile FN self-stabilized network-like films with native anti-parallel β-sheet structure produced here, could serve as stable ECM protein coatings to enhance cell attachment on in vitro cell culture substrates and planar implant materials. %0 journal article %@ 0887-2333 %A Lau, S.,Rangarajan, R.,Philidet, C.,Krüger-Genge, A.,Braune, S.,Kammerer, S.,Küpper, J.,Lendlein, A.,Jung, F. %D 2020 %J Toxicology in Vitro %N %P 104685 %R doi:10.1016/j.tiv.2019.104685 %T Effects of acrolein in comparison to its prodrug cyclophosphamide on human primary endothelial cells in vitro %U https://doi.org/10.1016/j.tiv.2019.104685 %X Cyclophosphamide (CPA) is one of the most successful anticancer prodrugs that becomes effective after biotransformation in the liver resulting in the toxic metabolite acrolein. Cancer is often accompanied by thromboembolic events, which might be a result of dysfunctional endothelial cells due to CPA treatment.,Here, the effect of 1 mM CPA or acrolein (10/50/100/500 μM) on human umbilical vein endothelial cells (HUVECs) was analyzed after two days of treatment.,The addition of CPA or 10 μM acrolein did not affect HUVECs. However, concentrations of 100 μM and 500 μM acrolein significantly reduced the number of adherent cells by 86 ± 13% and 99 ± 1% and cell viability by 51 ± 29% and 93 ± 8% compared to the control. Moreover, pronounced stress fibers as well as multiple nuclei were observed and von Willebrand factor (vWF) was completely released. Lactate dehydrogenase was 8.5 ± 7.0-fold and 252.9 ± 42.9-fold increased showing a loss of cell membrane integrity. The prostacyclin and thromboxane secretion was significantly increased by the addition of 500 μM acrolein (43.1 ± 17.6-fold and 246.4 ± 106.3-fold) indicating cell activation/pertubation.,High doses of acrolein led to HUVEC death and loss of vWF production. This effect might be associated with the increased incidence of thromboembolic events in cancer patients treated with high doses of CPA. %0 journal article %@ 1022-1336 %A Razzaq, M.,Behl, M.,Heuchel, M.,Lendlein, A. %D 2020 %J Macromolecular Rapid Communications %N 1 %P 1900440 %R doi:10.1002/marc.201900440 %T Matching Magnetic Heating and Thermal Actuation for Sequential Coupling in Hybrid Composites by Design %U https://doi.org/10.1002/marc.201900440 1 %X Sequentially coupling two material functions requires matching the output from the first with the input of the second function. Here, magnetic heating controls thermal actuation of a hybrid composite in a challenging system environment causing an elevated level of heat loss. The concept is a hierarchical design consisting of an inner actuator of nanocomposite material, which can be remotely heated by exposure to an alternating magnetic field (AMF) and outer layers of a porous composite system with a closed pore morphology. These porous layers act as heat insulators and as barriers to the surrounding water. By exposure to the AMF, a local bulk temperature of 71 °C enables the magnetic actuation of the device, while the temperature of the surrounding water is kept below 50 °C. Interestingly, the heat loss during magnetic heating leads to an increase of the water phase (small volume) temperature. The temperature increase is able to sequentially trigger an adjacent thermal actuator attached to the actuator composite. In this way it could be demonstrated how the AMF is able to initiate two kinds of independent actuations, which might be interesting for robotics operating in aqueous environments. %0 journal article %@ 1386-0291 %A Sun, X.,Tung, W.,Zou, J.,Wang, W.,Kratz, K.,Ma, N.,Lendlein, A. %D 2020 %J Clinical Hemorheology and Microcirculation %N 4 %P 405-415 %R doi:10.3233/CH-190696 %T Elasticity of fiber meshes from multiblock copolymers influences endothelial cell behavior %U https://doi.org/10.3233/CH-190696 4 %X BACKGROUND:,The behavior of endothelial cells is remarkably influenced by the physical and biochemical signals from their surrounding microenvironments.,OBJECTIVE:,Here, the elasticity of fiber meshes was studied as a design parameter of substrates for endothelial cells in order to modulate angiogenesis.,METHODS:,Human umbilical vein endothelial cells (HUVECs) were cultured on electrospun fiber meshes made from polyetheresterurethane (PEEU), differing in their elasticity. Cell morphology, proliferation, migration and angiogenesis of endothelial cells on the degradable substrate meshes were characterized.,RESULTS:,The aspect ratio of HUVECs cultured on the fiber meshes from PEEU materials increased with increasing stiffness of the materials. HUVECs cultured on fiber meshes with high stiffness (Young’s modulus E = 4.5±0.8 MPa) presented a higher proliferation rate and significantly faster migration velocity, as well as higher tube formation capability than the cells cultured on fiber meshes with low stiffness (E = 2.6±0.8 MPa).,CONCLUSIONS:,These results suggested that tuning the fiber meshes’ elasticity might be a potential strategy for modulating the formation or regeneration of blood vessels. %0 journal article %@ 2059-8521 %A Pang, J.,Wischke, C.,Lendlein, A. %D 2020 %J MRS Advances %N 12 - 13 %P 633-642 %R doi:10.1557/adv.2019.441 %T In vitro Degradation Analysis of 3D-architectured Gelatin-based Hydrogels %U https://doi.org/10.1557/adv.2019.441 12 - 13 %X Multifunctional biopolymer-based materials are promising candidates for next generation regenerative biomaterials. Understanding the degradation behavior of biomaterials is vital for ensuring biological safety, as well as for better control of degradation properties based on rational design of a material’s physical and chemical characteristics. In this study, we decipher the degradation of a hydrogel prepared from gelatin and lysine diisocyanate ethyl ester (LDI) using in vitro models, which simulate hydrolytic, oxidative and enzymatic degradation (collagenase). Gravimetrical, morphological, mechanical and chemical properties were evaluated. Notably, the hydrogels were relatively resistant to hydrolytic degradation, but degraded rapidly within 21 days (>95% mass loss) under oxidative and collagenase degradation. Oxidative and collagenase degradation rapidly decreased the storage and loss modulus of the hydrogels, and slightly increased their viscous component (tan δ). For each degradation condition, the results suggest different possible degradation pathways associated to the gelatin polypeptide backbone, urea linkages and ester groups. The primary degradation mechanisms for the investigated gelatin based hydrogels are oxidative and enzymatic in nature. The relative hydrolytic stability of the hydrogels should ensure minimal degradation during storage and handling prior to application in surgical theatres. %0 journal article %@ 2059-8521 %A Balk, M.,Behl, M.,Lendlein, A. %D 2020 %J MRS Advances %N 12 - 13 %P 655-666 %R doi:10.1557/adv.2019.447 %T Actuators Based on Oligo[(epsilon-caprolactone)-co-glycolide] with Accelerated Hydrolytic Degradation %U https://doi.org/10.1557/adv.2019.447 12 - 13 %X Polyester-based shape-memory polymer actuators are multifunctional materials providing reversible macroscopic shape shifts as well as hydrolytic degradability. Here, the function-function interdependencies (between shape shifts and degradation behaviour) will determine actuation performance and its life time.,In this work, glycolide units were incorporated in poly(ε-caprolactone) based actuator materials in order to achieve an accelerated hydrolytic degradation and to explore the function-function relationship. Three different oligo[(ε-caprolactone)-co-glycolide] copolymers (OCGs) with similar molecular weights (10.5 ± 0.5 kg∙mol−1) including a glycolide content of 8, 16, and 26 mol% (ratio 1:1:1 wt%) terminated with methacrylated moieties were crosslinked. The obtained actuators provided a broad melting transition in the range from 27 to 44 °C. The hydrolytic degradation of programmed OCG actuators (200% of elongation) resulted in a reduction of sample mass to 51 wt% within 21 days at pH = 7.4 and 40 °C. Degradation results in a decrease of Tm associated to the actuating units and increasing Tm associated to the skeleton forming units. The actuation capability decreased almost linear as function of time. After 11 days of hydrolytic degradation the shape-memory functionality was lost. Accordingly, a fast degradation behaviour as required, e.g., for actuator materials intended as implant material can be realized. %0 journal article %@ 2059-8521 %A Bäckemo, J.,Heuchel, M.,Reinthaler, M.,Kratz, K.,Lendlein, A. %D 2020 %J MRS Advances %N 12 - 13 %P 621-632 %R doi:10.1557/adv.2019.433 %T Predictive topography impact model for Electrical Discharge Machining (EDM) of metal surfaces %U https://doi.org/10.1557/adv.2019.433 12 - 13 %X Electrical discharge machining (EDM) is a method capable of modifying the microstructure of metal surfaces. Here, we present a predictive computer supported model of the roughness generated on the surface by this process. EDM is a stochastic process, in which charge generated between a metallic substrate and an electrode creates impacts, and thus is suitable for modeling through iterative simulations. The resulting virtual, modified surface structures were evaluated for roughness. Curvatures were analyzed using Abbott-Firestone curves. Three radii of impacts (10, 20, 30 μm) and two values for the depth to radius ratio (0.1, 0.3) were used as input parameters to compute a total of six simulations. It was found that the roughness parameters followed an inverse exponential trend as a function of impact number, and that the strongly concave curvatures reached equilibrium at an earlier impact number for lower depth to radius ratios. %0 journal article %@ 2059-8521 %A Zou, J.,Wang, W.,Sun, X.,Tung, W.,Ma, N.,Lendlein, A. %D 2020 %J MRS Advances %N 12 - 13 %P 601-607 %R doi:10.1557/adv.2019.402 %T AFM Assessment of the Mechanical Properties of Stem Cells During Differentiation %U https://doi.org/10.1557/adv.2019.402 12 - 13 %X The dynamic mechanical force transmitted through microenvironments during tissue formation and regeneration continuously impacts the mechanics of cells and thereby regulates gene and protein expression. The mechanical properties are altered during the process of stem cells differentiating into different lineages. At different stages of differentiation, stem cells display different mechanical properties in response to surrounding microenvironments, which depend on the subcellular structures, especially the cytoskeleton and nucleus. The mechanical properties of the cell nucleus affect protein folding and transport as well as the condensation of chromatin, through which the cell fate is regulated. These findings raise the question as to how cell mechanics change during differentiation. In this study, the mechanical properties of human bone marrow mesenchymal stem cells (hBMSCs) were determined during adipogenic and osteogenic differentiation by atomic force microscopy (AFM). The cytoskeletal structure and the modification of histone were investigated using laser confocal microscope and flow cytometry. The mechanical properties of cell nuclei at different stages of cell differentiation were compared. The stiffness of nuclei increased with time as osteogenesis was induced in hBMSCs. The H3K27me3 level increased during osteogenesis and adipogenesis according to flow cytometry analysis. Our results show conclusively that AFM is a facile and effective method to monitor stem cell differentiation. The measurement of cell mechanical properties by AFM improves our understanding on the connection between mechanics and stem cell fate. %0 journal article %@ 0027-8424 %A Deng, Z.,Wang, W.,Xu, X.,Gould, O.E.C,Kratz, K.,Ma, N.,Lendlein, A. %D 2020 %J Proceedings of the National Academy of Sciences of the United States of America: PNAS %N 4 %P 1895-1901 %R doi:10.1073/pnas.1910668117 %T Polymeric sheet actuators with programmable bioinstructivity %U https://doi.org/10.1073/pnas.1910668117 4 %X Stem cells are capable of sensing and processing environmental inputs, converting this information to output a specific cell lineage through signaling cascades. Despite the combinatorial nature of mechanical, thermal, and biochemical signals, these stimuli have typically been decoupled and applied independently, requiring continuous regulation by controlling units. We employ a programmable polymer actuator sheet to autonomously synchronize thermal and mechanical signals applied to mesenchymal stem cells (MSCs). Using a grid on its underside, the shape change of polymer sheet, as well as cell morphology, calcium (Ca2+) influx, and focal adhesion assembly, could be visualized and quantified. This paper gives compelling evidence that the temperature sensing and mechanosensing of MSCs are interconnected via intracellular Ca2+. Up-regulated Ca2+ levels lead to a remarkable alteration of histone H3K9 acetylation and activation of osteogenic related genes. The interplay of physical, thermal, and biochemical signaling was utilized to accelerate the cell differentiation toward osteogenic lineage. The approach of programmable bioinstructivity provides a fundamental principle for functional biomaterials exhibiting multifaceted stimuli on differentiation programs. Technological impact is expected in the tissue engineering of periosteum for treating bone defects. %0 journal article %@ 2059-8521 %A Nie, Y.,Deng, Z.,Wang, W.,Bhuvanesh, T.,Ma, N.,Lendlein, A. %D 2020 %J MRS Advances %N 12 - 13 %P 591-599 %R doi:10.1557/adv.2019.405 %T Polydopamine-mediated Surface Modification Promotes the Adhesion and Proliferation of Human Induced Pluripotent Stem Cells %U https://doi.org/10.1557/adv.2019.405 12 - 13 %X With their abilities of self-renewal and pluripotency to differentiate into all three germ layers, human induced pluripotent stem cells (hiPSCs) are a promising cell source for cell-based drug and implant testing. However, the large-scale expansion and maintenance of hiPSCs requires following strict protocols. There is high demand for advanced cell culture systems capable of generating high-quality hiPSCs to meet application requirements. In this study, we probe the possibility of modifying polymeric substrates for maintaining the self-renewal and pluripotency of hiPSCs. Here, polydopamine (PDA) was employed to immobilize the Laminin 521 (LN521) onto the surface of polyethylene terephthalate (PET). An aqueous solution of dopamine with concentrations ranging from 0 to 2.0 mg/mL was applied on PET surfaces. These PDA-modified surfaces were further functionalized with LN521. Surface wettability was evaluated by measuring the water contact angle (WCA) and surface properties of the modified substrate were analyzed using an atomic force microscope (AFM). Initial hiPSC attachment (1h after seeding) and cell proliferation were evaluated by counting the total cell number. The maintenance of pluripotency was evaluated at designed time points. WCA of the PDA-LN521 surfaces gradually decreased from 62.1°±6.3° to 8.1°±2.9°. The maximum peak-to-valley height roughness (Rt) of those surfaces determined by AFM increased in a dopamine-concentration-dependent manner, ranging from 43.9±1.6 nm to 126.7±7.6 nm. The Young’s modulus of these surfaces was substantially increased from 0.98±0.36 GPa to 4.81±2.41 GPa. There was a significant enhancement (13.0±7.2% and 24.2±8.1%) of hiPSC adhesion on PDA-LN521 (dopamine concentration at 0.125 and 0.25 mg/mL). When increasing the dopamine concentration to 0.5 and 1.0 mg/mL, there was no further increase in hiPSC adhesion on PDA-LN521 surfaces. Moreover, hiPSC proliferation was remarkably enhanced on PDA-LN521 surface (dopamine solution at concentration from 0.125 to 1.0 mg/mL). Pluripotency of hiPSCs was not affected by PDA treatment. In conclusion, PDA-mediated surface modification is an effective approach for the robust expansion and maintenance of hiPSCs on polymer substrates. %0 journal article %@ 1386-0291 %A Lau, S.,Rangarajan, R.,Krüger-Genge, A.,Braune, S.,Küpper, J.,Lendlein, A.,Jung, F. %D 2020 %J Clinical Hemorheology and Microcirculation %N 1 %P 93-107 %R doi:10.3233/CH-199238 %T Age-related morphology and function of human arterial endothelial cells %U https://doi.org/10.3233/CH-199238 1 %X Endothelialization of cardiovascular implants is regarded as a promising strategy for long-term compatibility. While umbilical vein endothelial cells are typically applied in research, human arterial endothelial cells (HAEC) from elderly donors would be the obvious source for autologous cellularization strategies.,In our approach, HAEC from 16 donors of varying age (16–63 years) were divided into two groups (<30 years and >30 years) and analyzed regarding morphology, viability, proliferation, function and senescence status.,No age-related differences were found regarding morphology, viability, density, prostacyclin and nitrite secretion or collagen and laminin production. However, the metabolic activity was slightly decreased (p = 0.0374) and the membrane integrity marginally impaired (p = 0.0404) in cells from older donors. Two out of three senescence assays detected more senescence markers in cells from older donors.,According to the assays applied here, HAEC from young and elderly donors up to the age of 63 years could be judged equally suitable for autologous cellularization strategies. However, this finding should be regarded with caution due to the extremely large variability between individual donors. Further studies comprising a larger sample size are necessary to investigate this issue more thoroughly. %0 journal article %@ 0014-3057 %A Izraylit, V.,Hommes-Schattmann, P.,Neffe, A.,Gould, O.,Lendlein, A. %D 2020 %J European Polymer Journal %N %P 109916 %R doi:10.1016/j.eurpolymj.2020.109916 %T Polyester urethane functionalizable through maleimide side-chains and cross-linkable by polylactide stereocomplexes %U https://doi.org/10.1016/j.eurpolymj.2020.109916 %X Sustainable multifunctional alternatives to fossil-derived materials, which can be functionalized and are degradable, can be envisioned by combining naturally derived starting materials with an established polymer design concept. Modularity and chemical flexibility of polyester urethanes (PEU) enable the combination of segments bearing functionalizable moieties and the tailoring of the mechanical and thermal properties. In this work, a PEU multiblock structure was synthesized from naturally derived L-lysine diisocyanate ethyl ester (LDI), poly(L-lactide) diol (PLLA) and N-(2,3-dihydroxypropyl)-maleimide (MID) in a one-step reaction. A maleimide side-chain (MID) provided a reactive site for the catalyst-free coupling of thiols shown for L-cysteine with a yield of 94%. Physical cross-links were generated by blending the PEU with poly(D-lactide) (PDLA), upon which the PLLA segments of the PEU and the PDLA formed stereocomplexes. Stereocomplexation occurred spontaneously during solution casting and was investigated with WAXS and DSC. Stereocomplex crystallites were observed in the blends, while isotactic PLA crystallization was not observed. The presented material platform with tailorable mechanical properties by blending is of specific interest for engineering biointerfaces of implants or carrier systems for bioactive molecules. %0 journal article %@ 0168-3659 %A Machatschek, R.,Lendlein, A. %D 2020 %J Journal of Controlled Release %N %P 276-284 %R doi:10.1016/j.jconrel.2019.12.044 %T Fundamental insights in PLGA degradation from thin film studies %U https://doi.org/10.1016/j.jconrel.2019.12.044 %X Poly(lactide-co-glycolide)s are commercially available degradable implant materials, which are typically selected based on specifications given by the manufacturer, one of which is their molecular weight. Here, we address the question whether variations in the chain length and their distribution affect the degradation behavior of Poly[(rac-lactide)-co-glycolide]s (PDLLGA). The hydrolysis was studied in ultrathin films at the air-water interface in order to rule out any morphological effects. We found that both for purely hydrolytic degradation as well as under enzymatic catalysis, the molecular weight has very little effect on the overall degradation kinetics of PDLLGAs. The quantitative analysis suggested a random scission mechanism. The monolayer experiments showed that an acidic micro-pH does not accelerate the degradation of PDLLGAs, in contrast to alkaline conditions. The degradation experiments were combined with interfacial rheology measurements, which showed a drastic decrease of the viscosity at little mass loss. The extrapolated molecular weight behaved similar to the viscosity, dropping to a value near to the solubility limit of PDLLGA oligomers before mass loss set in. This observation suggests a solubility controlled degradation of PDLLGA. Conclusively, the molecular weight affects the degradation of PDLLGA devices mostly in indirect ways, e.g. by determining their morphology and porosity during fabrication. Our study demonstrates the relevance of the presented Langmuir degradation method for the design of controlled release systems. %0 journal article %@ 2059-8521 %A Tarazona, N.,Machatschek, R.,Lendlein, A. %D 2020 %J MRS Advances %N 11 -12 %P 667-677 %R doi:10.1557/adv.2019.458 %T Relation between Surface Area and Surface Potential Change during (co)Polyesters Degradation as Langmuir Monolayer %U https://doi.org/10.1557/adv.2019.458 11 -12 %X Polyhydroxyalkanoates (PHAs) are degradable (co)polyesters synthesized by microorganisms with a variety of side-chains and co-monomer ratios. PHAs can be efficiently hydrolyzed under alkaline conditions and by PHA depolymerase enzymes, altering their physicochemical properties. Using 2D Langmuir monolayers as model system to study the degradation behavior of macromolecules, we aim to describe the the interdependency between the degradation of two PHAs and the surface potential, which influences material-proteins interaction and cell response. We hypothesize that the mechanism of hydrolysis of the labile ester bonds in (co)polyesters defines the evolution of the surface potential, owing to the rate of accumulation of charged insoluble degradation products. The alkaline hydrolysis and the enzymatically catalyzed hydrolysis of PHAs were previously defined as chain-end scission and random-scission mechanisms, respectively. In this study, these two distinct scenarios are used to validate our model. The surface potential change during the chain-end scission of poly(3-R-hydroxybutyrate) (PHB) under alkaline conditions was compared to that of the enzymatically catalyzed hydrolysis (random-scission) of poly[(3-R-hydroxyoctanoate)-co-(3-R-hydroxyhexanoate)] (PHOHHx), using the Langmuir monolayer technique. In the random-scission mechanism the dissolution of degradation products, measured as a decrease in the area per molecule, was preceded by a substantial change of the surface potential, provoked by the negative charge of the broken ester bonds accumulated in the air-water interface. In contrast, when chains degraded via the chain-ends, the surface potential changed in line with the dissolution of the material, presenting a kinetic dependent on the surface area of the monolayers. These results provide a basis for understanding PHAs degradation mechanism. Future research on (co)polymers with different main-chain lengths might extend the elucidation of the surface potential development of (co)polyesters as Langmuir monolayer. %0 journal article %@ 2059-8521 %A Machatschek, R.,Saretia, S.,Lendlein, A. %D 2020 %J MRS Advances %N 11 - 12 %P 679-691 %R doi:10.1557/adv.2019.457 %T The interplay between network morphology and degradation kinetics of polymers: Theoretical and experimental analysis by means of a 2D model system %U https://doi.org/10.1557/adv.2019.457 11 - 12 %X Network formation by cross-linking is a common method to incorporate functions like elastic deformability, shape-memory capability or hydrogel formation into polymer materials for medical applications. Since these materials are often intended to degrade, their design would benefit from a quantitative prediction of the interdependence between network architecture and degradation behavior. Here, we introduce a quantitative description of the degradation behavior of polymer networks. A simplified model was developed under the assumption of having an ideal network, where all network strands are terminated by network nodes and each node is connected to the same number of strands. To describe the degradation of real networks, the model was modified by allowing for a varying connectivity of network nodes, which also included free chain-ends. The models were validated by comparison with Langmuir monolayer degradation data from 2D networks formed by cross-linking oligo(ε-caprolactone)diols with dialdehydes. We found that both the ideal network hypothesis and the real network model were in excellent agreement with the experimental data, with the ideal network hypothesis requiring longer network strands than the real network to result in the same degradation behavior. The models were further used to calculate the degradation curves of the corresponding, non cross-linked molecules. By comparison, it was found that the network formation increases the time required to reach 50% degradation of oligo(ε-caprolactone)diols by only 20%. This difference mainly arises from attaching free chain ends to network points. %0 journal article %@ 2468-4511 %A Zhou, Y.,Mahapatra, C.,Chen, H.,Peng, X.,Ramakrishna, S.,Nanda, H. %D 2020 %J Current Opinion in Biomedical Engineering %N %P 16-24 %R doi:10.1016/j.cobme.2019.08.003 %T Recent developments in fluorescent aptasensors for detection of antibiotics %U https://doi.org/10.1016/j.cobme.2019.08.003 %X Antibiotic abuse is considered as a serious problem affecting human health, demanding great attention to explore robust, accurate, real-time, on-site, and sensitive methods for rapid evaluation (detection and quantification) of food and biological samples such as serum. To address this challenging problem, biosensors have been developed as a valuable and sensitive tool to detect and quantify the amount of antibiotics. Among various kinds of biosensors, recently, aptamer-based biosensors (aptasensors) based on the fluorescent strategy have evolved as an excellent candidate for rapid evaluation of antibiotics, owing to their superior selectivity, specificity, and sensitivity. This review encompasses an overview of various kinds of recently developed fluorescent aptasensors for antibiotic detection and gives an idea of important sensing mechanisms associated with the developed aptasensors. The current review focuses on aims to further encourage and inspire targeted readers to develop new approaches for fabricating more practical and mature fluorescent aptasensors for antibiotic detection in the future. %0 journal article %@ 2079-6412 %A Ahiwar, H.,Zhou, Y.,Mahapatra, C.,Ramakrishna, S.,Kumar, P.,Nanda, H. %D 2020 %J Coatings %N 3 %P 264 %R doi:10.3390/coatings10030264 %T Materials for Orthopedic Bioimplants: Modulating Degradation and Surface Modification Using Integrated Nanomaterials %U https://doi.org/10.3390/coatings10030264 3 %X Significant research and development in the field of biomedical implants has evoked the scope to treat a broad range of orthopedic ailments that include fracture fixation, total bone replacement, joint arthrodesis, dental screws, and others. Importantly, the success of a bioimplant depends not only upon its bulk properties, but also on its surface properties that influence its interaction with the host tissue. Various approaches of surface modification such as coating of nanomaterial have been employed to enhance antibacterial activities of a bioimplant. The modified surface facilitates directed modulation of the host cellular behavior and grafting of cell-binding peptides, extracellular matrix (ECM) proteins, and growth factors to further improve host acceptance of a bioimplant. These strategies showed promising results in orthopedics, e.g., improved bone repair and regeneration. However, the choice of materials, especially considering their degradation behavior and surface properties, plays a key role in long-term reliability and performance of bioimplants. Metallic biomaterials have evolved largely in terms of their bulk and surface properties including nano-structuring with nanomaterials to meet the requirements of new generation orthopedic bioimplants. In this review, we have discussed metals and metal alloys commonly used for manufacturing different orthopedic bioimplants and the biotic as well as abiotic factors affecting the failure and degradation of those bioimplants. The review also highlights the currently available nanomaterial-based surface modification technologies to augment the function and performance of these metallic bioimplants in a clinical setting. %0 journal article %@ 0266-3538 %A Wong, T.,Behl, M.,Yusoff, N.,Li, T.,Wahit, M.,Ismail, A.,Zhao, Q.,Lendlein, A. %D 2020 %J Composites Science and Technology %N %P 108138 %R doi:10.1016/j.compscitech.2020.108138 %T Bio-based composites from plant based precursors and hydroxyapatite with shape-memory capability %U https://doi.org/10.1016/j.compscitech.2020.108138 %X A series of bio-based composites consisting of degradable thermoset poly[xylitol-(1,12-dodecanedioate)] (PXD) and hydroxyapatite microparticles (HA) was prepared. Equimolar amounts of xylitol and 1,12-dodecanedioic acid were reacted under catalyst-free polyesterification and the synthesized composites (PXDHCy) consist HA particles ranging between 0 wt% and 20 wt%. Crystallinity of the polymer matrix decreased at low content of HA (5 wt%) as the microparticles hindered crystallization of 1,12-dodecanedioate segment and then increased when the content of HA was raised (from 10 wt% to 20 wt%) as the polymer chains crystallized on surface of microparticles. All PXD and PXDHCy are able to hydrolytically degrade with around 7 wt% to 20 wt% mass loss after 16 weeks incubation in water (rate depends on HA content). The capability of PXD and PXDHCy composites to keep a temporary shape after a deformation process correlated with the polymer crystallinity whereas the shape recovery was 99%. The switching temperatures of PXD and PXDHCy composites ranged around 50 °C (and correlated to the melting-transition temperature) and did not vary with the loading of HA. A prototype of PXDHCy composite smart fixation plug was demonstrated and showed excellent potential to be used as bio-based fixation device for household appliances. %0 journal article %@ 1022-1352 %A Abd-El-Aziz, A.S.,Antonietti, M.,Barner-Kowollik, C.,Binder, W.H.,Böker, A.,Boyer, C.,Buchmeiser, M.R.,Cheng, S.Z.D.,D’Agosto, F.,Floudas, G.,Frey, H.,Galli, G.,Genzer, J.,Hartmann, L.,Hoogenboom, R.,Ishizone, T.,Kaplan, D.L.,Leclerc, M.,Lendlein, A.,Liu, B.,Long, T.E.,Ludwigs, S.,Lutz, J.-F.,Matyjaszewski, K.,Meier, M.A.R.,Müllen, K.,Müllner, M.,Rieger, B.,Russell, T.P.,Savin, D.A.,Schlüter, A.D.,Schubert, U.S.,Seiffert, S.,Severing, K.,Soares, J.B.P.,Staffilani, M.,Sumerlin, B.S.,Sun, Y.,Tang, B.Z.,Tang, C.,Théato, P.,Tirelli, N.,Tsui, O.K.C.,Unterlass, M.M.,Vana, P.,Voit, B.,Vyazovkin, S.,Weder, C.,Wiesner, U.,Wong, W.-Y.,Wu, C.,Yagci, Y.,Yuan, J.,Zhang, G. %D 2020 %J Macromolecular Chemistry and Physics %N 16 %P 2000216 %R doi:10.1002/macp.202000216 %T The Next 100 Years of Polymer Science %U https://doi.org/10.1002/macp.202000216 16 %X The year 2020 marks the 100th anniversary of the first article on polymerization, published by Hermann Staudinger. It is Staudinger who realized that polymers consist of long chains of covalently linked building blocks. Polymers have had a tremendous impact on the society ever since this initial publication. People live in a world that is almost impossible to imagine without synthetic polymers. But what does the future hold for polymer science? In this article, the editors and advisory board of Macromolecular Chemistry and Physics reflect on this question. %0 journal article %@ 1438-7492 %A Liu, Y.,Gould, O.,Rudolph, T.,Fang, L.,Kratz, K.,Lendlein, A. %D 2020 %J Macromolecular Materials and Engineering %N 10 %P 2000333 %R doi:10.1002/mame.202000333 %T Polymeric Microcuboids Programmable for Temperature‐Memory %U https://doi.org/10.1002/mame.202000333 10 %X Microobjects with programmable mechanical functionality are highly desirable for the creation of flexible electronics, sensors, and microfluidic systems, where fabrication/programming and quantification methods are required to fully control and implement dynamic physical behavior. Here, programmable microcuboids with defined geometries are prepared by a template‐based method from crosslinked poly[ethylene‐co‐(vinyl acetate)] elastomers. These microobjects could be programmed to exhibit a temperature‐memory effect or a shape‐memory polymer actuation capability. Switching temperatures Tsw during shape recovery of 55 ± 2, 68 ± 2, 80 ± 2, and 86 ± 2 °C are achieved by tuning programming temperatures to 55, 70, 85, and 100 °C, respectively. Actuation is achieved with a reversible strain of 2.9 ± 0.2% to 6.7 ± 0.1%, whereby greater compression ratios and higher separation temperatures induce a more pronounced actuation. Micro‐geometry change is quantified using optical microscopy and atomic force microscopy. The realization and quantification of microparticles, capable of a tunable temperature responsive shape‐change or reversible actuation, represent a key development in the creation of soft microscale devices for drug delivery or microrobotics. %0 journal article %@ 1386-0291 %A Lee, S.,Ganesan, R.,Krüger-Genge, A.,Kratz, K.,Franke, R.,Lendlein, A.,Jung, F. %D 2020 %J Clinical Hemorheology and Microcirculation %N 1 %P 85-98 %R doi:10.3233/CH-190736 %T Substrate-enzyme affinity-based surface modification strategy for endothelial cell-specific binding under shear stress %U https://doi.org/10.3233/CH-190736 1 %X Establishing an endothelial cell (EC) monolayer on top of the blood contacting surface of grafts is considered to be a promising approach for creating a hemocompatible surface. Here we utilized the high affinity interactions between the EC plasma membrane expressed enzyme called endothelin converting enzyme-1 (ECE-1) and its corresponding substrate big Endothelin-1 (bigET-1) to engineer an EC-specific binding surface. Since enzymatic cleavage of substrates require physical interaction between the enzyme and its corresponding substrate, it was hypothesized that a surface with chemically immobilized synthetic bigET-1 will preferentially attract ECs over other types of cells found in vascular system such as vascular smooth muscle cells (VSMCs). First, the expression of ECE-1 was significantly higher in ECs, and ECs processed synthetic bigET-1 to produce ET-1 in a cell number-dependent manner. Such interaction between ECs and synthetic bigET-1 was also detectible in blood. Next, vinyl-terminated self-assembled monolayers (SAMs) were established, oxidized and activated on a glass substrate as a model to immobilize synthetic bigET-1 via amide bonds. The ECs cultured on the synthetic bigET-1-immobilized surface processed larger amount of synthetic bigET-1 to produce ET-1 compared to VSMCs (102.9±5.13 vs. 9.75±0.74 pg/ml). The number of ECs bound to the synthetic bigET-1-immobilized surface during 1 h of shearing (5dyne/cm2) was approximately 3-fold higher than that of VSMCs (46.25±12.61 vs. 15.25±3.69 cells/100×HPF). EC-specific binding of synthetic bigET-1-immobilized surface over a surface modified with collagen, a common substance for cell adhesion, was also observed. The present study demonstrated that using the substrate-enzyme affinity (SEA) of cell type-specific enzyme and its corresponding substrate can be an effective method to engineer a surface preferentially binds specific type of cells. This novel strategy might open a new route toward rapid endothelialization under dynamic conditions supporting the long-term patency of cardiovascular implants. %0 journal article %@ 0032-3861 %A Izraylit, V.,Heuchel, M.,Gould, O.,Kratz, K.,Lendlein, A. %D 2020 %J Polymer %N %P 122984 %R doi:10.1016/j.polymer.2020.122984 %T Strain recovery and stress relaxation behaviour of multiblock copolymer blends physically cross-linked with PLA stereocomplexation %U https://doi.org/10.1016/j.polymer.2020.122984 %X Polylactide (PLA) stereocomplexes have attracted attention due to their ability to improve the thermal stability of bioplastics. Here, we evaluate whether PLA stereocomplexes can form stable physical cross-links in blends of a multiblock copolymer with poly(l-lactide) and poly(ε-caprolactone) segments (PLLA-PCL) and a poly(d-lactide) oligomer (PDLA). Through the investigation of the strain recovery in step-cycle experiments and compliance of stress relaxation behaviour with a three-component model for the deformation of semi-crystalline polymers, PLA stereocomplexes were found to possess sufficient stability in the true strain range εH < 2.25 to be described as firm physical netpoints at 70 °C in the studied blends with PLA stereocomplex content ϕc SC ≥ 1.1 wt%, when the PCL domains are melted. Limiting ϕc SC ≤ 6 wt% broadens the behaviour inherent to elastic cross-linked networks to the strain values up until breakage of the samples, while the increase of ϕc SC triggers plastic deformations typical for semi-crystalline polymers. Redistributing of internal stresses from the amorphous to crystalline domains at increase of ϕc calculated with the adopted model was identified as reason of PLA stereocomplexes failure as stable physical network junctions at higher ϕc SC. Within the experimentally determined strain and composition ranges, in which PLA stereocomplexes possess structural stability, they can form robust cross-links in a polymer network. The knowledge gained here provides valuable design criteria for multifunctional thermoplastic elastomers. %0 journal article %@ 1525-7797 %A You, Z.,Behl, M.,Grage, S.,Bürck, J.,Zhao, Q.,Ulrich, A.,Lendlein, A. %D 2020 %J Biomacromolecules %N 2 %P 680-687 %R doi:10.1021/acs.biomac.9b01390 %T Shape-Memory Effect by Sequential Coupling of Functions over Different Length Scales in an Architectured Hydrogel %U https://doi.org/10.1021/acs.biomac.9b01390 2 %X The integration of functions in materials in order to gain macroscopic effects in response to environmental changes is an ongoing challenge in material science. Here, functions on different hierarchical levels are sequentially linked to translate a pH-triggered conformational transition from the molecular to the macroscopic level to induce directed movements in hydrogels. When the pH is increased, lysine-rich peptide molecules change their conformation into a β-hairpin structure because of the reduced electrostatic repulsion among the deprotonated amino groups. Coupled to this conformation change is the capability of the β-hairpin motifs to subsequently assemble into aggregates acting as reversible cross-links, which are used as controlling units to fix a temporary macroscopic shape. A structural function implemented into the hydrogel by a microporous architecture-enabled nondisruptive deformation upon compression by buckling of pore walls and their elastic recovery. Coupled to this structural function is the capability of the porous material to enhance the diffusion of ions into the hydrogel and to keep the dimension of the macroscopic systems almost constant when the additional cross-links are formed or cleaved as it limits the dimensional change of the pore walls. Covalent cross-linking of the hydrogel into a polymer network acted as gear shift to ensure translation of the function on the molecular level to the macroscopic dimension. In this way, the information of a directed shape-shift can be programmed into the material by mechanical deformation and pH-dependent formation of temporary net points. The information could be read out by lowering the pH. The peptides reverted back into their original random coil conformation and the porous polymer network could recover from the previously applied elastic deformation. The level of multifunctionality of the hydrogels can be increased by implementation of additional orthogonal functions such as antimicrobicity by proper selection of multifunctional peptides, which could enable sophisticated biomedical devices. %0 journal article %@ 0142-9612 %A Park, I.,Mahapatra, C.,Park, J.,Dashnyam, K.,Kim, J.,Ahn, J.,Chung, P.,Yoon, D.,Mandakhbayar, N.,Singh, R.,Lee, J.,Leong, K.,Kim, H. %D 2020 %J Biomaterials %N %P 119919 %R doi:10.1016/j.biomaterials.2020.119919 %T Revascularization and limb salvage following critical limb ischemia by nanoceria-induced Ref-1/APE1-dependent angiogenesis %U https://doi.org/10.1016/j.biomaterials.2020.119919 %X In critical limb ischemia (CLI), overproduction of reactive oxygen species (ROS) and impairment of neovascularization contribute to muscle damage and limb loss. Cerium oxide nanoparticles (CNP, or ‘nanoceria’) possess oxygen-modulating properties which have shown therapeutic utility in various disease models. Here we show that CNP exhibit pro-angiogenic activity in a mouse hindlimb ischemia model, and investigate the molecular mechanism underlying the pro-angiogenic effect. CNP were injected into a ligated region of a femoral artery, and tissue reperfusion and hindlimb salvage were monitored for 3 weeks. Tissue analysis revealed stimulation of pro-angiogenic markers, maturation of blood vessels, and remodeling of muscle tissue following CNP administration. At a dose of 0.6 mg CNP, mice showed reperfusion of blood vessels in the hindlimb and a high rate of limb salvage (71%, n = 7), while all untreated mice (n = 7) suffered foot necrosis or limb loss. In vitro, CNP promoted endothelial cell tubule formation via the Ref-1/APE1 signaling pathway, and the involvement of this pathway in the CNP response was confirmed in vivo using immunocompetent and immunodeficient mice and by siRNA knockdown of APE1. These results demonstrate that CNP provide an effective treatment of CLI with excessive ROS by scavenging ROS to improve endothelial survival and by inducing Ref-1/APE1-dependent angiogenesis to revascularize an ischemic limb. %0 journal article %@ 2352-3964 %A Wolfien, M.,Klatt, D.,Salybekov, A.A.,Ii, M.,Komatsu-Horii, M.,Gaebel, R.,Philippou-Massier, J.,Schrinner, E.,Akimaru, H.,Akimaru, E.,David, R.,Garbade, J.,Gummert, J.,Haverich, A.,Hennig, H.,Iwasaki, H.,Kaminski, A.,Kawamoto, A.,Klopsch, C.,Kowallick, J.T.,Krebs, S.,Nesteruk, J.,Reichenspurner, H.,Ritter, C.,Stamm, C.,Tani-Yokoyama, A.,Blum, H.,Wolkenhauer, O.,Schambach, A.,Asahara, T.,Steinhoff, G. %D 2020 %J EBioMedicine %N %P 102862 %R doi:10.1016/j.ebiom.2020.102862 %T Hematopoietic stem-cell senescence and myocardial repair - Coronary artery disease genotype/phenotype analysis of post-MI myocardial regeneration response induced by CABG/CD133+ bone marrow hematopoietic stem cell treatment in RCT PERFECT Phase 3 %U https://doi.org/10.1016/j.ebiom.2020.102862 %X Background,Bone marrow stem cell clonal dysfunction by somatic mutation is suspected to affect post-infarction myocardial regeneration after coronary bypass surgery (CABG).,Methods,Transcriptome and variant expression analysis was studied in the phase 3 PERFECT trial post myocardial infarction CABG and CD133+ bone marrow derived hematopoetic stem cells showing difference in left ventricular ejection fraction (∆LVEF) myocardial regeneration Responders (n=14; ∆LVEF +16% day 180/0) and Non-responders (n=9; ∆LVEF -1.1% day 180/0). Subsequently, the findings have been validated in an independent patient cohort (n=14) as well as in two preclinical mouse models investigating SH2B3/LNK antisense or knockout deficient conditions.,Findings,1. Clinical: R differed from NR in a total of 161 genes in differential expression (n=23, q<0•05) and 872 genes in coexpression analysis (n=23, q<0•05). Machine Learning clustering analysis revealed distinct RvsNR preoperative gene-expression signatures in peripheral blood acorrelated to SH2B3 (p<0.05). Mutation analysis revealed increased specific variants in RvsNR. (R: 48 genes; NR: 224 genes). 2. Preclinical: SH2B3/LNK-silenced hematopoietic stem cell (HSC) clones displayed significant overgrowth of myeloid and immune cells in bone marrow, peripheral blood, and tissue at day 160 after competitive bone-marrow transplantation into mice. SH2B3/LNK−/− mice demonstrated enhanced cardiac repair through augmenting the kinetics of bone marrow-derived endothelial progenitor cells, increased capillary density in ischemic myocardium, and reduced left ventricular fibrosis with preserved cardiac function. 3. Validation: Evaluation analysis in 14 additional patients revealed 85% RvsNR (12/14 patients) prediction accuracy for the identified biomarker signature.,Interpretation,Myocardial repair is affected by HSC gene response and somatic mutation. Machine Learning can be utilized to identify and predict pathological HSC response. %0 journal article %@ 2452-302X %A Shin, E.,Chon, M.,Jun, E.,Park, Y.,Lee, S.,Kim, J.,Shin, D.,Cho, M.,Reinthaler, M.,Park, J.,Nam, G.,Lederman, R.,Won, Y. %D 2020 %J JACC Basic to Translational Science %N 10 %P 988-998 %R doi:10.1016/j.jacbts.2020.08.006 %T Septal Reduction Using Transvenous Intramyocardial Cerclage Radiofrequency Ablation: Preclinical Feasibility %U https://doi.org/10.1016/j.jacbts.2020.08.006 10 %X Debulking of left ventricular septal mass is typically accomplished using surgical myectomy, which is morbid, or using transcoronary alcohol septal ablation, which can result in geographic miss and occasional catastrophic nontarget coronary injury. The authors developed and tested operational parameters in vitro and vivo for a device to accomplish transvenous intraseptal radiofrequency ablation to reduce ventricular septal mass using a technique derived from mitral cerclage, which the authors call cerclage ablation. Cerclage ablation appeared feasible in vitro and safe and effective in vivo. Cerclage ablation is an attractive new approach to debulk the interventricular septum in obstructive hypertrophic cardiomyopathy. These data support clinical investigation. %0 journal article %@ 2398-6352 %A Rank, N.,Pfahringer, B.,Kempfert, J.,Stamm, C.,Kühne, T.,Schoenrath, F.,Falk, V.,Eickhoff, C.,Meyer, A. %D 2020 %J npj Digital Medicine %N 1 %P 139 %R doi:10.1038/s41746-020-00346-8 %T Deep-learning-based real-time prediction of acute kidney injury outperforms human predictive performance %U https://doi.org/10.1038/s41746-020-00346-8 1 %X Acute kidney injury (AKI) is a major complication after cardiothoracic surgery. Early prediction of AKI could prompt preventive measures, but is challenging in the clinical routine. One important reason is that the amount of postoperative data is too massive and too high-dimensional to be effectively processed by the human operator. We therefore sought to develop a deep-learning-based algorithm that is able to predict postoperative AKI prior to the onset of symptoms and complications. Based on 96 routinely collected parameters we built a recurrent neural network (RNN) for real-time prediction of AKI after cardiothoracic surgery. From the data of 15,564 admissions we constructed a balanced training set (2224 admissions) for the development of the RNN. The model was then evaluated on an independent test set (350 admissions) and yielded an area under curve (AUC) (95% confidence interval) of 0.893 (0.862–0.924). We compared the performance of our model against that of experienced clinicians. The RNN significantly outperformed clinicians (AUC = 0.901 vs. 0.745, p < 0.001) and was overall well calibrated. This was not the case for the physicians, who systematically underestimated the risk (p < 0.001). In conclusion, the RNN was superior to physicians in the prediction of AKI after cardiothoracic surgery. It could potentially be integrated into hospitals’ electronic health records for real-time patient monitoring and may help to detect early AKI and hence modify the treatment in perioperative care. %0 journal article %@ 1386-0291 %A Curio, J.,Abulgasim, K.,Kasner, M.,Rroku, A.,Lauten, A.,Lendlein, A.,Landmesser, U.,Reinthaler, M. %D 2020 %J Clinical Hemorheology and Microcirculation %N 2 %P 199-210 %R doi:10.3233/CH-209211 %T Intracardiac echocardiography to enable successful edge-to-edge transcatheter tricuspid valve repair in patients with insufficient TEE quality %U https://doi.org/10.3233/CH-209211 2 %X BACKGROUND:Transesophageal echocardiography (TEE) as a guiding tool for edge-to-edge transcatheter tricuspid valve repair (EETVr) using MitraClip (Abbott Vascular, Santa Clara, USA) may not offer sufficient image quality in a significant proportion of patients. OBJECTIVES:Intracardiac echocardiography (ICE) as additional guiding tool in EETVr with the MitraClip device. METHODS:Appropriate angulations of the ICE catheter to visualize each commissure of the tricuspid valve were established in 3D printed heart models. In a single tertiary-care center ICE was used to support EETVr as additional guidance when TEE image quality was insufficient. Procedural safety and outcomes up to 30-days were compared between ICE/TEE and TEE only guided patients. RESULTS:In 6 of 11 patients (54.5%) undergoing EETVr with MitraClip TEE alone was unsatisfactory, necessitating additional ICE guidance. In 4 of these 6 patients ICE enabled a successful completion of the procedure. The steering maneuvers identified in the 3D models were well applicable in all patients, providing examples for potential future ICE implementation in EETVr. Under both TEE alone (n = 5) and ICE (n = 6) guidance the rate of procedural complications was 0%. According to vena contracta values at discharge significant TR reduction was achievable in the treated cohort (p = 0.011). At 30-days follow-up one patient (ICE guided) died following global heart failure, not associated with the procedure itself. CONCLUSIONS:ICE guidance may offer an additional tool to guide EETVr with the MitraClip device in patients with poor TEE quality, as it enables successful results without impairing procedural safety. %0 journal article %@ 2059-8521 %A Luetzow, K.,Weigel, T.,Lendlein, A. %D 2020 %J MRS Advances %N 14 - 15 %P 785-795 %R doi:10.1557/adv.2019.422 %T Solvent-based Fabrication Method for Magnetic, Shape-Memory Nanocomposite Foams %U https://doi.org/10.1557/adv.2019.422 14 - 15 %X This paper presents shape-memory foams that can be temporarily fixed in their compressed state and be expanded on demand. Highly porous, nanocomposite foams were prepared from a solution of polyeiherureihane with suspended nanoparticles (mean aggregate size 90 nm) which have an iron(III) oxide core with a silica shell. The polymer solution with suspended nanoparticles was cooled down to -20 °C in a two-stage process, which was followed by freeze-diying. The average pore size increases with decreasing concentration of nanoparticles from 158 μm to 230 jum while the foam porosity remained constant. After fixation of a temporaiy form of the nanocomposite foams, shape recovery can be triggered either by heat or by exposure to an alternating magnetic field. Compressed foams showed a recovery rate of up to 76 ± 4% in a thermochamber at 80 °C, and a slightly lower recovery rate of up to 65 ± 4% in a magnetic field. %0 journal article %@ 2059-8521 %A Liu, Y.,Gould, O.,Kratz, K.,Lendlein, A. %D 2020 %J MRS Advances %N 46 - 47 %P 2391-2399 %R doi:10.1557/adv.2020.276 %T Shape-Memory Actuation of Individual Micro-/Nanofibers %U https://doi.org/10.1557/adv.2020.276 46 - 47 %X Advances in the fabrication and characterization of polymeric nanomaterials has greatly advanced the miniaturization of soft actuators, creating materials capable of replicating the functional physical behavior previously limited to the macroscale. Here, we demonstrate how a reversible shape-memory polymer actuation can be generated in a single micro/nano object, where the shape change during actuation of an individual fiber can be dictated by programming using an AFM-based method. Electrospinning was used to prepare poly(ε-caprolactone) micro-/nanofibers, which were fixed and crosslinked on a structured silicon wafer. The programming as well as the observation of recovery and reversible displacement of the fiber were performed by vertical three point bending, using an AFM testing platform introduced here. A plateau tip was utilized to improve the stability of the fiber contact and working distance, enabling larger deformations and greater rbSMPA performance. Values for the reversible elongation of εrev = 3.4 ± 0.1% and 10.5 ± 0.1% were obtained for a single micro (d = 1.0 ± 0.2 μm) and nanofiber (d = 300 ± 100 nm) in cyclic testing between the temperatures 10 and 60 °C. The reversible actuation of the nanofiber was successfully characterized for 10 cycles. The demonstration and characterization of individual shape-memory nano and microfiber actuators represents an important step in the creation of miniaturized robotic devices capable of performing complex physical functions at the length scale of cells and structural component of the extracellular matrix. %0 journal article %@ 1386-0291 %A Haase, T.,Klopfleisch, R.,Krost, A.,Sauter, T.,Kratz, K.,Peter, J.,Jung, F.,Lendlein, A.,Zohlnhöfer, D.,Rüder, C. %D 2020 %J Clinical Hemorheology and Microcirculation %N 2 %P 163-176 %R doi:10.3233/CH-190748 %T In vivo biocompatibility study of degradable homo- versus multiblock copolymers and their (micro)structure compared to an established biomaterial %U https://doi.org/10.3233/CH-190748 2 %X Copolyetheresterurethane (PDC) is a biodegradable, shape-memory biomaterial, which has been shown to be of low toxicity and pro-angiogenic in vitro. In the present study we examined the in vivo compatibility of PDC as a compression molded film and as electrospun scaffolds and its well established constituent, the homopolymer poly(p-dioxanone) (PPDO), which were compared with the clinically used poly[(vinylidene fluoride)-co-hexafluoropropene] (PVDF) as reference material. The materials were implanted in the subcutaneous tissue of mice and the host responses were analyzed histologically 7 and 28 days after implantation. All materials induced a foreign body response (FRB) including the induction of foreign body giant cells and a peripheral fibrous capsule. PDC, PPDO and PVDF films showed no signs of degradation after 28 days. PDC films showed a significantly reduced associated macrophage layer and fibrous capsule on their surface. Few fragments of PDC and PPDO scaffolds were present at the implantation site, while PVDF scaffolds were still present in large amounts at day 28. Especially aligned electrospun PDC scaffold induced a significantly thinner fibrous and a slightly reduced inflammatory response after 28 days of implantation. In addition, only PDC aligned fibrous scaffold structures induced a significant increase in angiogenesis. In summary, PDC films outperformed PPDO and PVDF films in terms of compatibility, especially in capsule and macrophage layer thickness. Through microstructuring of PDC and PPDO into scaffolds an almost complete degradation was observed after 28 days, while their respective films remained almost unchanged. However, the capsule thickness of all scaffolds was comparable to the films after 28 days. Finally, the parallel arrangement of PDC fibers enabled a strong enhancement of angiogenesis within the scaffold. Hence, material chemistries influence overall compatibility in vivo, while angiogenesis could be influenced more strongly by microstructural parameters than chemical ones. %0 journal article %@ 0964-1726 %A Bastola, A.,Paudel, M.,Li, L.,Li, W. %D 2020 %J Smart Materials and Structures %N 12 %P 123002 %R doi:10.1088/1361-665X/abbc77 %T Recent progress of magnetorheological elastomers: a review %U https://doi.org/10.1088/1361-665X/abbc77 12 %X Magnetorheological elastomers (MREs) are one of the categories of smart materials, whose modulus increases considerably in the presence of a magnetic field. These elastomers are prepared by dispersing magnetic micro-sized particles into a soft solid carrier medium. The main feature of these elastomers is that they change their elastic and damping properties quickly in the presence of a magnetic field. The change in properties, also known as the magnetorheological (MR) effect of MREs are dependent on various parameters such as type of matrix material, distribution of magnetic particles, additives, working mode, and strength of the applied magnetic field. Various studies have been conducted to improve the MR effect and seek the possibility to implement the MREs in different applications including but not limited to vibration absorbers, isolators, soft actuators, and sensors. The focus of this review is to present the recent progress of MREs including materials used, fabrication strategies, MR effect, and potential applications. %0 journal article %@ 1479-5876 %A Liu, Z.,Klose, K.,Neuber, S.,Jiang, M.,Gossen, M.,Stamm, C. %D 2020 %J Journal of Translational Medicine %N %P 437 %R doi:10.1186/s12967-020-02605-4 %T Comparative analysis of adeno-associated virus serotypes for gene transfer in organotypic heart slices %U https://doi.org/10.1186/s12967-020-02605-4 %X Background,Vectors derived from adeno-associated viruses (AAVs) are widely used for gene transfer both in vitro and in vivo and have gained increasing interest as shuttle systems to deliver therapeutic genes to the heart. However, there is little information on their tissue penetration and cytotoxicity, as well as the optimal AAV serotype for transferring genes to diseased hearts. Therefore, we aimed to establish an organotypic heart slice culture system for mouse left ventricular (LV) myocardium and use this platform to analyze gene transfer efficiency, cell tropism, and toxicity of different AAV serotypes.,Methods,LV tissue slices, 300 µm thick, were prepared from 15- to 17-day-old transgenic alpha-myosin heavy-chain-mCherry mice using a vibrating microtome. Tissue slice viability in air-liquid culture was evaluated by calcein-acetoxymethyl ester staining, mCherry fluorescence intensity, and the tetrazolium assay. Four recombinant AAV serotypes (1, 2, 6, 8) expressing green fluorescent protein (GFP) under the CAG promoter were added to the slice surface. Gene transfer efficiency was quantified as the number of GFP-positive cells per slice. AAV cell tropism was examined by comparing the number of GFP-positive cardiomyocytes (CMs) and fibroblasts within heart slices.,Results,Slices retained viability in in vitro culture for at least 5 days. After adding AAV particles, AAV6-infected slices showed the highest number of GFP-expressing cells, almost exclusively CMs. Slice incubation with AAV1, 2, and 8 resulted in fewer GFP-positive cells, with AAV2 having the lowest gene transfer efficiency. None of the AAV serotypes tested caused significant cytotoxicity when compared to non-infected control slices.,Conclusions,We have established a readily available mouse organotypic heart slice culture model and provided evidence that AAV6 may be a promising gene therapy vector for heart failure and other cardiac diseases. %0 journal article %@ 0014-3057 %A Izraylit, V.,Hommes-Schattmann, P.,Neffe, A.,Gould, O.,Lendlein, A. %D 2020 %J European Polymer Journal %N %P 109908 %R doi:10.1016/j.eurpolymj.2020.109908 %T Alkynyl-functionalized chain-extended PCL for coupling to biological molecules %U https://doi.org/10.1016/j.eurpolymj.2020.109908 %X Chemical functionalization of poly(ε-caprolactone) (PCL) enables a molecular integration of additional function. Here, we report an approach to incorporate reactive alkynyl side-groups by synthesizing a chain-extended PCL, where the reactive site is introduced through the covalently functionalizable chain extender 3-(prop-2-yn-1-yloxy)propane-1,2-diol (YPD). Chain-extended PCL with Mw of 101 to 385 kg·mol−1 were successfully synthesized in a one-pot reaction from PCL-diols with various molar masses, L-lysine ethyl ester diisocyanate (LDI) or trimethyl(hexamethylene)diisocyanate (TMDI), and YPD, in which the density of functionalizable groups and spacing between them can be controlled by the composition of the polymer. The employed diisocyanate compounds and YPD possess an asymmetric structure and form a non-crystallizable segment leaving the PCL crystallites to dominate the material’s mechanical properties. The mixed glass transition temperature Tg = −60 to −46 °C of the PCL/polyurethane amorphous phase maintains the synthesized materials in a highly elastic state at ambient and physiological conditions. Reaction conditions for covalent attachment in copper(I)-catalyzed azide-alkyne-cycloaddition reactions (CuAAC) in solution were optimized in a series of model reactions between the alkyne moieties of the chain-extended PCL and benzyl azide, reaching conversions over 95% of the alkyne moieties and with yields of up to 94% for the purified functionalized PCL. This methodology was applied for reaction with the azide-functionalized cell adhesion peptide GRGDS. The required modification of the peptide provides selectivity in the coupling reactions. The obtained results suggest that YPD could potentially be employed as versatile molecular unit for the creation of a variety of functionalizable polyesters as well as polyurethanes and polycarbonates offering efficient and selective click-reactions. %0 journal article %@ 2157-6564 %A Nazari-Shafti, T.,Neuber, S.,Garcia Duran, A.,Xu, Z.,Beltsios, E.,Seifert, M.,Falk, V.,Stamm, C. %D 2020 %J Stem Cells Translational Medicine %N 12 %P 1558-1569 %R doi:10.1002/sctm.19-0432 %T Human mesenchymal stromal cells and derived extracellular vesicles: Translational strategies to increase their proangiogenic potential for the treatment of cardiovascular disease %U https://doi.org/10.1002/sctm.19-0432 12 %X Mesenchymal stromal cells (MSCs) offer great potential for the treatment of cardiovascular diseases (CVDs) such as myocardial infarction and heart failure. Studies have revealed that the efficacy of MSCs is mainly attributed to their capacity to secrete numerous trophic factors that promote angiogenesis, inhibit apoptosis, and modulate the immune response. There is growing evidence that MSC-derived extracellular vesicles (EVs) containing a cargo of lipids, proteins, metabolites, and RNAs play a key role in this paracrine mechanism. In particular, encapsulated microRNAs have been identified as important positive regulators of angiogenesis in pathological settings of insufficient blood supply to the heart, thus opening a new path for the treatment of CVD. In the present review, we discuss the current knowledge related to the proangiogenic potential of MSCs and MSC-derived EVs as well as methods to enhance their biological activities for improved cardiac tissue repair. Increasing our understanding of mechanisms supporting angiogenesis will help optimize future approaches to CVD intervention. %0 journal article %@ 2075-163X %A Gochev, G.,Ulaganathan, V.,Retzlaff, I.,Gehin-Delval, C.,Gunes, D.,Leser, M.,Kulozik, U.,Miller, R.,Braunschweig, B. %D 2020 %J Minerals %N 7 %P 636 %R doi:10.3390/min10070636 %T β-Lactoglobulin Adsorption Layers at the Water/Air Surface: 4. Impact on the Stability of Foam Films and Foams %U https://doi.org/10.3390/min10070636 7 %X The complexity and high sensitivity of proteins to environmental factors give rise to a multitude of variables, which affect the stabilization mechanisms in protein foams. Interfacial and foaming properties of proteins have been widely studied, but the reported unique effect of pH, which can be of great interest to applications, has been investigated to a lesser extent. In this paper, we focus on the impact of pH on the stability of black foam films and corresponding foams obtained from solutions of a model globular protein—the whey β-lactoglobulin (BLG). Foam stability was analyzed utilizing three characteristic parameters (deviation time, transition time and half-lifetime) for monitoring the foam decay, while foam film stability was measured in terms of the critical disjoining pressure of film rupture. We attempt to explain correlations between the macroscopic properties of a foam system and those of its major building blocks (foam films and interfaces), and thus, to identify structure-property relationships in foam. Good correlations were found between the stabilities of black foam films and foams, while relations to the properties of adsorption layers appeared to be intricate. That is because pH-dependent interfacial properties of proteins usually exhibit an extremum around the isoelectric point (pI), but the stability of BLG foam films increases with increasing pH (3–7), which is well reflected in the foam stability. We discuss the possible reasons behind these intriguingly different behaviors on the basis of pH-induced changes in the molecular properties of BLG, which seem to be determining the mechanism of film rupture at the critical disjoining pressure. %0 journal article %@ 1386-0291 %A Nie, Y.,Xu, X.,Wang, W.,Ma, N.,Lendlein, A. %D 2020 %J Clinical Hemorheology and Microcirculation %N 2 %P 329-340 %R doi:10.3233/CH-209217 %T Spheroid formation of human keratinocyte: Balancing between cell-substrate and cell-cell interaction %U https://doi.org/10.3233/CH-209217 2 %X BACKGROUND:,The formation of spheroids is tightly regulated by intrinsic cell-cell and cell-substrate interactions.,OBJECTIVE:,The chitosan (CS)-coating was applied to investigate the driven force directed the spheroid formation.,METHODS:,The effects of CS on cell functions were studied. Atomic force microscopy was employed to measure the cell- biomaterial interplay at single cell level.,RESULTS:,HaCaT cells shifted from their flattened sheet to a compact 3D spheroidal morphology when increasing CS coating concentration. The proliferative capacity of HaCaT was preserved in the spheroid. The expression and activation of integrin β1 (ITGB1) were enhanced on CS modified surfaces, while the active to total ratio of ITGB1 was decreased. The adhesive force of a single HaCaT cell to the tissue culture plate (TCP) was 4.84±0.72 nN. It decreased on CS-coated surfaces as CS concentration increased, from 2.16±0.26 nN to 0.96±0.17 nN. The adhesive force between the single HaCaT cell to its neighbor cell increased as CS concentration increased, from 1.15±0.09 nN to 2.60±0.51 nN.,CONCLUSIONS:,Conclusively, the decreased cell- substrate adhesion was the main driven force in the spheroid formation. This finding might serve as a design criterion for biomaterials facilitating the formation of epithelial spheroids. %0 journal article %@ 0946-2716 %A Moradian, H.,Lendlein, A.,Gossen, M. %D 2020 %J Journal of Molecular Medicine %N %P 1767-1779 %R doi:10.1007/s00109-020-01956-1 %T Strategies for simultaneous and successive delivery of RNA %U https://doi.org/10.1007/s00109-020-01956-1 %X Advanced non-viral gene delivery experiments often require co-delivery of multiple nucleic acids. Therefore, the availability of reliable and robust co-transfection methods and defined selection criteria for their use in, e.g., expression of multimeric proteins or mixed RNA/DNA delivery is of utmost importance. Here, we investigated different co- and successive transfection approaches, with particular focus on in vitro transcribed messenger RNA (IVT-mRNA). Expression levels and patterns of two fluorescent protein reporters were determined, using different IVT-mRNA doses, carriers, and cell types. Quantitative parameters determining the efficiency of co-delivery were analyzed for IVT-mRNAs premixed before nanocarrier formation (integrated co-transfection) and when simultaneously transfecting cells with separately formed nanocarriers (parallel co-transfection), which resulted in a much higher level of expression heterogeneity for the two reporters. Successive delivery of mRNA revealed a lower transfection efficiency in the second transfection round. All these differences proved to be more pronounced for low mRNA doses. Concurrent delivery of siRNA with mRNA also indicated the highest co-transfection efficiency for integrated method. However, the maximum efficacy was shown for successive delivery, due to the kinetically different peak output for the two discretely operating entities. Our findings provide guidance for selection of the co-delivery method best suited to accommodate experimental requirements, highlighting in particular the nucleic acid dose-response dependence on co-delivery on the single-cell level. %0 journal article %@ 1359-8368 %A Bastola, A.,Hossain, M. %D 2020 %J Composites. Part B, Engineering %N %P 108348 %R doi:10.1016/j.compositesb.2020.108348 %T A review on magneto-mechanical characterizations of magnetorheological elastomers %U https://doi.org/10.1016/j.compositesb.2020.108348 %X Magnetorheological elastomers (MREs) are a class of recently emerged smart materials whose moduli are largely influenced when exposed to an external magnetic field. The MREs are particulate composites, where micro-sized magnetic particles are dispersed inside a non-magnetic polymeric matrix. These elastomers are known for changing their mechanical and rheological properties in the presence of a magnetic field. This change in properties is widely known as the magnetorheological (MR) effect. The MR effect depends on a number of factors such as type of matrix materials, type, concentration and distribution of magnetic particles, use of additives, working modes, and magnetic field strength. The investigation of MREs’ mechanical properties in both off-field and on-field (i.e. absence and presence of a magnetic field) is crucial to deploy them in real engineering applications. The common magneto-mechanical characterization experiments of MREs include static and dynamic compression, tensile, and shear tests in both off-field and on-field. This review article aims to provide a comprehensive overview of the magneto-mechanical characterizations of MREs along with brief coverage of the MRE materials and their fabrication methods. %0 journal article %@ 0021-9606 %A Hoffmann, F.,Mulder, F.,Schäfer, L. %D 2020 %J The Journal of Chemical Physics %N 8 %P 084102 %R doi:10.1063/1.5135379 %T Predicting NMR relaxation of proteins from molecular dynamics simulations with accurate methyl rotation barriers %U https://doi.org/10.1063/1.5135379 8 %X The internal dynamics of proteins occurring on time scales from picoseconds to nanoseconds can be sensitively probed by nuclear magnetic resonance (NMR) spin relaxation experiments, as well as by molecular dynamics (MD) simulations. This complementarity offers unique opportunities, provided that the two methods are compared at a suitable level. Recently, several groups have used MD simulations to compute the spectral density of backbone and side chain molecular motions and to predict NMR relaxation rates from these. Unfortunately, in the case of methyl groups in protein side chains, inaccurate energy barriers to methyl rotation were responsible for a systematic discrepancy in the computed relaxation rates, as demonstrated for the AMBER ff99SB*-ILDN force field (and related parameter sets), impairing quantitative agreement between simulations and experiments. However, correspondence could be regained by emending the MD force field with accurate coupled cluster quantum chemical calculations. Spurred by this positive result, we tested whether this approach could be generally applicable, in spite of the fact that different MD force fields employ different water models. Improved methyl group rotation barriers for the CHARMM36 and AMBER ff15ipq protein force fields were derived, such that the NMR relaxation data obtained from the MD simulations even now display very good agreement with the experiment. Results herein showcase the performance of present-day MD force fields and manifest their refined ability to accurately describe internal protein dynamics. %0 journal article %@ 0032-3861 %A Kratz, K.,Heuchel, M.,Weigel, T.,Lendlein, A. %D 2020 %J Polymer %N %P 123045 %R doi:10.1016/j.polymer.2020.123045 %T Surface hydrophilization of highly porous poly(ether imide) microparticles by covalent attachment of poly(vinyl pyrrolidone) %U https://doi.org/10.1016/j.polymer.2020.123045 %X The realization of a permanent surface hydrophilization for highly porous microparticles designed for removing uremic toxins from the blood of renal failure patients, without altering their complex pore structure, represents a challenging task.,Here we report on the hydrophilic surface functionalization of porous poly (ether imide) (PEI) microparticles, having a mean diameter of 226 ± 14 μm, a porosity of around 84 ± 2% with a mean pore diameter of 230 ± 40 nm, by covalent attachment of amino-terminated poly (vinyl pyrrolidone) (PVP–NH2) with a number average molecular weight of Mn = 5400 g mol−1. X-ray photoelectron spectroscopy confirmed a successful surface modification by a change in the surface chemistry, in particular the N/C ratio. The PEI-PVP particles exhibited an advancing water contact angle of θadv = 75° ± 5° as determined in environmental scanning electron microscopy microwetting experiments. The obtained results from mercury intrusion porosimetry and nitrogen adsorption experiments documented the preservation of the porous structure of the particles in the cause of the modification, which could be visualized by electron microscopy. The presented approach enables a covalent hydrophilization of porous particles while preserving their nanoporous morphology. %0 journal article %@ 2059-8521 %A Hoffmann, F.,Machatschek, R.,Lendlein, A. %D 2020 %J MRS Advances %N 52 - 53 %P 2737-2749 %R doi:10.1557/adv.2020.386 %T Understanding the impact of crystal lamellae organization on small molecule diffusion using a Monte Carlo approach %U https://doi.org/10.1557/adv.2020.386 52 - 53 %X Many physicochemical processes depend on the diffusion of small molecules through solid materials. While crystallinity in polymers is advantageous with respect to structure performance, diffusion in such materials is difficult to predict. Here, we investigate the impact of crystal morphology and organization on the diffusion of small molecules using a lattice Monte Carlo approach. Interestingly, diffusion determined with this model does not depend on the internal morphology of the semi-crystalline regions. The obtained insight is highly valuable for developing predictive models for all processes in semi-crystalline polymers involving mass transport, like polymer degradation or drug release, and provide design criteria for the time-dependent functional behavior of multifunctional polymer systems. %0 journal article %@ 1042-3931 %A Curio, J.,Tarar, W.,Al-Hindwan, H.,Neumann, R.,Berger, C.,Hoting, M.,Kasner, M.,Lendlein, A.,Landmesser, U.,Reinthaler, M. %D 2020 %J The Journal of Invasive Cardiology %N 1 %P E1-E8 %T The MitraClip Procedure in Patients With Moderate Resting but Severe Exercise-Induced Mitral Regurgitation %U 1 %X Background. Optimal timing for percutaneous mitral regurgitation (MR) treatment using MitraClip (Abbott Vascular) remains unclear. We evaluated the outcome after MitraClip in patients with moderate resting MR, progressing to severe exercise-induced MR (MR2+) compared to patients with severe resting MR (MR3). Methods. We retrospectively investigated 221 patients undergoing MitraClip. All-cause deaths and heart failure (HF) hospitalizations were assessed as the combined primary endpoint. Results. We identified 55 MR2+ and 166 MR3 patients. At baseline, MR3 patients showed higher STS scores (6.7 ± 7.3 vs 4.4 ± 5.5; P<.01), more HF hospitalizations in the 2 years prior to the procedure (51% vs 29%; P<.01), worse left ventricular ejection fraction (44.9 ± 16.5% vs 52.5 ± 14.3%; P<.01), larger left ventricular end-diastolic diameter (LVEDd; 57.0 ± 9.3 mm vs 51.7 ± 8.2 mm; P<.001), and larger left atrial volumes (118.3 ± 55.8 mL vs 98.6 ± 35.2 mL; P=.02). Long-term outcome according to the combined endpoint was significantly worse in MR3 patients (P=.01). HF hospitalizations significantly declined in both groups 2 years after MitraClip (P<.001 in MR3 patients, P=.03 in MR2+ patients). Multivariate Cox regression analysis revealed LVEDd (hazard ratio, 1.035; 95% confidence interval, 1.005-1.066; P=.02) and previous HF hospitalizations (hazard ratio, 1.813; 95% confidence interval, 1.016-3.234; P=.04) as strong outcome predictors. Conclusions. Symptomatic patients with moderate resting and severe exercise-induced MR during handgrip echocardiography may represent an MR cohort at an earlier disease stage with improved treatment response following MitraClip implantation compared to individuals with severe resting MR. Larger left ventricular diameters and preprocedural HF hospitalizations were identified as independent adverse outcome predictors. %0 journal article %@ 1462-2912 %A Tarazona, N.,Hernández-Arriaga, A.,Kniewel, R.,Prieto, M. %D 2020 %J Environmental Microbiology %N 8 %P 3922-3936 %R doi:10.1111/1462-2920.15175 %T Phasin interactome reveals the interplay of PhaF with the polyhydroxyalkanoate transcriptional regulatory protein PhaD in Pseudomonas putida %U https://doi.org/10.1111/1462-2920.15175 8 %X Phasin PhaF, a multifunctional protein associated with the surface of polyhydroxyalkanoate (PHA) granules that also interacts with the nucleoid, contributes significantly to PHA biogenesis in pseudomonads. As a protein present on the surface of PHA granules, PhaF participates in granule stabilization and segregation, whereas its deletion has a notable impact on overall transcriptome, PHA accumulation and cell physiology, suggesting more extensive functions besides solely being a granule structural protein. Here, we followed a systematic approach to detect potential interactions of PhaF with other components of the cell, which could pinpoint unexplored functions of PhaF in the regulation of PHA production. We determined the PhaF interactome in Pseudomonas putida KT2440 via pull‐down‐mass spectrometry (PD‐MS) experiments. PhaF complexed with PHA‐related proteins, phasin PhaI and the transcriptional regulator PhaD, interactions that were verified to be direct using in vivo two‐hybrid analysis. The determination of the PHA granule proteome showed that PhaI and three other potential PhaF interacting partners, but not PhaD, were granule‐associated proteins. Analysis of the interaction of PhaF and PhaD with the phaI promoter by EMSA suggested a new role for PhaF in interacting with PhaD and raises new questions on the regulatory system controlling pha gene expression. %0 journal article %@ 2059-8521 %A Behl, M.,Razzaq, M.,Mazurek-Budzyñska, M.,Lendlein, A. %D 2020 %J MRS Advances %N 45 %P 2317-2330 %R doi:10.1557/adv.2020.345 %T Polyetheresterurethane Based Porous Scaffolds with Tailorable Architectures by Supercritical CO2 Foaming %U https://doi.org/10.1557/adv.2020.345 45 %X Porous three-dimensional (3D) scaffolds are promising treatment options in regenerative medicine. Supercritical and dense-phase fluid technologies provide an attractive alternative to solvent-based scaffold fabrication methods. In this work, we report on the fabrication of poly-etheresterurethane (PPDO-PCL) based porous scaffolds with tailorable pore size, porosity, and pore interconnectivity by using supercritical CO2 (scCO2) fluid-foaming. The influence of the processing parameters such as soaking time, soaking temperature and depressurization on porosity, pore size, and interconnectivity of the foams were investigated. The average pore diameter could be varied between 100–800 μm along with a porosity in the range from (19 ± 3 to 61 ± 6)% and interconnectivity of up to 82%. To demonstrate their applicability as scaffold materials, selected foams were sterilized via ethylene oxide sterilization. They showed negligible cytotoxicity in tests according to DIN EN ISO 10993-5 and 10993-12 using L929 cells. The study demonstrated that the pore size, porosity and the interconnectivity of this multi-phase semicrystalline polymer could be tailored by careful control of the processing parameters during the scCO2 foaming process. In this way, PPDO-PCL scaffolds with high porosity and interconnectivity are potential candidate materials for regenerative treatment options. %0 journal article %@ 1386-0291 %A Rickert, D.,Steinhart, H.,Lendlein, A. %D 2020 %J Clinical Hemorheology and Microcirculation %N 2 %P 179-189 %R doi:10.3233/CH-209212 %T Functional requirements for polymeric implant materials in head and neck surgery %U https://doi.org/10.3233/CH-209212 2 %X BACKGROUND:,The pharyngeal reconstruction is a challenging aspect after pharyngeal tumor resection. The pharyngeal passage has to be restored to enable oral alimentation and speech rehabilitation. Several techniques like local transposition of skin, mucosa and/or muscle, regional flaps and free vascularized flaps have been developed to reconstruct pharyngeal defects following surgery, in order to restore function and aesthetics. The reconstruction of the pharynx by degradable, multifunctional polymeric materials would be a novel therapeutical option in head and neck surgery.,MATERIALS AND METHODS:,Samples of an ethylene-oxide sterilized polymer (diameter 10 mm, 200μm thick) were implanted for the reconstruction of a standardized defect of the gastric wall in rats in a prospective study. The stomach is a model for a “worst case” application site to test the stability of the implant material under extreme chemical, enzymatical, bacterial, and mechanical load.,RESULTS:,Fundamental parameters investigated in this animal model were a local tight closure between the polymer and surrounding tissues, histological findings of tissue regeneration and systemic responses to inflammation. A tight anastomosis between the polymer and the adjacent stomach wall was found in all animals after polymer implantation (n = 42). Histologically, a regeneration with glandular epithelium was found in the polymer group. No differences in the systemic responses to inflammation were found between the polymer group (n = 42) and the control group (n = 21) with primary wound closure of the defect of the gastric wall.,CONCLUSIONS:,A sufficient stability of the polymeric material is a requirement for the pharyngeal reconstruction with implant materials. %0 journal article %@ 1386-0291 %A Nie, Y.,Xu, X.,Wang, W.,Ma, N.,Lendlein, A. %D 2020 %J Clinical Hemorheology and Microcirculation %N 2 %P 317-327 %R doi:10.3233/CH-209208 %T The effects of oscillatory temperature on HaCaT keratinocyte behaviors %U https://doi.org/10.3233/CH-209208 2 %X BACKGROUND:,Keratinocytes are exposed to a thermal gradient throughout epidermal layers in human skin depending on environmental temperatures.,OBJECTIVE:,Here, the effect of cyclic temperature changes (ΔT) on HaCaT cell behaviors was explored.,METHODS:,HaCaT cells were cultured at constant temperature (37°C or 25°C) or under ΔT conditions. The morphology, mechanics, cell cycle progression, proliferation, and lipid synthesis of HaCaT cells were determined.,RESULTS:,ΔT conditions led to the inhomogeneous arrangement of the cytoskeleton in HaCaT cells, which resulted in enlarged size, rounder shape, and increased stiffness. Accumulation in the G2/M phase in the cell cycle, a decreased proliferation rate, and a delayed lipogenesis were detected in HaCaT cells cultured under ΔT conditions.,CONCLUSIONS:,ΔT conditions resulted in the re-arrangement of the cytoskeleton in HaCaT cells, which showed similarity to the temperature-induced disassemble and re-assemble of cytoskeletons in keratinocyte in vivo. The altered cytoskeleton arrangement resulted in the cell enlargement and stiffening, which reflected the changes in cellular functions. The application of oscillatory temperature in the in vitro culture of keratinocytes provides a way to gain more insights into the role of skin in response to environmental stimuli and maintaining its homeostasis in vivo. %0 journal article %@ 1042-7147 %A Luetzow, K.,Hommes-Schattmann, P.J.,Neffe, A.T.,Ahmad, B.,Williams, G.R.,Lendlein, A. %D 2019 %J Polymers for Advanced Technologies %N 5 %P 1165-1172 %R doi:10.1002/pat.4331 %T Perfluorophenyl azide functionalization of electrospun poly(para-dioxanone) %U https://doi.org/10.1002/pat.4331 5 %X Strategies to surface‐functionalize scaffolds by covalent binding of biologically active compounds are of fundamental interest to control the interactions between scaffolds and biomolecules or cells. Poly(para‐dioxanone) (PPDO) is a clinically established polymer that has shown potential as temporary implant, eg, for the reconstruction of the inferior vena cava, as a nonwoven fiber mesh. However, PPDO lacks suitable chemical groups for covalent functionalization. Furthermore, PPDO is highly sensitive to hydrolysis, reflected by short in vivo half‐life times and degradation during storage. Establishing a method for covalent functionalization without degradation of this hydrolyzable polymer is therefore important to enable the surface tailoring for tissue engineering applications. It was hypothesized that treatment of PPDO with an N‐hydroxysuccinimide ester group bearing perfluorophenyl azide (PFPA) under UV irradiation would allow efficient surface functionalization of the scaffold. X‐ray photoelectron spectroscopy and attenuated total reflectance Fourier‐transformed infrared spectroscopy investigation revealed the successful binding, while a gel permeation chromatography study showed that degradation did not occur under these conditions. Coupling of a rhodamine dye to the N‐hydroxysuccinimide esters on the surface of a PFPA‐functionalized scaffold via its amine linker showed a homogenous staining of the PPDO in laser confocal microscopy. The PFPA method is therefore applicable even to the surface functionalization of hydrolytically labile polymers, and it was demonstrated that PFPA chemistry may serve as a versatile tool for the (bio‐)functionalization of PPDO scaffolds. %0 journal article %@ 1757-6512 %A Sarem, M.,Otto, O.,Tanaka, S.,Shastri, V.P. %D 2019 %J Stem Cell Research and Therapy %N %P 10 %R doi:10.1186/s13287-018-1103-y %T Cell number in mesenchymal stem cell aggregates dictates cell stiffness and chondrogenesis %U https://doi.org/10.1186/s13287-018-1103-y %X Background,Although mesenchymal stem/stromal cell (MSC) chondrogenic differentiation has been thoroughly investigated, the rudiments for enhancing chondrogenesis have remained largely dependent on external cues. Focus to date has been on extrinsic variables such as soluble signals, culture conditions (bioreactors), and mechanical stimulation. However, the role of intrinsic mechanisms of MSC programming-based mechanobiology remains to be explored. Since aggregation of MSCs, a prerequisite for chondrogenesis, generates tension within the cell agglomerate, we inquired if the initial number of cells forming the aggregate (aggregate cell number (ACN)) can impact chondrogenesis.,Methods,Aggregates of varying ACN were formed using well-established centrifugation approach. Progression of chondrogenic differentiation in the aggregates was assessed over 3 weeks in presence and absence of transforming growth factor-beta 1 (TGF-β1). Mechanical properties of the cells were characterized using high-throughput real-time deformability cytometry (RT-DC), and gene expression was analyzed using Affymetrix gene array. Expression of molecular markers linked to chondrogenesis was assessed using western blot and immunofluorescence.,Results,Reducing ACN from 500 k to 70 k lead to activation and acceleration of the chondrogenic differentiation, independent of soluble chondro-inductive factors, which involves changes to β-catenin-dependent TCF/LEF transcriptional activity and expression of anti-apoptotic protein survivin. RT-DC analysis revealed that stiffness and size of cells within aggregates are modulated by ACN. A direct correlation between progression of chondrogenesis and emergence of stiffer cell phenotype was found. Affymetrix gene array analysis revealed a downregulation of genes associated with lipid synthesis and regulation, which could account for observed changes in cell stiffness. Immunofluorescence and western blot analysis revealed that increasing ACN upregulates the expression of lipid raft protein caveolin-1, a β-catenin binding partner, and downregulates the expression of N-cadherin. As a demonstration of the relevance of these findings in MSC-based strategies for skeletal repair, it is shown that implanting aggregates within collagenous matrix not only decreases the necessity for high cell numbers but also leads to marked improvement in the quality of the deposited tissue.,Conclusions,This study presents a simple and donor-independent strategy to enhance the efficiency of MSC chondrogenic differentiation and identifies changes in cell mechanics coincident with MSC chondrogenesis with potential translational applications. %0 journal article %@ 0928-4931 %A Arya, N.,Forget, A.,Sarem, M.,Shastri, V.P. %D 2019 %J Materials Science and Engineering C %N %P 103-111 %R doi:10.1016/j.msec.2019.01.080 %T RGDSP functionalized carboxylated agarose as extrudable carriers for chondrocyte delivery %U https://doi.org/10.1016/j.msec.2019.01.080 %X The limited potential of cartilage to regenerate itself has led to development of new strategies and biomaterials for cartilage tissue engineering and regenerative medicine. Although de novo strategies for cartilage repair have been realized, extrudable hydrogels that can be administered in minimally invasive manner while simultaneously supporting chondrogenic differentiation could lead to development of new systems to deliver cells to cartilage lesions. In this work, we explored the suitability of thermo-reversible, extrudable gels derived from carboxylated agarose for maintaining human articular chondrocyte (HAC) phenotype. Towards this objective, we have investigated the impact of hydrogel stiffness and presence of integrin-binding peptide sequence GGGGRGDSP on HAC differentiation potential. We discovered that stiffer hydrogels (5.8 kPa) are more efficient than softer counterparts (0.6 kPa) in promoting chondrogenesis. Interestingly, in GGGGRGDSP modified gels, a synergy between stiffness and RGD signaling led to enhanced expression of chondrogenic related genes (aggrecan, collagen type II and sox9). These findings were also supported by quantitative analysis of sulfated glycosaminoglycans. Since carboxylated agarose are highly suitable as bioink for 3D bioprinting, we propose that extrudable GGGGRGDSP-linked stiff carboxylated agarose as a medium for direct printing of chondrocyte into cartilage lesion. %0 journal article %@ 1742-7061 %A Sotiri, I.,Robichaud, M.,Lee, Braune, S.,Gorbet, M.,Ratner, B.D.,Brash, J.L.,Latour, R.A.,Reviakine, I. %D 2019 %J Acta Biomaterialia %N %P 55-60 %R doi:10.1016/j.actbio.2019.01.032 %T BloodSurf 2017: News from the blood-biomaterial frontier %U https://doi.org/10.1016/j.actbio.2019.01.032 %X From stents and large-diameter vascular grafts, to mechanical heart valves and blood pumps, blood-contacting devices are enjoying significant clinical success owing to the application of systemic antiplatelet and anticoagulation therapies. On the contrary, research into material and device hemocompatibility aimed at alleviating the need for systemic therapies has suffered a decline. This research area is undergoing a renaissance fueled by recent fundamental insights into coagulation and inflammation that are offering new avenues of investigation, the growing recognition of the limitations facing existing therapeutic approaches, and the severity of the cardiovascular disorders epidemic. This Opinion article discusses clinical needs for hemocompatible materials and the emerging research directions for fulfilling those needs. Based on the 2017 BloodSurf conference that brought together clinicians, scientists, and engineers from academia, industry, and regulatory bodies, its purpose is to draw the attention of the wider clinical and scientific community to stimulate further growth.,Statement of Significance,The article highlights recent fundamental insights into coagulation, inflammation, and blood-biomaterial interactions that are fueling a renaissance in the field of material hemocompatibility. It will be useful for clinicians, scientists, engineers, representatives of industry and regulatory bodies working on the problem of developing hemocompatible materials and devices for treating cardiovascular disorders. %0 journal article %@ 1386-0291 %A Reinthaler, M.,Baeckemo-Johansson, J.,Braune, S.,Al-Hindwan, H.S.A.,Lendlein, A.,Jung, F. %D 2019 %J Clinical Hemorheology and Microcirculation %N 2 %P 183-191 %R doi:10.3233/CH-189410 %T Shear-induced platelet adherence and activation in an in-vitro dynamic multiwell-plate system %U https://doi.org/10.3233/CH-189410 2 %X Circulating blood cells are prone to varying flow conditions when contacting cardiovascular devices. For a profound understanding of the complex interplay between the blood components/cells and cardiovascular implant surfaces, testing under varying shear conditions is required. Here, we study the influence of arterial and venous shear conditions on the in vitro evaluation of the thrombogenicity of polymer-based implant materials.,Medical grade poly(dimethyl siloxane) (PDMS), polyethylene terephthalate (PET) and polytetrafluoroethylene (PTFE) films were included as reference materials. The polymers were exposed to whole blood from healthy humans. Blood was agitated orbitally at low (venous shear stress: 2.8 dyne · cm–2) and high (arterial shear stress: 22.2 dyne · cm–2) agitation speeds in a well-plate based test system. Numbers of non-adherent platelets, platelet activation (P-Selectin positive platelets), platelet function (PFA100 closure times) and platelet adhesion (laser scanning microscopy (LSM)) were determined.,Microscopic data and counting of the circulating cells revealed increasing numbers of material-surface adherent platelets with increasing agitation speed. Also, activation of the platelets was substantially increased when tested under the high shear conditions (P-Selectin levels, PFA-100 closure times). At low agitation speed, the platelet densities did not differ between the three materials. Tested at the high agitation speed, lowest platelet densities were observed on PDMS, intermediate levels on PET and highest on PTFE. While activation of the circulating platelets was affected by the implant surfaces in a similar manner, PFA closure times did not reflect this trend.,Differences in the thrombogenicity of the studied polymers were more pronounced when tested at high agitation speed due to the induced shear stresses. Testing under varying shear stresses, thus, led to a different evaluation of the implant thrombogenicity, which emphasizes the need for testing under various flow conditions. Our data further confirmed earlier findings where the same reference implants were tested under static (and not dynamic) conditions and with fresh human platelet rich plasma instead of whole blood. This supports that the application of common reference materials may improve inter-study comparisons, even under varying test conditions. %0 journal article %@ 1386-0291 %A Wang, W.,Xu, X.,Li, Z.,Kratz, K.,Ma, N.,Lendlein, A. %D 2019 %J Clinical Hemorheology and Microcirculation %N 2 %P 277-289 %R doi:10.3233/CH-189418 %T Modulating human mesenchymal stem cells using poly(Eta-butyl acrylate) networks in vitro with elasticity matching human arteries %U https://doi.org/10.3233/CH-189418 2 %X Non-swelling hydrophobic poly(n-butyl acrylate) network (cPnBA) is a candidate material for synthetic vascular grafts owing to its low toxicity and tailorable mechanical properties. Mesenchymal stem cells (MSCs) are an attractive cell type for accelerating endothelialization because of their superior anti-thrombosis and immune modulatory function. Further, they can differentiate into smooth muscle cells or endothelial-like cells and secret pro-angiogenic factors such as vascular endothelial growth factor (VEGF). MSCs are sensitive to the substrate mechanical properties, with the alteration of their major cellular behavior and functions as a response to substrate elasticity. Here, we cultured human adipose-derived mesenchymal stem cells (hADSCs) on cPnBAs with different mechanical properties (cPnBA250, Young’s modulus (E) = 250 kPa; cPnBA1100, E = 1100 kPa) matching the elasticity of native arteries, and investigated their cellular response to the materials including cell attachment, proliferation, viability, apoptosis, senescence and secretion. The cPnBA allowed high cell attachment and showed negligible cytotoxicity. F-actin assembly of hADSCs decreased on cPnBA films compared to classical tissue culture plate. The difference of cPnBA elasticity did not show dramatic effects on cell attachment, morphology, cytoskeleton assembly, apoptosis and senescence. Cells on cPnBA250, with lower proliferation rate, had significantly higher VEGF secretion activity. These results demonstrated that tuning polymer elasticity to regulate human stem cells might be a potential strategy for constructing stem cell-based artificial blood vessels. %0 journal article %@ 1386-0291 %A Mrowietz, C.,Franke, R.P.,Pindur, G.,Sternitzky, R.,Jung, F.,Wolf, U. %D 2019 %J Clinical Hemorheology and Microcirculation %N 2 %P 129-135 %R doi:10.3233/CH-189402 %T Evaluation of Laser-Doppler-Fluxmetry for the diagnosis of microcirculatory disorders %U https://doi.org/10.3233/CH-189402 2 %X BACKGROUND:,The laser Doppler fluxmetry (LDF) is a non-invasive method to assess skin blood perfusion, measuring the flow of blood cells inside a tissue volume without harming the tissue. In the diagnosis of skin circulation disorders, the results of the LDF measurement are generally used in such a way that “normal” (or non-ill) or “pathological” values are achieved by comparison with a reference sample, for example of apparently healthy subjects.,MATERIAL AND METHODS:,In this study, the values of LDF for the diagnosis of microcirculatory disorders in patients with coronary artery disease (n = 20) or in patients with microcirculatory disorders, already diagnosed by capillary microscopy (n = 46), were examined.,RESULTS:,The mean values of LD amplitudes in the four frequency windows for patients with coronary artery disease were in the reference range. However, some of the patients showed reduced LD values: in eleven of the twenty patients, one or more mean LD amplitudes were below the reference range. Four of the eleven patients had pathologically decreased capillary erythrocyte velocities of v ery = 0.09–0.21 [mm/s], while the other seven patients had normal blood circulation at rest.,For all patients with a proven cutaneous microcirculatory disorder, the mean LD amplitude in at least one of the frequency windows FF2 to FF4 was pathologically reduced.,CONCLUSION:,The Laser-Doppler fluxmetry method used in the study allows the reliable diagnosis of cutaneous microcirculatory disorders. %0 journal article %@ 2296-2646 %A Naolou, T.,Lendlein, A.,Neffe, A.T. %D 2019 %J Frontiers in Chemistry %N %P 346 %R doi:10.3389/fchem.2019.00346 %T Amides as Non-polymerizable Catalytic Adjuncts Enable the Ring-Opening Polymerization of Lactide With Ferrous Acetate Under Mild Conditions %U https://doi.org/10.3389/fchem.2019.00346 %X Sn-based catalysts are effective in the ring-opening polymerization (ROP) but are toxic. Fe(OAc)2 used as an alternative catalyst is suitable for the ROP of lactide only at higher temperatures (>170°C), associated with racemization. In the ROP of ester and amide group containing morpholinediones with Fe(OAc)2 to polydepsipeptides at 135°C, ester bonds were selectively opened. Here, it was hypothesized that ROP of lactones is possible with Fe(OAc)2 when amides are present in the reactions mixture as Fe-ligands could increase the solubility and activity of the metal catalytic center. The ROP of lactide in the melt with Fe(OAc)2 is possible at temperatures as low as 105°C, in the presence of N-ethylacetamide or N-methylbenzamide as non-polymerizable catalytic adjuncts (NPCA), with high conversion (up to 99 mol%) and yield (up to 88 mol%). Polydispersities of polylactide decreased with decreasing reaction temperature to ≤ 1.1. NMR as well as polarimetric studies showed that no racemization occurred at reaction temperatures ≤145°C. A kinetic study demonstrated a living chain-growth mechanism. MALDI analysis revealed that no side reactions (e.g., cyclization) occurred, though transesterification took place. %0 journal article %@ 2045-2322 %A Hausmann, C.,Zoschke, C.,Wolff, C.,Darvin, M.E.,Sochorova, M.,Kovacik, A.,Wanjiku, B.,Schumacher, F.,Tigges, J.,Kleuser, B.,Lademann, J.,Fritsche, E.,Vavrova, K.,Ma, N.,Schaefer-Korting, M. %D 2019 %J Scientific Reports %N %P 2913 %R doi:10.1038/s41598-019-39770-6 %T Fibroblast origin shapes tissue homeostasis, epidermal differentiation, and drug uptake %U https://doi.org/10.1038/s41598-019-39770-6 %X Preclinical studies frequently lack predictive value for human conditions. Human cell-based disease models that reflect patient heterogeneity may reduce the high failure rates of preclinical research. Herein, we investigated the impact of primary cell age and body region on skin homeostasis, epidermal differentiation, and drug uptake. Fibroblasts derived from the breast skin of female 20- to 30-year-olds or 60- to 70-year-olds and fibroblasts from juvenile foreskin (<10 years old) were compared in cell monolayers and in reconstructed human skin (RHS). RHS containing aged fibroblasts differed from its juvenile and adult counterparts, especially in terms of the dermal extracellular matrix composition and interleukin-6 levels. The site from which the fibroblasts were derived appeared to alter fibroblast-keratinocyte crosstalk by affecting, among other things, the levels of granulocyte-macrophage colony-stimulating factor. Consequently, the epidermal expression of filaggrin and e-cadherin was increased in RHS containing breast skin fibroblasts, as were lipid levels in the stratum corneum. In conclusion, the region of the body from which fibroblasts are derived appears to affect the epidermal differentiation of RHS, while the age of the fibroblast donors determines the expression of proteins involved in wound healing. Emulating patient heterogeneity in preclinical studies might improve the treatment of age-related skin conditions. %0 journal article %@ 0964-1726 %A Balk, M.,Behl, M.,Lendlein, A. %D 2019 %J Smart Materials and Structures %N 5 %P 055026 %R doi:10.1088/1361-665X/ab0e91 %T Quadruple-shape hydrogels %U https://doi.org/10.1088/1361-665X/ab0e91 5 %X The capability of directed movements by two subsequent shape changes could be implemented in shape-memory hydrogels by incorporation of two types of crystallizable side chains. While in non-swollen polymer networks even more directed movements could be realized, the creation of multi-shape hydrogels is still a challenge. We hypothesize that a quadruple-shape effect in hydrogels can be realized, when a swelling capacity almost independent of temperature is generated, whereby directed movements could be enabled, which are not related to swelling. In this case, entropy elastic recovery could be realized by hydrophilic segments and the fixation of different macroscopic shapes by means of three semi-crystalline side chains generating temporary crosslinks. Monomethacrylated semi-crystalline oligomers were connected as side chains in a hydrophilic polymer network via radical copolymerization. Computer assisted modelling was utilized to design a demonstrator capable of complex shape shifts by creating a casting mold via 3D printing from polyvinyl alcohol. The demonstrator was obtained after copolymerization of polymer network forming components within the mold, which was subsequently dissolved in water. A thermally-induced quadruple-shape effect was realized after equilibrium swelling of the polymer network in water. Three directed movements were successfully obtained when the temperature was continuously increased from 5 °C to 90 °C with a recovery ratio of the original shape above 90%. Hence, a thermally-induced quadruple-shape effect as new record for hydrogels was realized. Here, the temperature range for the multi-shape effect was limited by water as swelling media (0 °C–100 °C), simultaneously distinctly separated thermal transitions were required, and the overall elasticity indispensable for successive deformations was reduced as result of partially chain segment orientation induced by swelling in water. Conclusively the challenges for penta- or hexa-shape gels are the design of systems enabling higher elastic deformability and covering a larger temperature range by switching to a different solvent. %0 journal article %@ 1386-0291 %A Krüger-Genge, A.,Fuhrmann, R.,Franke, R.-P.,Jung, F. %D 2019 %J Clinical Hemorheology and Microcirculation %N 2 %P 175-181 %R doi:10.3233/CH-189409 %T Effect of lipopolysaccharide on the adherence of human umbilical vein endothelial cells (HUVEC) on a natural substrate %U https://doi.org/10.3233/CH-189409 2 %X Polymers are often contaminated with lipopolysaccharides also known as endotoxins. Even small amounts of endotoxins can have strong effects on endothelial cell function so that the endothelialisation of cardiovascular implants might be hampered. An open question is how endothelial cells seeded on a body foreign substrate respond to shear load after adding Lipid A (LPA), the domain, which is responsible for much of the toxicity of gram-negative bacteria, and whether morphological changes of endothelial cells occur.,LPA supplementation to the culture medium in increasing concentrations (5, 25 and 50μg/ml) resulted in progressive reductions of the density of adherent HUVEC after shear load (p < 0.001). 48% of the HUVEC in control cultures (0μg/ml LPA) were still adherent after 2 hours of shearing at 6 dyne/cm2, while 80 minutes after addition of 50μg/ml LPA, 88% of the HUVEC had already detached from the substrate and after 100 minutes no more HUVEC were attached.,The results demonstrate that endotoxins are of extreme importance for the behavior of HUVEC and that in vivo pathologies can be increasingly simulated in vitro. %0 journal article %@ 0300-483X %A Steinbrecht, S.,Koenig, R.,Schmidtke, K.-U.,Herzog, N.,Scheibner, K.,Krueger-Genge, A.,Jung, F.,Kammerer, S.,Kuepper, J.-H. %D 2019 %J Toxicology %N %P 37-47 %R doi:10.1016/j.tox.2018.11.008 %T Metabolic activity testing can underestimate acute drug cytotoxicity as revealed by HepG2 cell clones overexpressing cytochrome P450 2C19 and 3A4 %U https://doi.org/10.1016/j.tox.2018.11.008 %X Preclinical drug safety assessment includes in vitro studies with physiologically relevant cell cultures. As an in vitro system for hepatic toxicology testing, we have been generating cell clones of human hepatoblastoma cell line HepG2 by lentiviral transduction of phase I cytochrome P450 (CYP) enzymes. Here, we present a stable CYP2C19-overexpressing HepG2 cell clone (HepG2-2C19 C1) showing an enzyme activity of approximately 82 pmol x min−1 x mg−1 total cellular protein. The phenotypic stability over several passages of HepG2-2C19 C1 renders them to be a suitable reference cell clone for benchmarking CYP2C19 enzyme activity. In addition, we were interested to analyze acute cytotoxicity of the model drug cyclophosphamide (CPA) metabolized by HepG2-2C19 C1 and by a previously generated CYP3A4-overexpressing HepG2 cell clone. Upon 10 mM CPA exposure, we were able to detect its metabolites 4-hydroxy-cyclophosphamide and acrolein in CYP3A4- and CYP2C19-expressing cell clones, but not in parental HepG2 cell line. XTT and ATP assays showed a modest reduction of cell viability of not more than 50% with high dose (10 mM) CPA treatment. By contrast, dramatic acute cytotoxic effects of CPA were evident by the formation of nuclear γH2AX foci and by increased cell death events. These effects were paralleled by substantial decreases of cell membrane integrity as measured by the trypan blue exclusion test. Our data on CYP enzyme overexpressing HepG2 cell clones clearly show that cytotoxicity of CPA is dramatically underestimated by standard metabolic activity tests. Thus, additional tests to quantitate DNA damage formation and cell death induction might be required to realistically assess cytotoxicity of such compounds. %0 journal article %@ 1748-605X %A Bhuvanesh, T.,Machatschek, R.,Lysyakova, L.,Kratz, K.,Schulz, B.,Ma, N.,Lendlein, A. %D 2019 %J Biomedical Materials %N 2 %P 024101 %R doi:10.1088/1748-605X/aaf464 %T Collagen type-IV Langmuir and Langmuir-Schaefer layers as model biointerfaces to direct stem cell adhesion %U https://doi.org/10.1088/1748-605X/aaf464 2 %X In biomaterial development, the design of material surfaces that mimic the extra-cellular matrix (ECM) in order to achieve favorable cellular instruction is rather challenging. Collagen-type IV (Col-IV), the major scaffolding component of Basement membranes, a specialized ECM with multiple biological functions, has the propensity to form networks by self-assembly and supports adhesion of cells such as endothelial cells or stem cells. The preparation of biomimetic Col-IV network like layers to direct cell responses is difficult. We hypothesize that the morphology of the layer, and especially the density of the available adhesion sites, regulates the cellular adhesion to the layer. The Langmuir monolayer technique allows for preparation of thin layers with precisely controlled packing density at the air-water (A-W) interface. Transferring these layers onto cell culture substrates using the Langmuir Schäfer (LS) technique should therefore provide a pathway for preparation of BM mimicking layers with controlled cell adherence properties. In situ characterization using ellipsometry and polarization modulation-infrared reflection absorption spectroscopy of Col-IV layer during compression at the A-W interface reveal that there is linear increase of surface molecule concentration with negligible orientational changes up to a surface pressure of 25 mNcenterdotm<sup>-1</sup>. Smooth and homogeneous Col-IV network-like layers are successfully transferred by LS method at 15 mNcenterdotm<sup>-1</sup> onto poly(ethyleneterepthalate) (PET), which is a common substrate for cell culture. In contrast, the organization of Col-IV on PET prepared by the traditionally employed solution deposition method results in rather inhomogeneous layers with the appearance of aggregates and multilayers. Progressive increase in the number of early adherent mesenchymal stem cells (MSCs) after 24 h by controlling the Col-IV density by LS transfer at 10, 15 and 20 mNcenterdotm<sup>-1</sup> on PET is shown. LS method offers the possibility to control protein characteristics on biomaterial surfaces such as molecular density and thereby, modulate cell responses. %0 journal article %@ 1386-0291 %A da Silva, N.P.B.,Jung, E.M.,Jung, F.,Schlitt, H.J.,Hornung, M. %D 2019 %J Clinical Hemorheology and Microcirculation %N 4 %P 423-431 %R doi:10.3233/CH-189307 %T VueBox® perfusion analysis of Contrast-Enhanced Ultrasound (CEUS) examinations in patients with primary hyperparathyroidism for preoperative detection of parathyroid gland adenoma %U https://doi.org/10.3233/CH-189307 4 %X AIM:,Aim of this study was to firstly describe reproducible, objective perfusion parameters of contrast-enhanced ultrasound (CEUS) kinetics of parathyroid gland adenoma (PA) using perfusion analysis software (VueBox®, Bracco, Italy). Thereby the efficiency of quantitative CEUS for characterization of PA should be evaluated comparing US to postoperative histopathological findings after PA resection.,MATERIAL AND METHODS:,42 patients with symptoms/lab work suggestive of pHPT presented a parathyroid gland lesion in B-mode US, which was consequently analyzed by dynamic CEUS. CEUS was performed by one experienced examiner after i.v.-injection of max. 2.4 ml sulphurhexaflouride microbubbles saving digital DICOM cine loops (up to 25 s) and images. PA were evaluated during arterial, venous and late phase (up to 3 min.) for perfusion characterization. A retrospective, blinded VueBox® perfusion analysis of arterial phase of 28/42 PA was performed by a second, independent examiner placing 3 ROIs manually in the PA (center, rim of PA, surrounding thyroid gland tissue) to objectify findings. US findings were correlated to postoperative histology after PA resection.,RESULTS:,Out of 42 patients with PA findings in CEUS, perfusion analysis could be performed in 28/42 cases only as some CEUS cine loops had too much moving. In three cases the second examiner could not detect PA retrospectively, in 25 cases PA were characterized correctly resulting in a sensitivity rate of 89.3 %. VueBox® perfusion analysis confirmed that PA present a persisting hypervascularization of the rim with higher TTP (mean 7.93 s centrally, 8.36 s rim-sided), mTT (mean 56.6 s centrally, 64.5 s rim-sided) and lower PE (mean 10542.93 rm2 centrally, 8909.21 rm2 rim-sided) peripherally followed by a central wash-out during later phases. RT was comparable in all defined regions.,CONCLUSION:,VueBox® analysis of parathyroid gland CEUS examinations seemed to be a valuable tool for quantification of a PA’s perfusion and can help to detect and localize hyperfunctional parathyroid glands prior to surgery. %0 journal article %@ 1386-0291 %A Shin, E.-S.,Park, S.G.,Saleh, A.,Lam, Y.-Y.,Bhak, J.,Jung, F.,Morita, S.,Brachmann, J. %D 2019 %J Clinical Hemorheology and Microcirculation %N 4 %P 365-373 %R doi:10.3233/CH-189301 %T Magnetocardiography scoring system to predict the presence of obstructive coronary artery disease %U https://doi.org/10.3233/CH-189301 4 %X BACKGROUND:,Magnetocardiography (MCG) has been proposed as a non-invasive and functional technique with high accuracy for diagnosis of myocardial ischemia.,OBJECTIVE:,This study sought to develop a novel scoring system of MCG for predicting the presence of significant obstructive coronary artery disease (CAD).,METHODS:,In a training set of 108 subjects, predictors of ≥70% stenosis in at least one major coronary vessel were prospectively identified from MCG variables. The final model was then retrospectively validated in a separate set of 45 subjects.,RESULTS:,In the multivariable logistic regression, among those in the training set, elevated scores were predictive of ≥70% stenosis in all subjects (OR: 40.85; 95% CI: 6.28–265.90; p < 0.001). In the validation set, the score had an area under the receiver-operating characteristic curve of 0.91 (p < 0.001) for ≥70% stenosis. At an optimal cutoff, the score had 89% sensitivity, 77% specificity, 74% positive predictive value (PPV), 91% negative predictive value (NPV), and 82% accuracy for ≥70% stenosis. Partitioning the score into three levels of predicted risk, 91% of subjects could be identified or excluding CAD (81% PPV and 84% NPV).,CONCLUSION:,We described an MCG score with high accuracy for predicting the presence of anatomically significant CAD. %0 journal article %@ 0261-3069 %A Jiang, Y.,Mansfeld, U.,Fang, L.,Kratz, K.,Lendlein, A. %D 2019 %J Materials and Design %N %P 107530 %R doi:10.1016/j.matdes.2018.12.002 %T Temperature-induced evolution of microstructures on poly[ethylene-co-(vinyl acetate)] substrates switches their underwater wettability %U https://doi.org/10.1016/j.matdes.2018.12.002 %X Material surfaces with tailored aerophobicity are crucial for applications where gas bubble wettability has to be controlled, e.g., gas storage and transport, electrodes, bioreactors or medical devices.,Here, we present switchable underwater aerophobicity of hydrophobic polymeric substrates, which respond to heat with multilevel micro- and nanotopographical changes. The cross-linked poly[ethylene-co-(vinyl acetate)] substrates possess arrays of microcylinders with a nanorough top surface. It is hypothesized that the specific micro-/nanotopography of the surface allows trapping of a water film at the micro interspace and in this way generates the aerophobic behavior. The structured substrates were programmed to a temporarily stable, nanoscale flat substrate showing aerophilic behavior. Upon heating, the topographical changes caused a switch in contact angle from aerophilic to aerophobic for approaching air bubbles. In this way, the initial adhesion of air bubbles to the programmed flat substrate could be turned into repellence for the recovered substrate surface. The temperature at which the repellence of air bubbles starts can be adjusted from 58 ± 3 °C to 73 ± 3 °C by varying the deformation temperature applied during the temperature-memory programming procedure. The presented actively switching polymeric substrates are attractive candidates for applications, where an on-demand gas bubble repellence is advantageous. %0 journal article %@ 2059-8521 %A Razzaq, M.Y.,Behl, M.,Lendlein, A. %D 2019 %J MRS Advances %N 19 %P 1057-1065 %R doi:10.1557/adv.2019.123 %T Magneto-Mechanical Actuators with Reversible Stretching and Torsional Actuation Capabilities %U https://doi.org/10.1557/adv.2019.123 19 %X Composite actuators consisting of magnetic nanoparticles dispersed in a crystallizable multiphase polymer system can be remotely controlled by alternating magnetic fields (AMF). These actuators contain spatially segregated crystalline domains with chemically different compositions. Here, the crystalline domain associated to low melting transition range is responsible for actuation while the crystalline domain associated to the higher melting transition range determines the geometry of the shape change. This paper reports magneto-mechanical actuators which are based on a single crystalline domain of oligo(ω-pentadecalactone) (OPDL) along with covalently integrated iron(III) oxide nanoparticles (ioNPs). Different geometrical modes of actuation such as a reversible change in length or twisting were implemented by a magneto-mechanical programming procedure. For an individual actuation mode, the degree of actuation could be tailored by variation of the magnetic field strengths. This material design can be easily extended to other composites containing other magnetic nanoparticles, e.g. with a high magnetic susceptibility. %0 journal article %@ 0141-3910 %A Mazurek-Budzynska, M.,Behl, M.,Razzaq, M.Y.,Noechel, U.,Rokicki, G.,Lendlein, A. %D 2019 %J Polymer Degradation and Stability %N %P 283-297 %R doi:10.1016/j.polymdegradstab.2019.01.032 %T Hydrolytic stability of aliphatic poly(carbonate-urea-urethane)s: Influence of hydrocarbon chain length in soft segment %U https://doi.org/10.1016/j.polymdegradstab.2019.01.032 %X Poly(carbonate-urethane)s (PCUs) exhibit improved resistance to hydrolytic degradation and in vivo stress cracking compared to poly(ester-urethane)s and their degradation leads to lower inflammation of the surrounding tissues. Therefore, PCUs are promising implant materials and are considered for devices such as artificial heart or spine implants. In this work, the hydrolytic stability of different poly(carbonate-urethane–urea)s (PCUUs) was studied under variation of the length of hydrocarbon chain (6, 9, 10, and 12 methylene units) between the carbonate linkages in the precursors. PCUUs were synthesized from isophorone diisocyanate and oligo(alkylene carbonate) diols using the moisture-cure method. The changes of sample weight, thermal and mechanical properties, morphology, as well as the degradation products after immersion in a buffer solution (PBS, pH = 7.4) for up to 10 weeks at 37 °C were monitored and analyzed. In addition, mechanical properties after 20 weeks (in PBS, 37 °C) were investigated. The gel content was determined based on swelling experiments in chloroform.,Based on the DSC analysis, slight increases of melting transitions of PCUUs were observed, which were attributed to structure reorganization related to annealing at 37 °C rather than to the degradation of the PCUU. Tensile strength after 20 weeks of all investigated samples remained in the range of 29–39 MPa, whereas the elongation at break εm decreased only slightly and remained in the range between 670 and 800%. Based on the characterization of degradation products after up to 10 weeks of immersion it was assessed that oligomers are mainly consisting of hard segments containing urea linkages, which could be assigned to hindered-urea dissociation mechanism. The investigations confirmed good resistance of PCUUs to hydrolysis. Only minor changes in the crystallinity, as well as thermal and mechanical properties were observed and depended on hydrocarbon chain length in soft segment of PCUUs. %0 journal article %@ 1022-1336 %A Machatschek, R.,Schulz, B.,Lendlein, A. %D 2019 %J Macromolecular Rapid Communications %N 1 %P 1800611 %R doi:10.1002/marc.201800611 %T Langmuir Monolayers as Tools to Study Biodegradable Polymer Implant Materials %U https://doi.org/10.1002/marc.201800611 1 %X Langmuir monolayers provide a fast and elegant route to analyze the degradation behavior of biodegradable polymer materials. In contrast to bulk materials, diffusive transport of reactants and reaction products in the (partially degraded) material can be neglected at the air–water interface, allowing for the study of molecular degradation kinetics in experiments taking less than a day and in some cases just a few minutes, in contrast to experiments with bulk materials that can take years. Several aspects of the biodegradation behavior of polymer materials, such as the interaction with biomolecules and degradation products, are directly observable. Expanding the technique with surface‐sensitive instrumental techniques enables evaluating the evolution of the morphology, chemical composition, and the mechanical properties of the degrading material in situ. The potential of the Langmuir monolayer degradation technique as a predictive tool for implant degradation when combined with computational methods is outlined, and related open questions and strategies to overcome these challenges are pointed out. %0 journal article %@ 1386-0291 %A Krüger-Genge, A.,Dietze, S.,Yan, W.,Liu, Y.,Fang, L.,Kratz, K.,Lendlein, A.,Jung, F. %D 2019 %J Clinical Hemorheology and Microcirculation %N 4 %P 511-529 %R doi:10.3233/CH-189317 %T Endothelial cell migration, adhesion and proliferation on different polymeric substrates %U https://doi.org/10.3233/CH-189317 4 %X BACKGROUND:,The formation of a functionally-confluent endothelial cell (EC) monolayer affords proliferation of EC, which only happens in case of appropriate migratory activity.,AIM OF THE STUDY:,The migratory pathway of human umbilical endothelial cells (HUVEC) was investigated on different polymeric substrates.,MATERIAL AND METHODS:,Surface characterization of the polymers was performed by contact angle measurements and atomic force microscopy under wet conditions. 30,000 HUVEC per well were seeded on polytetrafluoroethylene (PTFE) (θadv = 119°±2°), on low-attachment plate LAP (θadv = 28°±2°) and on polystyrene based tissue culture plates (TCP, θadv = 22°±1°). HUVEC tracks (trajectories) were recorded by time lapse microscopy and the euclidean distance (straight line between starting and end point), the total distance and the velocities of HUVEC not leaving the vision field were determined.,RESULTS:,On PTFE, 42 HUVEC were in the vision field directly after seeding. The mean length of single migration steps (SML) was 6.1±5.2 μm, the mean velocity (MV) 0.40±0.3 μm·min-1 and the complete length of the trajectory (LT) was 710±440 μm. On TCP 82 HUVEC were in the vision field subsequent to seeding. The LT was 840±550 μm, the SML 6.1±5.2 μm and the MV 0.44±0.3 μm·min-1. The trajectories on LAP differed significantly in respect to SML (2.4±3.9 μm, p < 0.05), the MV (0.16±0.3 μm·min-1, p < 0.05) and the LT (410±300 μm, p < 0.05), compared to PTFE and TCP. Solely on TCP a nearly confluent EC monolayer developed after three days. While on TCP diffuse signals of vinculin were found over the whole basal cell surface organizing the binding of the cells by focal adhesions, on PTFE vinculin was merely arranged at the cell rims, and on the hydrophilic material (LAP) no focal adhesions were found.,CONCLUSION:,The study revealed that the wettability of polymers affected not only the initial adherence but also the migration of EC, which is of importance for the proliferation and ultimately the endothelialization of polymer-based biomaterials. %0 journal article %@ 2159-6859 %A Machatschek, R.,Schoene, A.-C.,Raschdorf, E.,Ihlenburg, R.B.J.,Schulz, B.,Lendlein, A. %D 2019 %J MRS Communications %N 1 %P 170-180 %R doi:10.1557/mrc.2019.21 %T Interfacial properties of morpholine-2,5-dione-based oligodepsipeptides and multiblock copolymers %U https://doi.org/10.1557/mrc.2019.21 1 %X Oligodepsipeptides (ODPs) with alternating amide and ester bonds prepared by ring-opening polymerization of morpholine-2,5-dione derivatives are promising matrices for drug delivery systems and building blocks for multifunctional biomaterials. Here, we elucidate the behavior of three telechelic ODPs and one multiblock copolymer containing ODP blocks at the air–water interface. Surprisingly, whereas the oligomers and multiblock copolymers crystallize in bulk, no crystallization is observed at the air–water interface. Furthermore, polarization modulation infrared reflection absorption spectroscopy is used to elucidate hydrogen bonding and secondary structures in ODP monolayers. The results will direct the development of the next ODP-based biomaterial generation with tailored properties for highly sophisticated applications. %0 journal article %@ 1386-0291 %A Nie, Y.,Wang, W.,Xu, X.,Zou, J.,Bhuvanesh, T.,Schulz, B.,Ma, N.,Lendlein, A. %D 2019 %J Clinical Hemorheology and Microcirculation %N 4 %P 531-542 %R doi:10.3233/CH-189318 %T Enhancement of human induced pluripotent stem cells adhesion through multilayer laminin coating %U https://doi.org/10.3233/CH-189318 4 %X Bioengineered cell substrates are a highly promising tool to govern the differentiation of stem cells in vitro and to modulate the cellular behavior in vivo. While this technology works fine for adult stem cells, the cultivation of human induced pluripotent stem cells (hiPSCs) is challenging as these cells typically show poor attachment on the bioengineered substrates, which among other effects causes substantial cell death. Thus, very limited types of surfaces have been demonstrated suitable for hiPSC cultures. The multilayer coating approach that renders the surface with diverse chemical compositions, architectures, and functions can be used to improve the adhesion of hiPSCs on the bioengineered substrates. We hypothesized that a multilayer formation based on the attraction of molecules with opposite charges could functionalize the polystyrene (PS) substrates to improve the adhesion of hiPSCs. Polymeric substrates were stepwise coated, first with dopamine to form a polydopamine (PDA) layer, second with polylysine and last with Laminin-521. The multilayer formation resulted in the variation of hydrophilicity and chemical functionality of the surfaces. Hydrophilicity was detected using captive bubble method and the amount of primary and secondary amines on the surface was quantified by fluorescent staining. The PDA layer effectively immobilized the upper layers and thereby improved the attachment of hiPSCs. Cell adhesion was enhanced on the surfaces coated with multilayers, as compared to those without PDA and/or polylysine. Moreover, hiPSCs spread well over this multilayer laminin substrate. These cells maintained their proliferation capacity and differentiation potential. The multilayer coating strategy is a promising attempt for engineering polymer-based substrates for the cultivation of hiPSCs and of interest for expanding the application scope of hiPSCs. %0 journal article %@ 0964-1726 %A Zhang, Q.,Rudolph, T.,Benitez, A.J.,Gould, O.E.C.,Behl, M.,Kratz, K.,Lendlein, A. %D 2019 %J Smart Materials and Structures %N 5 %P 055037 %R doi:10.1088/1361-665X/ab10a1 %T Temperature-controlled reversible pore size change of electrospun fibrous shape-memory polymer actuator based meshes %U https://doi.org/10.1088/1361-665X/ab10a1 5 %X Fibrous membranes capable of dynamically responding to external stimuli are highly desirable in textiles and biomedical materials, where adaptive behavior is required to accommodate complex environmental changes. For example, the creation of fabrics with temperature-dependent moisture permeability or self-regulating membranes for air filtration is dependent on the development of materials that exhibit a reversible stimuli-responsive pore size change. Here, by imbuing covalently crosslinked poly(ε-caprolactone) (cPCL) fibrous meshes with a reversible bidirectional shape-memory polymer actuation (rbSMPA) we create a material capable of temperature-controlled changes in porosity. Cyclic thermomechanical testing was used to characterize the mechanical properties of the meshes, which were composed of randomly arranged microfibers with diameters of 2.3 ± 0.6 μm giving an average pore size of approx. 10 μm. When subjected to programming strains of ε m = 300% and 100% reversible strain changes of εʹrev = 22% ± 1% and 6% ± 1% were measured, with switching temperature ranges of 10 °C–30 °C and 45 °C–60 °C for heating and cooling, respectively. The rbSMPA of cPCL fibrous meshes generated a microscale reversible pore size change of 11% ± 3% (an average of 1.5 ± 0.6 μm), as measured by scanning electron microscopy. The incorporation of a two-way shape-memory actuation capability into fibrous meshes is anticipated to advance the development and application of smart membrane materials, creating commercially viable textiles and devices with enhanced performance and novel functionality. %0 journal article %@ 0892-6638 %A Klose, K.,Gossen, M.,Stamm, C. %D 2019 %J The FASEB Journal %N 1 %P 49-70 %R doi:10.1096/fj.201800712R %T Turning fibroblasts into cardiomyocytes: technological review of cardiac transdifferentiation strategies %U https://doi.org/10.1096/fj.201800712R 1 %X To date, no viable therapeutic options exist for the effective and sustained reversal of cardiac failure, other than heart transplantation and mechanical circulatory assist devices. Therefore, divergent strategies aiming at the de novo formation of contractile tissue, as a prerequisite for the restoration of cardiac pump function, are currently being pursued. Clinical trials involving the transplantation of somatic progenitor cells failed. The search for alternative cell-based strategies to combat the consequences of ischemic injury has sparked widespread interest in the genetic and pharmacologic reprogramming of fibroblasts into cardiomyocytes, harnessing the abundant in vivo pool of cardiac fibroblasts. Here, we provide a comprehensive overview of in vitro and in vivo cardiac reprogramming studies identified in an extensive literature search. We systematically review and evaluate feasibility, efficiency, and reproducibility of the different technologies currently being explored. Finally, we discuss potential safety issues deduced from preclinical studies and identify obstacles that must be overcome before clinical translation.—Klose, K., Gossen, M., Stamm, C. Turning fibroblasts into cardiomyocytes: technological review of cardiac transdifferentiation strategies. %0 journal article %@ 1386-0291 %A Reinthaler, M.,Jung, F.,Empen, K. %D 2019 %J Clinical Hemorheology and Microcirculation %N 4 %P 381-389 %R doi:10.3233/CH-189303 %T Remote ischemic preconditioning of the heart: Combining lower limb ischemia and electronic stimulation oft he gastrocnemius muscle %U https://doi.org/10.3233/CH-189303 4 %X BACKGROUND:,Remote ischemic preconditioning (RIPC) has been demonstrated to induce potent cardioprotection in individuals experiencing coronary ischemia. A protocol combining limb ischemia and electronic muscle stimulation of the ischemic skeletal muscle (RIPC+), performed in advance of coronary artery occlusion, was superior in terms of infarct size reduction when compared to RIPC alone.,METHODS:,This study was performed to evaluate the benefit of RIPC + in humans compared to a standard RIPC protocol and a control group. Patients with a single vessel coronary artery disease undergoing elective PCI were eligible to participate in this study. ST-segment elevations from an intracoronary ECG during 3 brief episodes of coronary artery balloon occlusions/dilatation were used as the primary endpoint.,RESULTS:,ST-elevations significantly declined from the first to the third angioplasty in the control but remained at the same level in the RIPC and RIPC+groups. The RIPC group was characterized by the lowest ST-segment shift during coronary ischemia, which was comparable to coronary balloon occlusion number 3 in the control group, indicating successful preconditioning by the conventional RIPC method. In contrast, ST segment elevations were significantly higher in the RIPC + group. Troponin levels taken 24 h after the study procedure were significantly lower in the RIPC when compared to the control and the RIPC + group. %0 journal article %@ 1386-0291 %A Zou, J.,Wang, W.,Kratz, K.,Xu, X.,Nie, Y.,Ma, N.,Lendlein, A. %D 2019 %J Clinical Hemorheology and Microcirculation %N 4 %P 573-583 %R doi:10.3233/CH-189322 %T Evaluation of human mesenchymal stem cell senescence, differentiation and secretion behavior cultured on polycarbonate cell culture inserts %U https://doi.org/10.3233/CH-189322 4 %X Polycarbonate (PC) substrate is well suited for culturing human mesenchymal stem cells (MSCs) with high proliferation rate, low cell apoptosis rate and negligible cytotoxic effects. However, little is known about the influence of PC on MSC activity including senescence, differentiation and secretion. In this study, the PC cell culture insert was applied for human MSC culture and was compared with polystyrene (PS) and standard tissue culture plate (TCP). The results showed that MSCs were able to adhere on PC surface, exhibiting a spindle-shaped morphology. The size and distribution of focal adhesions of MSCs were similar on PC and TCP. The senescence level of MSCs on PC was comparable to that on TCP, but was significantly lower than that on PS. MSCs on PC were capable of self-renewal and differentiation into multiple cell lineages, including osteogenic and adipogenic lineages. MSCs cultured on PC secreted a higher level inflammatory cytokines and pro-angiogenic factors including FGF2 and VEGF. Conclusively, PC represents a promising cell culture material for human MSCs. %0 journal article %@ 1525-7797 %A Tarazona, N.A.,Machatschek, R.,Schulz, B.,Prieto, M.A.,Lendlein, A. %D 2019 %J Biomacromolecules %N 9 %P 3242-3252 %R doi:10.1021/acs.biomac.9b00069 %T Molecular Insights into the Physical Adsorption of Amphiphilic Protein PhaF onto Copolyester Surfaces %U https://doi.org/10.1021/acs.biomac.9b00069 9 %X Phasins are amphiphilic proteins located at the polymer–cytoplasm interface of bacterial polyhydroxyalkanoates (PHA). The immobilization of phasins on biomaterial surfaces is a promising way to enhance the hydrophilicity and supply cell-directing elements in bioinstructing processes. Optimizing the physical adsorption of phasins requires deep insights into molecular processes during polymer–protein interactions to preserve their structural conformation while optimizing surface coverage. Here, the assembly, organization, and stability of phasin PhaF from Pseudomonas putida at interfaces is disclosed. The Langmuir technique, combined with in situ microscopy and spectroscopic methods, revealed that PhaF forms stable and robust monolayers at different temperatures, with an almost flat orientation of its α-helix at the air–water interface. PhaF adsorption onto preformed monolayers of poly[(3-R-hydroxyoctanoate)-co-(3-R-hydroxyhexanoate)] (PHOHHx), yields stable mixed layers below π = ∼15.7 mN/m. Further insertion induces a molecular reorganization. PHOHHx with strong surface hydrophobicity is a more adequate substrate for PhaF adsorption than the less hydrophobic poly[(rac-lactide)-co-glycolide] (PLGA). The observed orientation of the main axis of the protein in relation to copolyester interfaces ensures the best exposure of the hydrophobic residues, providing a suitable coating strategy for polymer functionalization. %0 journal article %@ 1873-5061 %A Henning, A.F.,Roessler, U.,Boiti, F.,Hagen, M.von der,Gossen, M.,Kornak, U.,Stachelscheid, H. %D 2019 %J Stem Cell Research %N %P 101367 %R doi:10.1016/j.scr.2018.101367 %T Generation of a human induced pluripotent stem cell line (BIHi002-A) from a patient with CLCN7-related infantile malignant autosomal recessive osteopetrosis %U https://doi.org/10.1016/j.scr.2018.101367 %X Autosomal recessive osteopetrosis (ARO) is a genetic bone disease that can be caused by mutations in the CLCN7 gene preventing osteoclast-mediated bone resorption. We generated a human induced pluripotent stem cell (hiPSC) line, BIHi002-A, from peripheral blood mononuclear cells of an ARO patient carrying the CLCN7 mutations c.875G>A and c.1208G>A using Sendai viral vectors. The pluripotent identity of the BIHi002-A line was confirmed by their expression of typical markers for undifferentiated hiPSCs, their capacity to differentiate into cells of the three germ layers and by PluriTest analysis. The BIHi002-A line provides a tool for disease modelling and therapy development. %0 journal article %@ 2159-6859 %A Jiang, Y.,Mansfeld, U.,Kratz, K.,Lendlein, A. %D 2019 %J MRS Communications %N 1 %P 181-188 %R doi:10.1557/mrc.2019.24 %T Programmable microscale stiffness pattern of flat polymeric substrates by temperature-memory technology %U https://doi.org/10.1557/mrc.2019.24 1 %X Temperature-memory technology was utilized to generate flat substrates with a programmable stiffness pattern from cross-linked poly(ethylene-co-vinyl acetate) substrates with cylindrical microstructures. Programmed substrates were obtained by vertical compression at temperatures in the range from 60 to 100 °C and subsequent cooling, whereby a flat substrate was achieved by compression at 72 °C, as documented by scanning electron microscopy and atomic force microscopy (AFM). AFM nanoindentation experiments revealed that all programmed substrates exhibited the targeted stiffness pattern. The presented technology for generating polymeric substrates with programmable stiffness pattern should be attractive for applications such as touchpads, optical storage, or cell instructive substrates. %0 journal article %@ 1386-0291 %A Zou, J.,Wang, W.,Nie, Y.,Xu, X.,Ma, N.,Lendlein, A. %D 2019 %J Clinical Hemorheology and Microcirculation %N 1 %P 237-247 %R doi:10.3233/CH-199205 %T Microscale roughness regulates laminin-5 secretion of bone marrow mesenchymal stem cells %U https://doi.org/10.3233/CH-199205 1 %X Laminin-5 (Ln-5), an important ECM protein, plays a critical role in regulating the growth and differentiation of mesodermal tissues, including bone. Ln-5 can be secreted by the mesenchymal stem cells (MSCs), and Ln-5 promotes MSCs osteogenic differentiation. It has been demonstrated that substrate surface topography could regulate MSC secretion and differentiation. A better understanding of the mechanism of Ln-5 and surface roughness regulating MSC osteogenic differentiation, which would provide a guide way for the surface topography design and coating of orthopedic implants and cell culture substrates. However, few studies have investigated the relationship between surface roughness and the secretion of Ln-5 in the MSC osteogenic differentiation. Whether substrate surface topography regulates MSC differentiation via regulating Ln-5 secretion and how surface topography contributes to the secretion of Ln-5 are still not known. In this study, the influence of microscale roughness at different levels (R0, R1 and R2) on the secretion of Ln-5 of human bone marrow MSCs (hBMSCs) and subsequent osteogenic differentiation were examined. hBMSCs spreading, distribution and morphology were largely affected by different roughness levels. A significantly higher level of Ln-5 secretion was detected on R2, which correlated to the local cell density regulated by the rough surface. Ln-5 binding integrins (α2 and α3) were strongly activated on R2. In addition, the results from hBMSCs on R0 inserts with different cell densities further confirmed that local cell density regulated Ln-5 secretion and cell surface integrin activation. And the mineralization level of MSCs on R2 was remarkably higher than that on R0 and R1. These results suggested that hBMSC osteogenic differentiation level on R2 roughness was enhanced via increased Ln-5 secretion that was attributed to rough surface regulated local cell density. Thus, the microroughness could serve as effective topographical stimulus in cell culture devices and bone implant materials. %0 journal article %@ 2373-9878 %A Hauser, S.,Wodtke, R.,Tondera, C.,Wodtke, J.,Neffe, A.,Hampe, J.,Lendlein, A.,Löser, R.,Pietzsch, J. %D 2019 %J ACS Biomaterials Science & Engineering %N 11 %P 5979-5989 %R doi:10.1021/acsbiomaterials.9b01299 %T Characterization of Tissue Transglutaminase as a Potential Biomarker for Tissue Response toward Biomaterials %U https://doi.org/10.1021/acsbiomaterials.9b01299 11 %X Tissue transglutaminase (TGase 2) is proposed to be important for biomaterial–tissue interactions due to its presence and versatile functions in the extracellular environment. TGase 2 catalyzes the cross-linking of proteins through its Ca2+-dependent acyltransferase activity. Moreover, it enhances the interactions between fibronectin and integrins, which in turn mediates the adhesion, migration, and motility of the cells. TGase 2 is also a key player in the pathogenesis of fibrosis. In this study, we investigated whether TGase 2 is present at the biomaterial–tissue interface and might serve as an informative biomarker for the visualization of tissue response toward gelatin-based biomaterials. Two differently cross-linked hydrogels were used, which were obtained by the reaction of gelatin with lysine diisocyanate ethyl ester. The overall expression of TGase 2 by endothelial cells, macrophages, and granulocytes was partly influenced by contact to the hydrogels or their degradation products, although no clear correlation was evidenced. In contrast, the secretion of TGase 2 differed remarkably between the different cells, indicating that it might be involved in the cellular reaction toward gelatin-based hydrogels. The hydrogels were implanted subcutaneously in immunocompetent, hairless SKH1-Elite mice. Ex vivo immunohistochemical analysis of tissue sections over 112 days revealed enhanced expression of TGase 2 around the hydrogels, in particular at days 14 and 21 post-implantation. The incorporation of fluorescently labeled cadaverine derivatives for the detection of active TGase 2 was in accordance with the results of the expression analysis. The presence of an irreversible inhibitor of TGase 2 led to attenuated incorporation of the cadaverines, which verified the catalytic action of TGase 2. Our in vitro and ex vivo results verified TGase 2 as a potential biomarker for tissue response toward gelatin-based hydrogels. In vivo, no TGase 2 activity was detectable, which is mainly attributed to the unfavorable physicochemical properties of the cadaverine probe used. %0 journal article %@ 0168-3659 %A Brunacci, N.,Neffe, A.,Wischke, C.,Naolou, T.,Nöchel, U.,Lendlein, A. %D 2019 %J Journal of Controlled Release %N %P 146-156 %R doi:10.1016/j.jconrel.2019.03.004 %T Oligodepsipeptide (nano)carriers: Computational design and analysis of enhanced drug loading %U https://doi.org/10.1016/j.jconrel.2019.03.004 %X High drug loads of nanoparticles are essential to efficiently provide a desired dosage in the required timeframe, however, these conditions may not be reached with so far established degradable matrices. Our conceptual approach for increasing the drug load is based on strengthening the affinity between drug and matrix in combination with stabilizing drug-matrix-hybrids through strong intermolecular matrix interactions. Here, a method for designing such complex drug-matrix hybrids is introduced employing computational methods (molecular dynamics and docking) as well as experimental studies (affinity, drug loading and distribution, drug release from films and nanoparticles). As model system, dexamethasone (DXM), relevant for the treatment of inflammatory diseases, in combination with poly[(rac-lactide)-co-glycolide] (PLGA) as standard degradable matrix or oligo[(3-(S)-sec-butyl)morpholine-2,5-dione]diol (OBMD) as matrix with hypothesized stronger interaction with DXM were investigated. Docking studies predicted higher affinity of DXM to OBMD than PLGA and displayed amide bond participation in hydrogen bonding with OBMD. Experimental investigations on films and nanoparticles, i.e. matrices of different shapes and sizes, confirmed this phenomenon as shown e.g. by a ~10 times higher solid state solubility of DXM in OBMD than in PLGA. DXM-loaded particles of ~ 150 nm prepared by nanoprecipitation in aqueous environment had a drug loading (DL) up to 16 times higher when employing OBMD as matrix compared to PLGA carriers due to enhanced drug retention in the OBMD phase. Importantly, drug relase periods were not altered as the release from films and particles was mainly ruled by the diffusion length as well as matrix degradation rather than the matrix type, which can be assigned to water diffusing into the matrix and breaking up of drug-matrix hydrogen bonds. Overall, the presented design and fabrication scheme showed predictive power and might universally enable the screening of drug/matrix interactions particularly to expand the oligodepsipeptide platform technology, e.g. by varying the depsipeptide side chains, for drug carrier and release systems. %0 journal article %@ 1748-605X %A Saretia, S.,Machatschek, R.,Schulz, B.,Lendlein, A. %D 2019 %J Biomedical Materials %N 3 %P 034103 %R doi:10.1088/1748-605X/ab0cef %T Reversible 2D networks of oligo(Epsilon-caprolactone) at the air–water interface %U https://doi.org/10.1088/1748-605X/ab0cef 3 %X Hydroxyl terminated oligo(ε-caprolactone) (OCL) monolayers were reversibly cross-linked forming two dimensional networks (2D) at the air–water interface. The equilibrium reaction with glyoxal as the cross-linker is pH-sensitive. Pronounced contraction in the area of the prepared 2D OCL films in dependence of surface pressure and time revealed the process of the reaction. Cross-linking inhibited crystallization and retarded enzymatic degradation of the OCL film. Altering the subphase pH led to a cleavage of the covalent acetal cross-links. The reversibility of the covalent acetal cross-links was proved by observing an identical isotherm as non-cross-linked sample. Besides as model systems, these customizable reversible OCL 2D networks are intended for use as pH responsive drug delivery systems or functionalized cell culture substrates. %0 journal article %@ 0897-4756 %A Zhang, P.,Behl, M.,Peng, X.,Balk, M.,Lendlein, A. %D 2019 %J Chemistry of Materials %N 15 %P 5402-5407 %R doi:10.1021/acs.chemmater.9b00363 %T Chemoresponsive Shape-Memory Effect of Rhodium–Phosphine Coordination Polymer Networks %U https://doi.org/10.1021/acs.chemmater.9b00363 15 %X Chemoresponsive polymers are of technological significance for smart sensors or systems capable of molecular recognition. An important key requirement for these applications is the material’s structural integrity after stimulation. We explored whether covalently cross-linked metal ion–phosphine coordination polymers (MPN) can be shaped into any temporary shape and are capable of recovering from this upon chemoresponsive exposure to triphenylphosphine (Ph3P) ligands, whereas the MPN provide structural integrity. Depending on the metal-ion concentration used during synthesis of the MPN, the degree of swelling of the coordination polymer networks could be adjusted. Once the MPN was immersed into Ph3P solution, the reversible ligand-exchange reaction between the metal ions and the free Ph3P in solution causes a decrease of the coordination cross-link density in MPN again. The Ph3P-treated MPN was able to maintain its original shape, indicating a certain stability of shape even after stimulation. In this way, chemoresponsive control of the elastic properties (increase in volume and decrease of mechanical strength) of the MPN was demonstrated. This remarkable behavior motivated us to explore whether the MPN are capable of a chemoresponsive shape-memory effect. In initial experiments, shape fixity of around 60% and shape recovery of almost 90% were achieved when the MPN was exposed to Ph3P in case of rhodium. Potential applications for chemoresponsive shape-memory systems could be shapable semiconductors, e.g., for lighting or catalysts, which provide catalytic activity on demand. %0 journal article %@ 2059-8521 %A Friess, F.,Wischke, C.,Lendlein, A. %D 2019 %J MRS Advances %N 59 - 60 %P 3199-3206 %R doi:10.1557/adv.2019.392 %T Microscopic analysis of shape-shiftable oligo (ε-caprolactone) — based particles %U https://doi.org/10.1557/adv.2019.392 59 - 60 %X Spherical particles are routinely monitored and described by hydrodynamic diameters determined, e.g., by light scattering techniques. Non-spherical particles such as prolate ellipsoids require alternative techniques to characterize particle size as well as particle shape. In this study, oligo(ε-caprolactone) (oCL) based micronetwork (MN) particles with a shape-shifting function based on their shape-memory capability were programmed from spherical to prolate ellipsoidal shape aided by incorporation and stretching in a water-soluble phantom matrix. By applying light microscopy with automated contour detection and aspect ratio analysis, differences in characteristic aspect ratio distributions of non-crosslinked microparticles (MPs) and crosslinked MNs were detected when the degrees of phantom elongation (30-290%) are increased. The thermally induced shape recovery of programmed MNs starts in the body rather than from the tips of ellipsoids, which may be explained based on local differences in micronetwork deformation. By this approach, fascinating intermediate particle shapes with round bodies and two opposite sharp tips can be obtained, which could be of interest, e.g., in valves or other technical devices, in which the tips allow to temporarily encage the switchable particle in the desired position. %0 journal article %@ 1386-0291 %A Sun, X.,Tung, W.,Wang, W.,Xu, X.,Zou, J.,Gould, O.,Kratz, K.,Ma, N.,Lendlein, A. %D 2019 %J Clinical Hemorheology and Microcirculation %N 1 %P 219-228 %R doi:10.3233/CH-199206 %T The effect of stiffness variation of electrospun fiber meshes of multiblock copolymers on the osteogenic differentiation of human mesenchymal stem cells %U https://doi.org/10.3233/CH-199206 1 %X Electrospinning has attracted significant attention as a method to produce cell culture substrates whose fibrous structure mimics the native extracellular matrix (ECM). In this study, the influence of E-modulus of fibrous substrates on the lineage commitment of human adipose-derived stem cells (hADSCs) was studied using fiber meshes prepared via the electrospinning of a polyetheresterurethane (PEEU) consisting of poly(ρ-dioxanone) (PPDO) and poly(ɛ-caprolactone) (PCL) segments. The PPDO: PCL weight ratio was varied from 40:60 to 70:30 to adjust the physiochemical properties of the PEEU fibers. The cells attached on stiffer PEEU70 (PPDO:PCL,= 70:30) fiber meshes displayed an elongated morphology compared to those cultured on softer fibers. The nuclear aspect ratio (width vs. length of a nucleus) of hADSCs cultured on softer PEEU40 (PPDO:PCL = 40:60) fibers was lower than on stiffer fibers. The osteogenic differentiation of hADSCs was enhanced by culturing on stiffer fibers. Compared to PEEU40, a 73% increase of osteocalcin expression and a 34% enhancement of alkaline phosphatase (ALP) activity was observed in cells on PEEU70. These results demonstrated that the differentiation commitment of stem cells could be regulated via tailoring the mechanical properties of electrospun fibers. %0 journal article %@ 1386-0291 %A Tung, W.,Wang, W.,Liu, Y.,Gould, O.,Kratz, K.,Ma, N.,Lendlein, A. %D 2019 %J Clinical Hemorheology and Microcirculation %N 1 %P 229-236 %R doi:10.3233/CH-199201 %T Mechanical characterization of electrospun polyesteretherurethane (PEEU) meshes by atomic force microscopy %U https://doi.org/10.3233/CH-199201 1 %X The mechanical properties of electrospun fiber meshes typically are measured by tensile testing at the macro-scale without precisely addressing the spatial scale of living cells and their submicron architecture. Atomic force microscopy (AFM) enables the examination of the nano- and micro-mechanical properties of the fibers with potential to correlate the structural mechanical properties across length scales with composition and functional behavior. In this study, a polyesteretherurethane (PEEU) polymer containing poly(p-dioxanone) (PPDO) and poly(ɛ-caprolactone) (PCL) segments was electrospun into fiber meshes or suspended single fibers. We employed AFM three point bending testing and AFM force mapping to measure the elastic modulus and stiffness of individual micro/nanofibers and the fiber mesh. The local stiffness of the fiber mesh including the randomized, intersecting structure was also examined for each individual fiber. Force mapping results with a set point of 50 nN demonstrated the dependence of the elasticity of a single fiber on the fiber mesh architecture. The non-homogeneous stiffness along the same fiber was attributed to the intersecting structure of the supporting mesh morphology. The same fiber measured at a point with and without axial fiber support showed a remarkable difference in stiffness, ranging from 0.2 to 10 nN/nm respectively. For the region, where supporting fibers densely intersected, the stiffness was found to be considerably higher. In the region where the degrees of freedom of the fibers was not restricted, allowing greater displacement, the stiffness were observed to be lower. This study elucidates the relationship between architecture and the mechanical properties of a micro/nanofiber mesh. By providing a greater understanding of the role of spatial arrangement and organization on the surface mechanical properties of such materials, we hope to provide insight into the design of microenvironments capable of regulating cell functionality. %0 journal article %@ 2073-4409 %A Elango, J.,Robinson, J.,Zhang, J.,Bao, B.,Ma, N.,Maté Sánchez de Val, J.,Wu, W. %D 2019 %J Cells %N 5 %P 446 %R doi:10.3390/cells8050446 %T Collagen Peptide Upregulates Osteoblastogenesis from Bone Marrow Mesenchymal Stem Cells through MAPK-Runx2 %U https://doi.org/10.3390/cells8050446 5 %X Collagen is the most abundant extracellular fibrous protein that has been widely used for biomedical applications due to its excellent biochemical and biocompatibility features. It is believed that the smaller molecular weight collagen, i.e., collagen peptide (CP), has more potent activity than native collagen. However, the preparation of CP from fish bone collagen is a complex and time-consuming process. Additionally, the osteogenic effect of CP depends on its molecular weight and amino acid composition. Considering the above concept, the present work was undertaken to extract the CP directly from Mahi mahi fish (Coryphaena hippurus) bones and test its osteogenic potential using bone marrow mesenchymal stem (BMMS) cells. The hydrolyzed collagen contained triple alpha chains (110 kDa) and a peptide (~1 kDa) and the peptide was successfully separated from hydrolyzed collagen using molecular weight cut-off membrane. CP treatment was up-regulated BMMS cells proliferation and differentiation. Interestingly, CP accrued the mineral deposition in differentiated BMMS cells. Protein and mRNA expression revealed that the osteogenic biomarkers such as collagen, alkaline phosphatase, and osteocalcin levels were significantly increased by CP treatment in differentiated BMMS cells and also further elucidated the hypothesis that CP was upregulated osteogenesis through activating Runx2 via p38MAPK signaling pathway. The above results concluded that the CP from Mahi mahi bones with excellent osteogenic properties could be the suitable biomaterial for bone therapeutic application. %0 journal article %@ 2059-8521 %A Folikumah, M.,Neffe, A.,Behl, M.,Lendlein, A. %D 2019 %J MRS Advances %N 46 - 47 %P 2515-2525 %R doi:10.1557/adv.2019.308 %T Thiol Michael-Type Reactions of Optically Active Mercapto-Acids in Aqueous Medium %U https://doi.org/10.1557/adv.2019.308 46 - 47 %X Defined chemical reactions in a physiological environment are a prerequisite for the in situ synthesis of implant materials potentially serving as matrix for drug delivery systems, tissue fillers or surgical glues. ‘Click’ reactions like thiol Michael-type reactions have been successfully employed as bioorthogonal reaction. However, due to the individual stereo-electronic and physical properties of specific substrates, an exact understanding their chemical reactivity is required if they are to be used for in-situ biomaterial synthesis. The chiral (S)-2-mercapto-carboxylic acid analogues of L-phenylalanine (SH-Phe) and L-leucine (SH-Leu) which are subunits of certain collagenase sensitive synthetic peptides, were explored for their potential for in-situ biomaterial formation via the thiol Michael-type reaction.,In model reactions were investigated the kinetics, the specificity and influence of stereochemistry of this reaction. We could show that only reactions involving SH-Leu yielded the expected thiol-Michael product. The inability of SH-Phe to react was attributed to the steric hindrance of the bulky phenyl group. In aqueous media, successful reaction using SH-Leu is thought to proceed via the sodium salt formed in-situ by the addition of NaOH solution, which was intented to aid the solubility of the mercapto-acid in water. Fast reaction rates and complete acrylate/maleimide conversion were only realized at pH 7.2 or higher suggesting the possible use of SH-Leu under physiological conditions for thiol Michael-type reactions. This method of in-situ formed alkali salts could be used as a fast approach to screen mercapto-acids for thio Michael-type reactions without the synthesis of their corresponding esters. %0 journal article %@ 1386-0291 %A Lamby, P.,Krueger-Genge, A.,Franke, F.P.,Mrowietz, C.,Falter, J.,Graf, S.,Schellenberg, E.L.,Jung, F.,Prantl, L. %D 2019 %J Clinical Hemorheology and Microcirculation %N 1 %P 261-270 %R doi:10.3233/CH-199009 %T Effect of iodinated contrast media on the oxygen tension in the renal cortico-medullary region of pigs %U https://doi.org/10.3233/CH-199009 1 %X Repeated injections of iodinated contrast media (CM) can lead to a deterioration of the renal blood flow, can redistribute blood from the renal cortex to other parts of the kidney and can cause small decreases of the blood flow in cortical capillaries, a significant reduction in blood flow in peritubular capillaries and a significant reduction in blood flow in the vasa recta. Therefore, a study in pigs was designed, to show whether the repeated injection of CM boli, alone, can cause a reduction of oxygenation in the cortico-medullar renal tissue – the region with the highest oxygen demand in the kidney - of pigs.,While the mean pO2-value had only decreased by 0.3 mmHg from 29.9±4.3 mmHg to 29.6±4.3 mmHg (p = 0.8799) after the tenth Iodixanol bolus, it decreased by 5.9 mmHg from 34.0±4.3 mmHg to 28.1±4.3 mmHg after the tenth Iopromide bolus (p = 0.044). This revealed a remarkable difference in the influence of these CM on the oxygen partial pressure in the kidney.,Repeated applications of CM had a significant influence on the renal oxygen partial pressure. In line with earlier studies showing a redistribution of blood from the cortex to other renal areas, this study revealed that Iodixanol – in contrast to Iopromide - induced no changes in the pO2 in the cortico-medullar region which confirms that Iodixanol did not hinder the flow of blood through the renal micro-vessels. These results are in favor of a hypothesis from Brezis that a microcirculatory disorder might be the basis for the development of CI-AKI. %0 journal article %@ 2192-2659 %A Braune, S.,Latour, R.,Reinthaler, M.,Landmesser, U.,Lendlein, A.,Jung, F. %D 2019 %J Advanced Healthcare Materials %N 21 %P 1900527 %R doi:10.1002/adhm.201900527 %T In Vitro Thrombogenicity Testing of Biomaterials %U https://doi.org/10.1002/adhm.201900527 21 %X The short‐ and long‐term thrombogenicity of implant materials is still unpredictable, which is a significant challenge for the treatment of cardiovascular diseases. A knowledge‐based approach for implementing biofunctions in materials requires a detailed understanding of the medical device in the biological system. In particular, the interplay between material and blood components/cells as well as standardized and commonly acknowledged in vitro test methods allowing a reproducible categorization of the material thrombogenicity requires further attention. Here, the status of in vitro thrombogenicity testing methods for biomaterials is reviewed, particularly taking in view the preparation of test materials and references, the selection and characterization of donors and blood samples, the prerequisites for reproducible approaches and applied test systems. Recent joint approaches in finding common standards for a reproducible testing are summarized and perspectives for a more disease oriented in vitro thrombogenicity testing are discussed. %0 journal article %@ 1759-9954 %A Cook, A.B.,Peltier, R.,Zhang, J.,Gurnani, P.,Tanaka, J.,Burns, J.A.,Dallmann, R.,Hartlieb, M.,Perrier, S. %D 2019 %J Polymer Chemistry %N 10 %P 1202-1212 %R doi:10.1039/c8py01648h %T Hyperbranched poly(ethylenimine-co-oxazoline) by thiol–yne chemistry for non-viral gene delivery: investigating the role of polymer architecture %U https://doi.org/10.1039/c8py01648h 10 %X Cationic polymers have been widely employed as gene delivery vectors to help circumvent extracellular and intracellular delivery barriers. Among them, polyethylenimine (PEI) is the most commonly used despite its associated high cytotoxicity. PEI is typically obtained by uncontrolled ring opening polymerisation of aziridine, leading to either linear polymer architectures with only secondary amines, or branched architectures containing primary, secondary, and tertiary amines. In contrast, we describe the preparation of hyperbranched poly(ethylenimine-co-oxazoline) that contains only secondary amines, via a fast thiol–yne based one pot reaction. A small library of these compounds with varying PEI contents was then used to study the effect of polymer architecture on pDNA polyplex formation, cytotoxicity, and in vitro transfection studies with plasmid DNA. Hyperbranched poly(ethylenimine-co-oxazoline) was found to have reduced toxicity compared to the commercial standard 25 000 g mol−1 branched PEI (bPEI), with transfection efficiencies only slightly lower than its bPEI counterpart. Obtained results highlight the importance of the polymer architecture on the transfection efficiency of a gene delivery system, which was demonstrated by excluding other parameters such as molecular weight and charge density. %0 journal article %@ 1420-682X %A Liu, Y.,Niu, R.,Li, W.,Lin, J.,Stamm, C.,Steinhoff, G.,Ma, N. %D 2019 %J Cellular and Molecular Life Sciences %N 9 %P 1681-1695 %R doi:10.1007/s00018-019-03019-2 %T Therapeutic potential of menstrual blood-derived endometrial stem cells in cardiac diseases %U https://doi.org/10.1007/s00018-019-03019-2 9 %X Despite significant developments in medical and surgical strategies, cardiac diseases remain the leading causes of morbidity and mortality worldwide. Numerous studies involving preclinical and clinical trials have confirmed that stem cell transplantation can help improve cardiac function and regenerate damaged cardiac tissue, and stem cells isolated from bone marrow, heart tissue, adipose tissue and umbilical cord are the primary candidates for transplantation. During the past decade, menstrual blood-derived endometrial stem cells (MenSCs) have gradually become a promising alternative for stem cell-based therapy due to their comprehensive advantages, which include their ability to be periodically and non-invasively collected, their abundant source material, their ability to be regularly donated, their superior proliferative capacity and their ability to be used for autologous transplantation. MenSCs have shown positive therapeutic potential for the treatment of various diseases. Therefore, aside from a brief introduction of the biological characteristics of MenSCs, this review focuses on the progress being made in evaluating the functional improvement of damaged cardiac tissue after MenSC transplantation through preclinical and clinical studies. Based on published reports, we conclude that the paracrine effect, transdifferentiation and immunomodulation by MenSC promote both regeneration of damaged myocardium and improvement of cardiac function. %0 journal article %@ 2058-8437 %A Lendlein, A.,Gould, O.E.C. %D 2019 %J Nature Reviews : Materials %N %P 116-133 %R doi:10.1038/s41578-018-0078-8 %T Reprogrammable recovery and actuation behaviour of shape-memory polymers %U https://doi.org/10.1038/s41578-018-0078-8 %X Shape memory is the capability of a material to be deformed and fixed into a temporary shape. Recovery of the original shape can then be triggered only by an external stimulus. Shape-memory polymers are highly deformable materials that can be programmed to recover a memorized shape in response to a variety of environmental and spatially localized stimuli as a one-way effect. The shape-memory function can also be generated as a reversible effect enabling actuation behaviour through macroscale deformation and processing, specifically by dictating the macromolecular orientation of actuation units and of the skeleton structure of geometry-determining units in the polymers. Shape-memory polymers can be programmed and reprogrammed into arbitrary shapes. Both recovery and actuation behaviour are reprogrammable. In this Review, we outline the common basis and key differences between the two shape-memory behaviours of polymers in terms of mechanism, fabrication schemes and characterization methods. We discuss which combination of macromolecular architecture and macroscale processing is necessary for coordinated, decentralized and responsive physical behaviour. The extraction of relevant thermomechanical information is described, and design criteria are shown for microscale and macroscale morphologies to gain high levels of recovered or actuation strains as well as on-demand 2D-to-3D shape transformations. Finally, real-world applications and key future challenges are highlighted. %0 journal article %@ 1936-0851 %A Gould, O.E.C.,Box, S.J.,Boott, C.E.,Ward, A.D.,Winnik, M.A.,Miles, M.J.,Manners, I. %D 2019 %J ACS Nano %N 4 %P 3858-3866 %R doi:10.1021/acsnano.9b00342 %T Manipulation and Deposition of Complex, Functional Block Copolymer Nanostructures Using Optical Tweezers %U https://doi.org/10.1021/acsnano.9b00342 4 %X Block copolymer self-assembly has enabled the creation of a range of solution-phase nanostructures with applications from optoelectronics and biomedicine to catalysis. However, to incorporate such materials into devices a method that facilitates their precise manipulation and deposition is desirable. Herein we describe how optical tweezers can be used to trap, manipulate, and pattern individual cylindrical micelles and larger hybrid micellar materials. Through the combination of TIRF imaging and optical trapping we can precisely control the three-dimensional motion of individual cylindrical block copolymer micelles in solution, enabling the creation of customizable arrays. We also demonstrate that dynamic holographic assembly enables the creation of ordered customizable arrays of complex hybrid block copolymer structures. By creating a program which automatically identifies, traps, and then deposits multiple assemblies simultaneously we have been able to dramatically speed up this normally slow process, enabling the fabrication of arrays of hybrid structures containing hundreds of assemblies in minutes rather than hours. %0 journal article %@ 1386-0291 %A Deng, Z.,Zou, J.,Wang, W.,Nie, Y.,Tung, W.-T.,Ma, N.,Lendlein, A. %D 2019 %J Clinical Hemorheology and Microcirculation %N 4 %P 415-424 %R doi:10.3233/CH-199005 %T Dedifferentiation of mature adipocytes with periodic exposure to cold %U https://doi.org/10.3233/CH-199005 4 %X Lipid-containing adipocytes can dedifferentiate into fibroblast-like cells under appropriate culture conditions, which are known as dedifferentiated fat (DFAT) cells. However, the relative low dedifferentiation efficiency with the established protocols limit their widespread applications. In this study, we found that adipocyte dedifferentiation could be promoted via periodic exposure to cold (10°C) in vitro. The lipid droplets in mature adipocytes were reduced by culturing the cells in periodic cooling/heating cycles (10–37°C) for one week. The periodic temperature change led to the down-regulation of the adipogenic genes (FABP4, Leptin) and up-regulation of the mitochondrial uncoupling related genes (UCP1, PGC-1α, and PRDM16). In addition, the enhanced expression of the cell proliferation marker Ki67 was observed in the dedifferentiated fibroblast-like cells after periodic exposure to cold, as compared to the cells cultured in 37°C. Our in vitro model provides a simple and effective approach to promote lipolysis and can be used to improve the dedifferentiation efficiency of adipocytes towards multipotent DFAT cells. %0 journal article %@ 1386-0291 %A Shin, E.-S.,Chung, J.-H.,Park, S.G.,Saleh, A.,Lam, Y.-Y.,Bhak, J.,Jung, F.,Morita, S.,Brachmann, J. %D 2019 %J Clinical Hemorheology and Microcirculation %N 2 %P 283-291 %R doi:10.3233/CH-180485 %T Comparison of exercise electrocardiography and magnetocardiography for detection of coronary artery disease using ST-segment fluctuation score %U https://doi.org/10.3233/CH-180485 2 %X BACKGROUND:,Exercise electrocardiography (ECG) is frequently used as a diagnostic measure in patients with suspected coronary artery disease (CAD). However, it has low sensitivity for the detection of CAD. Magnetocardiography (MCG) has been proposed as an alternative tool to accurately diagnose CAD.,OBJECTIVE:,To date, a direct comparison of MCG to ECG has not been performed. This study sought to compare them for predicting the presence of significantly obstructive CAD.,METHODS:,The patients with chest pain or other symptoms suggestive of CAD were enrolled in the analysis. All the patients underwent a clinical evaluation, exercise ECG, a MCG exercise test, and coronary angiography (CA). CAD was defined as stenosis ≥70% stenosis in at least one major coronary artery on quantitative analysis of CA.,RESULTS:,We prospectively enrolled 202 consecutive patients who suggested CAD. The prevalence of CAD on CA was 39.1%. Sensitivity and accuracy for CAD diagnosis was higher for MCG compared with exercise ECG (sensitivities 68.4% and 40.5%, p <0.001, specificities 95.1% and 91.1%, p = 0.267, and accuracies 84.7% and 71.3%, p <0.001, respectively). There was no incremental diagnostic value of combined MCG and ECG to detect coronary artery disease (p = 0.357).,CONCLUSIONS:,For the patients with intermediate to high risk of CAD, MCG exercise test provides better diagnostic accuracy for the detection of relevant obstruction of the epicardial coronaries when directly compared to exercise ECG. %0 journal article %@ 2059-8521 %A Balk, M.,Behl, M.,Lendlein, A. %D 2019 %J MRS Advances %N 21 %P 1193-1205 %R doi:10.1557/adv.2019.202 %T Hydrolytic Degradation of Actuators Based on Copolymer Networks From Oligo(ε-caprolactone) Dimethacrylate and n-Butyl Acrylate %U https://doi.org/10.1557/adv.2019.202 21 %X Shape-memory polymer actuators often contain crystallizable polyester segments. Here, the influence of accelerated hydrolytic degradation on the actuation performance in copolymer networks based on oligo(ε-caprolactone) dimethacrylate (OCL) and n-butyl acrylate is studied. The semi-crystalline OCL was utilized as crosslinker with molecular weights of 2.3 and 15.2 kg∙mol−1 (ratio: 1:1 wt%) and n-butyl acrylate (25 wt% relative to OCL content) acted as softening agent creating the polymer main chain segments within the network architecture. The copolymer networks were programmed by 50% elongation and were degraded by means of alkaline hydrolysis utilizing sodium hydroxide solution (pH = 13). Experiments were performed in the range of the broad melting range of the actuators at 40 °C. The degradation of test specimen was monitored by the sample mass, which was reduced by 25 wt% within 105 d. As degradation products, fragments of OCL with molecular masses ranging from 400 to 50.000 g·mol-1 could be detected by NMR spectroscopy and GPC measurements. The cleavage of ester groups included in OCL segments resulted in a decrease of the melting temperature (Tm) related to the actuator domains (amorphous at the temperature of degradation) and simultaneously, the Tm associated to the skeleton domain was increased (semi-crystalline at the temperature of degradation).,The alkaline hydrolysis decreased the polymer chain orientation of OCL domains until a random alignment of crystalline domains was obtained. This result was confirmed by cyclic thermomechanical actuation tests. The performance of directed movements decreased almost linearly as function of degradation time resulting in the loss of functionality when the orientation of polymer chains disappeared. Here, actuators were able to provide reversible movements until 91 d when the accelerated bulk degradation procedure using alkaline hydrolysis (pH = 13) was applied. Accordingly, a lifetime of more than one year can be guaranteed under physiological conditions (pH = 7.4) when, e.g., artificial muscles for biomimetic robots as potential application for these kind of shape-memory polymer actuators will be addressed. %0 journal article %@ 0378-5173 %A Friess, F.,Roch, T.,Seifert, B.,Lendlein, A.,Wischke, C. %D 2019 %J International Journal of Pharmaceutics %N %P 118461 %R doi:10.1016/j.ijpharm.2019.118461 %T Phagocytosis of spherical and ellipsoidal micronetwork colloids from crosslinked poly(ε-caprolactone) %U https://doi.org/10.1016/j.ijpharm.2019.118461 %X The effect of non-spherical particle shapes on cellular uptake has been reported as a general design parameter to control cellular recognition of particulate drug carriers. Beside shape, also size and cell-particle ratio should mutually effect phagocytosis. Here, the capability to control cellular uptake of poly(ɛ-caprolactone) (PCL) based polymer micronetwork colloids (MNC), a carrier system that can be transferred to various shapes, is explored in vitro at test conditions allowing multiple cell-particle contacts. PCL-based MNC were synthesized as spheres with a diameter of ∼6, ∼10, and 13 µm, loaded with a fluorescent dye by a specific technique of swelling, re-dispersion and drying, and transferred into different ellipsoidal shapes by a phantom stretching method. The boundaries of MNC deformability to prolate ellipsoid target shapes were systematically analyzed and found to be at an aspect ratio AR of ∼4 as obtained by a phantom elongation εph of ∼150%. Uptake studies with a murine macrophages cell line showed shape dependency of phagocytosis for selected conditions when varying particle sizes (∼6 and 10 μm),and shapes (εph: 0, 75 or 150%), cell-particle ratios (1:1, 1:2, 1:10, 1:50), and time points (1–24 h). For larger-sized MNC, there was no significant shape effect on phagocytosis as these particles may associate with more than one cell, thus increasing the possibility of phagocytosis by any of these cells. Accordingly, controlling shape effects on phagocytosis for carriers made from degradable polymers relevant for medical applications requires considering further parameters besides shape, such as kinetic aspects of the exposure and uptake by cells. %0 journal article %@ 1386-0291 %A Kuhnla, A.,Reinthaler, M.,Braune, S.,Maier, A.,Pindur, G.,Lendlein, A.,Jung, F. %D 2019 %J Clinical Hemorheology and Microcirculation %N 4 %P 425-435 %R doi:10.3233/CH-199006 %T Spontaneous and induced platelet aggregation in apparently healthy subjects in relation to age %U https://doi.org/10.3233/CH-199006 4 %X Thrombotic disorders remain the leading cause of mortality and morbidity, despite the fact that anti-platelet therapies and vascular implants are successfully used today. As life expectancy is increasing in western societies, the specific knowledge about processes leading to thrombosis in elderly is essential for an adequate therapeutic management of platelet dysfunction and for tailoring blood contacting implants. This study addresses the limited available data on platelet function in apparently healthy subjects in relation to age, particularly in view of subjects of old age (80–98 years). Apparently healthy subjects between 20 and 98 years were included in this study. Platelet function was assessed by light transmission aggregometry and comprised experiments on spontaneous as well as ristocetin-, ADP- and collagen-induced platelet aggregation. The data of this study revealed a non-linear increase in the maximum spontaneous platelet aggregation (from 3.3% ±3.3% to 10.9% ±5.9%). The maximum induced aggregation decreased with age for ristocetin (from 85.8% ±7.2% to 75.0% ±7.8%), ADP (from 88.5% ±4.6% to 64.8% ±7.3%) and collagen (from 89.5% ±3.0% to 64.0% ±4.0%) in a non-linear manner (linear regression analysis). These observations indicate that during aging, circulating platelets become increasingly activated but lose their full aggregatory potential, a phenomenon that was earlier termed “platelet exhaustion”. In this study we extended the limited existing data for spontaneous and induced platelet aggregation of apparently healthy donors above the age of 75 years. The presented data indicate that the extrapolation of data from a middle age group does not necessarily predict platelet function in apparently healthy subjects of old age. It emphasizes the need for respective studies to improve our understanding of thrombotic processes in elderly humans. %0 journal article %@ 0036-8075 %A Yuan, J.,Neri, W.,Zakri, C.,Merzeau, P.,Kratz, K.,Lendlein, A.,Poulin, P. %D 2019 %J Science %N 6449 %P 155-158 %R doi:10.1126/science.aaw3722 %T Shape memory nanocomposite fibers for untethered high-energy microengines %U https://doi.org/10.1126/science.aaw3722 6449 %X Classic rotating engines are powerful and broadly used but are of complex design and difficult to miniaturize. It has long remained challenging to make large-stroke, high-speed, high-energy microengines that are simple and robust. We show that torsionally stiffened shape memory nanocomposite fibers can be transformed upon insertion of twist to store and provide fast and high-energy rotations. The twisted shape memory nanocomposite fibers combine high torque with large angles of rotation, delivering a gravimetric work capacity that is 60 times higher than that of natural skeletal muscles. The temperature that triggers fiber rotation can be tuned. This temperature memory effect provides an additional advantage over conventional engines by allowing for the tunability of the operation temperature and a stepwise release of stored energy. %0 journal article %@ 1525-7797 %A Lendlein, A.,Balk, M.,Tarazona, N.,Gould, O. %D 2019 %J Biomacromolecules %N 10 %P 3627-3640 %R doi:10.1021/acs.biomac.9b01074 %T Bioperspectives for Shape-Memory Polymers as Shape Programmable, Active Materials %U https://doi.org/10.1021/acs.biomac.9b01074 10 %X Within the natural world, organisms use information stored in their material structure to generate a physical response to a wide variety of environmental changes. The ability to program synthetic materials to intrinsically respond to environmental changes in a similar manner has the potential to revolutionize material science. By designing polymeric devices capable of responsively changing shape or behavior based on information encoded into their structure, we can create functional physical behavior, including a shape-memory and an actuation capability. Here we highlight the stimuli-responsiveness and shape-changing ability of biological materials and biopolymer-based materials, plus their potential biomedical application, providing a bioperspective on shape-memory materials. We address strategies to incorporate a shape-memory (actuation) function in polymeric materials, conceptualized in terms of its relationship with inputs (environmental stimuli) and outputs (shape change). Challenges and opportunities associated with the integration of several functions in a single material body to achieve multifunctionality are discussed. Finally, we describe how elements that sense, convert, and transmit stimuli have been used to create multisensitive materials. %0 journal article %@ 1946-6242 %A Baron, U.,Werner, J.,Schildknecht, K.,Schulze, J.J.,Mulu, A.,Liebert, U.-G.,Sack, U.,Speckmann, C.,Gossen, M.,Wong, R.J.,Stevenson, D.K.,Babel, N.,Schuermann, D.,Baldinger, T.,Bacchetta, R.,Gruetzkau, A.,Borte, S.,Olek, S. %D 2018 %J Science Translational Medicine %N 452 %P 3508 %R doi:10.1126/scitranslmed.aan3508 %T Epigenetic immune cell counting in human blood samples for immunodiagnostics %U https://doi.org/10.1126/scitranslmed.aan3508 452 %X Immune cell profiles provide valuable diagnostic information for hematologic and immunologic diseases. Although it is the most widely applied analytical approach, flow cytometry is limited to liquid blood. Moreover, either analysis must be performed with fresh samples or cell integrity needs to be guaranteed during storage and transport. We developed epigenetic real-time quantitative polymerase chain reaction (qPCR) assays for analysis of human leukocyte subpopulations. After method establishment, whole blood from 25 healthy donors and 97 HIV+ patients as well as dried spots from 250 healthy newborns and 24 newborns with primary immunodeficiencies were analyzed. Concordance between flow cytometric and epigenetic data for neutrophils and B, natural killer, CD3+ T, CD8+ T, CD4+ T, and FOXP3+ regulatory T cells was evaluated, demonstrating substantial equivalence between epigenetic qPCR analysis and flow cytometry. Epigenetic qPCR achieves both relative and absolute quantifications. Applied to dried blood spots, epigenetic immune cell quantification was shown to identify newborns suffering from various primary immunodeficiencies. Using epigenetic qPCR not only provides a precise means for immune cell counting in fresh-frozen blood but also extends applicability to dried blood spots. This method could expand the ability for screening immune defects and facilitates diagnostics of unobservantly collected samples, for example, in underdeveloped areas, where logistics are major barriers to screening. %0 journal article %@ 1386-0291 %A Krueger-Genge, A.,Schulz, C.,Kratz, K.,Lendlein, A.,Jung, F. %D 2018 %J Clinical Hemorheology and Microcirculation %N 3 %P 437-445 %R doi:10.3233/CH-189904 %T Comparison of two substrate materials used as negative control in endothelialization studies: Glass versus polymeric tissue culture plate %U https://doi.org/10.3233/CH-189904 3 %X The endothelialization of synthetic surfaces applied as cardiovascular implant materials is an important issue to ensure the anti-thrombotic quality of a biomaterial. However, the rapid and constant development of a functionally-confluent endothelial cell monolayer is challenging. In order to investigate the compatibility of potential implant materials with endothelial cells several in vitro studies are performed. Here, glass and tissue culture plates (TCP) are often used as reference materials for in vitro pre-testing. However, a direct comparison of both substrates is lacking.,Therefore, a comparison of study results is difficult, since results are often related to various reference materials. In this study, the endothelialization of glass and TCP was investigated in terms of adherence, morphology, integrity, viability and function using human umbilical vein endothelial cells (HUVEC).,On both substrates an almost functionally confluent HUVEC monolayer was developed after nine days of cell seeding with clearly visible cell rims, decreased stress fiber formation and a pronounced marginal filament band. The viability of HUVEC was comparable for both substrates nine days after cell seeding with only a few dead cells. According to that, the cell membrane integrity as well as the metabolic activity showed no differences between TCP and glass. However, a significant difference was observed for the secretion of IL-6 and IL-8. The concentration of both cytokines, which are associated with migratory activity, was increased in the supernatant of HUVEC seeded on TCP. This result matches well with the slightly increased number of adherent HUVEC on TCP.,In conclusion, these findings indicate that both reference materials are almost comparable and can be used equivalently as control materials in in vitro endothelialization studies. %0 journal article %@ 0009-286X %A Wischke, C.,Baehr, E.,Racheva, M.,Lendlein, A. %D 2018 %J Chemie - Ingenieur - Technik %N 9 %P 1292 %R doi:10.1002/cite.201855348 %T Tyrosinase als Biokatalysator: Synthese von Hydrogelen und Oberflaechenfunktionalisierung %U https://doi.org/10.1002/cite.201855348 9 %X No abstract %0 journal article %@ 2050-750X %A Chen, J.,Sun, J.,Han, W.,Wang, W.,Cheng, G.,Lin, J.,Ma, N.,Chen, H.,Ou, L.,Li, W. %D 2018 %J Journal of Materials Chemistry B %N 26 %P 4368-4379 %R doi:10.1039/c8tb00563j %T Computer-aided design of short peptide ligands targeting tumor necrosis factor-alpha for adsorbent applications %U https://doi.org/10.1039/c8tb00563j 26 %X Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine active in the bodily immune response and serious inflammatory diseases. Traditional ligands targeting TNF-α focus on antibodies and receptors, which always associate with low efficacy and specificity. In the present study, two peptide ligands (T1: Ac-RKEM-NH2 and T2: Ac-RHCLS-NH2) were designed by computer simulation technology considering the weak interactions between TNF-α and its receptor TNFR1. Calculations of binding free energy (BFE) were made by the Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) method between T1 or T2 and TNF-α (−22.68 and −14.23 kcal mol−1, respectively). To assess the affinity levels, short peptide ligands were fixed on polyvinyl alcohol (PVA) microspheres; adsorption tests showed a stronger affinity of both PVA-T1 and PVA-T2 to TNF-α in PBS buffer than PVA microspheres (79.20 ± 1.32 and 74.27 ± 1.10 vs. 39.03 ± 1.25 pg mg−1, respectively). Moreover, PVA-T1 (74.8%, 17.60 ± 2.98 pg mg−1) and PVA-T2 (63.2%, 15.30 ± 4.81 pg mg−1) exhibit significantly enhanced TNF-α adsorption from the plasma of rats with sepsis to blank PVA and commercial XAD-7 resin. In conclusion, our results show that T1 designed by computer-aided molecular design (CAMD) exhibits a stronger affinity to TNF-α and it can significantly enhance PVA microsphere adsorption efficiency of TNF-α in plasma. %0 journal article %@ 0026-8976 %A Angioletti-Uberti, S.,Ballauff, M.,Dzubiella, J. %D 2018 %J Molecular Physics %N 21-22 %P 3154-3163 %R doi:10.1080/00268976.2018.1467056 %T Competitive adsorption of multiple proteins to nanoparticles: the Vroman effect revisited %U https://doi.org/10.1080/00268976.2018.1467056 21-22 %X Proteins adsorbed from the blood plasma change nanoparticles interactions with the surrounding biological environment. In general, the adsorption of multiple proteins has a non-monotonic time dependence, that is, proteins adsorbed at first may slowly be replaced by others. This ‘Vroman effect’ leads to a highly dynamic protein corona on nanoparticles that profoundly influences the immune response of the body. Thus, the temporal evolution of the corona must be taken into account when considering applications of nanocarriers in, e.g., nanomedicine or drug delivery. Up to now, the Vroman effect is explained solely in terms of diffusion: Smaller proteins which diffuse faster are adsorbed first, while larger ones, having a stronger interaction with the surface, are preferred at equilibrium. Here we use dynamic density functional theory (DDFT) including steric and electrostatic interactions to provide a full model for the temporal evolution of the protein corona. In particular, we demonstrate that proper consideration of all interactions leads to Vroman-like adsorption signatures in widely different scenarios. Moreover, consideration of energetic terms predicts both competitive as well as cooperative adsorption. In this way, DDFT provides a reacher picture of the evolution of the dynamic protein corona. %0 journal article %@ 1386-0291 %A Jung, F.,Franke, F.-P. %D 2018 %J Clinical Hemorheology and Microcirculation %N 1 %P 1-3 %R doi:10.3233/CH-189900 %T Obituary: In memory of Prof. Dr. Holger Schmid-Schoenbein %U https://doi.org/10.3233/CH-189900 1 %X No abstract %0 journal article %@ 0009-286X %A Kratz, K.,Liu, Y.,Rudolph, T.,Lendlein, A. %D 2018 %J Chemie - Ingenieur - Technik %N 9 %P 1331-1332 %R doi:10.1002/cite.201855431 %T Einfluss von Deformations- und Separationstemperatur auf das Formgedaechtnisverhalten von polymeren Mikroquadern %U https://doi.org/10.1002/cite.201855431 9 %X No abstract %0 journal article %@ 1386-0291 %A Al-Hindwan, H.S.A.,Landmesser, U.,Staehli, B.,Alushi, B.,Curio, J.,Neumann, T.,Jung, F.,Lendlein, A.,Jacobs, S.,Reinthaler, M. %D 2018 %J Clinical Hemorheology and Microcirculation %N 1 %P 15-25 %R doi:10.3233/CH-189906 %T The predictive value of a modified Carpentier classification in patients with coincidental mitral regurgitation undergoing TAVI for severe aortic valve stenosis %U https://doi.org/10.3233/CH-189906 1 %X INTRODUCTION:,Concomitant mitral-regurgitation (MR) is frequently observed in patients undergoing trans-catheter aortic valve implantation (TAVI). The predictive value of MR etiology remains to be elucidated.,METHODS:,600 patients with coincidental MR (≥moderate) undergoing TAVI were categorized according to a modified Carpentier classification [Groups: no/mild MR, n = 477; left atrial (LA) functional MR, n = 18; MR due to left ventricular dilatation, n = 29; degenerative MR, n = 50; MR with restricted leaflet motion n = 26]. MR improvement and patient outcome was compared among the groups in a retrospective analysis.,RESULTS:,MR regression was most pronounced in patients with restricted leaflet motion after 6 months, although a significant improvement was observed in all subgroups. MR relief was predominantly observed within the first 30 days after TAVI. Only patients with restricted leaflet motion experienced further improvement thereafter.,In the entire cohort a total of 15 strokes (2.5%) during the first 30 days after TAVI were observed, with the highest incidence in the LA functional cohort (3 events, 17%; p = 0.008). In multivariate analysis, organic etiology was associated with an increased 1-year mortality.,In conclusion, despite significant MR regression in all MR groups, some individuals may require additional mitralvalve repair after TAVI. According to our data the timing of these procedures should be based on the underlying MR etiology. The Carpentier classification in patients with coincidental MR undergoing TAVI for severe AS may also have prognostic implications as we found an increased incidence of strokes in our LA functional cohort and a worse mortality rates in organic MR. %0 journal article %@ 1386-0291 %A Krueger-Genge, A.,Braune, S.,Walter, M.,Krengel, M.,Kratz, K.,Kuepper, J.-H.,Lendlein, A.,Jung, F. %D 2018 %J Clinical Hemorheology and Microcirculation %N 1-2 %P 305-316 %R doi:10.3233/CH-189130 %T Influence of different surface treatments of poly(Eta-butyl acrylate) networks on fibroblasts adhesion, morphology and viability %U https://doi.org/10.3233/CH-189130 1-2 %X BACKGROUND:,Physical and chemical characteristics of implant materials determine the fate of long-term cardiovascular devices. However, there is still a lack of fundamental understanding of the molecular mechanisms occurring in the material-tissue interphase. In a previous study, soft covalently crosslinked poly(n-butyl acrylate) networks (cPnBA) were introduced as sterilizable, non-toxic and immuno-compatible biomaterials with mechanical properties adjustable to blood vessels. Here we study the influence of different surface treatments in particular oxygen plasma modification and fibrinogen deposition as well as a combinatorial approach on the adhesion and viability of fibroblasts.,MATERIAL AND METHODS:,Two types of cPnBA networks with Young’s moduli of 0.19±0.01 MPa (cPnBA04) and 1.02±0.01 MPa (cPnBA73) were synthesized and post-modified using oxygen plasma treatment (OPT) or fibrinogen coating (FIB) or a combination of both (OPT+FIB). The water contact angles of the differently post-treated cPnBAs were studied to monitor changes in the wettability of the polymer surfaces. Because of the key role of vascular fibroblasts in regeneration processes around implant materials, here we selected L929 fibroblasts as model cell type to explore morphology, viability, metabolic activity, cell membrane integrity as well as characteristics of the focal adhesions and cell cytoskeleton on the cPnBA surfaces.,RESULTS:,Compared to non-treated cPnBAs the advancing water-contact angles were found to be reduced after all surface modifications (p < 0.05, each), while lowest values were observed after the combined surface treatment (OPT+FIB). The latter differed significantly from the single OPT and FIB. The number of adherent fibroblasts and their adherence behavior differed on both pristine cPnBA networks. The fibroblast density on cPnBA04 was 743±434 cells·mm-2, was about 6.5 times higher than on cPnBA73 with 115±73 cells·mm-2. On cPnBA04 about 20% of the cells were visible as very small, round and buckled cells while all other cells were in a migrating status. On cPnBA73, nearly 50% of fibroblasts were visible as very small, round and buckled cells. The surface functionalization either using oxygen plasma treatment or fibrinogen coating led to a significant increase of adherent fibroblasts, particularly the combination of both techniques, for both cPnBA networks. It is noteworthy to mention that the fibrinogen coating overruled the characteristics of the pristine surfaces; here, the fibroblast densities after seeding were identical for both cPnBA networks. Thus, the binding rather depended on the fibrinogen coating than on the substrate characteristics anymore. While the integrity of the fibroblasts membrane was comparable for both polymers, the MTS tests showed a decreased metabolic activity of the fibroblasts on cPnBA.,CONCLUSION:,The applied surface treatments of cPnBA successfully improved the adhesion of viable fibroblasts. Under resting conditions as well as after shearing the highest fibroblast densities were found on surfaces with combined post-treatment. %0 journal article %@ 1386-0291 %A Gori, T.,Jung, F. %D 2018 %J Clinical Hemorheology and Microcirculation %N 4 %P 331-332 %R doi:10.3233/-189902 %T Obituary: In memory of Prof. Dr. Sandro Forconi %U https://doi.org/10.3233/-189902 4 %X No abstract %0 journal article %@ 1386-0291 %A Krueger-Genge, A.,Steinbrecht, S.,Kuepper, J.-H.,Lendlein, A.,Jung, F. %D 2018 %J Clinical Hemorheology and Microcirculation %N 1-2 %P 267-276 %R doi:10.3233/CH-189125 %T Evidence for cytostatic effect of cyclophosphamide on human vein endothelial cells in cancer therapy: Preliminary in vitro results %U https://doi.org/10.3233/CH-189125 1-2 %X In cancer therapy, a number of drugs with different mechanisms of action are in clinical use, which act directly after administration without metabolism, while others only become active in the metabolites produced in the liver. Such drugs/metabolites – especially when administered parenterally – interact in high concentrations with the endothelium. Whether this induces adverse responses of the endothelial cells (EC) is barely studied for many medicaments.,This pilot in vitro study revealed that the addition of cyclophosphamide (CPA) to the culture medium (5 or 10 mM, respectively) showed a clear influence on EC compared to non-treated EC: The number of adherent human vein endothelial cells (HUVEC) decreased by the addition of CPA in a concentration-dependent manner compared to the untreated control, whereby the vitality of adherent cells was not affected. In addition, concomitant with activation of the adherent HUVEC, increased migratory activity occurred.,These results are in agreement with clinical events like thromboses in patients in compromised condition under therapy with CPA, as the detachment of EC might induce responses of circulating platelets leading to the adherence and aggregation with the risk of the formation of thrombi. Whether CPA acts directly or via toxic metabolites on EC will be examined in more detail in following studies. %0 journal article %@ 0942-9352 %A Volz, P.,Brodwolf, R.,Zoschke, C.,Haag, R.,Schaefer-Korting, M.,Alexiev, U. %D 2018 %J Zeitschrift fuer Physikalische Chemie %N 5-6 %P 671-688 %R doi:10.1515/zpch-2017-1050 %T White-Light Supercontinuum Laser-Based Multiple Wavelength Excitation for TCSPC-FLIM of Cutaneous Nanocarrier Uptake %U https://doi.org/10.1515/zpch-2017-1050 5-6 %X We report here on a custom-built time-correlated single photon-counting (TCSPC)-based fluorescence lifetime imaging microscopy (FLIM) setup with a continuously tunable white-light supercontinuum laser combined with acousto-optical tunable filters (AOTF) as an excitation source for simultaneous excitation of multiple spectrally separated fluorophores. We characterized the wavelength dependence of the white-light supercontinuum laser pulse properties and demonstrated the performance of the FLIM setup, aiming to show the experimental setup in depth together with a biomedical application. We herein summarize the physical-technical parameters as well as our approach to map the skin uptake of nanocarriers using FLIM with a resolution compared to spectroscopy. As an example, we focus on the penetration study of indocarbocyanine-labeled dendritic core-multishell nanocarriers (CMS-ICC) into reconstructed human epidermis. Unique fluorescence lifetime signatures of indocarbocyanine-labeled nanocarriers indicate nanocarrier-tissue interactions within reconstructed human epidermis, bringing FLIM close to spectroscopic analysis. %0 journal article %@ 1386-0291 %A Hiebl, B.,Ascher, L.,Luetzow, K.,Kratz, K.,Gruber, C.,Mrowietz, C.,Nehring, M.E.,Lendlein, A.,Franke, R.-P.,Jung, F. %D 2018 %J Clinical Hemorheology and Microcirculation %N 1-2 %P 317-326 %R doi:10.3233/CH-189108 %T Albumin solder covalently bound to a polymer membrane: New approach to improve binding strength in laser tissue soldering in-vitro %U https://doi.org/10.3233/CH-189108 1-2 %X Laser tissue soldering (LTS) based on indocyanine green (ICG)-mediated heat-denaturation of proteins might be a promising alternative technique for micro-suturing, but up to now the problem of too weak shear strength of the solder welds in comparison to sutures is not solved. Earlier reports gave promising results showing that solder supported by carrier materials can enhance the cohesive strength of the liquid solder. In these studies, the solder was applied to the carriers by dip coating. Higher reliability of the connection between the solder and the carrier material is expected when the solder is bound covalently to the carrier material. In the present study a poly(ether imide) (PEI) membrane served as carrier material and ICG-supplemented albumin as solder substrate. The latter was covalently coupled to the carrier membrane under physiological conditions to prevent structural protein changes. As laser source a diode continuous-wave laser emitting at 808 nm with intensities between 250 mW and 1500 mW was utilized. The albumin functionalized carrier membrane was placed onto the tunica media of explanted pig thoracic aortae forming an overlapping area of approximately 0.5×0.5 cm2. All tests were performed in a dry state to prevent laser light absorption by water. Infrared spectroscopy, spectro-photometrical determination of the secondary and primary amine groups after acid orange II staining, contact angle measurements, and atomic force microscopy proved the successful functionalization of the PEI membrane with albumin. A laser power of 450 mW LTS could generate a membrane-blood vessel connection which was characterized by a shear strength of 0.08±0.002 MPa, corresponding to 15% of the tensile strength of the native blood vessel. Theoretically, an overlapping zone of 4.1 mm around the entire circumference of the blood vessel could have provided shear strength of the PEI membrane-blood vessel compound identical to the tensile strength of the native blood vessel. These in-vitro results confirmed the beneficial effects of solder reinforcement by carrier membranes, and suggest LTS with covalently bound solders on PEI substrates for further studies in animal models. %0 journal article %@ 1386-0291 %A Felthaus, O.,Schoen, T.,Schiltz, D.,Aung, T.,Kuehlmann, B.,Jung, F.,Anker, A.,Klein, S.,Prantl, L. %D 2018 %J Clinical Hemorheology and Microcirculation %N 1-2 %P 141-151 %R doi:10.3233/CH-189107 %T Adipose tissue-derived stem cells from affected and unaffected areas in patients with multiple symmetric lipomatosis show differential regulation of mTOR pathway genes %U https://doi.org/10.3233/CH-189107 1-2 %X BACKGROUND:,Multiple symmetric lipomatosis is a rare disease characterized by the excessive growth of uncapsulated masses of adipose tissue. Although the etiology has yet to be elucidated, a connection to brown adipose tissue has been proposed recently. The mTOR pathway which is found to be regulated in lipomatous tissue as well as associated with brown adipose tissue can be inhibited by a compound called rapamycin.,METHODS:,We isolated adipose tissue derived stem cells from both affected and unaffected tissue and treated these cells with different concentrations of rapamycin.,RESULTS:,The differences in both proliferation and differentiation between adipose tissue derived stem cells (ASCs) from lipomatous and normal tissue decreased after mTOR pathway inhibition. In some patients regulation of mTOR genes was opposed in the ASCs from the two different tissues.,CONCLUSIONS:,Treatment with rapamycin might be a novel therapeutical approach for patients suffering from multiple symmetric lipomatosis. %0 journal article %@ 2051-6347 %A Wang, L.,Razzaq, M.Y.,Rudolph, T.,Heuchel, M.,Noechel, U.,Mansfeld, U.,Jiang, Y.,Gould, O.E.C.,Behl, M.,Kratz, K.,Lendlein, A. %D 2018 %J Materials Horizons %N 5 %P 861-867 %R doi:10.1039/C8MH00266E %T Reprogrammable, magnetically controlled polymeric nanocomposite actuators %U https://doi.org/10.1039/C8MH00266E 5 %X Soft robots and devices with the advanced capability to perform adaptive motions similar to that of human beings often have stimuli-sensitive polymeric materials as the key actuating component. The external signals triggering the smart polymers’ actuations can be transmitted either via a direct physical connection between actuator and controlling unit (tethered) or remotely without a connecting wire. However, the vast majority of such polymeric actuator materials are limited to one specific type of motion as their geometrical information is chemically fixed. Here, we present magnetically driven nanocomposite actuators, which can be reversibly reprogrammed to different actuation geometries by a solely physical procedure. Our approach is based on nanocomposite materials comprising spatially segregated crystallizable actuation and geometry determining units. Upon exposure to a specific magnetic field strength the actuators’ geometric memory is erased by the melting of the geometry determining units allowing the implementation of a new actuator shape. The actuation performance of the nanocomposites can be tuned and the technical significance was demonstrated in a multi-cyclic experiment with several hundreds of repetitive free-standing shape shifts without losing performance. %0 journal article %@ 1386-0291 %A Kumar, R.K.,Heuchel, M.,Kratz, K.,Lendlein, A.,Jankowski, J.,Tetali, S.D. %D 2018 %J Clinical Hemorheology and Microcirculation %N 1-2 %P 175-185 %R doi:10.3233/CH-189112 %T Effects of extracts prepared from modified porous poly(ether imide) microparticulate absorbers on cytotoxicity, macrophage differentiation and proinflammatory behavior of human monocytic (THP-1) cells %U https://doi.org/10.3233/CH-189112 1-2 %X Remaining uremic toxins in the blood of chronic renal failure patients represent one central challenge in hemodialysis therapies. Highly porous poly(ether imide) (PEI) microparticles have been recently introduced as candidate absorber materials, which show a high absorption capacity for uremic toxins and allow hydrophilic surface modification suitable for minimization of serum protein absorption. In this work, the effects of extracts prepared from PEI microparticles modified by nucleophilic reaction with low molecular weight polyethylene imine (Pei) or potassium hydroxide (KOH), on human monocytic (THP-1) cells are studied. The obtained results suggested that the extracts of Pei and KOH modified PEI absorbers have no negative effect on THP-1 cell viability and do not initiate the critical differentiation towards macrophages. The extracts did not enhance transcript or protein levels of investigated proinflammatory markers in THP-1 cells, namely, TNFμ, MCP1, IL6 and IL8. Based on these findings such modified PEI microparticles should be qualified for further pre-clinical evaluation i.e. in an in vivo animal experiment. %0 journal article %@ 2073-4360 %A Farhan, M.,Rudolph, T.,Noechel, U.,Kratz, K.,Lendlein, A. %D 2018 %J Polymers %N 3 %P 255 %R doi:10.3390/polym10030255 %T Extractable Free Polymer Chains Enhance Actuation Performance of Crystallizable Poly(Epsilon-caprolactone) Networks and Enable Self-Healing %U https://doi.org/10.3390/polym10030255 3 %X Crosslinking of thermoplastics is a versatile method to create crystallizable polymer networks, which are of high interest for shape-memory actuators. Here, crosslinked poly(ε-caprolactone) thermosets (cPCLs) were prepared from linear starting material, whereby the amount of extractable polymer was varied. Fractions of 5–60 wt % of non-crosslinked polymer chains, which freely interpenetrate the crosslinked network, were achieved leading to differences in the resulting phase of the bulk material. This can be described as “sponge-like” with open or closed compartments depending on the amount of interpenetrating polymer. The crosslinking density and the average network chain length remained in a similar range for all network structures, while the theoretical accessible volume for reptation of the free polymer content is affected. This feature could influence or introduce new functions into the material created by thermomechanical treatment. The effect of interpenetrating PCL in cPCLs on the reversible actuation was analyzed by cyclic, uniaxial tensile tests. Here, high reversible strains of up to ∆ε = 24% showed the enhanced actuation performance of networks with a non-crosslinked PCL content of 30 wt % resulting from the crystal formation in the phase of the non-crosslinked PCL and co-crystallization with network structures. Additional functionalities are reprogrammability and self-healing capabilities for networks with high contents of extractable polymer enabling reusability and providing durable actuator materials. %0 journal article %@ 2470-9476 %A Lendlein, A. %D 2018 %J Science Robotics %N 18 %P eaat9090 %R doi:10.1126/scirobotics.aat9090 %T Fabrication of reprogrammable shape-memory polymer actuators for robotics %U https://doi.org/10.1126/scirobotics.aat9090 18 %X Shape-memory polymer actuators, whose actuation geometry and switching temperatures are reprogrammable by physical fabrication schemes, were recently suggested for robotics with the option for self-healing and degradability. %0 journal article %@ 2059-8521 %A Balk, M.,Lendlein, A.,Behl, M. %D 2018 %J MRS Advances %N 49 %P 2965-2973 %R doi:10.1557/adv.2018.319 %T High-Throughput Synthesis of Oligo(Epsilon-caprolactone) / Oligotetrahydrofuran Based Polyurethanes %U https://doi.org/10.1557/adv.2018.319 49 %X Robot assisted synthesis as part of high-throughput (HT) technology can assist in the creation of polymer libraries, e.g. polymers with a variety of molecular weights, by automatizing similar reactions. Especially for multiblock copolymers like polyurethanes (PUs) synthesized from telechels via polyaddition reaction, the adjustment of equivalent molar amounts of reactants requires a comprehensive investigation of end group functionality.,In this work, PUs based on oligo(ε-caprolactone) (OCL) / oligotetrahydrofuran (OTHF) as model components were designed utilizing HT synthesis enabling the quantitative determination of the optimized ratio between reactive end-groups via fully automated syntheses without major characterization effort of end group functionality. The semi-crystalline oligomeric telechelics were connected with a diisocyanate and OCL with a molecular weight of 2, 4, or 8 kg∙mol-1 was integrated. Here, optimized molecular weights between 90 ± 10 kg∙mol-1 (in case of OCL 8 kg∙mol-1) and 260 ± 30 kg∙mol-1 (in case of OCL 2 kg∙mol-1) were obtained with an isocyanate content of 120 mol%, whereby 100 mol% of isocyanate groups resulted only in molecular weights between 60 ± 6 kg∙mol-1 (OCL 8 kg∙mol-1) and 80 ± 10 kg∙mol-1 (OCL 2 kg∙mol-1). In addition to the optimized ratio between isocyanate and hydroxy end groups, quantitative influences of the OCL chain length and overall molecular weights of PUs on thermal and mechanical properties were detected. The melting temperatures (Tms) of OCL and OTHF domains were well separated for PUs of low molecular weight, the temperature interval between the Tms decreased when the molecular weight of the PUs was increased, and were even overlapping towards one broad Tm, when OCL 2 kg∙mol-1 was incorporated. The storage modulus E’ was highly dependent on OCL chain length exhibiting an increase with increasing molecular weight of OCL from 220 MPa to 440 MPa at 0 °C and decreased with increasing chain length of PUs. The elongation at break (εb) was analyzed below and above Tm of OTHF resulting in εb = 780-870% at 0 °C and εb = 510-830% at 30 °C for PUs of high molecular weight. Accordingly, stretchability of PUs was almost independent of the state of OTHF (semi crystalline or amorphous) but correlated with the OCL precursor chain length (increasing εb with increasing chain length) and overall molecular weight of PUs (PUs at higher molecular weight exhibited higher εb). Hence, the analysis of these quantitative influences between macromolecular structure of multiblock copolymers and the resulting properties (well separated Tms versus overlapping melting transition, improvement of stretchability) would enable the design of new tailored PUs. %0 journal article %@ 1433-7851 %A Englert, C.,Nischang, I.,Bader, C.,Borchers, P.,Alex, J.,Proehl, M.,Hentschel, M.,Hartlieb, M.,Traeger, A.,Pohnert, G.,Schubert, S.,Gottschaldt, M.,Schubert, U.S. %D 2018 %J Angewandte Chemie - International Edition %N 9 %P 2479-2482 %R doi:10.1002/anie.201710756 %T Photocontrolled Release of Chemicals from Nano- and Microparticle Containers %U https://doi.org/10.1002/anie.201710756 9 %X A benzoin-derived diol linker was synthesized and used to generate biocompatible polyesters that can be fully decomposed on demand upon UV irradiation. Extensive structural optimization of the linker unit was performed to enable the defined encapsulation of diverse organic compounds in the polymeric structures and allow for a well-controllable polymer cleavage process. Selective tracking of the release kinetics of encapsulated model compounds from the polymeric nano- and microparticle containers was performed by confocal laser scanning microscopy in a proof‐of‐principle study. The physicochemical properties of the incorporated and released model compounds ranged from fully hydrophilic to fully hydrophobic. The demonstrated biocompatibility of the utilized polyesters and degradation products enables their use in advanced applications, for example, for the smart packaging of UV‐sensitive pharmaceuticals, nutritional components, or even in the area of spatially selective self‐healing processes. %0 journal article %@ 2059-8521 %A Mazurek-Budzynska, M.,Balk, M.,Behl, M.,Lendlein, A. %D 2018 %J MRS Advances %N 50 %P 3033-3040 %R doi:10.1557/adv.2018.407 %T Polyethyleneimine and Poly(ethylene glycol) Functionalized Oligoester Based Polycationic Particles %U https://doi.org/10.1557/adv.2018.407 50 %X Polycationic particles based on a degradable oligoester core are interesting candidate materials for the transfection of polyanionic macromolecules like DNA, which would enable the degradation after delivery of condensed molecules. Good transfection efficiencies can be obtained when the size of the polyplex (containing both polycationic nanoparticles and polyanionic macromolecules) does not exceed 120 nm. Therefore, here we explored how size, but also dispersity, and surface charge of these carrier systems can be adjusted by variation of the block copolymer composition or the presence and ratio of a co-assembly agent. Polycationic particles were obtained based on an amphiphilic triblock copolymer from oligo[(ε-caprolactone)-co-glycolide] (CG) functionalized with polyethyleneimine (PEI) and diblock copolymer based on poly(ethylene glycol) (PEG) modified with CG. A second series of particles was created, in which the oligoester blocks contained only ε-caprolactone units, therefore the effect of the presence of glycolide units was also studied. In both series, the ratio between di- and triblock copolymers was systematically varied. Nano-sized particles ranging from 34.5 ± 0.2 nm to 97.9 ± 0.3 nm with controllable positive surface charges between 2.9 ± 0.2 mV and 18.1 ± 0.5 mV were obtained by self-assembly in PBS solution under intensive stirring. The incorporation of PEG-C diblock copolymers resulted in an increase of particle size, however no specific relation between composition, size, and polydispersity was observed. In case of PEG-CG diblock copolymers a rather systematic increase of the particles’ size with increasing content of diblock copolymer was shown. Furthermore, with a decrease of content of diblock copolymer in the particle structure zeta potential strongly increased. Additionally, the content of glycolide units in triblock copolymer increased the zeta potential of PEI-CG-PEI-based particles in comparison to PEI-C-PEI-based ones. Therefore, obtained particles could be used as potential target-oriented polycationic macromolecules for carrier systems. %0 journal article %@ 1022-1336 %A Zhao, F.,Bonasera, A.,Noechel, U.,Behl, M.,Bleger, D. %D 2018 %J Macromolecular Rapid Communications %N 1 %P 1700527 %R doi:10.1002/marc.201700527 %T Reversible Modulation of Elasticity in Fluoroazobenzene-Containing Hydrogels Using Green and Blue Light %U https://doi.org/10.1002/marc.201700527 1 %X Hydrogels are soft materials that have found multiple applications in biomedicine and represent a good platform for the introduction of molecular switches and synthetic machines into macromolecular networks. Tuning their mechanical properties reversibly with light is appealing for a variety of advanced applications and has been demonstrated in the past; however, their activation typically requires the use of UV light, which displays several drawbacks related to its damaging character and limited penetration in tissues and materials. This study circumvents this limitation by introducing all‐visible ortho‐fluoroazobenzene switches into a hydrophilic network, which, as a result, can be activated with green or blue light. Photoisomerization of the photochromic moieties is accompanied by a reversible tuning of the elastic modulus. The translation of molecular isomerization within the network into macroscopic modulation of its mechanical properties is attributed to different aggregation tendencies of the E and Z isomers of the azobenzene derivatives. %0 journal article %@ 0935-9648 %A Cheng, C.,Zhang, J.,Li, S.,Xia, Y.,Nie, C.,Shi, Z.,Cuellar-Camacho, J.L.,Ma, N.,Haag, R. %D 2018 %J Advanced Materials %N 5 %P 1705452 %R doi:10.1002/adma.201705452 %T A Water-Processable and Bioactive Multivalent Graphene Nanoink for Highly Flexible Bioelectronic Films and Nanofibers %U https://doi.org/10.1002/adma.201705452 5 %X The capabilities of conductive nanomaterials to be produced in liquid form with well-defined chemical, physical, and biological properties are highly important for the construction of next-generation flexible bioelectronic devices. Although functional graphene nanomaterials can serve as attractive liquid nanoink platforms for the fabrication of bioelectronics, scalable synthesis of graphene nanoink with an integration of high colloidal stability, water processability, electrochemical activity, and especially bioactivity remains a major challenge. Here, a facile and scalable synthesis of supramolecular‐functionalized multivalent graphene nanoink (mGN‐ink) via [2+1] nitrene cycloaddition is reported. The mGN‐ink unambiguously displays a well‐defined and flat 2D morphology and shows good water processability and bioactivity. The uniquely chemical, physical, and biological properties of mGN‐ink endow the constructed bioelectronic films and nanofibers with high flexibility and durability, suitable conductivity and electrochemical activity, and most importantly, good cellular compatibility and a highly efficient control of stem‐cell spreading and orientation. Overall, for the first time, a water‐processable and bioactive mGN‐ink is developed for the design of flexible and electrochemically active bioelectronic composites and devices, which not only presents manifold possibilities for electronic‐cellular applications but also establishes a new pathway for adapting macroscopic usages of graphene nanomaterials in bionic, biomedical, electronic, and even energy fields. %0 journal article %@ 1616-5187 %A Weiss, V.M.,Lucas, H.,Mueller, T.,Chytil, P.,Etrych, T.,Naolou, T.,Kressler, J.,Maeder, K. %D 2018 %J Macromolecular Bioscience %N 1 %P 1700240 %R doi:10.1002/mabi.201700240 %T Intended and Unintended Targeting of Polymeric Nanocarriers: The Case of Modified Poly(glycerol adipate) Nanoparticles %U https://doi.org/10.1002/mabi.201700240 1 %X Biodegradable nanoparticles based on stearic acid-modified poly(glycerol adipate) (PGAS) are promising carriers for drug delivery. In order to investigate the impact of the particle interface characteristics on the biological fate, PGAS nanoparticles are covalently and noncovalently coated with N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers. HPMA copolymer-modified PGAS nanoparticles have similar particle sizes, but less negative zeta-potentials. Nanoparticles are double labeled with the fluorescent dyes DiR (noncovalently) and DYOMICS-676 (covalently bound to HPMA copolymer), and their biodistribution is investigated noninvasively by multispectral optical imaging. Both covalent and noncovalent coatings cause changes in the pharmacokinetics and biodistribution in healthy and tumor-bearing mice. In addition to the intended tumor accumulation, high signals of both fluorescent dyes are also observed in other organs, including liver, ovaries, adrenal glands, and bone. The unintended accumulation of nanocarriers needs further detailed and systematic investigations, especially with respect to the observed ovarian and adrenal gland accumulation. %0 journal article %@ 0021-9606 %A Ran, Q.,Xu, X.,Dey, P.,Yu, S.,Lu, Y.,Dzubiella, J.,Haag, R.,Ballauff, M. %D 2018 %J The Journal of Chemical Physics %N %P 163324 %R doi:10.1063/1.5030601 %T Interaction of human serum albumin with dendritic polyglycerol sulfate: Rationalizing the thermodynamics of binding %U https://doi.org/10.1063/1.5030601 %X We study the thermodynamics of the interaction between human serum albumin (HSA) and dendritic polyglycerol sulfate (dPGS) of different sizes (generations) by isothermal titration calorimetry (ITC) and computer simulations. The analysis by ITC revealed the formation of a 1:1 complex for the dPGS-G2 of second generation. The secondary structure of HSA remained unchanged in the presence of dPGS-G2, as shown by circular dichroism. For higher generations, several HSA are bound to one polymer (dPGS-G4: 2; dPGS-G5.5: 4). The Gibbs free energy ΔGb was determined at different temperatures and salt concentrations. The binding constant Kb exhibited a logarithmic dependence on the salt concentration thus indicating a marked contribution of counterion-release entropy to ΔGb. The number of released counterions (∼4) was found to be independent of temperature. In addition, the temperature dependence of ΔGb was small, whereas the enthalpy ΔHITC was found to vary strongly with temperature. The corresponding heat capacity change ΔCp,ITC for different generations was of similar values [8 kJ/(mol K)]. The nonlinear van’t Hoff analysis of ΔGb revealed a significant heat capacity change ΔCp,vH of similar magnitude [6 kJ/(mol K)] accompanied by a strong enthalpy-entropy compensation. ΔGb obtained by molecular dynamics simulation with implicit water and explicit ions coincided with experimental results. The agreement indicates that the enthalpy-entropy compensation assigned to hydration effects is practically total and the binding affinity is fully governed by electrostatic interactions. %0 journal article %@ 0887-624X %A Hertz, D.,Leiske, M.N.,Wloka, T.,Traeger, A.,Hartlieb, M.,Kessels, M.M.,Schubert, S.,Qualmann, B.,Schubert, U.S. %D 2018 %J Journal of Polymer Science A %N 12 %P 1210-1224 %R doi:10.1002/pola.29000 %T Comparison of random and gradient amino functionalized poly(2‐oxazoline)s: Can the transfection efficiency be tuned by the macromolecular structure? %U https://doi.org/10.1002/pola.29000 12 %X Poly(ethylene imine) can be considered as the gold standard for DNA delivery into cells in vitro, but severe cytotoxic side‐effects and inapplicability for targeted approaches in vivo urgently call for the design of new gene carriers. Since poly(2‐oxazoline)s (P(Ox)s) can be easily synthesized and modified, this polymer class might be ideal for the optimization of polymeric transfection processes. The utilization of 2‐methyl‐2‐oxazoline (MeOx) and 2‐ethyl‐2‐oxazoline (EtOx) is also known to be beneficial because these monomers were suggested to overcome solubility issues, mediate stealth behavior and, consequently, facilitate a reduction of cytotoxicity. A series of amino (AmOx) functionalized P(Ox) copolymers with either MeOx (gradient copolymers) or EtOx (random copolymers) was synthesized, deprotected and biochemically characterized regarding cytotoxicity, polyplex formation ability, cellular uptake, and transfection efficiency. Polymers with percentages of AmOx higher than 35 mol % showed stable polyplex formation and also an increase in cytotoxicity. All elucidated P(Ox)s revealed a poor transfection efficiency in both L929 and Hepa1‐6 cell lines. However, the investigations contribute to the understanding of the influence of stealth units (MeOx and EtOx) and their distribution within the polymer chain on selected properties of polyplexes and describe characteristics of amino functionalized P(Ox)s in different cell lines. %0 journal article %@ 1949-2553 %A Hoelzer, D.,Leiske, M.N.,Hartlieb, M.,Bus, T.,Pretzel, D.,Hoeppener, S.,Kempe, K.,Thierbach, R.,Schubert, U.S. %D 2018 %J Oncotarget %N 32 %P 22316-22331 %R doi:10.18632/oncotarget.24806 %T Tumor targeting with pH-responsive poly(2-oxazoline)-based nanogels for metronomic doxorubicin treatment %U https://doi.org/10.18632/oncotarget.24806 32 %X The synthesis of a new nanogel drug carrier system loaded with the anti-cancer drug doxorubicin (DOX) is presented. Poly(2-oxazoline) (POx) based nanogels from block copolymer micelles were cross-linked and covalently loaded with DOX using pH-sensitive Schiff’ base chemistry. DOX loaded POx based nanogels showed a toxicity profile comparable to the free drug, while unloaded drug carriers showed no toxicity. Hemolytic activity and erythrocyte aggregation of the drug delivery system was found to be low and cellular uptake was investigated by flow cytometry and fluorescence microscopy. While the amount of internalized drug was enhanced when incorporated into a nanogel, the release of the drug into the nucleus was delayed. For in vivo investigations the nanogel drug delivery system was combined with a metronomic treatment of DOX. Low doses of free DOX were compared to equivalent DOX loaded nanogels in a xenograft mouse model. Treatment with POx based nanogels revealed a significant tumor growth inhibition and increase in survival time, while pure DOX alone had no effect on tumor progression. The biodistribution was investigated by microscopy of organs of mice and revealed a predominant localization of DOX within tumorous tissue. Thus, the POx based nanogel system revealed a therapeutic efficiency despite the low DOX concentrations and could be a promising strategy to control tumor growth with fewer side effects. %0 journal article %@ 0002-8703 %A Reinthaler, M.,Ozga, A.-K.,Sinning, D.,Curio, J.,Al-Hindwan, H.S.,Baeckemo-Johansson, J.,Jung, F.,Lendlein, A.,Rauch, G.,Landmesser, U. %D 2018 %J American Heart Journal %N %P 95-102 %R doi:10.1016/j.ahj.2018.03.025 %T Revival of transcatheter PFO closure: A meta-analysis of randomized controlled trials - impact of shunt size and age %U https://doi.org/10.1016/j.ahj.2018.03.025 %X Background,Transcatheter foramen ovale closure (TPC) has emerged as a potential treatment option for patients with cryptogenic strokes and persistent foramen ovale (PFO). However, previous randomized controlled trials could hardly demonstrate any benefit compared to medical treatment (Med-Tx). Recently new data have become available which may change current practice of transcatheter PFO closure.,Methods,A systematic review and meta-analysis comparing TPC and Med-Tx based on all available multicentric randomized controlled trials was performed. The primary outcome of interest was the recurrence of stroke in both groups.,Results,Five studies met the inclusion criteria with 1829 patients in the TPC and 1622 in the Med-Tx group. The median follow-up was 4 years. In the intention-to-treat analysis we found a statistically significant relative risk reduction in recurrence of strokes in the TPC group compared to the Med-Tx group (pooled hazard ratio (HR): 0.32; 95% CI: 0.13–0.8; P = .018). Excluding one study due to potential publication bias resulted in a pooled HR of 0.48 (95% CI: 0.25–0.91, P = .024). Patients younger than 45 years of age (pooled HR: 0.35; 95% CI: 0.16–0.75; P = .007) and those with moderate to severe shunt (pooled HR: 0.28; 95% CI: 0.14–0.55; P < .001) were more likely to benefit from closure.,Conclusion,According to our meta-analysis TPC plus antiplatelets was superior in terms of stroke prevention when compared to Med-Tx. Furthermore, patients with moderate to severe shunts and those younger than 45 years of age were found to benefit most from TPC. %0 journal article %@ 2059-8521 %A Wischke, C.,Baehr, E.,Racheva, M.,Heuchel, M.,Weigel, T.,Lendlein, A. %D 2018 %J MRS Advances %N 63 %P 3875-3881 %R doi:10.1557/adv.2018.630 %T Surface immobilization strategies for tyrosinase as biocatalyst applicable to polymer network synthesis %U https://doi.org/10.1557/adv.2018.630 63 %X Enzymes have recently attracted increasing attention in material research based on their capacity to catalyze the conversion of polymer-bound moieties for synthesizing polymer networks, particularly bulk hydrogels. In this study, the surface immobilization of a relevant enzyme, mushroom tyrosinase, should be explored using glass as model surface. In a first step, the glass support was functionalized with silanes to introduce either amine or carboxyl groups, as confirmed e.g. by X-ray photoelectron spectroscopy. By applying glutaraldehyde and EDC/NHS chemistry, respectively, surfaces have been activated for subsequent successful coupling of tyrosinase. Via protein hydrolysis and amino acid characterization by HPLC, the quantity of bound tyrosinase was shown to correspond to a full surface coverage. Based on the visualized enzymatic conversion of a test substrate at the glass support, the functionalized surfaces may be explored for surface-associated material synthesis in the future. %0 journal article %@ 0939-6411 %A Miceli, E.,Wedepohl, S.,Osorio Blanco, E.R.,Rimondino, G.N.,Martinelli, M.,Strumia, M.,Molina, M.,Kar, M.,Calderon, M. %D 2018 %J European Journal of Pharmaceutics and Biopharmaceutics %N %P 115-122 %R doi:10.1016/j.ejpb.2018.06.023 %T Semi-interpenetrated, dendritic, dual-responsive nanogels with cytochrome c corona induce controlled apoptosis in HeLa cells %U https://doi.org/10.1016/j.ejpb.2018.06.023 %X The use of thermoresponsive nanogels (NGs) allows the controlled release of therapeutic molecules upon a thermal switch. Usually, this strategy involves the use of temperature increase to activate cargo expulsion from shrinking NGs. In this study, poly(N-isopropylacrylamide) (pNIPAM)-based NGs were involved in the release of a therapeutic protein corona by temperature decrease. NGs based on dendritic polyglycerol (dPG) and thermoresponsive pNIPAM were semi-interpenetrated with poly(4-acryloylamine-4-(carboxyethyl)heptanodioic acid) (pABC). The resulting semi-interpenetrated NGs retain the thermoresponsive properties of pNIPAM, together with pH-responsive, dendritic pABC as a secondary network, in one single nanoparticle. Semi-interpenetrated polymer network (SIPN) NGs are stable in physiological conditions, exhibit a reversible phase transition at 35 °C, together with tunable electrophoretic mobilities around the body temperature. The binding of cytochrome c (cyt c) was successful on SIPN NGs in their collapsed state at 37 °C. Upon cooling of the samples to room temperature, the swelling of the NG effectively boosted the release of cyt c, as compared with the same kept at constant 37 °C. These responsive SIPN NGs were able to deliver cyt c to cancer cells and specifically induce apoptosis at 30 °C, while the cells remained largely unaffected at 37 °C. In this way, we show therapeutic efficacy of thermoresponsive NGs as protein carriers and their efficacy triggered by temperature decrease. We envision the use of such thermal trigger as relevant for the treatment of superficial tumors, in which induction of apoptosis can be controlled by the application of local cooling agents. %0 journal article %@ 1616-5187 %A Peng, X.,Behl, M.,Zhang, P.,Mazurek-Budzyñska, M.,Feng, Y.,Lendlein, A. %D 2018 %J Macromolecular Bioscience %N 12 %P 1800257 %R doi:10.1002/mabi.201800257 %T Synthesis of Well-Defined Dihydroxy Telechelics by (Co)polymerization of Morpholine-2,5-Diones Catalyzed by Sn(IV) Alkoxide %U https://doi.org/10.1002/mabi.201800257 12 %X Well-defined dihydroxy telechelic oligodepsipeptides (oDPs), which have a high application potential as building blocks for scaffold materials for tissue engineering applications or particulate carrier systems for drug delivery applications are synthesized by ring-opening polymerization (ROP) of morpholine-2,5-diones (MDs) catalyzed by 1,1,6,6-tetra-n-butyl-1,6-distanna-2,5,7,10-tetraoxacyclodecane (Sn(IV) alkoxide). In contrast to ROP catalyzed by Sn(Oct)2, the usage of Sn(IV) alkoxide leads to oDPs, with less side products and well-defined end groups, which is crucial for potential pharmaceutical applications. A slightly faster reaction of the ROP catalyzed by Sn(IV) alkoxide compared to the ROP initiated by Sn(Oct)2/EG is found. Copolymerization of different MDs resulted in amorphous copolymers with T gs between 44 and 54 °C depending on the molar comonomer ratios in the range from 25% to 75%. Based on the well-defined telechelic character of the Sn(IV) alkoxide synthesized oDPs as determined by matrix-assisted laser desorption/ionization time of flight measurements, they resemble interesting building blocks for subsequent postfunctionalization or multifunctional materials based on multiblock copolymer systems whereas the amorphous oDP-based copolymers are interesting building blocks for matrices of drug delivery systems. %0 journal article %@ 1743-5889 %A Miceli, E.,Kuropka, B.,Rosenauer, C.,Osorio Blanco, E.R.,Theune, L.E.,Kar, M.,Weise, C.,Morsbach, S.,freund, C.,Calderon, M. %D 2018 %J Nanomedicine %N 20 %P 217 %R doi:10.2217/nnm-2018-0217 %T Understanding the elusive protein corona of thermoresponsive nanogels %U https://doi.org/10.2217/nnm-2018-0217 20 %X Aim: We analyzed the protein corona of thermoresponsive, poly(N-isopropylacrylamide)- or poly(N-isopropylmethacrylamide)-based nanogels. Materials & methods: Traces of protein corona detected after incubation in human serum were characterized by proteomics and dynamic light scattering in undiluted serum. Results: Apolipoprotein B-100 and albumin were the main components of the protein coronae. For dendritic polyglycerol-poly(N-isopropylacrylamide) nanogels at 37°C, an increase in adsorbed immunoglobulin light chains was detected, followed by partially reversible nanogel aggregation. All nanogels in their hydrophilic state are colloidally stable in serum and bear a dysopsonin-rich protein corona. Conclusion: We observed strong changes in NG stability upon slight alterations in the composition of the protein coronae according to nanogel solvation state. Nanogels in their hydrophilic state possess safe protein coronae. %0 journal article %@ 1613-6810 %A Balke, J.,Volz, P.,Neumann, F.,Brodwolf, R.,Wolf, A.,Pischon, H.,Radbruch, M.,Mundhenk, L.,Gruber, A.D.,Ma, N.,Alexiev, U. %D 2018 %J Small %N 23 %P 1800310 %R doi:10.1002/smll.201800310 %T Visualizing Oxidative Cellular Stress Induced by Nanoparticles in the Subcytotoxic Range Using Fluorescence Lifetime Imaging %U https://doi.org/10.1002/smll.201800310 23 %X Nanoparticles hold a great promise in biomedical science. However, due to their unique physical and chemical properties they can lead to overproduction of intracellular reactive oxygen species (ROS). As an important mechanism of nanotoxicity, there is a great need for sensitive and high‐throughput adaptable single‐cell ROS detection methods. Here, fluorescence lifetime imaging microscopy (FLIM) is employed for single‐cell ROS detection (FLIM‐ROX) providing increased sensitivity and enabling high‐throughput analysis in fixed and live cells. FLIM‐ROX owes its sensitivity to the discrimination of autofluorescence from the unique fluorescence lifetime of the ROS reporter dye. The effect of subcytotoxic amounts of cationic gold nanoparticles in J774A.1 cells and primary human macrophages on ROS generation is investigated. FLIM‐ROX measures very low ROS levels upon gold nanoparticle exposure, which is undetectable by the conventional method. It is demonstrated that cellular morphology changes, elevated senescence, and DNA damage link the resulting low‐level oxidative stress to cellular adverse effects and thus nanotoxicity. Multiphoton FLIM‐ROX enables the quantification of spatial ROS distribution in vivo, which is shown for skin tissue as a target for nanoparticle exposure. Thus, this innovative method allows identifying of low‐level ROS in vitro and in vivo and, subsequently, promotes understanding of ROS‐associated nanotoxicity. %0 journal article %@ 2059-8521 %A Farhan, M.,Rudolph, T.,Kratz, K.,Lendlein, A. %D 2018 %J MRS Advances %N 63 %P 3861-3868 %R doi:10.1557/adv.2018.621 %T Torsional Fiber Actuators from Shape-memory Polymer %U https://doi.org/10.1557/adv.2018.621 63 %X Humanoid robots, prosthetic limbs and exoskeletons require soft actuators to perform their primary function, which is controlled movement. In this work, we explored whether crosslinked poly[ethylene-co-(vinyl acetate)] (cPEVA) fibers, with different vinyl acetate (VA) content can serve as torsional fiber actuators, exhibiting temperature controlled reversible rotational changes. Broad melting transitions ranging from 50 to 90 °C for cPEVA18-165 or from 40 to 80 °C for cPEVA28-165 fibers in combination with complete crystallization at temperatures around 10 °C make them suitable actuating materials with adjustable actuation temperature ranges between 10 and 70 °C during repetitive cooling and heating. The obtained fibers exhibited a circular cross section with diameters around 0.4±0.1 mm, while a length of 4 cm was employed for the investigation of reversible rotational actuation after programming by twist insertion using 30 complete rotations at a temperature above melting transition. Repetitive heating and cooling between 10 to 60 °C or 70 °C of one-end-tethered programmed fibers revealed reversible rotations and torsional force. During cooling 3±1 complete rotations (Δθr = + 1080±360°) in twisting direction were observed, while 4±1 turns in the opposite direction (Δθr = - 1440±360°) were found during heating. Such torsional fiber actuators, which are capable of approximately one rotation per cm fiber length, can serve as miniaturized rotary motors to provide rotational actuation in futuristic humanoid robots. %0 journal article %@ 1742-7061 %A Sarem, M.,Arya, N.,Heizmann, M.,Neffe, A.,Barbero, A.,Gebauer, T.,Martin, I.,Lendlein, A.,Shastri, V. %D 2018 %J Acta Biomaterialia %N %P 83-94 %R doi:10.1016/j.actbio.2018.01.025 %T Interplay between stiffness and degradation of architectured gelatin hydrogels leads to differential modulation of chondrogenesis in vitro and in vivo %U https://doi.org/10.1016/j.actbio.2018.01.025 %X The limited capacity of cartilage to heal large lesions through endogenous mechanisms has led to extensive effort to develop materials to facilitate chondrogenesis. Although physical-chemical properties of biomaterials have been shown to impact in vitro chondrogenesis, whether these findings are translatable in vivo is subject of debate. Herein, architectured 3D hydrogel scaffolds (ArcGel) (produced by crosslinking gelatin with ethyl lysine diisocyanate (LDI)) were used as a model system to investigate the interplay between scaffold mechanical properties and degradation on matrix deposition by human articular chondrocytes (HAC) from healthy donors in vitro and in vivo. Using ArcGel scaffolds of different tensile and shear modulus, and degradation behavior; in this study, we compared the fate of ex vivo engineered ArcGels-chondrocytes constructs, i.e. the traditional tissue engineering approach, with the de novo formation of cartilaginous tissue in HAC laden ArcGels in an ectopic nude mouse model. While the softer and fast degrading ArcGel (LNCO3) was more efficient at promoting chondrogenic differentiation in vitro, upon ectopic implantation, the stiffer and slow degrading ArcGel (LNCO8) was superior in maintaining chondrogenic phenotype in HAC and retention of cartilaginous matrix. Furthermore, surprisingly the de novo formation of cartilage tissue was promoted only in LNCO8. Since HAC cultured for only three days in the LNCO8 environment showed upregulation of hypoxia-associated genes, this suggests a potential role for hypoxia in the observed in vivo outcomes. In summary, this study sheds light on how immediate environment (in vivo versus in vitro) can significantly impact the outcomes of cell-laden biomaterials. %0 journal article %@ 1439-4235 %A Fang, L.,Gould, O.E.C.,Lysyakova, L.,Jiang, Y.,Sauter, T.,Frank, O.,Becker, T.,Schossig, M.,Kratz, K.,Lendlein, A. %D 2018 %J ChemPhysChem %N 16 %P 2078-2084 %R doi:10.1002/cphc.201701362 %T Implementing and Quantifying the Shape-Memory Effect of Single Polymeric Micro/Nanowires with an Atomic Force Microscope %U https://doi.org/10.1002/cphc.201701362 16 %X The implementation of shape‐memory effects (SME) in polymeric micro‐ or nano‐objects currently relies on the application of indirect macroscopic manipulation techniques, for example, stretchable molds or phantoms, to ensembles of small objects. Here, we introduce a method capable of the controlled manipulation and SME quantification of individual micro‐ and nano‐objects in analogy to macroscopic thermomechanical test procedures. An atomic force microscope was utilized to address individual electro‐spun poly(ether urethane) (PEU) micro‐ or nanowires freely suspended between two micropillars on a micro‐structured silicon substrate. In this way, programming strains of 10±1% or 21±1% were realized, which could be successfully fixed. An almost complete restoration of the original free‐suspended shape during heating confirmed the excellent shape‐memory performance of the PEU wires. Apparent recovery stresses of σmax,app=1.2±0.1 and 33.3±0.1 MPa were obtained for a single microwire and nanowire, respectively. The universal AFM test platform described here enables the implementation and quantification of a thermomechanically induced function for individual polymeric micro‐ and nanosystems. %0 journal article %@ 2059-8521 %A Machatschek, R.,Schulz, B.,Lendlein, A. %D 2018 %J MRS Advances %N 63 %P 3883-3889 %R doi:10.1557/adv.2018.602 %T The influence of pH on the molecular degradation mechanism of PLGA %U https://doi.org/10.1557/adv.2018.602 63 %X Poly[(rac-lactide)-co-glycolide] (PLGA) is used in medicine to provide mechanical support for healing tissue or as matrix for controlled drug release. The properties of this copolymer depend on the evolution of the molecular weight of the material during degradation, which is determined by the kinetics of the cleavage of hydrolysable bonds. The generally accepted description of the degradation of PLGA is a random fragmentation that is autocatalyzed by the accumulation of acidic fragments inside the bulk material. Since mechanistic studies with lactide oligomers have concluded a chain-end scission mechanism and monolayer degradation experiments with polylactide found no accelerated degradation at lower pH, we hypothesize that the impact of acidic fragments on the molecular degradation kinetics of PLGA is overestimated. By means of the Langmuir monolayer degradation technique, the molecular degradation kinetics of PLGA at different pH could be determined. Protons did not catalyze the degradation of PLGA. The molecular mechanism at neutral pH and low pH is a combination of random and chainend-cut events, while the degradation under strongly alkaline conditions is determined by rapid chainend cuts. We suggest that the degradation of bulk PLGA is not catalyzed by the acidic degradation products. Instead, increased concentration of small fragments leads to accelerated mass loss via fast chain-end cut events. In the future, we aim to substantiate the proposed molecular degradation mechanism of PLGA with interfacial rheology. %0 journal article %@ 2059-8521 %A Razzaq, M.Y.,Behl, M.,Lendlein, A. %D 2018 %J MRS Advances %N 63 %P 3783-3791 %R doi:10.1557/adv.2018.613 %T Thermally-Induced Actuation of Magnetic Nanocomposites Based on Oligo(Omega-Pentadecalactone) and Covalently Integrated Magnetic Nanoparticles %U https://doi.org/10.1557/adv.2018.613 63 %X The incorporation of inorganic particles in a polymer matrix has been established as a method to adjust the mechanical performance of composite materials. We report on the influence of covalent integration of magnetic nanoparticles (MNP) on the actuation behavior and mechanical performance of hybrid nanocomposite (H-NC) based shape-memory polymer actuators (SMPA). The H-NC were synthesized by reacting two types of oligo(ω-pentadecalactone) (OPDL) based precursors with terminal hydroxy groups, a three arm OPDL (3AOPDL, Mn = 6000 g mol·1-1) and an OPDL (Mn =3300 g · mol-1) coated magnetite nanoparticle (Ø = 10 ± 2 nm), with a diisocyanate. These H-NC were compared to the homopolymer network regarding the actuation performance, contractual stress (σcontr) as well as thermal and mechanical properties. The melting range of the OPDL crystals (ΔTm,OPDL) was shifted in homo polymer networks from 36 °C – 76 °C to 41°C – 81 °C for H-NC with 9 wt% of MNP content. The actuators were explored by variation of separating temperature (Tsep), which splits the OPDL crystalline domain into actuating and geometry determining segments. Tsep was varied in the melting range of the nanocomposites and the actuation capability and contractual stress (σcontr) of the nanocomposite actuators could be adjusted. The reversible strain (εrev) was decreased from 11 ± 0.3% for homo polymer network to 3.2±0.3% for H-NC9 with 9 wt% of MNP indicating a restraining effect of the MNP on chain mobility. The results show that the performance of H-NCs in terms of thermal and elastic properties can be tailored by MNP content, however for higher reversible actuation, lower MNP contents are preferable. %0 journal article %@ 0896-4327 %A Curio, J.,Reinthaler, M.,Kasner, M.,Al-Hindwan, H.S.A.,Baeckemo-Johansson, J.,Neumann, T.,Jacobs, S.,Lauten, A.,Landmesser, U. %D 2018 %J Journal of Interventional Cardiology %N 1 %P 83-90 %R doi:10.1111/joic.12457 %T Repeated MitraClip procedure in patients with recurrent MR after a successful first procedure: Limitations and outcome %U https://doi.org/10.1111/joic.12457 1 %X Objectives,The present study aimed to evaluate the outcome and potential limitations of a repeated MitraClip procedure (ReClip).,Background,The MitraClip procedure has emerged as a treatment option in high surgical risk patients suffering from severe mitral regurgitation (MR). However, despite successful initial repair a significant number of patients develops severe recurrent MR.,Methods,Patients undergoing a ReClip procedure in our institution were retrospectively identified. Baseline data and the procedural outcome were assessed to identify potential limitations of such procedures.,Results,Fifteen out of 234 patients undergoing a mitral‐valve repair with the MitraClip device (Abbott Vascular) underwent a ReClip due to recurrent MR. In 11 patients, a MR reduction of at least one degree without causing mitral valve stenosis (trans‐mitral mean gradient ≥5 mmHg) was achieved by performing a ReClip. After 1 year, two patients developed severe recurrent MR again. Pulmonary artery pressures significantly decreased after the procedure in individuals with successful repair (MR reduction of at least one degree and mitral valve mean gradient <5 mmHg).,Conclusion,A ReClip procedure may be feasible in patients with recurrent MR but the risk benefit ratio should be carefully balanced against other treatment options. %0 journal article %@ 0168-3659 %A Ceylan Tuncaboylu, D.,Friess, F.,Wischke, C.,Lendlein, A. %D 2018 %J Journal of Controlled Release %N %P 240-247 %R doi:10.1016/j.jconrel.2018.06.022 %T A multifunctional multimaterial system for on-demand protein release %U https://doi.org/10.1016/j.jconrel.2018.06.022 %X In order to provide best control of the regeneration process for each individual patient, the release of protein drugs administered during surgery may need to be timely adapted and/or delayed according to the progress of healing/regeneration. This study aims to establish a multifunctional implant system for a local on-demand release, which is applicable for various types of proteins. It was hypothesized that a tubular multimaterial container kit, which hosts the protein of interest as a solution or gel formulation, would enable on-demand release if equipped with the capacity of diameter reduction upon external stimulation. Using devices from poly(ɛ-caprolactone) networks, it could be demonstrated that a shape-memory effect activated by heat or NIR light enabled on-demand tube shrinkage. The decrease of diameter of these shape-memory tubes (SMT) allowed expelling the payload as demonstrated for several proteins including SDF-1α, a therapeutically relevant chemotactic protein, to achieve e.g. continuous release with a triggered add-on dosing (open tube) or an on-demand onset of bolus or sustained release (sealed tube). Considering the clinical relevance of protein factors in (stem) cell attraction to lesions and the progress in monitoring biomarkers in body fluids, such on-demand release systems may be further explored e.g. in heart, nerve, or bone regeneration in the future. %0 journal article %@ 2059-8521 %A Yan, W.,Fang, L.,Noechel, U.,Gould, O.E.C.,Behl, M.,Kratz, K.,Lendlein, A. %D 2018 %J MRS Advances %N 63 %P 3741-3749 %R doi:10.1557/adv.2018.590 %T Investigating the Roles of Crystallizable and Glassy Switching Segments within Multiblock Copolymer Shape-Memory Materials %U https://doi.org/10.1557/adv.2018.590 63 %X The variation of the molecular architecture of multiblock copolymers has enabled the introduction of functional behaviour and the control of key mechanical properties. In the current study, we explore the synergistic relationship of two structural components in a shape-memory material formed of a multiblock copolymer with crystallizable poly(ε-caprolactone) and crystallizable poly[oligo(3S-iso-butylmorpholine-2,5-dione)] segments (PCL-PIBMD). The thermal and structural properties of PCL-PIBMD films were compared with PCL-PU and PIBMD-PU, investigated by means of DSC, SAXS and WAXS measurements. The shape-memory properties were quantified by cyclic, thermomechanical tensile tests, where deformation strains up to 900% were applied for programming PCL-PIBMD films at 50 °C. Toluene vapor treatment experiments demonstrated that the temporary shape was fixed mainly by glassy PIBMD domains at strains lower than 600%, with the PCL contribution to fixation increasing to 42±2% at programming strains of 900%. This study into the shape-memory mechanism of PCL-PIBMD provides insight into the structure-function relation in multiblock copolymers with both crystallizable and glassy switching segments. %0 journal article %@ 0935-9648 %A Eckert, A.,RudolphT.,Guo, J.,Mang, T.,Walther, A. %D 2018 %J Advanced Materials %N 32 %P 1802477 %R doi:10.1002/adma.201802477 %T Exceptionally Ductile and Tough Biomimetic Artificial Nacre with Gas Barrier Function %U https://doi.org/10.1002/adma.201802477 32 %X Synthetic mimics of natural high‐performance structural materials have shown great and partly unforeseen opportunities for the design of multifunctional materials. For nacre‐mimetic nanocomposites, it has remained extraordinarily challenging to make ductile materials with high stretchability at high fractions of reinforcements, which is however of crucial importance for flexible barrier materials. Here, highly ductile and tough nacre‐mimetic nanocomposites are presented, by implementing weak, but many hydrogen bonds in a ternary nacre‐mimetic system consisting of two polymers (poly(vinyl amine) and poly(vinyl alcohol)) and natural nanoclay (montmorillonite) to provide efficient energy dissipation and slippage at high nanoclay content (50 wt%). Tailored interactions enable exceptional combinations of ductility (close to 50% strain) and toughness (up to 27.5 MJ m−3). Extensive stress whitening, a clear sign of high internal dynamics at high internal cohesion, can be observed during mechanical deformation, and the materials can be folded like paper into origami planes without fracture. Overall, the new levels of ductility and toughness are unprecedented in highly reinforced bioinspired nanocomposites and are of critical importance to future applications, e.g., as barrier materials needed for encapsulation and as a printing substrate for flexible organic electronics. %0 journal article %@ 0014-3057 %A Piluso, S.,Vukicevic, R.,Noechel, U.,Braune, S.,Lendlein, A.,Neffe, A. %D 2018 %J European Polymer Journal %N %P 77-85 %R doi:10.1016/j.eurpolymj.2018.01.017 %T Sequential alkyne-azide cycloadditions for functionalized gelatin hydrogel formation %U https://doi.org/10.1016/j.eurpolymj.2018.01.017 %X While click chemistry reactions for biopolymer network formation are attractive as the defined reactions may allow good control of the network formation and enable subsequent functionalization, tailoring of gelatin network properties over a wide range of mechanical properties has yet to be shown. Here, it is demonstrated that copper-catalyzed alkyne-azide cycloaddition of alkyne functionalized gelatin with diazides gave hydrogel networks with properties tailorable by the ratio of diazide to gelatin and diazide rigidity. 4,4′-diazido-2,2′-stilbenedisulfonic acid, which has been used as rigid crosslinker, yielded hydrogels with Young’s moduli E of 50–390 kPa and swelling degrees Q of 150–250 vol.%, while the more flexible 1,8-diazidooctane resulted in hydrogels with E = 125–280 kPa and Q = 225–470 vol.%. Storage moduli could be varied by two orders of magnitude (G′ = 100–20,000 Pa). An indirect cytotoxicity test did not show cytotoxic properties. Even when employing 1:1 ratios of alkyne and azide moieties, the hydrogels were shown to contain both, unreacted alkyne groups on the gelatin backbone as well as dangling chains carrying azide groups as shown by reaction with functionalized fluorescein. The free groups, which can be tailored by the employed ratio of the reactants, are accessible for covalent attachment of drugs, as was demonstrated by functionalization with dexamethasone. The sequential network formation and functionalization with click chemistry allows access to multifunctional materials relevant for medical applications. %0 journal article %@ 1744-683X %A Nikam, R.,Xu, X.,Ballauff, M.,Kanduc, M.,Dzubiella, J. %D 2018 %J Soft Matter %N 21 %P 4300-4310 %R doi:10.1039/c8sm00714d %T Charge and hydration structure of dendritic polyelectrolytes: molecular simulations of polyglycerol sulphate %U https://doi.org/10.1039/c8sm00714d 21 %X Macromolecules based on dendritic or hyperbranched polyelectrolytes have been emerging as high potential candidates for biomedical applications. Here we study the charge and solvation structure of dendritic polyglycerol sulphate (dPGS) of generations 0 to 3 in aqueous sodium chloride solution by explicit-solvent molecular dynamics computer simulations. We characterize dPGS by calculating several important properties such as relevant dPGS radii, molecular distributions, the solvent accessible surface area, and the partial molecular volume. In particular, as the dPGS exhibits high charge renormalization effects, we address the challenges of how to obtain a well-defined effective charge and surface potential of dPGS for practical applications. We compare implicit- and explicit-solvent approaches in our all-atom simulations with the coarse-grained simulations from our previous work. We find consistent values for the effective electrostatic size (i.e., the location of the effective charge of a Debye–Hückel sphere) within all the approaches, deviating at most by the size of a water molecule. Finally, the excess chemical potential of water insertion into dPGS and its thermodynamic signature are presented and rationalized. %0 journal article %@ 1525-7797 %A Xu, X.,Ran, Q.,Dey, P.,Nikam, R.,Haag, R.,Ballauff, M.,Dzubiella, J. %D 2018 %J Biomacromolecules %N 2 %P 409-416 %R doi:10.1021/acs.biomac.7b01499 %T Counterion-Release Entropy Governs the Inhibition of Serum Proteins by Polyelectrolyte Drugs %U https://doi.org/10.1021/acs.biomac.7b01499 2 %X Dendritic polyelectrolytes constitute high potential drugs and carrier systems for biomedical purposes. Still, their biomolecular interaction modes, in particular those determining the binding affinity to proteins, have not been rationalized. We study the interaction of the drug candidate dendritic polyglycerol sulfate (dPGS) with serum proteins using isothermal titration calorimetry (ITC) interpreted and complemented with molecular computer simulations. Lysozyme is first studied as a well-defined model protein to verify theoretical concepts, which are then applied to the important cell adhesion protein family of selectins. We demonstrate that the driving force of the strong complexation, leading to a distinct protein corona, originates mainly from the release of only a few condensed counterions from the dPGS upon binding. The binding constant shows a surprisingly weak dependence on dPGS size (and bare charge) which can be understood by colloidal charge-renormalization effects and by the fact that the magnitude of the dominating counterion-release mechanism almost exclusively depends on the interfacial charge structure of the protein-specific binding patch. Our findings explain the high selectivity of P- and L-selectins over E-selectin for dPGS to act as a highly anti-inflammatory drug. The entire analysis demonstrates that the interaction of proteins with charged polymeric drugs can be predicted by simulations with unprecedented accuracy. Thus, our results open new perspectives for the rational design of charged polymeric drugs and carrier systems. %0 journal article %@ 1613-6810 %A Xiang, S.,Sarem, M.,Shah, S.,Shastri, V.P. %D 2018 %J Small %N 14 %P 1704245 %R doi:10.1002/smll.201704245 %T Liposomal Treatment of Cancer Cells Modulates Uptake Pathway of Polymeric Nanoparticles by Altering Membrane Stiffness %U https://doi.org/10.1002/smll.201704245 14 %X Nanomedicines can be taken up by cells via nonspecific and dynamin‐dependent (energy‐dependent) clathrin and caveolae‐mediated endocytosis. While significant effort has focused on targeting pathway‐specific transporters, the role of nanobiophysics in the cell lipid bilayer nanoparticle uptake pathway remains largely unexplored. In this study, it is demonstrated that stiffness of lipid bilayer is a key determinant of uptake of liposomes by mammalian cells. Dynamin‐mediated endocytosis (DME) of liposomes is found to correlate with its phase behavior, with transition toward solid phase promoting DME, and transition toward fluidic phase resulting in dynamin‐independent endocytosis. Since liposomes can transfer lipids to cell membrane, it is sought to engineer the biophysical properties of the membrane of breast epithelial tumor cells (MD‐MBA‐231) by treatment with phosphatidylcholine liposomes, and elucidate its effect on the uptake of polymeric nanoparticles. Analysis of the giant plasma membrane vesicles derived from treated cells using flicker spectroscopy reveals that liposome treatment alters membrane stiffness and DME of nanoparticles. Since liposomes have a history of use in drug delivery, localized priming of tumors with liposomes may present a hitherto unexploited means of targeting tumors based on biophysical interactions. %0 journal article %@ 0032-3861 %A Yu, S.,Kent, B.,Jafta, C.J.,Petzold, A.,Radulescu, A.,Schuchardt, M.,Toelle, M.,Giet, M.van der,Zidek, W.,Ballauff, M. %D 2018 %J Polymer %N %P 175-183 %R doi:10.1016/j.polymer.2018.02.060 %T Stability of human serum albumin structure upon toxin uptake explored by small angle neutron scattering %U https://doi.org/10.1016/j.polymer.2018.02.060 %X Possible denaturation or tertiary structural changes of the protein human serum albumin (HSA) upon adsorption of uremic toxin is investigated using small-angle neutron scattering (SANS). Calorimetric data in previous studies give proof of the binding between HSA and two classes of uremic toxins: i) small molecular weight and ii) middle molecular weight molecules. A representative polyelectrolyte of negative net charge is used as a model middle molecule and two molecules phenylacetic acid (PhAA) and indoxyl sulfate (IDS) represent the small molecular weight toxins. The present study find no proof of destabilization of the protein structure upon toxin uptake. Analyzing the structure factor of scattering intensities from high concentrated protein samples complexed with PhAA and IDS show that interaction between native and complexed HSA is also not altered. However, a small effect of the net charge of HSA is found in the case of urea modified proteins. %0 journal article %@ 0024-9297 %A Yan, W.,Rudolph, T.,Noechel, U.,Gould, O.,Behl, M.,Kratz, K.,Lendlein, A. %D 2018 %J Macromolecules %N 12 %P 4624-4632 %R doi:10.1021/acs.macromol.8b00322 %T Reversible Actuation of Thermoplastic Multiblock Copolymers with Overlapping Thermal Transitions of Crystalline and Glassy Domains %U https://doi.org/10.1021/acs.macromol.8b00322 12 %X Polymeric materials possessing specific features like programmability, high deformability, and easy processability are highly desirable for creating modern actuating systems. In this study, thermoplastic shape-memory polymer actuators obtained by combining crystallizable poly(ε-caprolactone) (PCL) and poly(3S-isobutylmorpholin-2,5-dione) (PIBMD) segments in multiblock copolymers are described. We designed these materials according to our hypothesis that the confinement of glassy PIBMD domains present at the upper actuation temperature contribute to the stability of the actuator skeleton, especially at large programming strains. The copolymers have a phase-segregated morphology, indicated by the well-separated melting and glass transition temperatures for PIBMD and PCL, but possess a partially overlapping Tm of PCL and Tg of PIBMD in the temperature interval from 40 to 60 °C. Crystalline PIBMD hard domains act as strong physical netpoints in the PIBMD−PCL bulk material enabling high deformability (up to 2000%) and good elastic recoverability (up to 80% at 50 °C above Tm,PCL). In the programmed thermoplastic actuators a high content of crystallizable PCL actuation domains ensures pronounced thermoreversible shape changes upon repetitive cooling and heating. The programmed actuator skeleton, composed of PCL crystals present at the upper actuation temperature Thigh and the remaining glassy PIBMD domains, enabled oriented crystallization upon cooling. The actuation performance of PIBMD-PCL could be tailored by balancing the interplay between actuation and skeleton, but also by varying the quantity of crystalline PIBMD hard domains via the copolymer composition, the applied programming strain, and the choice of Thigh. The actuator with 17 mol% PIBMD showed the highest reversible elongation of 11.4% when programmed to a strain of 900% at 50 °C. It is anticipated that the presented thermoplastic actuator materials can be applied as modern compression textiles. %0 journal article %@ 0027-8424 %A Sarem, M.,Heizmann, M.,Barbero, A.,Martin, I.,Shastri, V.P. %D 2018 %J Proceedings of the National Academy of Sciences of the United States of America: PNAS %N 27 %P E6135-E6144 %R doi:10.1073/pnas.1805159115 %T Hyperstimulation of CaSR in human MSCs by biomimetic apatite inhibits endochondral ossification via temporal down-regulation of PTH1R %U https://doi.org/10.1073/pnas.1805159115 27 %X In adult bone injuries, periosteum-derived mesenchymal stem/stromal cells (MSCs) form bone via endochondral ossification (EO), whereas those from bone marrow (BM)/endosteum form bone primarily through intramembranous ossification (IMO). We hypothesized that this phenomenon is influenced by the proximity of MSCs residing in the BM to the trabecular bone microenvironment. Herein, we investigated the impact of the bone mineral phase on human BM-derived MSCs’ choice of ossification pathway, using a biomimetic bone-like hydroxyapatite (BBHAp) interface. BBHAp induced hyperstimulation of extracellular calcium-sensing receptor (CaSR) and temporal down-regulation of parathyroid hormone 1 receptor (PTH1R), leading to inhibition of chondrogenic differentiation of MSCs even in the presence of chondroinductive factors, such as transforming growth factor-β1 (TGF-β1). Interestingly rescuing PTH1R expression using human PTH fragment (1–34) partially restored chondrogenesis in the BBHAp environment. In vivo studies in an ectopic site revealed that the BBHAp interface inhibits EO and strictly promotes IMO. Furthermore, CaSR knockdown (CaSR KD) disrupted the bone-forming potential of MSCs irrespective of the absence or presence of the BBHAp interface. Our findings confirm the expression of CaSR in human BM-derived MSCs and unravel a prominent role for the interplay between CaSR and PTH1R in regulating MSC fate and the choice of pathway for bone formation. %0 journal article %@ 2470-1343 %A Ran, Q.,Xu, X.,Dzubiella, J.,Haag, R.,Ballauff, M. %D 2018 %J ACS Omega %N 8 %P 9086-9095 %R doi:10.1021/acsomega.8b01493 %T Thermodynamics of the Binding of Lysozyme to a Dendritic Polyelectrolyte: Electrostatics Versus Hydration %U https://doi.org/10.1021/acsomega.8b01493 8 %X The interaction between dendritic polyglycerol sulfate (dPGS) of the second generation and lysozyme was studied by isothermal titration calorimetry (ITC) at different temperatures and salt concentrations. Analysis by ITC showed that 2–3 lysozyme molecules were bound to each dPGS. The resulting binding constant Kb and the Gibbs free energy ΔGo decreased markedly with increasing salt concentration but were nearly independent of temperature. The salt dependence of Kb led to the conclusion that ca. 3 counterions bound to dPGS were released upon complex formation. The gain in entropy ΔGci by this counterion-release scales logarithmically with salt concentration and is the main driving force for binding. The temperature dependence of ΔGo was analyzed by the nonlinear van’t Hoff plot, taking into account a finite heat capacity change ΔCp,vH. This evaluation led to the binding enthalpy ΔHvH and the binding entropy ΔSvH. Both quantities varied strongly with temperature and even changed sign, but they compensated each other throughout the entire range of temperature. Coarse-grained computer simulations with explicit salt and implicit water were used to obtain the binding free energies that agreed with ITC results. Thus, electrostatic factors were the driving forces for binding whereas all hydration contributions leading to the strongly varying ΔHvH and ΔSvH canceled out. The calorimetric enthalpy ΔHITC measured directly by ITC differed largely from ΔHvH. ITC measurements done in two buffer systems with different ionization enthalpies revealed that binding was linked to buffer ionization and a partial protonation of the protein. %0 journal article %@ 1932-6203 %A Stervbo, U.,Pohlmann, D.,Baron, U.,Bozzetti, C.,Juerchott, K.,Maelzer, J.N.,Nienen, M.,Olek, S.,roch, T.,Schulz, A.R.,Warth, S.,Neumann, A.,Thiel, A.,Gruetzkau, A.,Babel, N. %D 2017 %J PLoS One %N 7 %P e0181161 %R doi:10.1371/journal.pone.0181161 %T Age dependent differences in the kinetics of GammaDelta T cells after influenza vaccination %U https://doi.org/10.1371/journal.pone.0181161 7 %X Immunosenescence is a hallmark of the aging immune system and is considered the main cause of a reduced vaccine efficacy in the elderly. Although γδ T cells can become activated by recombinant influenza hemagglutinin, their age-related immunocompetence during a virus-induced immune response has so far not been investigated. In this study we evaluate the kinetics of γδ T cells after vaccination with the trivalent 2011/2012 northern hemisphere seasonal influenza vaccine. We applied multi-parametric flow cytometry to a cohort of 21 young (19–30 years) and 23 elderly (53–67 years) healthy individuals. Activated and proliferating γδ T cells, as identified by CD38 and Ki67 expression, were quantified on the days 0, 3, 7, 10, 14, 17, and 21. We observed a significantly lower number of activated and proliferating γδ T cells at baseline and following vaccination in elderly as compared to young individuals. The kinetics changes of activated γδ T cells were much stronger in the young, while corresponding changes in the elderly occurred slower. In addition, we observed an association between day 21 HAI titers of influenza A and the frequencies of Ki67+ γδ T cells at day 7 in the young. In conclusion, aging induces alterations of the γδ T cell response that might have negative implications for vaccination efficacy. %0 journal article %@ 1944-8244 %A Farhan, M.,Rudolph, T.,Noechel, U.,Yan, W.,Kratz, K.,Lendlein, A. %D 2017 %J ACS Applied Materials and Interfaces %N 39 %P 33559-33564 %R doi:10.1021/acsami.7b11316 %T Noncontinuously Responding Polymeric Actuators %U https://doi.org/10.1021/acsami.7b11316 39 %X Reversible movements of current polymeric actuators stem from the continuous response to signals from a controlling unit, and subsequently cannot be interrupted without stopping or eliminating the input trigger. Here, we present actuators based on cross-linked blends of two crystallizable polymers capable of pausing their movements in a defined manner upon continuous cyclic heating and cooling. This noncontinuous actuation can be adjusted by varying the applied heating and cooling rates. The feasibility of these devices for technological applications was shown in a 140 cycle experiment of free-standing noncontinuous shape shifts, as well as by various demonstrators. %0 journal article %@ 2059-8521 %A Xu, X.,Wang, W.,Li, Z.,Kratz, K.,Ma, N.,Lendlein, A. %D 2017 %J MRS Advances %N 47 %P 2561-2570 %R doi:10.1557/adv.2017.487 %T Microwell Geometry Modulates Interleukin-6 Secretion in Human Mesenchymal Stem Cells %U https://doi.org/10.1557/adv.2017.487 47 %X The therapeutic effect of mesenchymal stem cells (MSCs) has been investigated in various clinical applications, in which their functional benefits are mainly attributed to the secretion of soluble factors. The enhancement of their therapeutic potential by physical and chemical properties of cell culture substrate is a safe and effective strategy, since they are highly sensitive to their microenvironment such as the elasticity and surface topography. In this study, we demonstrated that the geometry of polymeric substrate regulated the interleukin-6 (IL-6) secretion of human adipose derived MSCs. Polystyrene substrates comprising arrays of square-shaped (S50) or round-shaped (R50) microwells (side length or diameter of 50 μm and depth of 10 μm) were prepared by injection molding. Cellular apoptototic rate of MSCs was not affected by the microwell geometry, while the upregulated secretion of IL-6 and the enhancement of nuclear transcription factor STAT3 were detected in MSCs seeded on S50 substrate. The geometry-dependent modulatory effect was highly associated with ROCK signaling cascade. The inhibition of ROCK abolished the disparity in IL-6 secretion. These findings highlight the possibility to steer the secretion profile of stem cells via microwell geometry in combination with the manipulation of ROCK signaling pathway. %0 journal article %@ 2050-750X %A Li, Z.,Wang, W.,Xu, X.,Kratz, K.,Zou, J.,Lysyakova, L.,Heuchel, M.,Kurtz, A.,Gossen, M.,Ma, N.,Lendlein, A. %D 2017 %J Journal of Materials Chemistry B %N 35 %P 7415-7425 %R doi:10.1039/C7TB01232B %T Integrin β1 activation by micro-scale curvature promotes pro-angiogenic secretion of human mesenchymal stem cells %U https://doi.org/10.1039/C7TB01232B 35 %X Fine tuning of the substrate properties to modulate the function of mesenchymal stem cells (MSCs) has emerged as an attractive strategy to optimize their therapeutic potential. In the context of the mechanotransduction process, the conformational change of integrin (integrin activation) plays a critical role in perceiving and transmitting various signals. In this study, polymeric cell culture inserts with defined bottom roughness were fabricated as a model system for cell cultivation. We showed that the conformational change of integrin and its downstream signaling cascade of human adipose-derived mesenchymal stem cells (hADSCs) could be modulated by the curvature of the cell–material interface. The curvature of the substrate surface with a roughness in the size range of a single cell could strongly increase the high-affinity β1 integrin level of hADSCs without alteration of the total β1 integrin level. Further, the integrin downstream FAK/ERK and Rho/ROCK pathways were activated and resulted in upregulated VEGF secretion of hADSCs. A conditioned medium on such a surface exhibited a strong pro-angiogenic effect, with an increased formation of the tubular structure, a higher migration velocity of endothelial cells and an enhanced blood vessel density in an ex vivo hen's egg test-chorioallantoic membrane (HET-CAM). These results highlighted the clinical potential to manipulate the topographic features of the cell culture substrate, whereby to regulate integrin affinity states and further control MSC functions. %0 journal article %@ 0340-5761 %A Grohmann, L.,Becker, D.,Rademann, J.,Ma, N.,Schaefer-Korting, M.,Weindl, G. %D 2017 %J Archives of Toxicology %N 10 %P 3307-3316 %R doi:10.1007/s00204-017-1954-5 %T Biotransformation of 2,4-toluenediamine in human skin and reconstructed tissues %U https://doi.org/10.1007/s00204-017-1954-5 10 %X Reconstructed human epidermis (RHE) is used for risk assessment of chemicals and cosmetics and RHE as well as reconstructed human full-thickness skin (RHS) become important for e.g., the pre-clinical development of drugs. Yet, the knowledge regarding their biotransformation capacity is still limited, although the metabolic activity is highly relevant for skin sensitization, genotoxicity, and the efficacy of topical dermatics. The biotransformation of the aromatic amine 2,4-toluenediamine (2,4-TDA) has been compared in two commercially available RHS to normal human skin ex vivo, and in primary epidermal keratinocytes and dermal fibroblasts as well as in vitro generated epidermal Langerhans cells and dermal dendritic cells. The mono N-acetylated derivative N-(3-amino-4-methyl-phenyl)acetamide (M1) was the only metabolite detectable in substantial amounts indicating the predominance of N-acetylation. RHS exceeded human skin ex vivo in N-acetyltransferase activity and in cell cultures metabolite formation ranked as follows: keratinocytes > fibroblasts ~ Langerhans cells ~ dendritic cells. In conclusion, our results underline the principal suitability of RHS as an adequate test matrix for the investigation of N-acetylation of xenobiotics which is most relevant for risk assessment associated with cutaneous exposure to aromatic amines. %0 journal article %@ 1386-0291 %A Zou, J.,Wang, W.,Neffe, A.T.,Xu, X.,Li, Z.,Deng, Z.,Sun, X. Ma, N.,Lendlein, A. %D 2017 %J Clinical Hemorheology and Microcirculation %N 3-4 %P 297-307 %R doi:10.3233/CH-179210 %T Adipogenic differentiation of human adipose derived mesenchymal stem cells in 3D architectured gelatin based hydrogels (ArcGel) %U https://doi.org/10.3233/CH-179210 3-4 %X Polymeric matrices mimicking multiple functions of the ECM are expected to enable a material induced regeneration of tissues. Here, we investigated the adipogenic differentiation of human adipose derived mesenchymal stem cells (hADSCs) in a 3D architectured gelatin based hydrogel (ArcGel) prepared from gelatin and L-lysine diisocyanate ethyl ester (LDI) in an one-step process, in which the formation of an open porous morphology and the chemical network formation were integrated. The ArcGel was designed to support adipose tissue regeneration with its 3D porous structure, high cell biocompatibility, and mechanical properties compatible with human subcutaneous adipose tissue. The ArcGel could support initial cell adhesion and survival of hADSCs. Under static culture condition, the cells could migrate into the inner part of the scaffold with a depth of 840±120 μm after 4 days, and distributed in the whole scaffold (2 mm in thickness) within 14 days. The cells proliferated in the scaffold and the fold increase of cell number after 7 days of culture was 2.55±0.08. The apoptotic rate of hADSCs in the scaffold was similar to that of cells maintained on tissue culture plates. When cultured in adipogenic induction medium, the hADSCs in the scaffold differentiated into adipocytes with a high efficiency (93±1%). Conclusively, this gelatin based 3D scaffold presented high cell compatibility for hADSC cultivation and differentiation, which could serve as a potential implant material in clinical applications for adipose tissue reparation and regeneration. %0 journal article %@ 1386-0291 %A Li, Z.,Xu, X.,Wang, W.,Kratz, K.,Sun, X.,Zou, J.,Deng, Z.,Jung, F.,Gossen, M.,Ma, N.,Lendlein, A. %D 2017 %J Clinical Hemorheology and Microcirculation %N 3-4 %P 267-278 %R doi:10.3233/CH-179208 %T Modulation of the mesenchymal stem cell migration capacity via preconditioning with topographic microstructure %U https://doi.org/10.3233/CH-179208 3-4 %X Controlling mesenchymal stem cells (MSCs) behavior is necessary to fully exploit their therapeutic potential. Various approaches are employed to effectively influence the migration capacity of MSCs. Here, topographic microstructures with different microscale roughness were created on polystyrene (PS) culture vessel surfaces as a feasible physical preconditioning strategy to modulate MSC migration. By analyzing trajectories of cells migrating after reseeding, we demonstrated that the mobilization velocity of human adipose derived mesenchymal stem cells (hADSCs) could be promoted by and persisted after brief preconditioning with the appropriate microtopography. Moreover, the elevated activation levels of focal adhesion kinase (FAK) and mitogen-activated protein kinase (MAPK) in hADSCs were also observed during and after the preconditioning process. These findings underline the potential enhancement of in vivo therapeutic efficacy in regenerative medicine via transplantation of topographic microstructure preconditioned stem cells. %0 journal article %@ 1386-0291 %A Wang, W.,Li, W.,Wang, J.,Hu, Q.,Balk, M.,Bieback, K.,Stamm, C.,Jung, F.,Tang, G.,Lendlein, A.,Ma, N. %D 2017 %J Clinical Hemorheology and Microcirculation %N 3-4 %P 279-295 %R doi:10.3233/CH-179209 %T Folate receptor mediated genetic modification of human mesenchymal stem cells via folic acid-polyethylenimine-grafted poly(N-3-hydroxypropyl)aspartamide %U https://doi.org/10.3233/CH-179209 3-4 %X Mesenchymal stem cells (MSCs) are targeted as vehicles for cell mediated gene therapy. Here we report on a macromolecular carrier, which was designed aiming at successful targeted gene delivery into MSCs through the mediation of folate receptor and reduced cytotoxicity compared to established cationic polymer vector – polyethylenimine with a weight average molecular weight (Mw) of 25,000 Dalton (PEI25K). The carrier PHPA-PEI1800-FA was synthesized in a two-step procedure. PHPA-PEI1800 was prepared by grafting polyethylenimine with a Mw of 1800 Dalton (PEI1800) onto the α,β-poly(N-3-hydroxypropyl)-D,L-aspartamide (PHPA) backbone. PHPA-PEI1800-FA was obtained by chemically conjugating folic acid onto PHPA-PEI1800. The grafting degree of PEI1800 was 3.9±0.2% in relation to the CH groups of PHPA and the molar ratio of folic acid conjugated to PEI1800 (χFA) was 1.8±0.1 as calculated by NMR spectroscopy. The copolymers were biodegradable and exhibited lower cytotoxicity than PEI25K. Compared to PHPA-PEI1800, PHPA-PEI1800-FA led to a significantly higher transfection efficiency in human MSCs, which could be attributed to the mediation of folate receptor during the transfection process as confirmed by folic acid competition assay. Both marker gene (GFP) and therapeutic gene (VEGF) were delivered into human MSCs from multi-donors using PHPA-PEI1800-FA. The percentage of GFP+ MSCs showed an average value of 2.85±1.60% but a large variation for different samples. The VEGF expression level of the PHPA-PEI1800-FA transfected cells was significantly higher than that of either untransfected or naked DNA transfected cells. Conclusively, PHPA-PEI1800-FA is a suitable vector to deliver genes into human MSCs through the interaction with folate receptor. %0 journal article %@ 1042-7147 %A Yan, W.,Fang, L.,Weigel, T.,Behl, M.,Kratz, K.,Lendlein, A. %D 2017 %J Polymers for Advanced Technologies %N 10 %P 1339-1345 %R doi:10.1002/pat.3953 %T The influence of thermal treatment on the morphology in differently prepared films of a oligodepsipeptide based multiblock copolymer %U https://doi.org/10.1002/pat.3953 10 %X Degradable multiblock copolymers prepared from equal weight amounts of poly(ε-caprolactone)-diol (PCL-diol) and poly[oligo(3S-iso-butylmorpholine-2,5-dione)]-diol (PIBMD-diol), named PCL-PIBMD, provide a phase-segregated morphology. It exhibits a low melting temperature from PCL domains (Tm,PCL) of 38 ± 2 °C and a high Tm,PIBMD of 170 ± 2 °C with a glass transition temperature (Tg,PIBMD) at 42 ± 2 °C from PIBMD domains.,In this study, we explored the influence of applying different thermal treatments on the resulting morphologies of solution-cast and spin-coated PCL-PIBMD thin films, which showed different initial surface morphologies. Differential scanning calorimetry results and atomic force microscopy images after different thermal treatments indicated that PCL and PIBMD domains showed similar crystallization behaviors in 270 ± 30 µm thick solution-cast films as well as in 30 ± 2 and 8 ± 1 nm thick spin-coated PCL-PIBMD films. Existing PIBMD crystalline domains highly restricted the generation of PCL crystalline domains during cooling when the sample was annealed at 180 °C. By annealing the sample above 120 °C, the PIBMD domains crystallized sufficiently and covered the free surface, which restricted the crystallization of PCL domains during cooling. The PCL domains can crystallize by hindering the crystallization of PIBMD domains via the fast vitrification of PIBMD domains when the sample was cooled/quenched in liquid nitrogen after annealing at 180 °C. These findings contribute to a better fundamental understanding of the crystallization mechanism of multi-block copolymers containing two crystallizable domains whereby the Tg of the higher melting domain type is in the same temperature range as the Tm of the lower melting domain type. %0 journal article %@ 1616-5187 %A Dimde, M.,Steinhilber, D.,Neumann, F.,Li, Y.,Paulus, F.,Ma, N.,Haag, R. %D 2017 %J Macromolecular Bioscience %N S 1 %P 1600190 %R doi:10.1002/mabi.201600190 %T Synthesis of pH-Cleavable dPG-Amines for Gene Delivery Application %U https://doi.org/10.1002/mabi.201600190 S 1 %X The development of effective nonviral vectors for gene therapy is still a challenge in research, due to the high toxicity of many existing polycationic nanocarriers. In this paper, the development of two pH-cleavable polyglycerol-amine-based nanocarriers is described. The benz­acetal bond represents the pH-sensitive cleavage site between dendritic polyglycerol (dPG) and glycerol-based 1,2-diamines that can complex genetic material. Due to the acid lability of the acetal moiety, the cleavable dPG-amines are less toxic in vitro. Cell-mediated degradation results in non-toxic dPG with low amine functionalization and low molecular weight cleavage products (cp). The genetic material is released because of the loss of multivalent amine groups. Interestingly, the release kinetics at the endosomal pH could be controlled by simple chemical modification of the acetals. In vitro experiments demonstrate the ability of the cleavable dPG-amine to transfect HeLa cells with GFP-DNA, which resulted in cell-compatible cleavage products. %0 journal article %@ 0939-6411 %A Edlich, A.,Gerecke, C.,Giulbudagian, M.,Neumann, F.,Hedtrich, S.,Schaefer-Korting, M.,Ma, N.,Calderon, M.,Kleuser, B. %D 2017 %J European Journal of Pharmaceutics and Biopharmaceutics %N %P 155-163 %R doi:10.1016/j.ejpb.2016.12.016 %T Specific uptake mechanisms of well-tolerated thermoresponsive polyglycerol-based nanogels in antigen-presenting cells of the skin %U https://doi.org/10.1016/j.ejpb.2016.12.016 %X Engineered nanogels are of high value for a targeted and controlled transport of compounds due to the ability to change their chemical properties by external stimuli. As it has been indicated that nanogels possess a high ability to penetrate the stratum corneum, it cannot be excluded that nanogels interact with dermal dendritic cells, especially in diseased skin. In this study the potential crosstalk of the thermoresponsive nanogels (tNGs) with the dendritic cells of the skin was investigated with the aim to determine the immunotoxicological properties of the nanogels. The investigated tNGs were made of dendritic polyglycerol (dPG) and poly(glycidyl methyl ether-co-ethyl glycidyl ether) (p(GME-co-EGE)), as polymer conferring thermoresponsive properties. Although the tNGs were taken up, they displayed neither cytotoxic and genotoxic effects nor any induction of reactive oxygen species in the tested cells. Interestingly, specific uptake mechanisms of the tNGs by the dendritic cells were depending on the nanogels cloud point temperature (Tcp), which determines the phase transition of the nanoparticle. The study points to caveolae-mediated endocytosis as being the major tNGs uptake mechanism at 37 °C, which is above the Tcp of the tNGs. Remarkably, an additional uptake mechanism, beside caveolae-mediated endocytosis, was observed at 29 °C, which is the Tcp of the tNGs. At this temperature, which is characterized by two different states of the tNGs, macropinocytosis was involved as well. In summary, our study highlights the impact of thermoresponsivity on the cellular uptake mechanisms which has to be taken into account if the tNGs are used as a drug delivery system. %0 journal article %@ 1743-5390 %A Gerecke, C.,Edlich, A.,Giulbudagian, M.,Schumacher, F.,Zhang, N.,Said, A.,Yealland, G.,Lohan, S.B.,Neumann, F.,Meinke, M.C.,Ma, N.,Calderon, M.,Hedtrich, S.,Schaefer-Korting, M.,Kleuser, B. %D 2017 %J Nanotoxicology %N 2 %P 267-277 %R doi:10.1080/17435390.2017.1292371 %T Biocompatibility and characterization of polyglycerol-based thermoresponsive nanogels designed as novel drug-delivery systems and their intracellular localization in keratinocytes %U https://doi.org/10.1080/17435390.2017.1292371 2 %X Novel nanogels that possess the capacity to change their physico-chemical properties in response to external stimuli are promising drug-delivery candidates for the treatment of severe skin diseases. As thermoresponsive nanogels (tNGs) are capable of enhancing penetration through biological barriers such as the stratum corneum and are taken up by keratinocytes of human skin, potential adverse consequences of their exposure must be elucidated. In this study, tNGs were synthesized from dendritic polyglycerol (dPG) and two thermoresponsive polymers. tNG_dPG_tPG are the combination of dPG with poly(glycidyl methyl ether-co-ethyl glycidyl ether) (p(GME-co-EGE)) and tNG_dPG_pNIPAM the one with poly(N-isopropylacrylamide) (pNIPAM). Both thermoresponsive nanogels are able to incorporate high amounts of dexamethasone and tacrolimus, drugs used in the treatment of severe skin diseases. Cellular uptake, intracellular localization and the toxicological properties of the tNGs were comprehensively characterized in primary normal human keratinocytes (NHK) and in spontaneously transformed aneuploid immortal keratinocyte cell line from adult human skin (HaCaT). Laser scanning confocal microscopy revealed fluorescently labeled tNGs entered into the cells and localized predominantly within lysosomal compartments. MTT assay, comet assay and carboxy-H2DCFDA assay, demonstrated neither cytotoxic or genotoxic effects, nor any induction of reactive oxygen species of the tNGs in keratinocytes. In addition, both tNGs were devoid of eye irritation potential as shown by bovine corneal opacity and permeability (BCOP) test and red blood cell (RBC) hemolysis assay. Therefore, our study provides evidence that tNGs are locally well tolerated and underlines their potential for cutaneous drug delivery. %0 journal article %@ 2045-2322 %A Phan, Q.V.,Contzen, J.,Seemann, P.,Gossen, M. %D 2017 %J Scientific Reports %N %P 17771 %R doi:10.1038/s41598-017-17651-0 %T Site-specific chromosomal gene insertion: Flp recombinase versus Cas9 nuclease %U https://doi.org/10.1038/s41598-017-17651-0 %X Site-specific recombination systems like those based on the Flp recombinase proved themselves as efficient tools for cell line engineering. The recent emergence of designer nucleases, especially RNA guided endonucleases like Cas9, has considerably broadened the available toolbox for applications like targeted transgene insertions. Here we established a recombinase-mediated cassette exchange (RMCE) protocol for the fast and effective, drug-free isolation of recombinant cells. Distinct fluorescent protein patterns identified the recombination status of individual cells. In derivatives of a CHO master cell line the expression of the introduced transgene of interest could be dramatically increased almost 20-fold by subsequent deletion of the fluorescent protein gene that provided the initial isolation principle. The same master cell line was employed in a comparative analysis using CRISPR/Cas9 for transgene integration in identical loci. Even though the overall targeting efficacy was comparable, multi-loci targeting was considerably more effective for Cas9-mediated transgene insertion when compared to RMCE. While Cas9 is inherently more flexible, our results also alert to the risk of aberrant recombination events around the cut site. Together, this study points at the individual strengths in performance of both systems and provides guidance for their appropriate use. %0 journal article %@ 2050-750X %A Zhao, J.,Li, Q.,Hao, X.,Ren, X.,Guo, J.,Feng, Y.,Shi, C. %D 2017 %J Journal of Materials Chemistry B %N 40 %P 8035-8051 %R doi:10.1039/C7TB02012K %T Multi-targeting peptides for gene carriers with high transfection efficiency %U https://doi.org/10.1039/C7TB02012K 40 %X Non-viral gene carriers for gene therapy have been developed for many years. But the gene transfection is generally limited by deficient cellular uptake, low endo/lysosome escape, and weak nuclear translocation. Some targeting peptides have been conjugated onto gene carriers for highly efficient gene delivery. These targeting carriers can overcome some of these limitations to efficiently deliver therapeutic genes into desired cells. In this review, we will summarize the recent development of multi-targeting peptide immobilized non-viral gene carriers for efficient gene therapy, especially for the targeting and suppression of tumor cells, and the transfection and proliferation of endothelial cells. The peptide functionalization of gene carriers is a promising strategy to promote the elimination of solid tumors and the rapid endothelialization of artificial blood vessels. %0 journal article %@ 1860-7314 %A Roch, T.,Hahne, S.,Kratz, K.,Ma, N.,Lendlein, A. %D 2017 %J Biotechnology Journal %N 12 %P 1700334 %R doi:10.1002/biot.201700334 %T Transparent Substrates Prepared From Different Amorphous Polymers Can Directly Modulate Primary Human B cell functions %U https://doi.org/10.1002/biot.201700334 12 %X Manipulation of B cell functions such as antibody and cytokine secretion, is of clinical and biotechnological interest and can be achieved by soluble ligands activating cell surface receptors. Alternatively, the exposure to suitable solid substrates would offer the possibility to transiently induced cell signaling, since the signaling is interrupted when the cells are removed from the substrate. Cell/substrate interactions are mediated by physical valences such as, hydrogen bonds or hydrophobic forces on the substrate surface. Therefore, in this study B cells were cultivated on polymeric substrates, differing in their chemical composition and thus their capacity to undergo physical interactions. Activated B cells cultivated on polystyrene (PS) showed an altered cytokine response indicated by increased IL-10 and decreased IL-6 secretion. Interestingly, B cells cultivated on polyetherurethane (PEU), which has among all tested polymers the highest potential to form strong hydrogen bonds showed an impaired activation, which could be restored by re-cultivation on tissue culture polystyrene. The results indicate that B cell behavior can transiently be manipulated solely by interacting with polymeric surface, which could be explained by receptor activation mediated by physical interaction with the substrate or by altering the availability of the soluble stimulatory reagents by adsorption processes. %0 journal article %@ 0024-9297 %A Liu, Y.,Razzaq, M.Y.,Rudolph, T.,Fang, L.,Kratz, K.,Lendlein, A. %D 2017 %J Macromolecules %N 6 %P 2518-2527 %R doi:10.1021/acs.macromol.6b02237 %T Two-Level Shape Changes of Polymeric Microcuboids Prepared from Crystallizable Copolymer Networks %U https://doi.org/10.1021/acs.macromol.6b02237 6 %X Polymeric microdevices bearing features like nonspherical shapes or spatially segregated surface properties are of increasing importance in biological and medical analysis, drug delivery, and bioimaging or microfluidic systems as well as in micromechanics, sensors, information storage, or data carrier devices. Here, a method to fabricate programmable microcuboids with shape-memory capability and the quantification of their recovery at different levels is reported. The method uses the soft lithographic technique to create microcuboids with well-defined sizes and surface properties. Microcuboids having an edge length of 25 μm and a height of 10 μm were prepared from cross-linked poly[ethylene-co-(vinyl acetate)] (cPEVA) with different vinyl acetate contents and were programmed by compression with various deformation degrees at elevated temperatures. The microlevel shape-recovery of the cuboidal geometry during heating was monitored by optical microscopy (OM) and atomic force microscopy (AFM) studying the related changes in the projected area (PA) or height, while the nanolevel changes of the nanosurface roughness were investigated by in situ AFM. The shape-memory effect at the microlevel was quantified by the recovery ratio of cuboids (Rr,micro), while at the nanolevel, the recovery ratio of the nanoroughness (Rr,nano) was measured. The values of Rr,micro could be tailored in a range from 42 ± 1% to 102 ± 1% and Rr,nano from 89 ± 6% to 136 ± 21% depending on the applied compression ratio and the amount of vinyl acetate content in the cPEVA microcuboids. %0 journal article %@ 1525-7797 %A Wang, W.,Naolou, T.,Ma, N.,Deng, Z.,Xu, X.,Mansfeld, U.,Wischke, C.,Gossen, M.,Neffe, A.T.,Lendlein, A. %D 2017 %J Biomacromolecules %N 11 %P 3819-3833 %R doi:10.1021/acs.biomac.7b01034 %T Polydepsipeptide Block-Stabilized Polyplexes for Efficient Transfection of Primary Human Cells %U https://doi.org/10.1021/acs.biomac.7b01034 11 %X The rational design of a polyplex gene carrier aims to balance maximal effectiveness of nucleic acid transfection into cells with minimal adverse effects. Depsipeptide blocks with an Mn ∼ 5 kDa exhibiting strong physical interactions were conjugated with PEI moieties (2.5 or 10 kDa) to di- and triblock copolymers. Upon nanoparticle formation and complexation with DNA, the resulting polyplexes (sizes typically 60–150 nm) showed remarkable stability compared to PEI-only or lipoplex and facilitated efficient gene delivery. Intracellular trafficking was visualized by observing fluorescence-labeled pDNA and highlighted the effective cytoplasmic uptake of polyplexes and release of DNA to the perinuclear space. Specifically, a triblock copolymer with a middle depsipeptide block and two 10 kDa PEI swallowtail structures mediated the highest levels of transgenic VEGF secretion in mesenchymal stem cells with low cytotoxicity. These nanocarriers form the basis for a delivery platform technology, especially for gene transfer to primary human cells. %0 journal article %@ 1944-8244 %A Yu, L.,Hou, Y.,Cheng, C.,Schlaich, C.,Noeske, P.-L.M.,Wei, Q.,Haag, R. %D 2017 %J ACS Applied Materials and Interfaces %N 51 %P 44281-44292 %R doi:10.1021/acsami.7b13515 %T High-Antifouling Polymer Brush Coatings on Nonpolar Surfaces via Adsorption-Cross-Linking Strategy %U https://doi.org/10.1021/acsami.7b13515 51 %X A new “adsorption-cross-linking” technology is presented to generate a highly dense polymer brush coating on various nonpolar substrates, including the most inert and low-energy surfaces of poly(dimethylsiloxane) and poly(tetrafluoroethylene). This prospective surface modification strategy is based on a tailored bifunctional amphiphilic block copolymer with benzophenone units as the hydrophobic anchor/chemical cross-linker and terminal azide groups for in situ postmodification. The resulting polymer brushes exhibited long-term and ultralow protein adsorption and cell adhesion benefiting from the high density and high hydration ability of polyglycerol blocks. The presented antifouling brushes provided a highly stable and robust bioinert background for biospecific adsorption of desired proteins and bacteria after secondary modification with bioactive ligands, e.g., mannose for selective ConA and Escherichia coli binding. %0 journal article %@ 2050-750X %A Miceli, E.,Kar, M.,Calderon, M. %D 2017 %J Journal of Materials Chemistry B %N 23 %P 4393-4405 %R doi:10.1039/C7TB00146K %T Interactions of organic nanoparticles with proteins in physiological conditions %U https://doi.org/10.1039/C7TB00146K 23 %X Nanoparticles (NPs) are widely explored for various biomedical applications to make more efficient therapeutics and to develop advanced diagnostic tools. The majority of NP-based systems that have been proven to successfully achieve therapeutic efficacy in vitro did not pass the in vivo conditions because of adverse effects, which have led to systemic toxicity and an unpredicted long-term outcome. Therefore, several NP-based therapeutic systems face challenges for their applicability in clinical trials. These discrepancies in the biological outcome could originate from the binding of proteins on the surface of NPs, thereby achieving a brand new biological identity. It is fundamentally important to understand the so-called “protein corona” around NPs for the development of successful products for therapeutics as well as in other biomedical applications. This review will focus on studies of protein corona formation onto the soft, organic-based NPs, upon incubation in biological media such as human plasma or serum and their physicochemical characteristics. These studies aim to describe these supramolecular structures in relationship with the resultant effects at the interface that might impact the therapeutic efficacy of the designed NPs. %0 journal article %@ 2047-4849 %A Yang, X.,Liu, W.,Li, N.,Wang, M.,Liang, B.,Ullah, I.,Neve, A.L.,Feng, Y.,Chen, H.,Shi, C. %D 2017 %J Biomaterials Science %N 12 %P 2357-2368 %R doi:10.1039/C7BM00554G %T Design and development of polysaccharide hemostatic materials and their hemostatic mechanism %U https://doi.org/10.1039/C7BM00554G 12 %X The formation of stable blood clots or hemostasis is essential to prevent major blood loss and death from excessive bleeding. However, the body's own coagulation process is not able to accomplish timely hemostasis without the assistance of hemostatic agents. For developing novel topical hemostatic agents, tissue adhesives and sealants, it is necessary to understand the coagulation process and the hemostasis mechanism of different materials. Among hemostatic materials, polysaccharides are naturally derived polymers having excellent biodegradable and biocompatible properties. This review provides an overview of polysaccharide-based hemostatic materials and agents, including their advantages and drawbacks in hemostatic applications. Furthermore, polysaccharide-based hemostatic materials with anti-microbial and healing functions are also introduced. %0 journal article %@ 0743-7463 %A Duo, X.,Li, Q.,Wang, J.,Lv, J.,Hao, X.,Feng, Y.,Ren, X.,Shi, C.,Zhang, W. %D 2017 %J Langmuir %N 46 %P 13315-13325 %R doi:10.1021/acs.langmuir.7b02934 %T Core/Shell Gene Carriers with Different Lengths of PLGA Chains to Transfect Endothelial Cells %U https://doi.org/10.1021/acs.langmuir.7b02934 46 %X In order to improve the transfection efficiency and reduce the cytotoxicity of gene carriers, many strategies have been used to develop novel gene carriers. In this study, five complex micelles (MSP(2 k), MSP(4 k), MSP(6 k), MSP(8 k), and MSP(10 k)) were prepared from methoxy-poly(ethylene glycol)-b-poly(d,l-lactide-co-glycolide) (mPEG-b-PLGA) and sorbitol-poly(d,l-lactide-co-glycolide)-graft-PEI (sorbitol-PLGA-g-PEI, where the designed molecular weights of PLGA chains were 2 kDa, 4 kDa, 6 kDa, 8 kDa, and 10 kDa, respectively) copolymers by a self-assembly method, and the mass ratio of mPEG-b-PLGA to sorbitol-PLGA-g-PEI was 1/3. These complex micelles and their gene complexes had appropriate sizes and zeta potentials, and pEGFP-ZNF580 (pDNA) could be efficiently internalized into EA.hy926 cells by their gene complexes (MSP(2 k)/pDNA, MSP(4 k)/pDNA, MSP(6 k)/pDNA, MSP(8 k)/pDNA, and MSP(10 k)/pDNA). The MTT assay results demonstrated that the gene complexes had low cytotoxicity in vitro. When the hydrophobic PLGA chain increased above 6 kDa, the gene complexes showed higher performance than that prepared from short hydrophobic chains. Moreover, the relative ZNF580 protein expression levels in MSP(6 k)/pDNA, MSP(8 k)/pDNA, and MSP(10 k)/pDNA) groups were 79.6%, 71.2%, and 73%, respectively. These gene complexes could promote the transfection of endothelial cells, while providing important information and insight for the design of new and effective gene carriers to promote the proliferation and migration of endothelial cells. %0 journal article %@ 2047-4849 %A Dimde, M.,Neumann, F.,Reisbeck, F.,Ehrmann, S.,Cuellar-Camacho, J.L.,Steinhilber, D.,Ma, N.,Haag, R. %D 2017 %J Biomaterials Science %N 11 %P 2328-2336 %R doi:10.1039/C7BM00729A %T Defined pH-sensitive nanogels as gene delivery platform for siRNA mediated in vitro gene silencing %U https://doi.org/10.1039/C7BM00729A 11 %X In the present study, a pH sensitive nanogel platform for gene delivery was developed. The cationic nanogels based on dendritic polyglycerol (dPG) and low molecular weight polyethylenimine units were able to encapsulate siRNA during the manufacturing process. The thiol-Michael nanoprecipitation method, which operates under mild conditions and did not require any catalyst or surfactant, was used to develop tailor-made nanogels in the sub-100 nm range. The incorporation of pH sensitive benzacetal-bonds inside the nanogel network enables the controlled intracellular release of the cargo. The functionality to transport therapeutic biomolecules was tested by an in vitro GFP-siRNA transfection assay. Encapsulated siRNA could silence GFP expressing HeLa cells (up to 71% silencing in GFP). Furthermore, significantly reduced toxicity of the nanogel platform compared to the non-degradable PEI was observed. These properties realize a new carrier platform in the field of gene therapy. %0 journal article %@ 2045-2322 %A Lamby, P.,Jung, F.,Graf, S.,Schellenberg, L.,Falter, J.,Platz-da-Silva, N.,Schreml, S.,Prantl, L.,Franke, R.P.,Jung, E.M. %D 2017 %J Scientific Reports %N %P 13125 %R doi:10.1038/s41598-017-13253-y %T Effect of iodinated contrast media on renal perfusion: A randomized comparison study in pigs using quantitative contrast-enhanced ultrasound (CEUS) %U https://doi.org/10.1038/s41598-017-13253-y %X The administration of iodinated contrast media (CM) can cause microcirculatory disorder leading to acute renal dysfunction. In a prospective, randomized investigation two CM (Iodixanol vs Iopromide) were compared in 16 pigs. Each animal received 10 intra-aortal injections (5 ml Iodixanol or 4.32 ml Iopromide). Microcirculation was assessed using contrast-enhanced ultrasound (CEUS) directly on the kidney surface using time-to-peak (TTP) and blood-volume-analysis. Macroscopic observations were documented. Post mortem residual CM distribution in the kidneys was detected using X-ray. TTP was significantly prolonged over the descending vasa recta of the Iopromide group. This coincided with a visible marble-like pattern on the kidney surface occurring in 30 out of 80 Iopromide-injections but in 4 out of 80 Iodixanol-injections (p = 0.007). The blood volume over the entire kidney did not change after Iodixanol-application, but decreased by about 6.1% after Iopromide-application. The regional blood volume in the renal cortex showed a tendency to decrease by about 13.5% (p = 0.094) after Iodixanol-application, and clearly decreased by about 31.7% (p = 0.022) after Iopromide-application. The study revealed a consistent influence of repeated injections of two different CM on the kidney perfusion using three different imaging methods (CEUS analysis, macroscopic observation and X-ray analysis). %0 journal article %@ 1944-8244 %A Kuroki, A.,Sangwan, P.,Qu, Y.,Peltier, R.,Sanchez-Cano, C.,Moat, J.,Dowson, C.G.,Williams, E.G.L.,Locock, K.E.S.,Hartlieb, M.,Perrier, S. %D 2017 %J ACS Applied Materials and Interfaces %N 46 %P 40117-40126 %R doi:10.1021/acsami.7b14996 %T Sequence Control as a Powerful Tool for Improving the Selectivity of Antimicrobial Polymers %U https://doi.org/10.1021/acsami.7b14996 46 %X Antimicrobial polymers appear as a promising alternative to tackle the current development of bacterial resistance against conventional antibiotics as they rely on bacterial membrane disruption. This study investigates the effect of segmentation of hydrophobic and cationic functionalities on antimicrobial polymers over their selectivity between bacteria and mammalian cells. Using RAFT technology, statistical, diblock, and highly segmented multiblock copolymers were synthesized in a controlled manner. Polymers were analyzed by HPLC, and the segmentation was found to have a significant influence on their overall hydrophobicity. In addition, the amount of incorporated cationic comonomer was varied to yield a small library of bioactive macromolecules. The antimicrobial properties of these compounds were probed against pathogenic bacteria (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis), and their biocompatibility was tested using hemolysis and erythrocyte aggregation assays, as well as mammalian cell viability assays. In all cases, diblock and multiblock copolymers were found to outperform statistical copolymers, and for polymers with a low content of cationic comonomer, the multiblock showed a tremendously increased selectivity for P. aeruginosa and S. epidermidis compared to its statistical and diblock analogue. This work highlights the remarkable effect of segmentation on both the physical properties of the materials as well as their interaction with biological systems. Due to the outstanding selectivity of multiblock copolymers toward certain bacteria strains, the presented materials are a promising platform for the treatment of infections and a valuable tool to combat antimicrobial resistance. %0 journal article %@ 1944-8244 %A Li, M.,Gao, L.,Schlaich, C.,Zhang, J.,Donskyi, I.S.,Yu, G.,Li, W.,Tu, Z.,Rolff, J.,Schwerdtle, T.,Haag, R.,Ma, N. %D 2017 %J ACS Applied Materials and Interfaces %N 40 %P 35411-35418 %R doi:10.1021/acsami.7b10541 %T Construction of Functional Coatings with Durable and Broad-Spectrum Antibacterial Potential Based on Mussel-Inspired Dendritic Polyglycerol and in Situ-Formed Copper Nanoparticles %U https://doi.org/10.1021/acsami.7b10541 40 %X A novel surface coating with durable broad-spectrum antibacterial ability was prepared based on mussel-inspired dendritic polyglycerol (MI-dPG) embedded with copper nanoparticles (Cu NPs). The functional surface coating is fabricated via a facile dip-coating process followed by in situ reduction of copper ions with a MI-dPG coating to introduce Cu NPs into the coating matrix. This coating has been demonstrated to possess efficient long-term antibacterial properties against Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and kanamycin-resistant E. coli through an “attract–kill–release” strategy. The synergistic antibacterial activity of the coating was shown by the combination of two functions of the contact killing, reactive oxygen species production and Cu ions released from the coating. Furthermore, this coating inhibited biofilm formation and showed good compatibility to eukaryotic cells. Thus, this newly developed Cu NP-incorporated MI-dPG surface coating may find potential application in the design of antimicrobial coating, such as implantable devices. %0 journal article %@ 1381-6128 %A Wang, W.,Deng, Z.,Xu, X.,Li, Z.,Jung, F.,Ma, N.,Lendlein, A. %D 2017 %J Current Pharmaceutical Design %N 26 %P 3814-3832 %R doi:10.2174/1381612823666170622110654 %T Functional Nanoparticles and their Interactions with Mesenchymal Stem Cells %U https://doi.org/10.2174/1381612823666170622110654 26 %X Mesenchymal stem cells (MSCs) have become one of the most important cell sources for regenerative medicine. However, some mechanisms of MSC-based therapy are still not fully understood. The clinical outcome may be restricted by some MSC-related obstacles such as the low survival rate, differentiation into undesired lineages and malignant transformation. In recent years, with the emergence of nanotechnology, various types of multifunctional nanoparticles (NPs) have been designed, prepared and explored for bio-related applications. There is high potential of NPs in biomedical applications, attributed to the high capacity of cellular internalization in MSCs and their multiple functionalities. They can be used either as labeling agent to track MSCs for mechanism study or as gene/drug delivery carriers to regulate the cellular behavior and functions of MSCs. However, the application of NPs may be accompanied by some undesirable effects, as some NPs can induce cell death, inhibit cell proliferation or influence the differentiation of MSCs. Aiming to provide a comprehensive understanding of the interaction between NPs and MSCs, recent progress in the design and preparation of multifunctional NPs is summarized in this review, mechanisms of cellular internalization of the NPs are discussed, the main applications of multifunctional NPs in MSCs are highlighted and overview about cellular response of MSCs to different NPs is given. Future studies aiming on design and development of NPs with multifunctionality may open a new field of applying nanotechnology in stem cell-based therapy. %0 journal article %@ 1042-7147 %A Mazurek-Budzynska, M.,Razzaq, M.Y.,Tomczyk, K.,Rokicki, G.,Behl, M.,Lendlein, A. %D 2017 %J Polymers for Advanced Technologies %N 10 %P 1285-1293 %R doi:10.1002/pat.3948 %T Poly(carbonate‐urea‐urethane) networks exhibiting high‐strain shape‐memory effect %U https://doi.org/10.1002/pat.3948 10 %X A challenge in the design of shape-memory polymers (SMPs) is to achieve high deformability with a simultaneous high shape recovery ratio. Here we explored, whether SMPs featuring large deformation capability and high shape recovery ratios can be created as polymer networks providing two kinds of netpoints based on covalent bonds and physical interactions. As a model system, we selected poly(carbonate-urea-urethane)s (PCUUs) synthesized by a precursor route, based on oligo(alkylene carbonate) diols, isophorone diisocyanate (IPDI), and water vapor. The PCUU networks exhibited a one-way shape-memory effect (1W-SME) with programmed strains up to εprog = 1000% whereby they provided excellent shape fixity (92–97%) and shape recovery (≥99%) ratios. The switching temperatures (Tsw) varied between 36 and 65 °C and increased with the increasing molecular weight of the oligo(alkylene carbonate) diol and length of the hydrocarbon chain between the carbonate linkages. Tsw was also influenced by the strain applied during programming (εprog). Poly(carbonate-urethane)s have been reported to have good biocompatibility and biostability, which in the combination of high-strain capacity and high Young's modulus makes the obtained PCUUs interesting candidate materials suitable for medical devices such as medical sutures or vascular stents. %0 journal article %@ 0898-6568 %A Hildebrand, L.,Stange, K.,Deichsel, A.,Gossen, M.,Seemann, P. %D 2017 %J Cellular Signalling %N %P 23-30 %R doi:10.1016/j.cellsig.2016.10.001 %T The Fibrodysplasia Ossificans Progressiva (FOP) mutation p.R206H in ACVR1 confers an altered ligand response %U https://doi.org/10.1016/j.cellsig.2016.10.001 %X Patients with Fibrodysplasia Ossificans Progressiva (FOP) suffer from ectopic bone formation, which progresses during life and results in dramatic movement restrictions. Cause of the disease are point mutations in the Activin A receptor type 1 (ACVR1), with p.R206H being most common.,In this study we compared the signalling responses of ACVR1WT and ACVR1R206H to different ligands. ACVR1WT, but not ACVR1R206H inhibited BMP signalling of BMP2 or BMP4 in a ligand binding domain independent manner. Likewise, the basal BMP signalling activity of the receptor BMPR1A or BMPR1B was inhibited by ACVR1WT, but enhanced by ACVR1R206H. In comparison, BMP6 or BMP7 activated ACVR1WT and caused a hyper-activation of ACVR1R206H. These effects were dependent on an intact ligand binding domain. Finally, the neofunction of Activin A in FOP was tested and found to depend on the ligand binding domain for activating ACVR1R206H. We conclude that the FOP mutation ACVR1R206H is more sensitive to a number of natural ligands. The mutant receptor apparently lost some essential inhibitory interactions with its ligands and co-receptors, thereby conferring an enhanced ligand-dependent signalling and stimulating ectopic bone formation as observed in the patients. %0 journal article %@ 0743-7463 %A Schlaich, C.,Wei, Q.,Haag, R. %D 2017 %J Langmuir %N 38 %P 9508-9520 %R doi:10.1021/acs.langmuir.7b01291 %T Mussel-Inspired Polyglycerol Coatings with Controlled Wettability: From Superhydrophilic to Superhydrophobic Surface Coatings %U https://doi.org/10.1021/acs.langmuir.7b01291 38 %X Facile approaches to substrate-independent surface coatings with special wettability properties, such as superhydrophobicity, superhydrophilicity, and superamphiphobicity, have been limited. To address this problem, we combined two separate biomimetic concepts of mussel-inspired adhesion and highly hierarchical lotuslike surface structures to develop a universal fabrication method for various superwetting systems on any kind of material. In this feature article, we summarize our work on mussel-inspired polyglycerol (MI-dPG) and its application in the area of superwetting interfacial materials. MI-dPG mimics not only the functional groups of mfp-5 but also their molecular weight and molecular structure, which results in strong and rapid adhesion to the substrate. Furthermore, the MI-dPG coating process provides precise roughness control. The construction of highly hierarchical and superhydrophilic structures was achieved either directly by pH-controlled aggregation or in combination with nanoparticles. Subsequent postmodification of these highly hierarchical structures with different fluorinated or nonfluorinated hydrophobic molecules yielded a surface with superhydrophobic and even superamphiphobic properties. %0 journal article %@ 0939-6411 %A Zhang, N.,Said, A.,Wischke, C.,Kral, V.,Brodwolf, R.,Volz, P.,Boreham, A.,Gerecke, C.,Li, W.,Neffe, A.T.,Kleuser, B.,Alexiev, U.,Lendlein, A.,Schaefer-Korting, M. %D 2017 %J European Journal of Pharmaceutics and Biopharmaceutics %N %P 66-75 %R doi:10.1016/j.ejpb.2016.10.019 %T Poly[acrylonitrile-co-(N-vinyl pyrrolidone)] nanoparticles – Composition-dependent skin penetration enhancement of a dye probe and biocompatibility %U https://doi.org/10.1016/j.ejpb.2016.10.019 %X Nanoparticles can improve topical drug delivery: size, surface properties and flexibility of polymer nanoparticles are defining its interaction with the skin. Only few studies have explored skin penetration for one series of structurally related polymer particles with systematic alteration of material composition. Here, a series of rigid poly[acrylonitrile-co-(N-vinyl pyrrolidone)] model nanoparticles stably loaded with Nile Red or Rhodamin B, respectively, was comprehensively studied for biocompatibility and functionality. Surface properties were altered by varying the molar content of hydrophilic NVP from 0 to 24.1% and particle size ranged from 35 to 244 nm. Whereas irritancy and genotoxicity were not revealed, lipophilic and hydrophilic nanoparticles taken up by keratinocytes affected cell viability. Skin absorption of the particles into viable skin ex vivo was studied using Nile Red as fluorescent probe. Whilst an intact stratum corneum efficiently prevented penetration, almost complete removal of the horny layer allowed nanoparticles of smaller size and hydrophilic particles to penetrate into viable epidermis and dermis. %0 journal article %@ 1742-5689 %A Schoene, A.-C.,Roch, T.,Schulz, B.,Lendlein, A. %D 2017 %J Journal of the Royal Society Interface %N 130 %P 20161028 %R doi:10.1098/rsif.2016.1028 %T Evaluating polymeric biomaterial–environment interfaces by Langmuir monolayer techniques %U https://doi.org/10.1098/rsif.2016.1028 130 %X Polymeric biomaterials are of specific relevance in medical and pharmaceutical applications due to their wide range of tailorable properties and functionalities. The knowledge about interactions of biomaterials with their biological environment is of crucial importance for developing highly sophisticated medical devices. To achieve optimal in vivo performance, a description at the molecular level is required to gain better understanding about the surface of synthetic materials for tailoring their properties. This is still challenging and requires the comprehensive characterization of morphological structures, polymer chain arrangements and degradation behaviour. The review discusses selected aspects for evaluating polymeric biomaterial–environment interfaces by Langmuir monolayer methods as powerful techniques for studying interfacial properties, such as morphological and degradation processes. The combination of spectroscopic, microscopic and scattering methods with the Langmuir techniques adapted to polymers can substantially improve the understanding of their in vivo behaviour. %0 journal article %@ 2192-2640 %A Braune, S.,Latour, R.A.,Lendlein, A.,Jung, F. %D 2017 %J Advanced Healthcare Materials %N 17 %P 1700294 %R doi:10.1002/adhm.201700294 %T Comment on: “Hemocompatibility of Superhemophobic Titania Surfaces” %U https://doi.org/10.1002/adhm.201700294 17 %X No abstract %0 journal article %@ 0171-9335 %A Meyer, I.,Peter, T.,Batsios, P.,Kuhnert, O.,Krueger-Genge, A.,Camurca, C.,Graef, R. %D 2017 %J European Journal of Cell Biology %N 2 %P 119-130 %R doi:10.1016/j.ejcb.2017.01.004 %T CP39, CP75 and CP91 are major structural components of the Dictyostelium centrosome’s core structure %U https://doi.org/10.1016/j.ejcb.2017.01.004 2 %X The acentriolar Dictyostelium centrosome is a nucleus-associated body consisting of a core structure with three plaque-like layers, which are surrounded by a microtubule-nucleating corona. The core duplicates once per cell cycle at the G2/M transition, whereby its central layer disappears and the two outer layers form the mitotic spindle poles. Through proteomic analysis of isolated centrosomes, we have identified CP39 and CP75, two essential components of the core structure. Both proteins can be assigned to the central core layer as their centrosomal presence is correlated to the disappearance and reappearance of the central core layer in the course of centrosome duplication. Both proteins contain domains with centrosome-binding activity in their N- and C-terminal halves, whereby the respective N-terminal half is required for cell cycle-dependent regulation. CP39 is capable of self-interaction and GFP-CP39 overexpression elicited supernumerary microtubule-organizing centers and pre-centrosomal cytosolic clusters. Underexpression stopped cell growth and reversed the MTOC amplification phenotype. In contrast, in case of CP75 underexpression of the protein by RNAi treatment elicited supernumerary MTOCs. In addition, CP75RNAi affects correct chromosome segregation and causes co-depletion of CP39 and CP91, another central core layer component. CP39 and CP75 interact with each other directly in a yeast two-hybrid assay. Furthermore, CP39, CP75 and CP91 mutually interact in a proximity-dependent biotin identification (BioID) assay. Our data indicate that these three proteins are all required for proper centrosome biogenesis and make up the major structural components of core structure's central layer. %0 journal article %@ 1381-5148 %A Ceylan Tuncaboylu, D.,Wischke, C.,Stoermann, F.,Lendlein, A. %D 2017 %J Reactive and Functional Polymers %N %P 68-73 %R doi:10.1016/j.reactfunctpolym.2016.12.015 %T Microgels from microfluidic templating and photoinduced crosslinking of cinnamylidene acetic acid modified precursors %U https://doi.org/10.1016/j.reactfunctpolym.2016.12.015 %X So far, a number of approaches to synthesize microgel networks have been followed, while only in few cases a detailed control of the network architecture has been possible. Here, the photoinduced [2 + 2] cycloaddition reaction of cinnamylidene acetic acid (CAA) moieties coupled to four-arm star shaped oligo(ethylene glycol) (OEG) precursors was explored for the creation of microgels with defined polymer network structures. Based on a rational solvent selection and precursor dispersion in glass-capillary microfluidics, microgels could be successfully prepared by the proposed synthesis approach. Model reactions confirmed a quantitative network formation. Therefore, compared to common radical polymerization for microgel crosslinking, CAA-dimerization may be an alternative approach particularly when well defined network structures are desired. %0 journal article %@ 0142-9612 %A Lohmann, P.,Willuweit, A.,Neffe, A.T.,Geisler, S.,Gebauer, T.P.,Beer, S.,Coenen, H.H.,Fischer, H.,Hermanns-Sachweh, B.,Lendlein, A.,Shah, N.J.,Kiessling, F.,Langen, K.-J. %D 2017 %J Biomaterials %N %P 158-169 %R doi:10.1016/j.biomaterials.2016.10.039 %T Bone regeneration induced by a 3D architectured hydrogel in a rat critical-size calvarial defect %U https://doi.org/10.1016/j.biomaterials.2016.10.039 %X Bone regeneration can be stimulated by implantation of biomaterials, which is especially important for larger bone defects. Here, healing potency of the porous ArcGel was evaluated in a critical-size calvarial bone defect in rats in comparison with clinical standard autologous bone and Bio-Oss® Collagen (BioOss), a bone graft material frequently used in clinics. Bone healing and metabolic processes involved were monitored longitudinally by [18F]-fluoride and [18F]-FDG μ-PET/CT 1d, 3d, 3w, 6w, and 12w post implantation. Differences in quality of bone healing were assessed by ex vivo μ-CT, mechanical tests and histomorphometry. The amount of bone formed after implantation of ArcGel was comparable to autologous bone and superior to BioOss (histomorphometry). Furthermore, microarchitecture of newly formed bone was more physiological and better functional in case of ArcGel (push-out tests). [18F]-FDG uptake increased until 3d after implantation, and decreased until 12w for both ArcGel and BioOss. [18F]-fluoride uptake increased until 3w post implantation for all materials, but persisted significantly longer at higher levels for BioOss, which indicates a prolonged remodelling phase. The study demonstrates the potential of ArcGel to induce restitutio ad integrum comparable with clinical standard autologous bone and better bone regeneration in large defects compared to a commercial state-of-the-art biomaterial. %0 journal article %@ 1932-6254 %A Haase, T.,Krost, A.,Sauter, T.,Kratz, K.,Peter, J.,Kamann, S.,Jung, F.,Lendlein, A.,Zohlnhöfer, D.,Rüder, C. %D 2017 %J Journal of Tissue Engineering and Regenerative Medicine %N 4 %P 1034-1044 %R doi:10.1002/term.2002 %T In vivo biocompatibility assessment of poly (ether imide) electrospun scaffolds %U https://doi.org/10.1002/term.2002 4 %X Poly(ether imide) (PEI), which can be chemically functionalized with biologically active ligands, has emerged as a potential biomaterial for medical implants. Electrospun PEI scaffolds have shown advantageous properties, such as enhanced endothelial cell adherence, proliferation and low platelet adhesion in in vitro experiments. In this study, the in vivo behaviour of electrospun PEI scaffolds and PEI films was examined in a murine subcutaneous implantation model. Electrospun PEI scaffolds and films were surgically implanted subcutaneously in the dorsae of mice. The surrounding subcutaneous tissue response was examined via histopathological examination at 7 and 28 days after implantation. No serious adverse events were observed for both types of PEI implants. The presence of macrophages or foreign body giant cells in the vicinity of the implants and the formation of a fibrous capsule indicated a normal foreign body reaction towards PEI films and scaffolds. Capsule thickness and inflammatory infiltration cells significantly decreased for PEI scaffolds during days 7–28 while remaining unchanged for PEI films. The infiltration of cells into the implant was observed for PEI scaffolds 7 days after implantation and remained stable until 28 days of implantation. Additionally some, but not all, PEI scaffold implants induced the formation of functional blood vessels in the vicinity of the implants. Conclusively, this study demonstrates the in vivo biocompatibility of PEI implants, with favourable properties of electrospun PEI scaffolds regarding tissue integration and wound healing. %0 journal article %@ 0167-7799 %A Hauser, S.,Jung, F.,Pietzsch, J. %D 2017 %J Trends in Biotechnology %N 3 %P 265-277 %R doi:10.1016/j.tibtech.2016.09.007 %T Human Endothelial Cell Models in Biomaterial Research %U https://doi.org/10.1016/j.tibtech.2016.09.007 3 %X Endothelial cell (EC) models have evolved as important tools in biomaterial research due to ubiquitously occurring interactions between implanted materials and the endothelium. However, screening the available literature has revealed a gap between material scientists and physiologists in terms of their understanding of these biomaterial–endothelium interactions and their relative importance. Consequently, EC models are often applied in nonphysiological experimental setups, or too extensive conclusions are drawn from their results. The question arises whether this might be one reason why, among the many potential biomaterials, only a few have found their way into the clinic. In this review, we provide an overview of established EC models and possible selection criteria to enable researchers to determine the most reliable and relevant EC model to use. %0 journal article %@ 1944-8244 %A Yu, L.,Cheng, C.,Ran, Q.,Schlaich, C.,Noeske, P.-L.M.,Li, W.,Wei, Q.,Haag, R. %D 2017 %J ACS Applied Materials and Interfaces %N 7 %P 6624-6633 %R doi:10.1021/acsami.6b15834 %T Bioinspired Universal Monolayer Coatings by Combining Concepts from Blood Protein Adsorption and Mussel Adhesion %U https://doi.org/10.1021/acsami.6b15834 7 %X Despite the increasing need for universal polymer coating strategies, only a few approaches have been successfully developed, and most of them are suffering from color, high thickness, or high roughness. In this paper, we present for the first time a universal monolayer coating that is only a few nanometers thick and independent of the composition, size, shape, and structure of the substrate. The coating is based on a bioinspired synthetic amphiphilic block copolymer that combines two concepts from blood protein adsorption and mussel adhesion. This polymer can be rapidly tethered on various substrates including both planar surfaces and nanosystems with high grafting density. The resulting monolayer coatings are, on the one hand, inert to the adsorption of multiple polymer layers and prevent biofouling. On the other hand, they are chemically active for secondary functionalization and provide a new platform for selective material surface modification. %0 journal article %@ 1042-7147 %A Blocki, A.,Loewenberg, C.,Jiang, Y.,Kratz, K.,Neffe, A.T.,Jung, F.,Lendlein, A. %D 2017 %J Polymers for Advanced Technologies %N 10 %P 1245-1251 %R doi:10.1002/pat.3947 %T Response of encapsulated cells to a gelatin matrix with varied bulk and microenvironmental elastic properties %U https://doi.org/10.1002/pat.3947 10 %X Gelatin-based hydrogels offer various biochemical cues that support encapsulated cells and are therefore suitable as cell delivery vehicles in regenerative medicine. However, besides the biochemical signals, biomechanical cues are crucial to ensure an optimal support of encapsulated cells. Hence, we aimed to correlate the cellular response of encapsulated cells to macroscopic and microscopic elastic properties of glycidylmethacrylate (GMA)-functionalized gelatin-based hydrogels. To ensure that different observations in cellular behavior could be attributed to differences in elastic properties, an identical concentration as well as degree of functionalization of biopolymers was utilized to form covalently crosslinked hydrogels. Elastic properties were merely altered by varying the average gelatin-chain length. Hydrogels exhibited an increased degree of swelling and a decreased bulk elastic modulus G′ with prolonged autoclaving of the starting solution. This was accompanied by an increase of hydrogel mesh size and thus by a reduction of crosslinking density. Tougher hydrogels retained the largest amount of cells; however, they also interfered with cell viability. Softer gels contained a lower cell density, but supported cell elongation and viability. Observed differences could be partially attributed to differences in bulk properties, as high crosslinking densities interfere with diffusion and cell spreading and thus can impede cell viability. Interestingly, a microscopic elastic modulus in the range of native soft tissue supported cell viability and elongation best while ensuring a good cell entrapment. In conclusion, gelatin-based hydrogels providing a soft tissue-like microenvironment represent adequate cell delivery vehicles for tissue engineering approaches. %0 journal article %@ 0927-7765 %A Braune, S.,Sperling, C.,Maitz, M.F.,Steinseifer, U.,Clauser, J.,Hiebl, B.,Krajewski, S.,Wendel, H.P.,Jung, F. %D 2017 %J Colloids and Surfaces B %N %P 416-422 %R doi:10.1016/j.colsurfb.2017.06.053 %T Evaluation of platelet adhesion and activation on polymers: Round-robin study to assess inter-center variability %U https://doi.org/10.1016/j.colsurfb.2017.06.053 %X The regulatory agencies provide recommendations rather than protocols or standard operation procedures for the hemocompatibility evaluation of novel materials e.g. for cardiovascular applications. Thus, there is a lack of specifications with regard to test setups and procedures. As a consequence, laboratories worldwide perform in vitro assays under substantially different test conditions, so that inter-laboratory and inter-study comparisons are impossible. Here, we report about a prospective, randomized and double-blind multicenter trial which demonstrates that standardization of in vitro test protocols allows a reproducible assessment of platelet adhesion and activation from fresh human platelet rich plasma as possible indicators of the thrombogenicity of cardiovascular implants. Standardization of the reported static in vitro setup resulted in a laboratory independent scoring of the following materials: poly(dimethyl siloxane) (PDMS), poly(ethylene terephthalate) (PET) and poly(tetrafluoro ethylene) (PTFE). The results of this in vitro study provide evidence that inter-laboratory and inter-study comparisons can be achieved for the evaluation of the adhesion and activation of platelets on blood-contacting biomaterials by stringent standardization of test protocols. %0 journal article %@ 1931-7573 %A Radbruch, M.,Pischon, H.,Ostrowski, A.,Volz, P.,Brodwolf, R.,Neumann, F.,Unbehauen, M.,Kleuser, B.,Haag, R.,Ma, N.,Alexiev, U.,Mundhenk, L.,Gruber, A.D. %D 2017 %J Nanoscale Research Letters %N %P 64 %R doi:10.1186/s11671-017-1835-0 %T Dendritic Core-Multishell Nanocarriers in Murine Models of Healthy and Atopic Skin %U https://doi.org/10.1186/s11671-017-1835-0 %X Dendritic hPG-amid-C18-mPEG core-multishell nanocarriers (CMS) represent a novel class of unimolecular micelles that hold great potential as drug transporters, e.g., to facilitate topical therapy in skin diseases. Atopic dermatitis is among the most common inflammatory skin disorders with complex barrier alterations which may affect the efficacy of topical treatment.,Here, we tested the penetration behavior and identified target structures of unloaded CMS after topical administration in healthy mice and in mice with oxazolone-induced atopic dermatitis. We further examined whole body distribution and possible systemic side effects after simulating high dosage dermal penetration by subcutaneous injection.,Following topical administration, CMS accumulated in the stratum corneum without penetration into deeper viable epidermal layers. The same was observed in atopic dermatitis mice, indicating that barrier alterations in atopic dermatitis had no influence on the penetration of CMS. Following subcutaneous injection, CMS were deposited in the regional lymph nodes as well as in liver, spleen, lung, and kidney. However, in vitro toxicity tests, clinical data, and morphometry-assisted histopathological analyses yielded no evidence of any toxic or otherwise adverse local or systemic effects of CMS, nor did they affect the severity or course of atopic dermatitis.,Taken together, CMS accumulate in the stratum corneum in both healthy and inflammatory skin and appear to be highly biocompatible in the mouse even under conditions of atopic dermatitis and thus could potentially serve to create a depot for anti-inflammatory drugs in the skin. %0 journal article %@ 0167-5273 %A Shin, E.-S.,Lam, Y.-Y.,Her, A.-Y.,Brachmann, J.,Jung, F.,Park, J.-W. %D 2017 %J International Journal of Cardiology %N %P 948-952 %R doi:10.1016/j.ijcard.2016.11.165 %T Incremental diagnostic value of combined quantitative and qualitative parameters of magnetocardiography to detect coronary artery disease %U https://doi.org/10.1016/j.ijcard.2016.11.165 %X Background/objectives,Magnetocardiography (MCG) has been proposed as a non-invasive and functional technique with high accuracy for diagnosis of myocardial ischemia. This study sought to investigate the incremental diagnostic value of combined quantitative and qualitative parameters of MCG to detect coronary artery disease (CAD).,Methods,Ninety six patients with suspected CAD who underwent coronary angiography were enrolled in the analysis to test the diagnostic accuracy of 2 MCG parameters (a quantitative parameter of the percent change of ST-segment fluctuation score and a qualitative parameter of non-dipole phenomenon).,Results,The best cut-off value for the percent change of ST-segment fluctuation score was − 51.0%. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 78.1, 73.9, 82.0, 79.1, and 77.4, in the percent change of ST-segment fluctuation score and 86.5, 84.8, 88.0, 86.7, and 86.3 in non-dipole phenomenon. The area under the curve of receiver-operating characteristics was 0.79 for the percent change of ST-segment fluctuation score and 0.86 for non-dipole phenomenon (p < 0.001). However, the incorporation of non-dipole phenomenon into a model with the percent change of ST-segment fluctuation score significantly improved C-statistics, indicating the enhancement of diagnostic performance in the detection of significant CAD (0.790 to 0.930; p < 0.001).,Conclusions,Qualitative assessment of non-dipole phenomenon has a better diagnostic value than the quantitative parameter of percent change of ST-segment fluctuation score in the detection of significant CAD. Furthermore, this study found that the incorporation of non-dipole phenomenon into the percent change of ST-segment fluctuation score significantly improved the diagnostic performance of CAD detection. %0 journal article %@ 2073-4360 %A Duo, X.,Wang, J.,Li, Q.,Neve, A.L.,Akpanyung, M.,Nejjari, A.,Ali, Z.S.S.,Feng, Y.,Zhang, W.,Shi, C. %D 2017 %J Polymers %N 5 %P 158 %R doi:10.3390/polym9050158 %T CAGW Peptide Modified Biodegradable Cationic Copolymer for Effective Gene Delivery %U https://doi.org/10.3390/polym9050158 5 %X In recent years, gene therapy has become a promising technology to enhance endothelialization of artificial vascular grafts. The ideal gene therapy requires a gene carrier with low cytotoxicity and high transfection efficiency. In this paper, we prepared a biodegradable cationic copolymer poly(d,l-lactide-co-glycolide)-graft-PEI (PLGA-g-PEI), grafted Cys-Ala-Gly-Trp (CAGW) peptide onto this copolymer via the thiol-ene Click-reaction, and then prepared micelles by a self-assembly method. pEGFP-ZNF580 plasmids (pDNA) were condensed by these micelles via electrostatic interaction to form gene complexes. The CAGW peptide enables these gene complexes with special recognition for endothelial cells, which could enhance their transfection. As a gene carrier system, the PLGA-g-PEI-g-CAGW/pDNA gene complexes were evaluated and the results showed that they had suitable diameter and zeta potential for cellular uptake, and exhibited low cytotoxicity and high transfection efficiency for EA.hy926 cells. %0 journal article %@ 0268-960X %A Reviakine, I.,Jung, F.,Braune, S.,Brash, J.L.,Latour, R.,Gorbet, M.,Oeveren, W.van %D 2017 %J Blood Reviews %N 1 %P 11-21 %R doi:10.1016/j.blre.2016.07.003 %T Stirred, shaken, or stagnant: What goes on at the blood-biomaterial interface %U https://doi.org/10.1016/j.blre.2016.07.003 1 %X There is a widely recognized need to improve the performance of vascular implants and external medical devices that come into contact with blood by reducing adverse reactions they cause, such as thrombosis and inflammation. These reactions lead to major adverse cardiovascular events such as heart attacks and strokes. Currently, they are managed therapeutically. This need remains unmet by the biomaterials research community. Recognized stagnation of the blood–biomaterial interface research translates into waning interest from clinicians, funding agencies, and practitioners of adjacent fields. The purpose of this contribution is to stir things up. It follows the 2014 BloodSurf meeting (74th International IUVSTA Workshop on Blood–Biomaterial Interactions), offers reflections on the situation in the field, and a three-pronged strategy integrating different perspectives on the biological mechanisms underlying blood–biomaterial interactions. The success of this strategy depends on reengaging clinicians and on the renewed cooperation of the funding agencies to support long-term efforts. %0 journal article %@ 0743-7463 %A Yigit, C.,Kanduc, M.,Ballauff, M.,Dzubiella, J. %D 2017 %J Langmuir %N 1 %P 417-427 %R doi:10.1021/acs.langmuir.6b03797 %T Interaction of Charged Patchy Protein Models with Like-Charged Polyelectrolyte Brushes %U https://doi.org/10.1021/acs.langmuir.6b03797 1 %X We study the adsorption of charged patchy particle models (CPPMs) on a thin film of a like-charged and dense polyelectrolyte (PE) brush (of 50 monomers per chain) by means of implicit-solvent, explicit-salt Langevin dynamics computer simulations. Our previously introduced set of CPPMs embraces well-defined one- and two-patched spherical globules, each of the same net charge and (nanometer) size, with mono- and multipole moments comparable to those of small globular proteins. We focus on electrostatic effects on the adsorption far away from the isoelectric point of typical proteins, i.e., where charge regulation plays no role. Despite the same net charge of the brush and globule, we observe large binding affinities up to tens of the thermal energy, kBT, which are enhanced by decreasing salt concentration and increasing charge of the patch(es). Our analysis of the distance-resolved potentials of mean force together with a phenomenological description of all leading interaction contributions shows that the attraction is strongest at the brush surface, driven by multipolar, Born (self-energy), and counterion-release contributions, dominating locally over the monopolar and steric repulsions. %0 journal article %@ 1743-5889 %A Molina, M.,Wedepohl, S.,Miceli, E.,Calderon, M. %D 2017 %J Nanomedicine %N 2 %P 117-129 %R doi:10.2217/nnm-2016-0308 %T Overcoming drug resistance with on-demand charged thermoresponsive dendritic nanogels %U https://doi.org/10.2217/nnm-2016-0308 2 %X To develop nanogels (NG) able to modulate the encapsulation and release of drugs, in order to,circumvent drug resistance mechanisms in cancer cells. Materials & methods: Poly-Nisopropylacrylamide–,dendritic polyglycerol NG were semi-interpenetrated with 2-acrylamido-2-,methylpropane sulfonic acid or (2-dimethylamino) ethyl methacrylate. Physico-chemical properties of,the NGs as well as doxorubicin (DOXO) loading and release were characterized. Drug delivery,performance was investigated in vitro and in vivo in a multidrug-resistant tumor model. Results: Both,the DOXO loaded semi-interpenetrating polymer network NGs were more efficient in multidrug,resistant cancer cell proliferation inhibition studies. In vivo, the DOXO loaded NG semiinterpenetrated with 2-acrylamido-2-methylpropane sulfonic acid was able to overcome drug resistance and reduce the tumor volume to about 25%. Conclusion: The innovative semiinterpenetrating,polymer network NGs appear to be promising drug carriers for drug resistant cancer therapy. %0 journal article %@ 1042-7147 %A Hommes-Schattmann, P.J.,Neffe, A.T.,Ahmad, B.,Williams, G.R.,M´Bele, G.,Vanneaux, V.,Menasche, P.,Kalfa, D.,Lendlein, A. %D 2017 %J Polymers for Advanced Technologies %N 10 %P 1312-1317 %R doi:10.1002/pat.3963 %T RGD constructs with physical anchor groups as polymer co-electrospinnable cell adhesives %U https://doi.org/10.1002/pat.3963 10 %X The tissue integration of synthetic polymers can be promoted by displaying RGD peptides at the biointerface with the objective of enhancing colonization of the material by endogenous cells. A firm but flexible attachment of the peptide to the polymer matrix, still allowing interaction with receptors, is therefore of interest. Here, the covalent coupling of flexible physical anchor groups, allowing for temporary immobilization on polymeric surfaces via hydrophobic or dipole–dipole interactions, to a RGD peptide was investigated. For this purpose, a stearate or an oligo(ethylene glycol) (OEG) was attached to GRGDS in 51–69% yield. The obtained RGD linker constructs were characterized by NMR, IR and MALDI-ToF mass spectrometry, revealing that the commercially available OEG and stearate linkers are in fact mixtures of similar compounds. The RGD linker constructs were co-electrospun with poly(p-dioxanone) (PPDO). After electrospinning, nitrogen could be detected on the surface of the PPDO fibers by X-ray photoelectron spectroscopy. The nitrogen content exceeded the calculated value for the homogeneous material mixture suggesting a pronounced presentation of the peptide on the fiber surface. Increasing amounts of RGD linker constructs in the electrospinning solution did not lead to a detection of an increased amount of peptide on the scaffold surface, suggesting inhomogeneous distribution of the peptide on the PPDO fiber surface. Human adipose-derived stem cells cultured on the patches showed similar viability as when cultured on PPDO containing pristine RGD. The fully characterized RGD linker constructs could serve as valuable tools for the further development of tissue-integrating polymeric scaffolds. %0 journal article %@ 1616-5187 %A Tschiche, A.,Thota, B.N.S.,Neumann, F.,Schaefer, A.,Ma, N.,Haag, R. %D 2017 %J Macromolecular Bioscience %N 2 %P 1600533 %R doi:10.1002/mabi.201600533 %T Correction: Crosslinked Redox-Responsive Micelles Based on Lipoic Acid-Derived Amphiphiles for Enhanced siRNA Delivery %U https://doi.org/10.1002/mabi.201600533 2 %X No abstract %0 journal article %@ 0743-7463 %A Adroher-Benitez, I.,Moncho-Jorda, A.,Dzubiella, J. %D 2017 %J Langmuir %N 18 %P 4567-4577 %R doi:10.1021/acs.langmuir.7b00356 %T Sorption and Spatial Distribution of Protein Globules in Charged Hydrogel Particles %U https://doi.org/10.1021/acs.langmuir.7b00356 18 %X We have theoretically studied the uptake of a nonuniformly charged biomolecule suitable for representing a globular protein or a drug by a charged hydrogel carrier in the presence of a 1:1 electrolyte. On the basis of the analysis of a physical interaction Hamiltonian including monopolar, dipolar, and Born (self-energy) contributions derived from linear electrostatic theory of the unperturbed homogeneous hydrogel, we have identified five different sorption states of the system, from complete repulsion of the molecule to its full sorption deep inside the hydrogel, passing through metastable and stable surface adsorption states. The results are summarized in state diagrams that also explore the effects of varying the electrolyte concentration, the sign of the net electric charge of the biomolecule, and the role of including excluded-volume (steric) or hydrophobic biomolecule–hydrogel interactions. We show that the dipole moment of the biomolecule is a key parameter controlling the spatial distribution of the globules. In particular, biomolecules with a large dipole moment tend to be adsorbed at the external surface of the hydrogel, even if like-charged, whereas uniformly charged biomolecules tend to partition toward the internal core of an oppositely charged hydrogel. Hydrophobic attraction shifts the states toward the internal sorption of the biomolecule, whereas steric repulsion promotes surface adsorption for oppositely charged biomolecules or for the total exclusion of likely charged ones. Our results establish a guideline for the spatial partitioning of proteins and drugs in hydrogel carriers, tunable by the hydrogel charge, pH, and salt concentration. %0 journal article %@ 1042-7147 %A Bhuvanesh, T.,Saretia, S.,Roch, T.,Schoene, A.-C.,Rottke, F.O.,Kratz, K.,Wang, W.,Ma, N.,Schulz, B.,Lendlein, A. %D 2017 %J Polymers for Advanced Technologies %N 10 %P 1305-1311 %R doi:10.1002/pat.3910 %T Langmuir–Schaefer films of fibronectin as designed biointerfaces for culturing stem cells %U https://doi.org/10.1002/pat.3910 10 %X Glycoproteins adsorbing on an implant upon contact with body fluids can affect the biological response in vitro and in vivo, depending on the type and conformation of the adsorbed biomacromolecules. However, this process is poorly characterized and so far not controllable. Here, protein monolayers of high molecular cohesion with defined density are transferred onto polymeric substrates by the Langmuir–Schaefer (LS) technique and were compared with solution deposition (SO) method. It is hypothesized that on polydimethylsiloxane (PDMS), a substrate with poor cell adhesion capacity, the fibronectin (FN) layers generated by the LS and SO methods will differ in their organization, subsequently facilitating differential stem cell adhesion behavior. Indeed, atomic force microscopy visualization and immunofluorescence images indicated that organization of the FN layer immobilized on PDMS was uniform and homogeneous. In contrast, FN deposited by SO method was rather heterogeneous with appearance of structures resembling protein aggregates. Human mesenchymal stem cells showed reduced absolute numbers of adherent cells, and the vinculin expression seemed to be higher and more homogenously distributed after seeding on PDMS equipped with FN by LS in comparison with PDMS equipped with FN by SO. These divergent responses could be attributed to differences in the availability of adhesion molecule ligands such as the Arg-Gly-Asp (RGD) peptide sequence presented at the interface. The LS method allows to control the protein layer characteristics, including the thickness and the protein orientation or conformation, which can be harnessed to direct stem cell responses to defined outcomes, including migration and differentiation. %0 journal article %@ 1354-3784 %A Spahn, V.,Stein, C. %D 2017 %J Expert Opinion on Investigational Drugs %N 2 %P 155-160 %R doi:10.1080/13543784.2017.1275562 %T Targeting delta opioid receptors for pain treatment: drugs in phase I and II clinical development %U https://doi.org/10.1080/13543784.2017.1275562 2 %X Introduction: Opioids are widely used to treat severe pain. Most clinically used opioids activate µ-opioid receptors (MOR). Their ligands induce potent analgesia but also adverse effects. The δ-opioid receptor (DOR) is another member of the opioid receptor family that has been under intense investigation with the aim to avoid MOR-induced side effects.,Areas covered: This article reviews DOR ligands which appeared to be promising after preclinical evaluation. A literature search using Pubmed, Cochrane library, ClinicalTrials.gov, EudraCT, AdisInsight database and EBSCO Online Library was conducted. Out of numerous newly synthesized molecules, only few candidates entered phase I and/or II clinical investigation. The publicly accessible results are presented here.,Expert opinion: Many compounds showed potent DOR-specific pain inhibition in preclinical studies. ADL5859 and ADL5747 entered clinical trials and successfully passed phase I. However, in phase II studies the primary endpoint (pain reduction) was not met and further investigation was terminated. A third compound, NP2, is in phase II clinical evaluation and results are pending. These findings suggest a potential of DOR ligands according to preclinical studies. Further clinical research and secondary analysis of unpublished data is needed to identify molecules which are useful in humans. %0 journal article %@ 1420-3049 %A Boreham, A.,Brodwolf, R.,Walker, K.,Haag, R.,Alexiev, U. %D 2017 %J Molecules %N 1 %P 17 %R doi:10.3390/molecules22010017 %T Time-Resolved Fluorescence Spectroscopy and Fluorescence Lifetime Imaging Microscopy for Characterization of Dendritic Polymer Nanoparticles and Applications in Nanomedicine %U https://doi.org/10.3390/molecules22010017 1 %X The emerging field of nanomedicine provides new approaches for the diagnosis and treatment of diseases, for symptom relief and for monitoring of disease progression. One route of realizing this approach is through carefully constructed nanoparticles. Due to the small size inherent to the nanoparticles a proper characterization is not trivial. This review highlights the application of time-resolved fluorescence spectroscopy and fluorescence lifetime imaging microscopy (FLIM) for the analysis of nanoparticles, covering aspects ranging from molecular properties to particle detection in tissue samples. The latter technique is particularly important as FLIM allows for distinguishing of target molecules from the autofluorescent background and, due to the environmental sensitivity of the fluorescence lifetime, also offers insights into the local environment of the nanoparticle or its interactions with other biomolecules. Thus, these techniques offer highly suitable tools in the fields of particle development, such as organic chemistry, and in the fields of particle application, such as in experimental dermatology or pharmaceutical research. %0 journal article %@ 1549-3296 %A Klopfleisch, R.,Jung, F. %D 2017 %J Journal of Biomedical Materials Research A %N 3 %P 927-940 %R doi:10.1002/jbm.a.35958 %T The pathology of the foreign body reaction against biomaterials %U https://doi.org/10.1002/jbm.a.35958 3 %X The healing process after implantation of biomaterials involves the interaction of many contributing factors. Besides their in vivo functionality, biomaterials also require characteristics that allow their integration into the designated tissue without eliciting an overshooting foreign body reaction (FBR). The targeted design of biomaterials with these features, thus, needs understanding of the molecular mechanisms of the FBR. Much effort has been put into research on the interaction of engineered materials and the host tissue. This elucidated many aspects of the five FBR phases, that is protein adsorption, acute inflammation, chronic inflammation, foreign body giant cell formation, and fibrous capsule formation. However, in practice, it is still difficult to predict the response against a newly designed biomaterial purely based on the knowledge of its physical–chemical surface features. This insufficient knowledge leads to a high number of factors potentially influencing the FBR, which have to be analyzed in complex animal experiments including appropriate data-based sample sizes. This review is focused on the current knowledge on the general mechanisms of the FBR against biomaterials and the influence of biomaterial surface topography and chemical and physical features on the quality and quantity of the reaction. %0 journal article %@ 1042-7147 %A Heuchel, M.,Gerber, D.,Kratz, K.,Lendlein, A. %D 2017 %J Polymers for Advanced Technologies %N 10 %P 1269-1277 %R doi:10.1002/pat.3973 %T Morphological analysis of differently sized highly porous poly(ether imide) microparticles by mercury porosimetry %U https://doi.org/10.1002/pat.3973 10 %X Highly porous poly(ether imide) (PEI) microparticles prepared by a spraying/coagulation process are discussed as candidate adsorber materials for apheresis applications, i.e. removal of uremic toxins from the blood of renal failure patients. PEI particles obtained by the aforementioned procedure can have a broad size distribution with particle diameters ranging from 20 to 800 µm. In order to further estimate the adsorption behavior of PEI microparticles packed in application relevant apheresis modules, a quantitative information about the relation between particle size and pore morphology is required. In this study, we explored whether the intraparticle porosity of PEI microparticles varies with altering the diameter of the particulate adsorbers. By an analytical wet sieving procedure, the obtained PEI microparticles were separated into five size fractions, which were analyzed by mercury intrusion porosimetry, nitrogen adsorption, and scanning electron microscopy. Mercury intrusion porosimetry revealed for all size fractions high porosity values in the range from 78% to 84% with pore diameters in the range from 10 to 1000 nm. A bimodal pore size distribution was found having a first peak at around 100 nm, while a second pronounced peak maximum was found at higher pore sizes that increased with raising particle diameter from 300 nm for the smallest particle size fraction (50–100 µm) to 700 nm for particles with a diameter of 200 to 250 µm. %0 journal article %@ 2046-2069 %A Bai, L.,Li, Q.,Duo, X.,Hao, X.,Zhang, W.,Shi, C.,Guo, J.,Ren, X.,Feng, Y. %D 2017 %J RSC Advances %N 63 %P 39452-39464 %R doi:10.1039/c7ra06253b %T Electrospun PCL-PIBMD/SF blend scaffolds with plasmid complexes for endothelial cell proliferation %U https://doi.org/10.1039/c7ra06253b 63 %X Tissue engineering scaffolds with gene delivery function play an important role in DNA-based vascular tissue engineering. In the present work, we used biodegradable polyester–polydepsipeptide, silk fibroin (SF) and gene complexes to prepare electrospun scaffolds encapsulating gene complexes in order to enhance the proliferation of endothelial cells. A series of nanofibrous scaffolds with different properties including fiber diameter, hydrophilicity, porosity and mechanical properties were prepared by electrospinning technology with adjusting the weight ratio of poly(ε-caprolactone)-b-poly(isobutyl-morpholine-2,5-dione) (PCL-PIBMD) and SF. PCL-PIBMD/SF blend scaffolds were optimized to obtain the scaffolds with a weight ratio of 90/10 to have superior mechanical performance and good biocompatibility. pEGFP-ZNF580 plasmid (pZNF580) complexes were electrosprayed onto these PCL-PIBMD/SF blend scaffolds to promote the proliferation of endothelial cells. In order to maintain the stability and integrity of plasmid complexes loaded in scaffolds, the composite scaffolds were fabricated by alternatively layer-by-layer electrospinning and electrospraying techniques. These composite scaffolds showed obviously low platelet adhesion and good histocompatibility. They could effectively enhance the adhesion, spreading and proliferation of human umbilical vein endothelial cells. These results indicated that the composite scaffolds could serve as an attractive platform to deliver therapeutic genes for vascular tissue engineering. %0 journal article %@ 2050-084X %A Gonzalez-Rodriguez, S.,Quadir, M.A.,Gupta, S.,Walker, K.A.,Zhang, X.,Spahn, V.,Labuz, D.,Rodriguez-Gaztelumendi, A.,Schmelz, M.,Joseph, J.,Parr, M.K.,Machelska, H.,Haag, R.,Stein, C. %D 2017 %J eLife %N %P e27081 %R doi:10.7554/eLife.27081 %T Polyglycerol-opioid conjugate produces analgesia devoid of side effects %U https://doi.org/10.7554/eLife.27081 %X Novel painkillers are urgently needed. The activation of opioid receptors in peripheral inflamed tissue can reduce pain without central adverse effects such as sedation, apnoea, or addiction. Here, we use an unprecedented strategy and report the synthesis and analgesic efficacy of the standard opioid morphine covalently attached to hyperbranched polyglycerol (PG-M) by a cleavable linker. With its high-molecular weight and hydrophilicity, this conjugate is designed to selectively release morphine in injured tissue and to prevent blood-brain barrier permeation. In contrast to conventional morphine, intravenous PG-M exclusively activated peripheral opioid receptors to produce analgesia in inflamed rat paws without major side effects such as sedation or constipation. Concentrations of morphine in the brain, blood, paw tissue, and in vitro confirmed the selective release of morphine in the inflamed milieu. Thus, PG-M may serve as prototype of a peripherally restricted opioid formulation designed to forego central and intestinal side effects. %0 journal article %@ 1386-0291 %A Mrowietz, C.,Franke, F.P.,Pindur, G.,Wolf, U.,Jung, F. %D 2017 %J Clinical Hemorheology and Microcirculation %N 3-4 %P 347-353 %R doi:10.3233/CH-179215 %T Reference range and variability of Laser-Doppler-Fluxmetry %U https://doi.org/10.3233/CH-179215 3-4 %X The Laser Doppler technique, a noninvasive method to estimate skin blood flow (LDF), is frequently used in research and clinical routine [1]. Here, the measurements were carried out with a new Laser Doppler system, the DOPsystem, which allows to measure frequency spectra in four different frequency windows according to the velocities in venules (low velocity), capillaries (low to medium velocities), and in arteries (with high and very high velocities). However, the diagnostic reliability or the effectiveness of the LDF has not yet been evaluated sufficiently, which is indispensable, where medical diagnostics and therapy controls are concerned. For a valid interpretation of LDF values of individual patients, the knowledge of the reference range and the variability of the measured parameters is required.,In four successive studies the reference range (62 apparently healthy subjects), the circadian variability (8 subjects), the variability from day-to-day (6 subjects) and over one year with monthly measurements (6 subjects) were evaluated.,With the knowledge of the reference range, microcirculatory disorders can now be diagnosed with the DOP method used. Following a standard measurement procedure there was no dependence of the measured data on the day or season of measurement. %0 journal article %@ 0001-4842 %A Löwenberg, C.,Balk, M.,Wischke, C.,Behl, M.,Lendlein, A. %D 2017 %J Accounts of Chemical Research %N 4 %P 723-732 %R doi:10.1021/acs.accounts.6b00584 %T Shape-Memory Hydrogels: Evolution of Structural Principles To Enable Shape Switching of Hydrophilic Polymer Networks %U https://doi.org/10.1021/acs.accounts.6b00584 4 %X The ability of hydrophilic chain segments in polymer networks to strongly interact with water allows the volumetric expansion of the material and formation of a hydrogel. When polymer chain segments undergo reversible hydration depending on environmental conditions, smart hydrogels can be realized, which are able to shrink/swell and thus alter their volume on demand. In contrast, implementing the capacity of hydrogels to switch their shape rather than volume demands more sophisticated chemical approaches and structural concepts.,In this Account, the principles of hydrogel network design, incorporation of molecular switches, and hydrogel microstructures are summarized that enable a spatially directed actuation of hydrogels by a shape-memory effect (SME) without major volume alteration. The SME involves an elastic deformation (programming) of samples, which are temporarily fixed by reversible covalent or physical cross-links resulting in a temporary shape. The material can reverse to the original shape when these molecular switches are affected by application of a suitable stimulus. Hydrophobic shape-memory polymers (SMPs), which are established with complex functions including multiple or reversible shape-switching, may provide inspiration for the molecular architecture of shape-memory hydrogels (SMHs), but cannot be identically copied in the world of hydrophilic soft materials. For instance, fixation of the temporary shape requires cross-links to be formed also in an aqueous environment, which may not be realized, for example, by crystalline domains from the hydrophilic main chains as these may dissolve in presence of water. Accordingly, dual-shape hydrogels have evolved, where, for example, hydrophobic crystallizable side chains have been linked into hydrophilic polymer networks to act as temperature-sensitive temporary cross-links. By incorporating a second type of such side chains, triple-shape hydrogels can be realized. Considering the typically given light permeability of hydrogels and the fully hydrated state with easy permeation by small molecules, other types of stimuli like light, pH, or ions can be employed that may not be easily used in hydrophobic SMPs. In some cases, those molecular switches can respond to more than one stimulus, thus increasing the number of opportunities to induce actuation of these synthetic hydrogels. Beyond this, biopolymer-based hydrogels can be equipped with a shape switching function when facilitating, for example, triple helix formation in proteins or ionic interactions in polysaccharides. Eventually, microstructured SMHs such as hybrid or porous structures can combine the shape-switching function with an improved performance by helping to overcome frequent shortcomings of hydrogels such as low mechanical strength or volume change upon temporary cross-link cleavage. Specifically, shape switching without major volume alteration is possible in porous SMHs by decoupling small volume changes of pore walls on the microscale and the macroscopic sample size. Furthermore, oligomeric rather than short aliphatic side chains as molecular switches allow stabilization of the sample volumes. Based on those structural principles and switching functionalities, SMHs have already entered into applications as soft actuators and are considered, for example, for cell manipulation in biomedicine. In the context of those applications, switching kinetics, switching forces, and reversibility of switching are aspects to be further explored. %0 journal article %@ 1022-1336 %A Chen, D.,Xia, X.,Wong, T.W.,Bai, H.,Behl, M.,Zhao, Q.,Lendlein, A.,Xie, T. %D 2017 %J Macromolecular Rapid Communications %N 7 %P 1600746 %R doi:10.1002/marc.201600746 %T Omnidirectional Shape Memory Effect via Lyophilization of PEG Hydrogels %U https://doi.org/10.1002/marc.201600746 7 %X Device applications of shape memory polymers demand diverse shape changing geometries, which are currently limited to non-omnidirectional movement. This restriction originates from traditional thermomechanical programming methods such as uniaxial, biaxial stretching, bending, or compression. A solvent-modulated programming method is reported to achieve an omnidirectional shape memory behavior. The method utilizes freeze drying of hydrogels of polyethylene glycol networks with a melting transition temperature around 50 °C in their dry state. Such a process creates temporarily fixed macroporosity, which collapses upon heating, leading to significant omnidirectional shrinkage. These shrunken materials can swell in water to form hydrogels again and the omnidirectional programming and recovery can be repeated. The fixity ratio (R f) and recovery ratio (R r) can be maintained at 90% and 98% respectively upon shape memory multicycling. The maximum linear recoverable strain, as limited by the maximum swelling, is ≈90%. Amongst various application potentials, one can envision the fabrication of multiphase composites by taking advantages of the omnidirectional shrinkage from a porous polymer to a denser structure. %0 journal article %@ 1042-7147 %A Balk, M.,Grijpma, D.W.,Lendlein, A. %D 2017 %J Polymers for Advanced Technologies %N 10 %P 1203-1205 %R doi:10.1002/pat.3980 %T Design and processing of advanced functional polymers for medicine %U https://doi.org/10.1002/pat.3980 10 %X No abstract %0 journal article %@ 0939-6411 %A Brunacci, N.,Wischke, C.,Naolou, T.,Neffe, A.T.,Lendlein, A. %D 2017 %J European Journal of Pharmaceutics and Biopharmaceutics %N %P 61-65 %R doi:10.1016/j.ejpb.2016.11.011 %T Influence of surfactants on depsipeptide submicron particle formation %U https://doi.org/10.1016/j.ejpb.2016.11.011 %X Surfactants are required for the formation and stabilization of hydrophobic polymeric particles in aqueous environment. In order to form submicron particles of varying sizes from oligo[3-(S)-sec-butylmorpholine-2,5-dione]diols ((OBMD)-diol), different surfactants were investigated. As new surfactants, four-armed star-shaped oligo(ethylene glycol)s of molecular weights of 5–20 kDa functionalized with desamino-tyrosine (sOEG-DAT) resulted in smaller particles with lower PDI than with desaminotyrosyl tyrosine (sOEG-DATT) in an emulsion/solvent evaporation method. In a second set of experiments, sOEG-DAT of Mn = 10 kDa was compared with the commonly employed emulsifiers polyvinylalcohol (PVA), polyoxyethylene (20) sorbitan monolaurate (Tween 20), and D-α-tocopherol polyethylene glycol succinate (VIT E-TPGS) for OBMD particle preparation. sOEG-DAT allowed to systematically change sizes in a range of 300 up to 900 nm with narrow polydispersity, while in the other cases, a lower size range (250–400 nm, PVA; ∼300 nm, Tween 20) or no effective particle formation was observed. The ability of tailoring particle size in a broad range makes sOEG-DAT of particular interest for the formation of oligodepsipeptide particles, which can further be investigated as drug carriers for controlled delivery. %0 journal article %@ 1042-7147 %A Balk, M.,Behl, M.,Yang, J.,Li, Q.,Wischke, C.,Feng, Y.,Lendlein, A. %D 2017 %J Polymers for Advanced Technologies %N 10 %P 1278-1284 %R doi:10.1002/pat.3911 %T Design of polycationic micelles by self‐assembly of polyethyleneimine functionalized oligo[(ε‐caprolactone)‐co‐glycolide] ABA block copolymers %U https://doi.org/10.1002/pat.3911 10 %X Cationic polymeric micelles are of interest as delivery materials for nucleotides allowing condensation and transport of anionic macromolecules and enabling the reduction of cytotoxicity of polyethyleneimine, the current standard of vectors for non-viral nucleic acid delivery. In addition, micelles based on a degradable core would be capable to degrade hydrolytically and release their payload, which should preferably occur after uptake in early endosomes providing a pH of 5.5. We explored whether degradable and amphiphilic ABA block copolymers from hyperbranched polyethyleneimine A blocks and B blocks based on hydrophobic oligoesters (CG) can be created, which can degrade in a pH range relevant for the early endosomes. CG was synthesized by ring-opening polymerization of ε-caprolactone and diglycolide. Polycationic micelles with particle sizes between 19 ± 1 and 43 ± 2 nm were obtained by self-assembly of the ABA block copolymers with different chain lengths of B blocks and/or co-assembly with a diblock copolymer from poly(ethylene glycol) (PEG) functionalized CG oligoester in phosphate-buffered saline solution. Mixed micelles containing PEG-CG showed a decreased zeta potential, suggesting a shielding by dangling PEG chains at the micelle surfaces. Sizes of cationic micelles were stable at pH = 7.4 over the studied time period of 2 weeks at 37 °C. The hydrolytic degradation was controlled by the composition of the CG core and was accelerated when the pH was decreased to 5.5 as detected by increasing micelle sizes. In this way, the polycationic micelles may act as an on-demand delivery system of condensed macromolecules. %0 journal article %@ 1042-7147 %A Piluso, S.,Lendlein, A.,Neffe, A.T. %D 2017 %J Polymers for Advanced Technologies %N 10 %P 1318-1324 %R doi:10.1002/pat.3962 %T Enzymatic action as switch of bulk to surface degradation of clicked gelatin-based networks %U https://doi.org/10.1002/pat.3962 10 %X Polymer degradation occurs under physiological conditions in vitro and in vivo, especially when bonds susceptible to hydrolysis are present in the polymer. Understanding of the degradation mechanism, changes of material properties over time, and overall rate of degradation is a necessary prerequisite for the knowledge-based design of polymers with applications in biomedicine. Here, hydrolytic degradation studies of gelatin-based networks synthesized by copper-catalyzed azide-alkyne cycloaddition reaction are reported, which were performed with or without addition of an enzyme. In all cases, networks with a stilbene as crosslinker proofed to be more resistant to degradation than when an octyl diazide was used. Without addition of an enzyme, the rate of degradation was ruled by the crosslinking density of the network and proceeded via a bulk degradation mechanism. Addition of Clostridium histolyticum collagenase resulted in a much enhanced rate of degradation, which furthermore occurred via surface erosion. The mesh size of the hydrogels (>7 nm) was in all cases larger than the hydrodynamic radius of the enzyme (4.5 nm) so that even in very hydrophilic networks with large mesh size enzymes may be used to induce a fast surface degradation mechanism. This observation is of general interest when designing hydrogels to be applied in the presence of enzymes, as the degradation mechanism and material performance are closely interlinked. %0 journal article %@ 1042-7147 %A Dal Bianco, A.,Wischke, C.,Zhou, S.,Lendlein, A. %D 2017 %J Polymers for Advanced Technologies %N 10 %P 1263-1268 %R doi:10.1002/pat.3917 %T Controlling surface properties and permeability of polyglycerol network films %U https://doi.org/10.1002/pat.3917 10 %X While branched polyglycerol (PG)-based molecules are well established as hydrophilic particles, the capacity of utilizing PG in bulk materials and opportunities arising by their further surface functionalization have only recently been considered. Here we investigated how the mold used in PG network synthesis may affect surface composition and how the permeability of substances through PG can be controlled by altering network structure, i.e. introducing 20 mol% oligoethylene glycol (OEG) bifunctional spacer molecules. Overall, PG-based bulk network materials were shown to be tailorable, hydrophilic, low swelling and relatively stiff polyether-based materials, with low impact of salt onto material properties. Based on these features, but also on the principal capacity of free hydroxyl groups to be used for functionalization reactions, these materials may be an interesting platform for medical and technical applications, e.g. as diffusion-rate controlling membrane in aqueous environment. %0 journal article %@ 2046-2069 %A Mazurek-Budzynska, M.,Razzaq, M.Y.,Rokicki, G.,Behl, M.,Lendlein, A. %D 2017 %J MRS Advances %N 47 %P 2529-2536 %R doi:10.1557/adv.2017.471 %T High-Strain Shape-Memory Properties of Poly(Carbonate-Urea-Urethane)s Based on Aliphatic Oligocarbonates and L-Lysine Diisocyanate %U https://doi.org/10.1557/adv.2017.471 47 %X The simultaneous capability of high-strain deformation and high shape recovery ratio constitutes a great challenge in design of the shape-memory polymers. Here we report on poly(carbonate-urea-urethane)s (PCUUs) synthesized by a precursor route, based on oligo(alkylene carbonate) diols, L-lysine diisocyanate (LDI), and water vapor. When programed with a strain of ε prog = 800%, the PCUU networks exhibited a one-way shape-memory effect (1W-SME) with excellent shape fixity (> 97%) and shape recovery (> 99%) ratios. The switching temperatures (T sw) varied between 50 and 56 °C and correlated to the melting transitions of the switching domains. The obtained PCUUs capable of high-strain are interesting candidate materials for degradable biomaterials as required in smart medical devices. %0 journal article %@ 2059-8521 %A You, Z.,Behl, M.,Loewenberg, C.,Lendlein, A. %D 2017 %J MRS Advances %N 47 %P 2571-2579 %R doi:10.1557/adv.2017.491 %T pH-sensitivity and Conformation Change of the N-terminal Methacrylated Peptide VK20 %U https://doi.org/10.1557/adv.2017.491 47 %X N-terminal methacrylation of peptide MAX1, which is capable of conformational changes by variation of the pH, results in a peptide, named VK20. Increasing the reactivity of this terminal group enables further coupling reactions or chemical modifications of the peptide. However, this end group functionalization may influence the ability of conformational changes of VK20, as well as its properties. In this paper, the influence of pH on the transition between random coil and ß-sheet conformation of VK20, including the transition kinetics, were investigated. At pH values of 9 and higher, the kinetics of ß-sheet formation increased for VK20, compared to MAX1. The self-assembly into ß-sheets recognized by the formation of a physically crosslinked gel was furthermore indicated by a significant increase of G’. An increase in pH (from 9 to 9.5) led to a faster gelation of the peptide VK20. Simultaneously, G’ was increased from 460 ± 70 Pa (at pH 9) to 1520 ± 180 Pa (at pH 9.5). At the nanoscale, the gel showed a highly interconnected fibrillary network structure with uniform fibril widths of approximately 3.4 ± 0.5 nm (N=30). The recovery of the peptide conformation back to random coil resulted in the dissolution of the gel, whereby the kinetics of the recovery depended on the pH. Conclusively, the ability of MAX1 to undergo conformational changes was not affected by N-terminal methacrylation whereas the kinetics of pH-sensitive ß-sheet formations has been increased. %0 journal article %@ 2059-8521 %A Peng, X.,Behl, M.,Zhang, P.,Mazurek-Budzynska, M.,Feng, Y.,Lendlein, A. %D 2017 %J MRS Advances %N 47 %P 2551-2559 %R doi:10.1557/adv.2017.486 %T Synthesis and Characterization of Multiblock Poly(Ester-Amide-Urethane)s %U https://doi.org/10.1557/adv.2017.486 47 %X In this study, a multiblock copolymer containing oligo(3-methyl-morpholine-2,5-dione) (oMMD) and oligo(3-sec-butyl-morpholine-2,5-dione) (oBMD) building blocks obtained by ring-opening polymerization (ROP) of the corresponding monomers, was synthesized in a polyaddition reaction using an aliphatic diisocyanate. The multiblock copolymer (pBMD-MMD) provided a molecular weight of 40,000 g·mol−1, determined by gel permeation chromatography (GPC). Incorporation of both oligodepsipeptide segments in multiblock copolymers was confirmed by 1H NMR and Matrix Assisted Laser Desorption/Ionization Time Of Flight Mass Spectroscopy (MALDI-TOF MS) analysis. pBMD-MMD showed two separated glass transition temperatures (61 °C and 74 °C) indicating a microphase separation. Furthermore, a broad glass transition was observed by DMTA, which can be attributed to strong physical interaction i.e. by H-bonds formed between amide, ester, and urethane groups of the investigated copolymers. The obtained multiblock copolymer is supposed to own the capability to exhibit strong physical interactions. %0 journal article %@ 2050-750X %A Li, Q.,Hao, X.,Lv, J.,Ren, X.,Zhang, K.,Ullah, I.,Feng, Y.,Shi, C.,Zhang, W. %D 2017 %J Journal of Materials Chemistry B %N 8 %P 1673-1687 %R doi:10.1039/C6TB02212J %T Mixed micelles obtained by co-assembling comb-like and grafting copolymers as gene carriers for efficient gene delivery and expression in endothelial cells %U https://doi.org/10.1039/C6TB02212J 8 %X Gene delivery can enhance the endothelialization of biomaterial surfaces. However, the lack of efficient target function is still the major concern that hinders the clinical application of gene therapy. With the aim to develop a specific targeting gene carrier for endothelial cells (ECs), the Cys-Arg-Glu-Asp-Val-Trp (CREDVW) peptide was linked to the comb-like copolymer of poly(lactide-co-3(S)-methyl-morpholine-2,5-dione)-poly(poly(ethylene glycol) monomethacrylate) (PLMD-PPEGMA) to form the CREDVW modified copolymer PLMD-PPEGMA-CREDVW, which could enhance the special recognition of ECs. Mixed micelles were then prepared by co-assembling this comb-like copolymer and the amphiphilic grafting copolymer poly(lactide-co-3(S)-methyl-morpholine-2,5-dione)-g-polyethylenimine (PLMD-g-PEI). These mixed micelles with the CREDVW-functional peptide exhibited good pEGFP-ZNF580 (pDNA) binding ability and could condense it into complexes with proper size and positive zeta potential. The MTT results demonstrated the low cytotoxicity of the CREDVW-modified mixed micelle/pDNA complexes. The internalization efficiency of the CREDVW-modified complexes with targeting function was about two times higher than the dysfunctional CREVDW-modified complexes. Besides, the transfection efficiency of these complexes was more pronounced, compared to the control group, PEI(10 kDa)/pDNA, as detected by means of in vitro transfection studies. Western blot analysis demonstrated relatively high protein levels in the transfected cells by CREDVW-modified mixed micelle/pDNA complexes, up to 75%, in comparison to the control group (26%). In addition, the cell migration ability was significantly improved as demonstrated by the wound healing assay. These results indicated that the mixed micelles could act as an active targeting gene carrier, having both tunable gene transfection efficiency and low cytotoxicity, which are beneficial for the endothelialization of biomaterial surface. %0 journal article %@ 1386-0291 %A Lamby, P.,Prantl, L.Krueger-Genge, A.,Franke, R.P.,Jung, E.M.,Jung, F. %D 2017 %J Clinical Hemorheology and Microcirculation %N 3-4 %P 211-214 %R doi:10.3233/CH-179201 %T Influence of Ultrasound Microbubbles on kidney oxygen tension %U https://doi.org/10.3233/CH-179201 3-4 %X Ultrasound contrast agents (USCA) allows the dynamic detection of blood flow of both the macro and microvasculature. An obvious prerequisite for USCAs is the unhindered passage of clinically relevant dose levels through the microcirculation especially of the lungue, where they have to pass capillaries with diameters of around 4 μm. While smaller microbubbles rapidly passed through the microcirculation along with the red blood cells, larger microbubbles, however, were observed to coalesce and interrupt the blood flow. Whether this might influence the tissue oxygen tension is unclear up to now.,To examine this question a bolus of 2.4 ml SonoVue™ was injected into the suprarenal aorta at a flow rate of 10 ml/s (a dosage usually applied in the clinic). The pO2 in the outer medulla of the kidney was continuously measured using a flexible pO2 microcatheter. In addition, the SonoVue™ injection and its passage through the renal vasculature were documented by the CEUS technology to assess whether the microbubbles passed the kidney.,The study revealed that SonoVue™ induced no changes of the mean oxygen partial pressure in the outer medulla which confirms that these microbubbles on their way through the medullar capillaries did not hinder the co-flow of blood through the renal microvessels in a big animal model with a renal morphology and function comparable to human kidneys. These results demonstrate that the CEUS diagnostic itself did not influence the system to be examined which is a most important prerequisite for any diagnostic method.,With the introduction of ultrasound contrast agents (USCA), diagnostic ultrasound has entered a new era that allows the dynamic detection of blood flow of both the macro and microvasculature [1]. USCAs are shell-coated gas-filled microbubbles that are administered to the systemic circulation. As there is a great difference in echogenicity between the gas in the microbubbles and the soft tissue of the body such microbubbles are used to image the vasculature as well as the blood flow in veins, arteries and also microvessels [2]. An obvious prerequisite for USCAs is the free, unhindered passage of clinically relevant dose levels through the microcirculation. So, microbubbles have to be able to pass capillaries with diameters of around 4 μm [3]. The mean diameter of the microbubbles of SonoVue™ (Bracco, Konstanz, Germany) was described to be 2.5 μm, and more than 90% of the bubbles are smaller than 8 μm [4]. Bigger bubbles traversing the capillary bed would have to deform and adapt their shape to the diameter of the capillaries. Feinstein et al. showed that the smaller microbubbles rapidly passed through the microcirculation along with the red blood cells. Larger microbubbles, however, were observed to coalesce and interrupt the blood flow (subsequently they collapse or shrink [5]). Up to now it is unclear, whether such USCA-induced drop of blood flow might impair the oxygen tension (pO2) in kidneys [6, 7]. The decisive question is, whether the rate of flow disturbance induced by the injection of SonoVue™ could become so relevant as to influence and limit the oxygen supply to the surrounding kidney tissue.,To examine whether an injection of SonoVue™ might influence the pO2 in the tissue of the downstream microcirculation, a bolus of 2.4 ml was injected into the suprarenal aorta at a flow rate of 10 ml/s (a dosage usually applied in the clinic [8]. It was immediately followed by 10 ml of isotonic sodium chloride solution. The pO2 in the outer medulla of the kidney was continuously measured using a flexible pO2 microcather [9]. SonoVue™ injection and its passage through the renal vasculature were documented by the CEUS technology to assess whether the microbubbles passed the kidney [9].,The Bavarian Institutional Animal Care and Use Committee approved the study protocol for the experiments performed in this study (AZ.: 54-2532.1-31/13). %0 journal article %@ 1386-0291 %A Blocki, A.,Loeper, F.,Chirico, N.,Neffe, A.T.,Jung, F.,Stamm, C.,Lendlein, A. %D 2017 %J Clinical Hemorheology and Microcirculation %N 3-4 %P 251-259 %R doi:10.3233/CH-179206 %T Engineering of cell-laden gelatin-based microcapsules for cell delivery and immobilization in regenerative therapies %U https://doi.org/10.3233/CH-179206 3-4 %X Cell-based therapies often face the challenge of low cell retention and viability upon transplantation. Hence, biomaterials, which can immobilize transplanted cells, while at the same time support cell viability, are essential for successful clinical application. Noteworthy, biomaterials in the micrometer range such as microcapsules have the advantage of a minimally invasive introduction into tissue.,Hence, we established an approach to generate gelatin-based cell carriers in the form of microspherical hydrogels. Fibroblasts were microencapsulated in glycidylmethacrylate (GMA)-functionalized gelatin by photopolymerization. While the degree of GMA-functionalization was kept constant, the hydrogel cross-linking density was adjusted by varying the time of irradiation, or the average gelatin-chain length.,Stable microcapsules could be achieved with 10 wt% GMA-gelatin solutions for all irradiation periods tested (0.5 –2 min). Evaluation of cell viability revealed that microgels with the same weight content of biopolymer but with decreased cross-linking densities and thus decreasing storage, and E moduli resulted in best cell support. Noteworthy, encapsulated cells partially migrated out of the microcapsules and attached to the spherical surface.,10 wt% GMA-gelatin-based hydrogels with E moduli properties comparable to the native cellular niche proved to be a promising biomaterial suitable for the production of cell-laden microcapsules and shall be evaluated further for biomedical application. %0 journal article %@ 1386-0291 %A Krueger-Genge, A.,Hiebl, B.,Franke, R.P.,Lendlein, A.,Jung, F. %D 2017 %J Clinical Hemorheology and Microcirculation %N 3-4 %P 309-318 %R doi:10.3233/CH-179211 %T Effects of Tacrolimus or Sirolimus on the adhesion of vascular wall cells: Controlled in-vitro comparison study %U https://doi.org/10.3233/CH-179211 3-4 %X In drug eluting stents the cytostatic drugs Sirolimus or Tacrolimus are used to inhibit blood vessel restenosis by limiting the proliferation of smooth muscle cells. However, the cytostatic activity of both drugs was shown to be not cell specific and could also affect the stent endothelialisation, respectively. Currently, only limited in vitro data are available about the impact of Sirolimus and Tacrolimus on endothelial cell proliferation over a broad concentration range. To answer this question the following study was performed.,Commercially obtained HUVEC were expanded with DMEM cell culture medium (GIBCO, Germany) supplemented with 5 vol% fetal calf serum on non-coated regular polystyrene-based 24-multiwell plates. For drug testings 2×104 cells/cm2 were seeded and grown for 24 h until 30–40% of the multiwell surfaces were covered and then exposed to Sirolimus (1.0×10–11–1.0×10–5 mol/l) or Tacrolimus (2.0×10–8–6.2×10–5 mol/l), both dissolved in DMSO. 12, 24 and 48 h after adding the drugs cell numbers per area were quantified by counting the cells in six wells with four fields of view per well, representing 0.6 mm2, using a confocal laser microscope.,After 48 h of cell growth in the drug-free cell culture medium, the HUVEC number increased from 2.0×104 to 3.55×104 cells/cm2 (mean cell doubling time: 53.6 h, n = 6). At lower concentrations (≤2.0×10–6 mol/l) Tacrolimus reduced the number of adherent HUVEC significantly less than Sirolimus (p < 0.05). However, at higher concentrations (≥2.07×10–5 mol/l) the effect of Tacrolimus on the number of adherent endothelial cells was significantly greater than that of Sirolimus (p < 0.05). At the highest concentration applied (6.22×10–5 mol/l), Tacrolimus induced detachment of all HUVECs within 12 h after drug application. The number of adherent HUVEC decreased only slightly (about 9%) after Sirolimus application at the highest concentration (1.09×10–5 mol/l).,These data show that in a non-flow model the cytostatic drug Tacrolimus reduced the number of adherent endothelial cells less than Sirolimus, as long as the drug concentration did not surpass 10–6 mol/l. At the limits of solubility, Sirolimus (1×10–5 mol/l) reduced the number of adherent endothelial cells less than Tacrolimus (6×10–5 mol/l), which induced detachment of endothelial cells. %0 journal article %@ 2046-2069 %A Yu, S.,Schuchardt, M.,Toelle, M.,Giet, M.van der,Zidek, W.,Dzubiella, J.,Ballauff, M. %D 2017 %J RSC Advances %N 45 %P 27913-27922 %R doi:10.1039/c7ra02838e %T Interaction of human serum albumin with uremic toxins: a thermodynamic study %U https://doi.org/10.1039/c7ra02838e 45 %X We present a comprehensive study of the interaction of human serum albumin (HSA) with two uremic toxins, namely phenylacetic acid (PhAA) and indoxyl sulfate (IDS) in aqueous solution. The interaction of HSA with PhAA is studied for a series of salt concentrations (20–150 mM) and temperature (25, 30 and 37 °C). The effect of in vitro urea modification of HSA upon its binding affinity towards the uremic toxins, is studied under the highest and lowest salt concentrations and the different temperatures. Isothermal titration calorimetry (ITC) is used to study the interaction by analyzing binding affinities and related thermodynamic data. It is found that two PhAA molecules bind to HSA in a sequential binding process with a binding constant kb in the order of ≈104 and ≈103 for the first and second binding respectively. In contrast, IDS binds much stronger to HSA with a total of ≈3 molecules to a high and low affinity binding site in the order of ≈105 and ≈103. Binding of uremic toxins to HSA in all cases show a decreasing binding affinity trend with increasing temperature and higher ionic strength. Thus binding of a second uremic toxin is strongly weakened at 37 °C and 150 mM. Urea induced HSA modification have only minor effect on the binding interaction of the uremic toxins. %0 journal article %@ 1944-8244 %A Yang, J.,Hao, X.,Li, Q.,Akpanyung, M.,Nejjari, A.,Neve, A.L.,Ren, X.,Guo, J.,Feng, Y.,Shi, C.,Zhang, W. %D 2017 %J ACS Applied Materials and Interfaces %N 5 %P 4485-4497 %R doi:10.1021/acsami.6b14769 %T CAGW Peptide- and PEG-Modified Gene Carrier for Selective Gene Delivery and Promotion of Angiogenesis in HUVECs in Vivo %U https://doi.org/10.1021/acsami.6b14769 5 %X Gene therapy is a promising strategy for angiogenesis, but developing gene carriers with low cytotoxicity and high gene delivery efficiency in vivo is a key issue. In the present study, we synthesized the CAGW peptide- and poly(ethylene glycol) (PEG)-modified amphiphilic copolymers. CAGW peptide serves as a targeting ligand for endothelial cells (ECs). Different amounts of CAGW peptide were effectively conjugated to the amphiphilic copolymer via heterofunctional poly(ethylene glycol). These CAG- and PEG-modified copolymers could form nanoparticles (NPs) by self-assembly method and were used as gene carriers for the pEGFP-ZNF580 (pZNF580) plasmid. CAGW and PEG modification coordinately improved the hemocompatibility and cytocompatibility of NPs. The results of cellular uptake showed significantly enhanced internalization efficiency of pZNF580 after CAGW modification. Gene expression at mRNA and protein levels demonstrated that EC-targeted NPs possessed high gene delivery efficiency, especially the NPs with higher content of CAGW peptide (1.16 wt %). Furthermore, in vitro and in vivo vascularization assays also showed outstanding vascularization ability of human umbilical vein endothelial cells treated by the NP/pZNF580 complexes. This study demonstrates that the CAGW peptide-modified NP is a promising candidate for gene therapy in angiogenesis. %0 journal article %@ 0024-9297 %A Xu, X.,Ran, Q.,Haag, R.,Ballauff, M.,Dzubiella, J. %D 2017 %J Macromolecules %N 12 %P 4759-4769 %R doi:10.1021/acs.macromol.7b00742 %T Charged Dendrimers Revisited: Effective Charge and Surface Potential of Dendritic Polyglycerol Sulfate %U https://doi.org/10.1021/acs.macromol.7b00742 12 %X We investigate key electrostatic features of charged dendrimers at hand of the biomedically important dendritic polyglycerol sulfate (dPGS) macromolecule using multiscale computer simulations and Zetasizer experiments. In our simulation study, we first develop an effective mesoscale Hamiltonian specific to dPGS based on input from all-atom, explicit-water simulations of dPGS of low generation. Employing this in coarse-grained, implicit-solvent/explicit-salt Langevin dynamics simulations, we then study dPGS structural and electrostatic properties up to the sixth generation. By systematically mapping then the calculated electrostatic potential onto the Debye–Hückel form—that serves as a basic defining equation for the effective charge—we determine well-defined effective net charges and corresponding radii, surface charge densities, and surface potentials of dPGS. The latter are found to be up to 1 order of magnitude smaller than the bare values and consistent with previously derived theories on charge renormalization and weak saturation for high dendrimer generations (charges). Finally, we find that the surface potentials of the dendrimers estimated from the simulations compare very well with our new electrophoretic experiments. %0 journal article %@ 2050-750X %A Ullah, I.,Muhammad, K.,Akpanyung, M.,Nejjari, A.,Neve, A.L.,Guo, J.,Feng, Y.,Shi, C. %D 2017 %J Journal of Materials Chemistry B %N 18 %P 3253-3276 %R doi:10.1039/c7tb00275k %T Bioreducible, hydrolytically degradable and targeting polymers for gene delivery %U https://doi.org/10.1039/c7tb00275k 18 %X Recently, synthetic gene carriers have been intensively developed owing to their promising application in gene therapy and considered as a suitable alternative to viral vectors because of several benefits. But cationic polymers still face some problems like low transfection efficiency, cytotoxicity, and poor cell recognition and internalization. The emerging engineered and smart polymers can respond to some changes in the biological environment like pH change, ionic strength change and redox potential, which is beneficial for cellular uptake. Redox-sensitive disulfide based and hydrolytically degradable cationic polymers serve as gene carriers with excellent transfection efficiency and good biocompatibility owing to degradation in the cytoplasm. Additionally, biodegradable polymeric micelles with cell-targeting function are recently emerging gene carriers, especially for the transfection of endothelial cells. In this review, some strategies for gene carriers based on these bioreducible and hydrolytically degradable polymers will be illustrated. %0 journal article %@ 1742-7061 %A Sarem, M.,Vonwil, D.,Luedeke, S.,Shastri, V.P. %D 2017 %J Acta Biomaterialia %N %P 285-292 %R doi:10.1016/j.actbio.2017.05.021 %T Direct quantification of dual protein adsorption dynamics in three dimensional systems in presence of cells %U https://doi.org/10.1016/j.actbio.2017.05.021 %X Understanding the composition of the adsorbed protein layer on a biomaterial surface is of an extreme importance as it directs the primary biological response. Direct detection using labeled proteins and indirect detection based on enzymatic assays or changes to mass, refractive index or density of a surface have been so far established. Nevertheless, using current methodologies, detection of multiple proteins simultaneously and particularly in a three-dimensional (3D) substrates is challenging, with the exception of radiolabeling. Here using fluorescence molecular tomography (FMT), we present a non-destructive and versatile approach to quantify adsorption of multiple proteins within 3D environments and reveal the dynamics of adsorption of human serum albumin (HSA) and fibrinogen (Fib) on 3D polymeric scaffold. Furthermore, we show that serum starved human articular chondrocytes in 3D environment preferentially uptake HSA over Fib and to our knowledge this represents the first example of direct visualization and quantification of protein adsorption in a 3D cell culture system.,Statement of Significance,The biomaterial surface upon exposure to biological fluids is covered by a layer of proteins, which is modified over a period of time and dictates the fate of the biomaterial. In this study, we present and validate a new methodology for quantification of protein adsorption on to a three-dimensional polymer scaffold from unitary and binary systems, using fluorescence molecular tomography, an optical trans-illumination technique with picomolar sensitivity. In additional to being able to follow behavior of two proteins simultaneously, this methodology is also suitable for studying protein uptake in cells situated in a polymer environment. The ability to follow protein adsorption/uptake in a continuous manner opens up new possibilities to study the role of serum proteins in biomaterial compatibility. %0 journal article %@ 0935-9648 %A Sarem, M.,Luedeke, S.,Thomann, R.,Salavei, P.,Zou, Z.,Habraken, W.,Masic, A.,Shastri, V.P. %D 2017 %J Advanced Materials %N 35 %P 1701629 %R doi:10.1002/adma.201701629 %T Disordered Conformation with Low Pii Helix in Phosphoproteins Orchestrates Biomimetic Apatite Formation %U https://doi.org/10.1002/adma.201701629 35 %X The interplay between noncollagenous proteins and biomineralization is widely accepted, yet the contribution of their secondary structure in mineral formation remains to be clarified. This study demonstrates a role for phosvitin, an intrinsically disordered phosphoprotein, in chick embryo skeletal development, and using circular dichroism and matrix least-squares Henderson–Hasselbalch global fitting, unravels three distinct pH-dependent secondary structures in phosvitin. By sequestering phosvitin on a biomimetic 3D insoluble cationic framework at defined pHs, access is gained to phosvitin in various conformational states. Induction of biomimetic mineralization at near physiological conditions reveals that a disordered secondary structure with a low content of PII helix is remarkably efficient at promoting calcium adsorption, and results in the formation of biomimetic hydroxyapatite through an amorphous calcium phosphate precursor. By extending this finding to phosphorylated full-length human recombinant dentin matrix protein-1 (17-513 AA), this bioinspired approach provides compelling evidence for the role of a disordered secondary structure in phosphoproteins in bone-like apatite formation. %0 journal article %@ 1525-7797 %A Obst, K.,Yealland, G.,Balzus, B.,Miceli, E.,Dimde, M.,Weise, C.,Eravci, M.,Bodmeier, R.,Haag, R.,Calderon, M.,Charbaji, N.,Hedtrich, S. %D 2017 %J Biomacromolecules %N 6 %P 1762-1771 %R doi:10.1021/acs.biomac.7b00158 %T Protein Corona Formation on Colloidal Polymeric Nanoparticles and Polymeric Nanogels: Impact on Cellular Uptake, Toxicity, Immunogenicity, and Drug Release Properties %U https://doi.org/10.1021/acs.biomac.7b00158 6 %X The adsorption of biomolecules to the surface of nanoparticles (NPs) following administration into biological environments is widely recognized. In particular, the “protein corona” is well understood in terms of formation kinetics and impact upon the biological interactions of NPs. Its presence is an essential consideration in the design of therapeutic NPs. In the present study, the protein coronas of six polymeric nanoparticles of prospective therapeutic use were investigated. These included three colloidal NPs—soft core–multishell (CMS) NPs, plus solid cationic Eudragit RS (EGRS), and anionic ethyl cellulose (EC) nanoparticles—and three nanogels (NGs)—thermoresponsive dendritic-polyglycerol (dPG) nanogels (NGs) and two amino-functionalized dPG-NGs. Following incubation with human plasma, protein coronas were characterized and their biological interactions compared with pristine NPs. All NPs demonstrated protein adsorption and increased hydrodynamic diameters, although the solid EGRS and EC NPs bound notably more protein than the other tested particles. Shifts toward moderately negative surface charges were also observed for all corona bearing NPs, despite varied zeta potentials in their pristine states. While the uptake and cellular adhesion of the colloidal NPs in primary human keratinocytes and human umbilical vein endothelial cells were significantly decreased when bearing the protein corona, no obvious impact was seen in the NGs. By contrast, corona bearing NGs induced marked increases in cytokine release from primary human macrophages not seen with corona bearing colloidal NPs. Despite this, no apparent enhancement to in vitro toxicity was noted. Finally, drug release from EGRS and EC NPs was assessed, where a decrease was seen in the EGRS NPs alone. Together these results provide a direct comparison of the physical and biological impact the protein corona has on NPs of widely varied character and in particular highlights a distinction between the corona’s effects on NGs and colloidal NPs. %0 journal article %@ 2047-4849 %A Lv, J.,Hao, X.,Li, Q.,Akpanyung, M.,Nejjari, A.,Neve, A.L.,Ren, X.,Feng, Y.,Shi, C.,Zhang, W. %D 2017 %J Biomaterials Science %N 3 %P 511-522 %R doi:10.1039/c6bm00856a %T Star-shaped copolymer grafted PEI and REDV as a gene carrier to improve migration of endothelial cells %U https://doi.org/10.1039/c6bm00856a 3 %X In this work, a biodegradable star-shaped copolymer poly(lactide-co-3(S)-methyl-morpholine-2,5-dione)6 (Star-(PLMD)6) was synthesized via ring-opening polymerization (ROP), and subsequently a gene carrier Star-PLMD-g-PEI-g-PEG-CREDVW was prepared by grafting polyethyleneimine (PEI), polyethylene glycol (PEG) and targeting peptide REDV onto Star-(PLMD)6. This gene carrier could form stable micelles to condense pEGFP-ZNF580 through electrostatic interaction. The resulting complexes were biocompatible and showed high efficiency in gene delivery. In addition, these complexes exhibited high selectivity for endothelial cells (ECs), high transfection efficiency and enhanced migration of ECs. The protein level of ZNF580 expression was significantly high (up to 85%), while the control group was only 51%. This combination of degradability, targeting ligand and star-structure strategy exhibits a significant advantage in transfection efficiency and migration of ECs. %0 journal article %@ 1386-0291 %A Mandlik, V.,Kehrer, A.,Jiga, L.,Hoinoiu, B.,Ionac, M.,Jung, F.,Staudenmaier, R.,Prantl, L. %D 2016 %J Clinical Hemorheology and Microcirculation %N 3 %P 319-331 %R doi:10.3233/C-168120 %T Prefabrication and free transfer of a Tissue Engineered Composite Flap – An experimental model in the rat %U https://doi.org/10.3233/C-168120 3 %X BACKGROUND: The technique of flap-prefabrication has been successfully established in tissue engineering: missing intrinsic vascularisation of engineered tissue can be generated in vivo by microsurgical vesselloop construction. It is possible to move engineered tissue into a defect with microsurgery. In the literature, the combination of engineered tissue covered with skin is not widely reported.,OBJECTIVE: Aim of this study was to establish a model to investigate scaffold prefabrication with full thickness skin graft coverage with subsequent free tissue transfer.,METHODS: 8 Wistar rats were operated in 2 separate steps: 1) after creating an arteriovenous loop with the femoral vessels, a porous scaffold was placed on the loop and covered with an inguinally based skin flap. A control was implanted without loop into the contralateral groin. 2) 6 weeks later the prefabricated composite flaps were microsurgically transferred to the cervical region. Skin-island monitoring was performed with Laser Doppler-scanner after the transfer.,RESULTS: Continuous loss of the skin islands was observed within 72 hours. Complications included wound-dehiscence, thrombosis and death from anaesthesia; in spite of consistent loop viability.,CONCLUSION: Evaluation showed that modifications are necessary to maintain the skin-island cove. %0 journal article %@ 1386-0291 %A Krueger-Genge, A.,Jung, F.,Fuhrmann, R.,Franke, R.-P. %D 2016 %J Clinical Hemorheology and Microcirculation %N 3 %P 383-389 %R doi:10.3233/CH-168111 %T Shear resistance of endothelial cells in a pathological environment %U https://doi.org/10.3233/CH-168111 3 %X BACKGROUND: Endothelial cells (EC) in vivo are strongly influenced by changes of the milieu exterieur. Under pathological conditions EC can become activated e.g. in hypoxic areas or during sepsis. In general, the endothelialization of implant materials is evaluated in vitro under physiological conditions. Though, in patients who receive implant materials pathological conditions are often present. An open question is therefore, how ECs seeded on a body foreign substrate behave in a pathologic microenvironment. In this in vitro study a microenvironment was created mimicking the conditions present in septic patients. To simulate this situation in vitro, serum of patients with septic shock was added to the culture medium of EC cultured on glass. The samples were sheared in a cone-plate rheometer (shear rate of 6 dyn/cm2) with subsequent analysis of the morphology, the microfilament organization and the shear resistance and compared to control cultures of EC without shock serum supplementation. Aim of the study was to investigate whether this in vitro model provides information about the functionality of an EC monolayer on a body foreign surface under pathological conditions.,RESULTS: Septic conditions induced severe changes of the morphology of the adherent cells: there was a strong induction of stress fibers. In addition, lots of cells or cell groups were detached visible as denuded areas in the EC monolayer. After shear stress exposure only 28.7% of EC seeded in cell medium supplemented with serum of septic patients remained adherent (control cells: 96.8%).,CONCLUSION: The study demonstrates that the microenvironment is of extreme importance for the behavior of EC and that in vivo pathologies can be simulated in vitro. This opens the possibility to evaluate new implant materials under physiological but more important also under certain pathological conditions - simulating the implant size and the disease of the host. %0 journal article %@ 1386-0291 %A Lamby, P.,Jung, F.,Falter, J.,Mrowietz, C.,Graf, S.,Schellenberg, L.,Platz Batista da Silva, N.,Prantl, L.,Franke, R.-P.,Jung, E.M. %D 2016 %J Clinical Hemorheology and Microcirculation %N 3 %P 287-295 %R doi:10.3233/CH-168110 %T Effect of radiographic contrast media on renal perfusion – First results %U https://doi.org/10.3233/CH-168110 3 %X BACKGROUND: Intra-arterial administration of radiographic contrast media (CM) is discussed to impair renal perfusion. The pathogenesis of contrast-induced Nephropathy (CIN) is still not clarified.,OBJECTIVE: This trial was performed to prove the effects of two CM with different molecular structure on renal perfusion.,METHODS: A prospective, randomized study on 16 pigs was designed to compare the outcome after application of a low-osmolar iodinated CM (770 mOsm/kg H2O – Group1) and an iso-osmolar iodinated CM (290 mOsm/kg H2o – Group2).,Color Coded Doppler Sonography (LOGIQ E9, GE, Milwaukee, USA) was applied for measuring the Renal Resistive Index (RRI) before and after the first, fifth, and tenth bolus of CM. Statistics was performed using analysis of variance for repeated measurements with the Factor “CM”.,RESULTS: All flow spectra were documented free of artifacts and Peak Systolic Velocity (PSV), Enddiastolic Velocity (EDV) and RRI respectively could be calculated. Mean PSV in Group 1 led to a decrease while in Group 2 PSV showed a significant increase after CM (p = 0,042). The course of the mean EDV in both groups deferred accordingly (p = 0,033). Mean RRI over time significantly deferred in both groups (p = 0,001). It showed a biphasic course in Group 2 and a decrease over time in Group 2.,CONCLUSION: While iso-osmolar CM induced an increase of PSV and EDV together with a decrease of RRI, low-osmolar CM could not show this effect or rather led to the opposite. %0 journal article %@ 0014-3057 %A Naolou, T.,Lendlein, A.,Neffe A.T. %D 2016 %J European Polymer Journal %N %P 139-149 %R doi:10.1016/j.eurpolymj.2016.10.011 %T Influence of metal softness on the metal-organic catalyzed polymerization of morpholin-2,5-diones to oligodepsipeptides %U https://doi.org/10.1016/j.eurpolymj.2016.10.011 %X Synthetic access to oligodepsipeptides (ODP), polymers with high potential in biomedicine, is given by the ring-opening polymerization (ROP) of morpholine-2,5-diones (MDs). Classically, the ROP of MDs is mostly conducted by coordination-insertion polymerization using metal-organics as a catalyst e.g. tin(II) di(2-ethyl hexanoate) (Sn(Oct)2). This ROP has been shown to be significantly more difficult to conduct than the corresponding ROP of dilactide, which was related to different electronic properties of the monomers and potential steric crowding. Here, we investigated the ROP of 3-(S)-sec-butylmorpholine-2,5-dione (BMD) by varying the catalyst’s hardness, comparing Sn(Oct)2 with the ethoxides of indium, magnesium, aluminum and iron(III), as well as with iron(II) acetate. The ROP of BMD with Sn(Oct)2 in bulk at 135 °C for 24 h gave ODP with a number-average molecular weight (Mn) = 4.5 kDa. Mg(OEt)2 gave the best results among the other investigated metal ethoxides with ODP of Mn = 4 kDa and a conversion ratio of 57 mol%. On the other hand, high polymerization temperature was needed (160 °C) in the case of In(OEt)3, which resulted in partial degradation, while Al(OEt)3 and Fe(OEt)3 did not result in polymerization. Very effective for the ROP of the studied MD proofed to be Fe(OAc)2, giving OBMD with a Mn = 5.8 kDa, a polydispersity of 1.1, a conversion ratio of 86 mol%, and no racemization. This catalyst likewise performed well in the polymerization of Ser- and Tyr-based MDs. Fe(II) is softer than Sn(II) and may support the ROP by promoting the alkoxide transfer step of the polymerization, while suppressing the formation of unreactive coordination complexes. In contrast, the metal alkoxides investigated were harder than Fe(II) or Sn(II), but had low steric demand. The results suggest that the hardness of the central atom is the key property in the polymerization, while steric considerations are of lower importance. In addition, a synthesis of MDs with protected side chains in improved yields was introduced. This was achieved by in situ formation of an alkyl iodide that is very effective in the ring closing reaction. %0 journal article %@ 2365-6549 %A Beyer, S.,Prinz, C.,Schuermann, R.,Feldmann, I.,Zimathies, A.,Blocki, A.M.,Bald, I.,Schneider, R.J.,Emmerling, F. %D 2016 %J Chemistry Select %N 18 %P 5905-5908 %R doi:10.1002/slct.201601513 %T Ultra-Sonication of ZIF-67 Crystals Results in ZIF-67 Nano-Flakes %U https://doi.org/10.1002/slct.201601513 18 %X Zeolitic Imidazolate Frameworks (ZIFs) are crystalline materials that comprise of metal nodes and Imidazole derivatives as linkers. ZIF-67 is often used in polymer composite materials e. g. for gas separation membranes. Post-synthesis treatment of ZIF-67 crystals with ultrasound leads to unforeseen plasticity that resulted in sintered ZIF-67 and ZIF-67 nano-flakes. Consequently, ultrasound increases the external surface area of ZIF-67 which might improve e. g. blending with polymers in composite materials. These new morphologies of ZIF-67 were characterized by transmission electron, scanning electron, and atomic force microscopy. The ultrasound treatment of ZIF-67 did not result in the formation of an amorphous framework or a meta-stable crystal structure as indicated by powder x-ray diffraction. In addition, ultra-sonicated ZIF-67 retained the high gas adsorption capacity and pore size compared to synthesized ZIF-67. The morphological changes are hard to detect with standard analytical methods that are usually utilized for MOF characterization. These findings also suggest that sonochemical treatment of ZIFs leads to structural effects beyond increasing the amount of nucleation clusters during sono-chemical synthesis, which is currently not addressed in the field. %0 journal article %@ 0887-6266 %A Yan, W.,Fang, L.,Noechel, U.,Kratz, K.,Lendlein, A. %D 2016 %J Journal of Polymer Science B %N 19 %P 1935-1943 %R doi:10.1002/polb.24097 %T Influence of programming strain rates on the shape-memory performance of semicrystalline multiblock copolymers %U https://doi.org/10.1002/polb.24097 19 %X Multiblock copolymers named PCL-PIBMD consisting of crystallizable poly(ε-caprolactone) segments and crystallizable poly[oligo(3S-iso-butylmorpholine-2,5-dione)] segments coupled by trimethyl hexamethylene diisocyanate provide a versatile molecular architecture for achieving shape-memory effects (SMEs) in polymers. The mechanical properties as well as the SME performance of PCL-PIBMD can be tailored by the variation of physical parameters during programming such as deformation strain or applied temperature protocols. In this study, we explored the influence of applying different strain rates during programming on the resulting nanostructure of PCL-PIBMD. Programming was conducted at 50 °C by elongation to εm = 50% with strain rates of 1 or 10 or 50 mm min−1. The nanostructural changes were visualized by atomic force microscopy (AFM) measurements and investigated by in situ wide and small angle X-ray scattering experiments. With increasing the strain rate, a higher degree of orientation was observed in the amorphous domains. Simultaneously the strain-induced formation of new PIBMD crystals as well as the fragmentation of existing large PIBMD crystals occurred. The observed differences in shape fixity ratio and recovery stress of samples deformed with various strain rates can be attributed to their different nanostructures. The achieved findings can be relevant parameters for programming the shape-memory polymers with designed recovery forces. %0 journal article %@ 1759-9954 %A Schlaich, C.,Yu, L.,Cuellar Camacho, L.,Wei, Q.,Haag, R. %D 2016 %J Polymer Chemistry %N 48 %P 7446-7454 %R doi:10.1039/c6py01596d %T Fluorine-free superwetting systems: construction of environmentally friendly superhydrophilic, superhydrophobic, and slippery surfaces on various substrates %U https://doi.org/10.1039/c6py01596d 48 %X Surfaces that exhibit extreme wetting properties such as superhydrophobic and/or slippery liquid-infused porous surfaces (SLIPS) rely heavily on their surface energy and roughness. Although the bioaccumulation and dramatic ecological impact of perfluorinated building blocks are obvious, perfluorination of surfaces is still the most utilized method for lowering the surface energy. Herein we present a simple, substrate-independent, completely fluorine free and environmentally friendly concept for the construction of various super-wetting systems. Taking advantage of a mussel-inspired polyglycerol we successfully fabricated superhydrophilic, superhydrophobic and slippery surfaces by the precise design of a highly hierarchical structure. Additionally, the superhydrophobic coating was used to transfer commercially available cellulose and polystyrene 3D sponges into stable superhydrophobic but superoleophilic absorbent materials for oil/water separation. Moreover, the alkylated, hierarchical structure can serve as a matrix to efficiently capture hydrocarbon liquids as a lubricant that results in SLIPS. Surprisingly, common sunflower oil from the supermarket showed the same performance as pure chemicals such as hexadecane. Both the superhydrophobic and the slippery surfaces showed a similar performance regarding liquid and cell repellency in comparison to their fluorinated analog. %0 journal article %@ 1022-1336 %A Schoene, A.-C.,Schulz, B.,Lendlein, A. %D 2016 %J Macromolecular Rapid Communications %N 23 %P 1856-1859 %R doi:10.1002/marc.201600650 %T Stimuli Responsive and Multifunctional Polymers: Progress in Materials and Applications %U https://doi.org/10.1002/marc.201600650 23 %X No abstract %0 journal article %@ 1543-8384 %A Zhang, Y.,Wischke, C.,Mittal, S.,Mitra, A.,Schwendeman, S.P. %D 2016 %J Molecular Pharmaceutics %N 8 %P 2622-2630 %R doi:10.1021/acs.molpharmaceut.5b00961 %T Design of Controlled Release PLGA Microspheres for Hydrophobic Fenretinide %U https://doi.org/10.1021/acs.molpharmaceut.5b00961 8 %X Fenretinide, a chemotherapeutic agent for cancer, is water-insoluble and has a very low oral bioavailability. Hence, the objective was to deliver it as an injectable depot and improve the drug solubility and release behavior from poly(lactide-co-glycolide) (PLGA) microspheres by incorporating nonionic surfactants with fenretinide. Enhancement of drug solubilization was observed with Brij 35 or 98, Tween 20, and Pluronic F127, but not Pluronic F68. Co-incorporation of Brij 98 with fenretinide significantly changed the microsphere morphology and improved the fenretinide release profile. The most optimal microsphere formulation, with 20% Brij 98 as excipient, showed an initial in vitro burst around 20% and a sustained release over 28 days in a solubilizing release medium at 37 °C. The effect of addition of MgCO3, drug loading, and polymer blending on the release of fenretinide from PLGA microspheres was also investigated and observed to enhance the drug release. Two sustained release formulations, one incorporating 20% Brij 98 and the other incorporating 3% MgCO3 in the oil phase, were selected for dosing in Sprague–Dawley rats and compared to a single injection of an equivalent dose of fenretinide drug suspension. These two formulations were chosen due to their high encapsulation efficiency, high cumulative release, and desirable in vitro release profile. The drug suspension resulted in a higher initial release in rats compared to the polymeric formulations, however, sustained release was also observed beyond 2 weeks, which may be attributed to the physiological disposition of the drug in vivo. The two PLGA based test formulations provided the desired low initial burst of fenretinide followed by 4 weeks of in vivo sustained release. %0 journal article %@ 1559-4106 %A Jung, F.,Braune, S. %D 2016 %J Biointerphases %N 2 %P 029601 %R doi:10.1116/1.4938557 %T Thrombogenicity and hemocompatibility of biomaterials %U https://doi.org/10.1116/1.4938557 2 %X No abstract %0 journal article %@ 1552-4973 %A Braune, S.,Gross, M.,Walter, M.,Zhou, S.,Dietze, S.,Rutschow, S.,Lendlein, A.,Tschoepe, C.,Jung, F. %D 2016 %J Journal of Biomedical Materials Research B %N 1 %P 210-217 %R doi:10.1002/jbm.b.33366 %T Adhesion and activation of platelets from subjects with coronary artery disease and apparently healthy individuals on biomaterials %U https://doi.org/10.1002/jbm.b.33366 1 %X On the basis of the clinical studies in patients with coronary artery disease (CAD) presenting an increased percentage of activated platelets, we hypothesized that hemocompatibility testing utilizing platelets from healthy individuals may result in an underestimation of the materials' thrombogenicity. Therefore, we investigated the interaction of polymer-based biomaterials with platelets from CAD patients in comparison to platelets from apparently healthy individuals. In vitro static thrombogenicity tests revealed that adherent platelet densities and total platelet covered areas were significantly increased for the low (polydimethylsiloxane, PDMS) and medium (Collagen) thrombogenic surfaces in the CAD group compared to the healthy subjects group. The area per single platelet—indicating the spreading and activation of the platelets—was markedly increased on PDMS treated with PRP from CAD subjects. This could not be observed for collagen or polytetrafluoroethylene (PTFE). For the latter material, platelet adhesion and surface coverage did not differ between the two groups. Irrespective of the substrate, the variability of these parameters was increased for CAD patients compared to healthy subjects. This indicates a higher reactivity of platelets from CAD patients compared to the healthy individuals. Our results revealed, for the first time, that utilizing platelets from apparently healthy donors bears the risk of underestimating the thrombogenicity of polymer-based biomaterials. %0 journal article %@ 1386-0291 %A Braune, S.,Froehlich, G.M.,Lendlein, A.,Jung, F. %D 2016 %J Clinical Hemorheology and Microcirculation %N 4 %P 681-688 %R doi:10.3233/CH-152028 %T Effect of temperature on platelet adherence %U https://doi.org/10.3233/CH-152028 4 %X BACKGROUND:,Thrombogenicity is one of the main parameters tested in vitro to evaluate the hemocompatibility of artificial surfaces. While the influence of the temperature on platelet aggregation has been addressed by several studies, the temperature influence on the adherence of platelets to body foreign surfaces as an important aspect of biomedical device handling has not yet been explored. Therefore, we analyzed the influence of two typically applied incubation-temperatures (22°C and 37°C) on the adhesion of platelets to biomaterials.,MATERIAL AND METHODS:,Thrombogenicity of three different polymers - medical grade poly(dimethyl siloxane) (PDMS), polytetrafluoroethylene (PTFE) and polyethylene terephthalate (PET) - were studied in an in vitro static test. Platelet adhesion was studied with stringently characterized blood from apparently healthy subjects. Collection of whole blood and preparation of platelet rich plasma (PRP) was carried out at room temperature (22°C). PRP was incubated with the polymers either at 22°C or 37°C. Surface adherent platelets were fixed, fluorescently labelled and assessed by an image-based approach.,RESULTS AND DISCUSSION:,Differences in the density of adherent platelets after incubation at 22°C and 37°C occurred on PDMS and PET. Similar levels of adherent platelets were observed on the very thrombogenic PTFE. The covered surface areas per single platelet were analyzed to measure the state of platelet activation and revealed no differences between the two incubation temperatures for any of the analyzed polymers. Irrespective of the observed differences between the low and medium thrombogenic PDMS and PET and the higher variability at 22°C, the thrombogenicity of the three investigated polymers was evaluated being comparable at both incubation temperatures. %0 journal article %@ 1386-0291 %A Tetali, S.D.,Jankowski, V.,Luetzow, K.,Kratz, K.,Lendlein, A.,Jankowski, J. %D 2016 %J Clinical Hemorheology and Microcirculation %N 4 %P 657-665 %R doi:10.3233/CH-152026 %T Adsorption capacity of poly(ether imide) microparticles to uremic toxins %U https://doi.org/10.3233/CH-152026 4 %X Uremia is a phenomenon caused by retention of uremic toxins in the plasma due to functional impairment of kidneys in the elimination of urinary waste products. Uremia is presently treated by dialysis techniques like hemofiltration, dialysis or hemodiafiltration. However, these techniques in use are more favorable towards removing hydrophilic than hydrophobic uremic toxins. Hydrophobic uremic toxins, such as hydroxy hipuric acid (OH-HPA), phenylacetic acid (PAA), indoxyl sulfate (IDS) and p-cresylsulfate (pCRS), contribute substantially to the progression of chronic kidney disease (CKD) and cardiovascular disease. Therefore, objective of the present study is to test adsorption capacity of highly porous microparticles prepared from poly( ether imide) (PEI) as an alternative technique for the removal of uremic toxins. Two types of nanoporous, spherically shaped microparticles were prepared from PEI by a spraying/coagulation process. PEI particles were packed into a preparative HPLC column to which a mixture of the four types of uremic toxins was injected and eluted with ethanol. Eluted toxins were quantified by analytical HPLC. PEI particles were able to adsorb all four toxins, with the highest affinity for PAA and pCR. IDS and OH-HPA showed a partially non-reversible binding. In summary, PEI particles are interesting candidates to be explored for future application in CKD. %0 journal article %@ 1386-0291 %A Kumar, R.K.,Basu, S.,Lemke, H.-D.,Jankowski, J.,Kratz, K.,Lendlein, A.,Tetali, S.D. %D 2016 %J Clinical Hemorheology and Microcirculation %N 4 %P 667-680 %R doi:10.3233/CH-152027 %T Effect of extracts of poly(ether imide) microparticles on cytotoxicity, ROS generation and proinflammatory effects on human monocytic (THP-1) cells %U https://doi.org/10.3233/CH-152027 4 %X Current haemodialysis techniques are not capable to remove efficiently low molecular weight hydrophobic uremic toxins from the blood of patients suffering from chronic renal failure.With respect to the hydrophobic characteristics and the high level of protein binding of these uremic toxins, hydrophobic adsorber materials might be an alternative to remove these substances from the plasma of the chronic kidney disease (CKD) patients. Here nanoporous microparticles prepared from poly(ether imide)(PEI) with an average diameter of 90±30m and a porosity around 88±2% prepared by a spraying/coagulation process are,considered as candidate adsorber materials. A prerequisite for the clinical application of such particles is their biocompatibility,,which can be examined i.e. indirectly in cell culture experiments with the particles’ extracts. In this work we studied the effects,of aqueous extracts of PEI microparticles on the viability of THP-1 cells, a human leukemia monocytic cell line, as well as their,macrophage differentiation, reactive oxygen species (ROS) generation and inflammation.,A high cell viability of around 99±18% and 99±5% was observed when THP-1 cells were cultured in the presence of,aqueous extracts of the PEI microparticles in medium A and medium B respectively. The obtained microscopic data suggested,that PEI particle extracts have no significant effect on cell death, oxidative stress or differentiation to macrophages. It was,further found that the investigated proinflammatory markers in THP-1 cells were not up-regulated. These results are promising,with regard to the biocompatibility of PEI microparticles and in a next step the hemocompatibility of the microparticles will be,examined. %0 journal article %@ 1742-7061 %A Federico, S.,Noechel, U.,Loewenberg, C.,Lendlein, A.,Neffe, A.T. %D 2016 %J Acta Biomaterialia %N %P 1-10 %R doi:10.1016/j.actbio.2016.04.018 %T Supramolecular hydrogel networks formed by molecular recognition of collagen and a peptide grafted to hyaluronic acid %U https://doi.org/10.1016/j.actbio.2016.04.018 %X The extracellular matrix (ECM) is a nano-structured, highly complex hydrogel, in which the macromolecules are organized primarily by non-covalent interactions. Here, in a biomimetic approach, the decorin-derived collagen-binding peptide LSELRLHNN was grafted to hyaluronic acid (HA) in order to enable the formation of a supramolecular hydrogel network together with collagen. The storage modulus of a mixture of collagen and HA was increased by more than one order of magnitude (G′ = 157 Pa) in the presence of the HA-grafted peptide compared to a mixture of collagen and HA (G′ = 6 Pa). The collagen fibril diameter was decreased, as quantified using electron microscopy, in the presence of the HA-grafted peptide. Here, the peptide mimicked the function of decorin by spatially organizing collagen. The advantage of this approach is that the non-covalent crosslinks between collagen molecules and the HA chains created by the peptide form a reversible and dynamic hydrogel, which could be employed for a diverse range of applications in regenerative medicine. %0 journal article %@ 2352-3697 %A Hiebl, B.,Scharnagl, N.,Kaessmeyer, S.,Gemeinhardt, O.,Gemeinhardt, I.,Niehues, S.M.,Peters, S.,Jung, F. %D 2016 %J Journal of Cellular Biotechnology %N 2 %P 145-150 %R doi:10.3233/JCB-15014 %T Influence of the blood exposure time in dynamic hemocompatibility testing on coagulation and C5a activation %U https://doi.org/10.3233/JCB-15014 2 %X Within the hemocompatibility testing portfolio of medical devices a range of dynamic models were established in recent years. In contrast to the static hemocompatibility testing method the dynamic models allow considering the impact of hemorheological and hemodynamic blood characteristics on the hemocompatibility of medical devices. Unfortunately the EN DIN ISO 10993-4 for the biological evaluation of medical devices for interaction with blood gives no hints towards the period of time during which the medical devices should be exposed to the blood in these tests. To examine whether different exposure times impact the comparability of hemocompatibility test results low density polyethylene (LD-PE) tubes and nitinol stents were tested exemplarily in a closed loop model for changes of the fibrinogen content, the prothrombin time, the thrombin time, and the C5a activity after 30 and 90 min exposure to the blood. Low density polyethylene was used as negative control because it is one of the European reference materials for hemocompatibility testing. After 90 min blood exposure to the LD-PE tubing and the nitinol stents the prothrombin time was significantly longer and the fibrinogen content significantly lower (p < 0.05) than after 30 min. In contrast the thrombin time and the C5a were comparable after 30 and 90 min blood exposure time. These results might recommend to an initial 30 min exposure time, which is followed by a 90 min exposure time in cases of unclear results. %0 journal article %@ 2073-4360 %A Feng, Y.,Liu, W.,Ren, X.,Lu, W.,Guo, M.,Behl, M.,Lendlein, A.,Zhang, W. %D 2016 %J Polymers %N 3 %P 58 %R doi:10.3390/polym8030058 %T Evaluation of Electrospun PCL-PIBMD Meshes Modified with Plasmid Complexes in Vitro and in Vivo %U https://doi.org/10.3390/polym8030058 3 %X Functional artificial vascular meshes from biodegradable polymers have been widely explored for certain tissue engineered meshes. Still, the foreign body reaction and limitation in endothelialization are challenges for such devices. Here, degradable meshes from phase-segregated multiblock copolymers consisting of poly(ε-caprolactone) (PCL) and polydepsipeptide segments are successfully prepared by electrospinning and electrospraying techniques. The pEGFP-ZNF580 plasmid microparticles (MPs-pZNF580) were loaded into the electrospun meshes to enhance endothelialization. These functional meshes were evaluated in vitro and in vivo. The adhesion and proliferation of endothelial cells on the meshes were enhanced in loaded mesh groups. Moreover, the hemocompatibility and the tissue response of the meshes were further tested. The complete tests showed that the vascular meshes modified with MPs-pZNF580 possessed satisfactory performance with an average fiber diameter of 550 ± 160 nm, tensile strength of 27 ± 3 MPa, Young’s modulus of 1. 9 ± 0.2 MPa, water contact angle of 95° ± 2°, relative cell number of 122% ± 1% after 7 days of culture, and low blood platelet adhesion as well as weak inflammatory reactions compared to control groups. %0 journal article %@ 1386-0291 %A Roch, T.,Kratz, K.,Ma, N.,Lendlein, A. %D 2016 %J Clinical Hemorheology and Microcirculation %N 4 %P 899-910 %R doi:10.3233/CH-168033 %T Inflammatory responses of primary human dendritic cells towards polydimethylsiloxane and polytetrafluoroethylene %U https://doi.org/10.3233/CH-168033 4 %X Although frequently used as implants materials, both polydimethylsiloxane (PDMS) and polytetrafluoroethylene (PTFE) are often associated with adverse effects including foreign body responses. Dendritic cells (DC) are crucial for the initiation of immune reactions and could also play a role in foreign body associated inflammations. Therefore, the interaction of DC with PDMS and PTFE was investigated regarding their capacity to induce undesired cell activation. Medical grade PDMS and PTFE films were embedded into polystyrene PS inserts via injection molding to prevent the DC from migrating below the substrate and thereby, interacting not only with the test sample but also with the culture vessel material. The viability, the expression of co-stimulatory molecules, and the cytokine/chemokine profiles were determined after 24 hours incubation of the DC with PDMS or PTFE. Blank PS inserts and tissue culture polystyrene (TCP) served as reference materials. The viability of DC was not substantially influenced after incubation with PDMS and PTFE. However, both polymers induced DC activation indicated by the upregulation of co-stimulatory molecules. The release profiles of 14 soluble inflammatory mediators showed substantial differences between PDMS, PTFE, PS, and TCP. This study showed the potential of PTFE and PDMS to activate primary human dendritic cells, which could be an explanation for the often observed inflammatory events associated with the implantation of these polymers. %0 journal article %@ 2073-4360 %A Zharinova, E.,Heuchel, M.,Weigel, T.,Gerber, D.,Kratz, K.,Lendlein, A. %D 2016 %J Polymers %N 12 %P 412 %R doi:10.3390/polym8120412 %T Water-Blown Polyurethane Foams Showing a Reversible Shape-Memory Effect %U https://doi.org/10.3390/polym8120412 12 %X Water-blown polyurethane (PU) foams are of enormous technological interest as they are widely applied in various fields, i.e., consumer goods, medicine, automotive or aerospace industries. The discovery of the one-way shape-memory effect in PU foams provided a fresh impetus for extensive investigations on porous polymeric actuators over the past decades. High expansion ratios during the shape-recovery are of special interest when big volume changes are required, for example to fill an aneurysm during micro-invasive surgery or save space during transportation. However, the need to program the foams before each operation cycle could be a drawback impeding the entry of shape-memory polymeric (SMP) foams to our daily life. Here, we showed that a reversible shape-memory effect (rSME) is achievable for polyurethane water-blown semicrystalline foams. We selected commercially available crystallizable poly(ε-caprolactone)-diols of different molecular weight for foams synthesis, followed by investigations of morphology, thermal, thermomechanical and shape-memory properties of obtained compositions. Densities of synthesized foams varied from 110 to 180 kg∙m−3, while peak melting temperatures were composition-dependent and changed from 36 to 47 °C, while the melting temperature interval was around 15 K. All semicrystalline foams exhibited excellent one-way SME with shape-fixity ratios slightly above 100% and shape-recovery ratios from the second cycle of 99%. The composition with broad distribution of molecular weights of poly(ε-caprolactone)-diols exhibited an rSME of about 12% upon cyclic heating and cooling from Tlow = 10 °C and Thigh = 47 °C. We anticipate that our experimental study opens a field of systematic investigation of rSMEs in porous polymeric materials on macro and micro scale and extend the application of water-blown polyurethane foams to, e.g., protective covers with zero thermal expansion or even cushions adjustable to a certain body shape. %0 journal article %@ 1420-3049 %A Boreham, A.,Pikkemaat, J.,Volz, P.,Brodwolf, R.,Kuehne, C.,Licha, K.,Haag, R.,Dernedde, J.,Alexiev, U. %D 2016 %J Molecules %N 1 %P 22 %R doi:10.3390/molecules21010022 %T Detecting and Quantifying Biomolecular Interactions of a Dendritic Polyglycerol Sulfate Nanoparticle Using Fluorescence Lifetime Measurements %U https://doi.org/10.3390/molecules21010022 1 %X Interactions of nanoparticles with biomaterials determine the biological activity that is key for the physiological response. Dendritic polyglycerol sulfates (dPGS) were found recently to act as an inhibitor of inflammation by blocking selectins. Systemic application of dPGS would present this nanoparticle to various biological molecules that rapidly adsorb to the nanoparticle surface or lead to adsorption of the nanoparticle to cellular structures such as lipid membranes. In the past, fluorescence lifetime measurements of fluorescently tagged nanoparticles at a molecular and cellular/tissue level have been proven to reveal valuable information on the local nanoparticle environment via characteristic fluorescent lifetime signatures of the nanoparticle bound dye. Here, we established fluorescence lifetime measurements as a tool to determine the binding affinity to fluorescently tagged dPGS (dPGS-ICC; ICC: indocarbocyanine). The binding to a cell adhesion molecule (L-selectin) and a human complement protein (C1q) to dPGS-ICC was evaluated by the concentration dependent change in the unique fluorescence lifetime signature of dPGS-ICC. The apparent binding affinity was found to be in the nanomolar range for both proteins (L-selectin: 87 ± 4 nM and C1q: 42 ± 12 nM). Furthermore, the effect of human serum on the unique fluorescence lifetime signature of dPGS-ICC was measured and found to be different from the interactions with the two proteins and lipid membranes. A comparison between the unique lifetime signatures of dPGS-ICC in different biological environments shows that fluorescence lifetime measurements of unique dPGS-ICC fluorescence lifetime signatures are a versatile tool to probe the microenvironment of dPGS in cells and tissue. %0 journal article %@ 1022-1336 %A Roßberg, J.,Rottke, F.O.,Schulz, B.,Lendlein, A. %D 2016 %J Macromolecular Rapid Communications %N 23 %P 1966-1971 %R doi:10.1002/marc.201600471 %T Enzymatic Degradation of Oligo(ε‐caprolactone)s End‐Capped with Phenylboronic Acid Derivatives at the Air–Water Interface %U https://doi.org/10.1002/marc.201600471 23 %X The influence of terminal functionalization of oligo(ε-caprolactone)s (OCL) with phenylboronic acid pinacol ester or phenylboronic acid on the enzymatic degradation behavior at the air–water interface is investigated by the Langmuir monolayer degradation technique. While the unsubstituted OCL immediately degrades after injection of the enzyme lipase from Pseudomonas cepacia, enzyme molecules are incorporated into the films based on end-capped OCL before degradation. This incorporation of enzymes does not inhibit or suppress the film degradation, but retards it significantly. A specific binding of lipase to the polymer monolayer allows studying the enzymatic activity of bound proteins and the influence on the degradation process. The functionalization of a macromolecule with phenyl boronic acid groups is an approach to investigate their interactions with diol-containing biomolecules like sugars and to monitor their specified impact on the enzymatic degradation behavior at the air–water interface. %0 journal article %@ 1386-0291 %A Li, Z.,Wang, W.,Kratz, K.,Kuechler, J.,Xu, X.,Zou, J.,Deng, Z.,Sun, X.,Gossen, M.,Ma, N.,Lendlein, A. %D 2016 %J Clinical Hemorheology and Microcirculation %N 3 %P 355-366 %R doi:10.3233/CH-168121 %T Influence of surface roughness on neural differentiation of human induced pluripotent stem cells %U https://doi.org/10.3233/CH-168121 3 %X Induced pluripotent stem cells (iPSCs) own the capacity to develop into all cell types of the adult body, presenting high potential in regenerative medicine. Regulating and controlling the differentiation of iPSCs using the surface topographic cues of biomaterials is a promising and safe approach to enhance their therapeutic efficacy. In this study, we tested the effects of surface roughness on differentiation of human iPSCs into neural progenitor cells and dopaminergic neuron cells using polystyrene with different roughness (R0: flat surface; R1: rough surface, Rq ∼ 6 μm; R2: rough surface, Rq ∼ 38 μm). Neural differentiation of human iPSCs could be influenced by surface roughness. Up-regulated neuronal markers were found in cells on rough surface, as examined by real-time PCR and immunostaining. Particularly, the R1 surface significantly improved the neuronal marker expression, as compared to R0 and R2 surface. This study demonstrates the significance of surface roughness, depending on the roughness level, in promoting differentiation of human iPSCs towards the neuronal lineage. Our study suggests the potential applications of surface roughness in iPSCs based treatment of neural disorder diseases, and highlights the importance of design and development of biomaterials with effective surface structures to regulate stem cells. %0 journal article %@ 1022-1336 %A Yang, J.,Li, Q.,Yang, X.,Feng, Y.,Ren, X.,Shi, C.,Zhang, W. %D 2016 %J Macromolecular Rapid Communications %N 23 %P 1926-1931 %R doi:10.1002/marc.201600345 %T Multitargeting Gene Delivery Systems for Enhancing the Transfection of Endothelial Cells %U https://doi.org/10.1002/marc.201600345 23 %X Gene therapy demonstrates promising prospects on cardiovascular diseases. However, nonviral gene delivery system has relatively low transfection efficiency, especially for endothelial cells (ECs). Herein, typical cell-penetrating peptide (TAT), nuclear localization signals (NLSs), and REDV functional peptide have been used to prepare multitargeting complexes. These complexes exhibit higher transfection efficiency owing to the targeting sequences of REDV and NLSs as well as the cell-penetrating function of TAT. The multifunction of the complexes provides high cell uptake, endo/lysosomal escape, and nucleus accumulation of the encapsulated DNA. Thus these multitargeting complexes can provide a potential platform for gene delivery, especially for EC transfection. %0 journal article %@ 1471-2407 %A Lamichhane, S.P.,Arya, N.,Kohler, E.,Xiang, S.,Christensen, J.,Prasad Shastri, V. %D 2016 %J BMC Cancer %N %P 581 %R doi:10.1186/s12885-016-2634-1 %T Recapitulating epithelial tumor microenvironment in vitro using three dimensional tri-culture of human epithelial, endothelial, and mesenchymal cells %U https://doi.org/10.1186/s12885-016-2634-1 %X Background,Three-dimensional (3-D) cultures of cancer cells can potentially bridge the gap between 2-D drug screening and in vivo xenografts. The objective of this study was to characterize the cellular and extracellular matrix characteristics of spheroids composed of human lung epithelial cells (epi), pulmonary vascular endothelial (endo) cells, and human marrow-derived mesenchymal stems cells (MSCs).,Methods,Spheroids composed of epi/endo/MSCs, termed herein as synthetic tumor microenvironment mimics (STEMs), were prepared by the hanging drop method. Cellular composition and distribution in the STEMs was characterized using fluorescence microscopy. Induction of reactive oxygen species and upregulation of efflux transporters was quantified using fluorometry and PCR, respectively, and phenotypic markers were qualitatively assessed using immunohistochemistry.,Results,STEMs exhibited three unique characteristics not captured in other spheroid cultures namely, the presence of a spheroid core devoid of epithelial cells and primarily composed of MSCs, a small viable population of endothelial cells hypothesized to be closely associated with MSCs within the hypoxic core, and discrete regions with high expression for vimentin and cytokeratin-18, whose co-expression is co-related with enhanced metastasis. Although cells within STEMs show elevated levels of reactive oxygen species and mRNA for ABC-B1, an efflux transporter associated with drug resistance, they exhibited only modest resistance to paclitaxel and gemcitabine in comparison to 2-D tri-cultures.,Conclusions,The epi/endo/MSC spheroid model described herein offers a promising platform for understanding tumor biology and drug testing in vitro. %0 journal article %@ 1386-0291 %A Xu, X.,Wang, W.,Li, Z.,Kratz, K.,Ma, N.,Lendlein, A. %D 2016 %J Clinical Hemorheology and Microcirculation %N 3 %P 367-382 %R doi:10.3233/CH-168107 %T Surface geometry of poly(ether imide) boosts mouse pluripotent stem cell spontaneous cardiomyogenesis via modulating the embryoid body formation process %U https://doi.org/10.3233/CH-168107 3 %X The permanent loss of cardiomyocytes may lead to the irreversible damage of myocardium in cardiovascular diseases. The induced pluripotent stem cells (iPSCs) with the capacity of differentiation into a variety of cell types including cardiomyocytes showed high potential for efficient heart regeneration. The iPSCs and iPSC-derived embryoid bodies (EBs) as well as the differentiated cardiomyocytes are highly sensitive to the biophysical cues of their microenvironment, and accordingly their behavior and function can be largely modulated by microstructure of the cell culture surface. In this study, we investigated the regulatory effect of microscale roughness on both cardiomyogenesis and secretion of EBs using poly(ether imide) (PEI) cell culture inserts with different levels of bottom roughness (R0: flat surface; R1: rough surface, Rq ∼ 4 μm; R2: rough surface, Rq ∼ 23 μm). The proliferation rate and cardiomyogenesis of EBs increased with the increase of surface roughness. The EB secretome derived from R2 surface remarkably enhanced the in vitro new vessel formation of endothelial cells, as compared to those from R0 and R1. These findings highlight the potential to improve the iPSC/EB-based restoration of cardiovascular function via microstructured biomaterials. %0 journal article %@ 1178-2013 %A Feng, Y.,Guo, M.,Liu, W.,Hao, X.,Lu, W.,Ren, X.,Shi, C.,Zhang, W. %D 2016 %J International Journal of Nanomedicine %N %P 137-149 %R doi:10.2147/IJN.S107593 %T Co-self-assembly of cationic microparticles to deliver pEGFP-ZNF580 for promoting the transfection and migration of endothelial cells %U https://doi.org/10.2147/IJN.S107593 %X The gene transfection efficiency of polyethylenimine (PEI) varies with its molecular weight. Usually, high molecular weight of PEI means high gene transfection, as well as high cytotoxicity in gene delivery in vivo. In order to enhance the transfection efficiency and reduce the cytotoxicity of PEI-based gene carriers, a novel cationic gene carrier was developed by co-self-assembly of cationic copolymers. First, a star-shaped copolymer poly(3(S)-methyl-morpholine-2,5-dione-co-lactide) (P(MMD-co-LA)) was synthesized using D-sorbitol as an initiator, and the cationic copolymer (P(MMD-co-LA)-g-PEI) was obtained after grafting low-molecular weight PEI. Then, by co-self-assembly of this cationic copolymer and a diblock copolymer methoxy-poly(ethylene glycol) (mPEG)-b-P(MMD-co-LA), microparticles (MPs) were formed. The core of MPs consisted of a biodegradable block of P(MMD-co-LA), and the shell was formed by mPEG and PEI blocks. Finally, after condensation of pEGFP-ZNF580 by these MPs, the plasmids were protected from enzymatic hydrolysis effectively. The result indicated that pEGFP-ZNF580-loaded MP complexes were suitable for cellular uptake and gene transfection. When the mass ratio of mPEG-b-P(MMD-co-LA) to P(MMD-co-LA)-g-PEI reached 3/1, the cytotoxicity of the complexes was very low at low concentration (20 µg mL-1). Additionally, pEGFP-ZNF580 could be transported into endothelial cells (ECs) effectively via the complexes of MPs/pEGFP-ZNF580. Wound-healing assay showed that the transfected ECs recovered in 24 h. Cationic MPs designed in the present study could be used as an applicable gene carrier for the endothelialization of artificial blood vessels. %0 journal article %@ 1944-8244 %A Nöchel, U.,Behl, M.,Balk, M.,Lendlein, A. %D 2016 %J ACS Applied Materials and Interfaces %N 41 %P 28068-28076 %R doi:10.1021/acsami.6b09581 %T Thermally-Induced Triple-Shape Hydrogels: Soft Materials Enabling Complex Movements %U https://doi.org/10.1021/acsami.6b09581 41 %X Shape-memory hydrogels enable directed movements of a specimen in response to temperature, whereby crystallizable switching segments incorporated as side chains resulted in constant degrees of swelling during the shape-memory cycle. Here we report about hydrogels exhibiting a thermally induced triple-shape effect that allows complex movements of soft materials with two almost independent shape changes. Potential applications for those soft triple-shape materials are two-step self-unfolding devices or temperature-sensitive hydrogel actuators, for example, smart valves for flow rate control in aqueous media. Series of hydrogels with two different hydrophobic crystallizable switching segments were prepared. The degrees of swelling of the triple-shape hydrogels were not affected for different shapes or temperatures, which avoided in this way interferences on the shape shifts. During the two-step programming procedure, two distinct shapes can be implemented as reflected by shape fixity ratios of generally >50%. Structural analysis of the switching domains during the triple-shape cycle by means of X-ray scattering indicates that longer side chains gain lower orientation after deformation and that shorter side chains orient perpendicular to the hydrophilic main chain. Furthermore, it is observed that increased orientation of the switching domains is not a key requirement for adequate shape fixity and recovery ratios of the triple-shape effect in hydrogels, thus longer side chains can be utilized as switching segments in other shape-memory hydrogels. %0 journal article %@ 2073-4360 %A Feng, Y.,Lu, W.,Ren, X.,Liu, W.,Guo, M.,Ullah, I.,Zhang, W. %D 2016 %J Polymers %N 2 %P 13 %R doi:10.3390/polym8020013 %T Electrospun Poly(lactide-co-glycolide-co-3(S)-methyl-morpholine-2,5-dione) Nanofibrous Scaffolds for Tissue Engineering %U https://doi.org/10.3390/polym8020013 2 %X Biomimetic scaffolds have been investigated in vascular tissue engineering for many years. Excellent biodegradable materials are desired as temporary scaffolds to support cell growth and disappear gradually with the progress of guided tissue regeneration. In the present paper, a series of biodegradable copolymers were synthesized and used to prepared micro/nanofibrous scaffolds for vascular tissue engineering. Poly(lactide-co-glycolide-co-3(S)-methyl-morpholine-2,5-dione) [P(LA-co-GA-co-MMD)] copolymers with different l-lactide (LA), glycolide (GA), and 3(S)-methyl-2,5-morpholinedione (MMD) contents were synthesized using stannous octoate as a catalyst. Moreover, the P(LA-co-GA-co-MMD) nanofibrous scaffolds were prepared by electrospinning technology. The morphology of scaffolds was analyzed by scanning electron microscopy (SEM), and the results showed that the fibers are smooth, regular, and randomly oriented with diameters of 700 ± 100 nm. The weight loss of scaffolds increased significantly with the increasing content of MMD, indicating good biodegradable property of the scaffolds. In addition, the cytocompatibility of electrospun nanofibrous scaffolds was tested by human umbilical vein endothelial cells. It is demonstrated that the cells could attach and proliferate well on P(LA-co-GA-co-MMD) scaffolds and, consequently, form a cell monolayer fully covering on the scaffold surface. Furthermore, the P(LA-co-GA-co-MMD) scaffolds benefit to excellent cell infiltration after subcutaneous implantation. These results indicated that the P(LA-co-GA-co-MMD) nanofibrous scaffolds could be potential candidates for vascular tissue engineering. %0 journal article %@ 1079-5642 %A Hytoenen, J.,Leppaenen, O.,Braesen, J.H.,Schunck, W.-H.,Mueller, D.,Jung, F.,Mrowietz, C.,Jastroch, M.,Bergwelt-Baildon, M.V.,Kappert, K.,Heuser, A.,Drenckhahn, J.-D.,Pieske, B.,Thierfelder, L.,Ylae-Herttuala, S.,Blaschke, F. %D 2016 %J Arteriosclerosis, Thrombosis, and Vascular Biology : ATVB %N 8 %P 1534-1548 %R doi:10.1161/ATVBAHA.115.306962 %T Activation of Peroxisome Proliferator–Activated Receptor-Delta as Novel Therapeutic Strategy to Prevent In-Stent Restenosis and Stent Thrombosis %U https://doi.org/10.1161/ATVBAHA.115.306962 8 %X Objective—Drug-eluting coronary stents reduce restenosis rate and late lumen loss compared with bare-metal stents; however, drug-eluting coronary stents may delay vascular healing and increase late stent thrombosis. The peroxisome proliferator–activated receptor-delta (PPARδ) exhibits actions that could favorably influence outcomes after drug-eluting coronary stents placement.,Approach and Results—Here, we report that PPARδ ligand–coated stents strongly reduce the development of neointima and luminal narrowing in a rabbit model of experimental atherosclerosis. Inhibition of inflammatory gene expression and vascular smooth muscle cell (VSMC) proliferation and migration, prevention of thrombocyte activation and aggregation, and proproliferative effects on endothelial cells were identified as key mechanisms for the prevention of restenosis. Using normal and PPARδ-depleted VSMCs, we show that the observed effects of PPARδ ligand GW0742 on VSMCs and thrombocytes are PPARδ receptor dependent. PPARδ ligand treatment induces expression of pyruvate dehydrogenase kinase isozyme 4 and downregulates the glucose transporter 1 in VSMCs, thus impairing the ability of VSMCs to provide the increased energy demands required for growth factor–stimulated proliferation and migration.,Conclusions—In contrast to commonly used drugs for stent coating, PPARδ ligands not only inhibit inflammatory response and proliferation of VSMCs but also prevent thrombocyte activation and support vessel re-endothelialization. Thus, pharmacological PPARδ activation could be a promising novel strategy to improve drug-eluting coronary stents outcomes. %0 journal article %@ 2059-8521 %A Friess, F.,Lendlein, A.,Wischke, C. %D 2016 %J MRS Advances %N 27 %P 2019-2024 %R doi:10.1557/adv.2016.493 %T Two phase microfluidics with inviscid drops: Effects of total flow rate and delayed surfactant addition %U https://doi.org/10.1557/adv.2016.493 27 %X The microfluidic production of droplets is a well controllable process, which allows templating small spherical containers that can subsequently be transferred into uniformly sized polymer microgel particles by a crosslinking reaction. Recently, the per-channel production rate of N-isopropylacrylamide (NIPAAm) droplets (w-phase) dispersed in a low-viscosity fluorocarbon oil (o-phase) could be increased by a delayed surfactant addition, while maintaining the advantageous dripping regime. Here it should be evaluated, if delayed surfactant addition can be applied to enhance droplet production also for high viscosity continuous phases, which is associated with a change to an inviscid drop scenario compared to the previously used setting of viscous drops. It could be illustrated that the concept of delayed surfactant addition holds true also for viscous continuous phases and allows ∼8 fold increased flow rates in the dripping regime. Surprisingly, the droplet size increased at higher total flow rate with constant flow rate ratios of w- and o-phases, which is discussed in the light of viscous dissipation, microchannel bulging and viscosity of the continuous phase. More rigid microchannels such as from glass may allow further exploring this phenomenon in the future. %0 journal article %@ 2059-8521 %A Baudis, S.,Balk, M.,Lendlein, A.,Behl, M. %D 2016 %J MRS Advances %N 27 %P 2003-2009 %R doi:10.1557/adv.2016.411 %T Robot Assisted Polyurethane Chain Extension of Dihydroxy Telechelic Depsipeptides %U https://doi.org/10.1557/adv.2016.411 27 %X Depsipeptide-based multiblock copolymers synthesized from dihydroxy telechelic oligodepsipeptide precursors are promising candidate materials for biomedical and pharmaceutical applications. High molecular weight polymers in polyaddition reactions e.g. of diols with diisocyanates can only be reached when reactive groups are equivalent and a high conversion for this step growth polymerization is obtained. However, in depsipeptide-based multiblock urethanes reported so far, the stoichiometric ratio of the diisocyanate compound exceeded the theoretical value of 100% by far. In order to investigate the influence of the dosing system in this unusual behavior of the stoichiometric reaction two dosing devices, a solid dosing unit (SDU) and a gravimetric dosing unit (GDU) were used for a gravimetric transfer of an oligo(3-sec-butylmorpholine-2.5-dione) (OBMD) as model oligodepsipeptide. The OBMD precursor, which was transferred as a solid or as a highly viscous solution, was reacted with an isomeric mixture of 2,2,4- and 2,4,4-trimethylhexamethylene diisocyanate (TMDI) as chain extender. Two series of 49 reactions were performed and the chain extension efficacy of the building block was compared between the SDU and GDU as well as with respect to the Carothers equation. When the GDU was used the chain extension yielded higher molecular weights, proving the high accuracy of the dosing device, and the molar ratio of TMDI required for the high-throughput synthesis of the depsipeptide-based multiblock copolymers was similar to depsipeptide-based multiblock copolymers created in a classical synthesis approach. %0 journal article %@ 1386-0291 %A Braune, S.,Basu, S.,Kratz, K.,Johansson, J.B.,Reinthaler, M.,Lendlein, A.,Jung, F. %D 2016 %J Clinical Hemorheology and Microcirculation %N 3 %P 345-353 %R doi:10.3233/CH-168114 %T Strategy for the hemocompatibility testing of microparticles %U https://doi.org/10.3233/CH-168114 3 %X Polymer-based microparticles are applied as non-thrombogenic or thrombogenic materials in a wide variety of intra- or extra-corporeal medical devices. As demanded by the regulatory agencies, the hemocompatibility of these blood contacting biomaterials has to be evaluated in vitro to ensure that the particle systems appropriately fulfill the envisioned function without causing undesired events such as thrombosis or inflammation. Currently described in vitro assays for hemocompatibility testing of particles comprise tests with different single cell types (e.g. erythrocytes or leukocytes), varying concentrations/dilutions of the used blood cells or whole blood, which are not standardized.,Here, we report about an in vitro dynamic test system for studying the hemocompatibility of polymeric microparticles utilizing fresh human whole blood from apparently healthy subjects, collected and processed under standardized conditions. Spherical poly(ether imide) microparticles with an average diameter of 140±30 μm were utilized as model systems. Reported as candidate materials for the removal of uremic toxins, these microparticles are anticipated to facilitate optimal flow conditions in a dialyzer with minimal backflow and blood cell damage. Pristine (PEI) and potassium hydroxide (PEI-KOH) functionalized microparticles exhibited similarly nanoporous surfaces (PEI: ØExternal pore = 90±60 nm; PEI-KOH ØExternal pore = 150±130 nm) but varying water wettabilities (PEI: θadv = 112±10° PEI-KOH θadv = 60±2°). The nanoporosity of the microparticle surfaces allows the exchange of toxic solutes from blood towards the interconnective pores in the particle core, while an immigration of the substantially larger blood cells is inhibited.,Sterilized PEI microparticles were incorporated –air-free –in a syringe-based test system and exposed to whole blood for 60 minutes under gentle agitation. Thereafter, thrombi formation on the particles surfaces were analyzed microscopically. In the collected whole blood the non-adherent/circulating single blood cells were quantified via a differentiated complete blood cell count and the activation of platelets (P-Selectin expression, secretion and release), platelet function (PFA100 closure time) as well as thrombin formation (thrombin-antithrombin-complex) was analyzed. Free hemoglobin (HGB) levels were quantified as a measure of hemolysis.,Microscopic evaluation revealed thrombi formation and particle aggregates for all tested microparticles. Reduction of circulating blood cells differed significantly between the particle types. Particularly, platelet and monocyte counts decreased up to 50% compared to the control (syringe filled with whole blood but without microparticles). In accordance, platelet activation, thrombin levels and degrees of hemolysis were clearly elevated in the particle loaded test systems and allowed a differentiation between the particle types. Increased PFA100 closure times (as activating agent a combination of collagen/ADP was used) indicated a similarly reduced ability of platelets to adhere and form stable aggregates independent from the particle type tested. This observation is most probably a consequence of the strong thrombus formation in the test system, which is associated with a reduction of the circulating blood cells.,The reported in vitro dynamic whole blood test system allowed the sensitive analysis of the hemocompatibility of polymer-based microparticles and was successfully validated for porous PEI microparticles with different water wettabilities. Beyond the qualitative and quantitative analysis of cell-material interactions, the test also allowed the functional evaluation of platelets in whole blood. %0 journal article %@ 1556-9845 %A Wilbring, M.,Jung, F.,Weber, C.,Matschke, K.,Knaut, M. %D 2016 %J Innovations %N 1 %P 24-30 %R doi:10.1097/IMI.0000000000000231 %T Reduced Incidence of Thromboembolic Events After Surgical Closure of Left Atrial Appendage in Patients With Atrial Fibrillation %U https://doi.org/10.1097/IMI.0000000000000231 1 %X Objective: Most of the detected thrombi in patients with atrial fibrillation (AF) can be found in the left atrial appendage (LAA). Interventional LAA closure recently proved to be noninferior to warfarin therapy. Whether these results can be fully translated into surgical LAA closure remains unclear. Corresponding data are still lacking. The present observational study evaluated the impact of surgical LAA closure in patients with AF undergoing cardiac surgery on postoperative thromboembolic events.,Methods: A prospective registry enrolled 398 patients with permanent AF undergoing cardiac surgery. Concomitant procedures were isolated surgical ablation (group I, n = 71), isolated LAA closure (group II, n = 44), and combined surgical ablation and LAA closure (group III, n = 196). The control group consisted of 87 patients without concomitant surgical ablation or LAA closure. One-year follow-up was completed in all patients. End points were thromboembolic events and death from any cause.,Results: Clinical baseline characteristics were comparable among the groups. General hospital mortality was 5.5% and likewise differed not significantly. Postoperatively, mean (SD) CHAD2S2-VASc score of 3.5 (1.3) differed not significantly among the groups, indicating comparable thromboembolic risk. Follow-up referred to all hospital survivors (n = 376). Herein, overall incidence of thromboembolic events was 9.8% (n = 37), with an associated mortality of 41.0%. Patients with LAA closure alone or in combination with surgical ablation had a significantly reduced incidence of thromboembolic events (6.6% vs 20.5%, P < 0.01) and consecutively improved survival after 1 year of follow-up (7.0% vs 17.1%, P < 0.01).,Conclusions: Left atrial appendage closure alone or in combination with surgical ablation was associated with a significantly reduced rate of thromboembolic events and consecutively improved survival after 1 year of follow-up. %0 journal article %@ 1386-0291 %A Kaessmeyer, S.,Sehl, J.,Khiao In, M.,Hiebl, B.,Merle, R.,Jung, F.,Franke, R.P.,Plendl, J. %D 2016 %J Clinical Hemorheology and Microcirculation %N 3 %P 391-402 %R doi:10.3233/CH-168119 %T Organotypic soft-tissue co-cultures: Morphological changes in microvascular endothelial tubes after incubation with iodinated contrast media %U https://doi.org/10.3233/CH-168119 3 %X INTRODUCTION: Clinical complications like thrombosis or anaphylaxis have been described to go along with the intra-venous or intra-arterial injection of iodinated contrast media (CM). It has been suggested that the administration of CM affects rheological parameters and thereby causes reduced blood velocity in microvessels. In vitro studies revealed significant buckling of endothelial cells after exposure to CM reducing the lumen of vessels. The aim of this study was to test the influence of CM on three-dimensional microvascular tubules with open lumina within an organotypic soft-tissue co-culture assay in vitro. This model, which is based on the co-culture of endothelial cells and fibroblasts, allows the analysis and quantitation of different parameters of microvascular endothelial capillary structures.,MATERIAL AND METHODS: Human dermal fibroblasts and human dermal microvascular endothelial cells were co-cultured for 10 days. Fibroblasts were adapted to the endothelial cell medium before co-culture and allowed to proliferate as well as produce extracellular matrix. The co-cultures were exposed to three different CM, i.e., Iomeprol (Imeron 400MCT), Iodixanol (Visipaque 320) or Iohexol (Accupaque 350) for 1.5 minutes or 5.0 minutes, respectively. For this, a mixture of CM and cell culture medium in a ratio of 30% CM by volume was prepared. After fixation in methanol/acetone, the endothelial cells were immunolabeled with the endothelial marker anti-CD31 and the tubular structures were assessed morphometrically.,RESULTS: In the organotypic soft-tissue co-cultures with fibroblasts, the endothelial cells developed three-dimensional capillary-like structures which expanded via sprouting branches. After incubation with the different CM, the numbers of endothelial tubes (p = 0.001) and their lengths (p = 0.003) were significantly lower after the 5 minutes incubation time, when compared to the 1.5 minutes incubation time. The tubular diameters were significantly reduced after 5 minutes (p < 0.001), when compared to the 1.5 minutes incubation duration. Interestingly, Iomeprol and Iodixanol induced an elongation of the tubular branches during incubation duration of 1.5 minutes (p = 0.015). However, after 5 minutes incubation, the tubular branches were drastically shorter in the presence of Iomeprol and Iodixanol than the tubular branches of the control (p = 0.007). %0 journal article %@ 1386-0291 %A Tzoneva, R.,Uzunova, V.,Apostolova, S.,Krueger-Genge, A.,Neffe, A.T.,Jung, F.,Lendlein, A. %D 2016 %J Clinical Hemorheology and Microcirculation %N 4 %P 941-949 %R doi:10.3233/CH-168040 %T Angiogenic potential of endothelial and tumor cells seeded on gelatin–based hydrogels in response to electrical stimulations %U https://doi.org/10.3233/CH-168040 4 %X Angiogenesis is one of the key processes during development, wound healing and tumor formation. Prerequisite for its existence is the presence of endogenous electrical fields (EFs) generated by active ion transport across polarized epithelia and endothelia, and appearance of the transcellular potentials. During angiogenesis cellular factor as endothelial growth factor (VEGF), synthesis of adhesive proteins and membrane metalloproteinases (MMPs) govern the angiogenic response to different external stimuli as biomaterials interactions and/or exogenous EF. Gelatin-based hydrogels with elasticities comparable to human tissues have shown to influence cell behavior as well as cell attachment, protein synthesis, VEGF and MMP’s production after the application of EF. Gelatin-based matrices with 3 (G10_LNCO3), 5 (G10_LNCO5), and 8 (G10_LNCO8) fold excess of isocyanate groups per mol of amine groups present in gelatin were used. Human umbilical endothelial cells (HUVEC) (Lonza Basel, Switzerland) and highly invasive breast cancer MDA-MB-231 cells (ATCC®HTB-26TM) were used. For an estimation of the amount of VEGF released from cells a commercially available VEGF ELISA (Thermo Fisher Scientific, Germany) kit was used. Fibronectin (FN) enzyme immunoassay (EIA) was used to analyze the secreted amount of FN by cells seeded on the materials. Secreted MMPs were analyzed by zymography. Gelatin-based hydrogels attracted HUVEC adhesion and diminished the adhesion of MDA-MB-231 cells. The applied direct current (DC) EF induced an almost 5–fold increase in VEGF production by HUVEC seeded on gelatin-based hydrogels, while in contrast, the applied EF decreased the production of VEGF by cancer cells. FN synthesis was elevated in HUVEC cells seeded on gelatin-based materials in comparison to FN synthesis by cancer cells. HUVEC seeded on gelatin hydrogels showed an expression mainly of MMP-2. The application of EF increased the production of MMP-2 in HUVEC seeded on gelatin materials. In contrast, for MDA-MB-231 the production of MMPs on gelatin materials was lower compared to control materials. With the application of EF the levels of MMP-9 decreased but MMP-2 expression raised significantly for gelatin materials. Overall, the results showed that studied gelatin materials suppressed attachment of cancerous cells, as well as suppressed their angiogenic potential revealed by decreased VEGF and MMP production. Thus, this study approved gelatin-based hydrogels with proper elasticity characteristics and different degradation behavior as useful matrices for use in vascular tissue regeneration or in restriction of tumor growth after tumor resection. %0 journal article %@ 1386-0291 %A Gerk, U.,Mrowietz, C.,Sternitzky, R.,Franke, R.P.,Spitzer, S.G.,Jung, F. %D 2016 %J Clinical Hemorheology and Microcirculation %N 3 %P 297-304 %R doi:10.3233/CH-168101 %T Effect of Ioxaglate on the cutaneous microcirculation in patients with coronary artery disease: Randomized, double blind, placebo-controlled study %U https://doi.org/10.3233/CH-168101 3 %X Radiographic contrast media (RCM) can initiate microcirculatory disorders. This study was performed to investigate effects of Ioxaglate on the cutaneous microcirculation. The investigation was carried out as prospective randomized double-blind comparison in parallel-group design on two groups of n = 10 patients each who had to undergo a diagnostic coronary angiography.,The confirmatory parameter of the study was mean erythrocyte capillary velocity [vRBC in mm/sec]. VRBC in the ipsilateral nail-fold capillaries was recorded continuously for 3 min before and 6 min after injection of RCM or isotonic saline solution in the A. axillaris respectively, and was evaluated off-line.,VRBC in nailfold capillaries was found to be decreased by Ioxaglate by 34% 150 seconds after injection, while isotonic NaCl solution immediately induced a slight increase of 14%. %0 journal article %@ 1559-4106 %A Reinthaler, M.,Braune, S.,Lendlein, A.,Landmesser, U.,Jung, F. %D 2016 %J Biointerphases %N 2 %P 029702 %R doi:10.1116/1.4953246 %T Platelets and coronary artery disease: Interactions with the blood vessel wall and cardiovascular devices %U https://doi.org/10.1116/1.4953246 2 %X In view of the rare presence of studies concerning platelet function as risk factor in atherosclerotic patients, processes underlying thromboembolic events are reviewed in this paper. The morphology and the structural organization—membrane receptors, the open canalicular and dense tubular systems, the cytoskeleton, mitochondria, granules, lysosomes, and peroxisomes—of platelets are described. Platelet function under physiological conditions in atherosclerosis and after implantation of cardiovascular devices is summarized. %0 journal article %@ 1616-5187 %A Schulz, C.,Hecht, J.,Krueger-Genge, A.,Kratz, K.,Jung, F.,Lendlein, A. %D 2016 %J Macromolecular Bioscience %N 12 %P 1776-1791 %R doi:10.1002/mabi.201600319 %T Generating Aptamers Interacting with Polymeric Surfaces for Biofunctionalization %U https://doi.org/10.1002/mabi.201600319 12 %X Common strategies for biofunctionalization of surfaces comprise the immobilization of bioactive molecules used as cell-binding ligands for cell recruitment. Besides covalent binding, multivalent noncovalent physical forces between substrate and ligand are an alternative way to equip surfaces with biomacromolecules. In this study, polymer binding ligands are screened by means of a DNA-based in vitro selection process. As candidate biomaterials poly(ether imide) (PEI), polystyrene, and poly[ethylene-co-(vinyl acetate)] are selected, due to their different chemical structure, but similar macroscopic interface properties, allowing physical interaction with nucleotide bases by varying valences. Multivalent interacting aptamers are successfully enriched by SELEX method and an area-wide surface functionalization is achieved, which can be used for further binding of bioactive molecules. In vitro selection against the polymers result in thymine-dominated aptamer binding motifs. The preferential interaction with thymine is attributed to its chemical structure, connected with a decreased electrostatic repulsion of the π-system and the hydrophobic character maximizing entropy. The aptamer binding stability correlates with available valences for interaction, resulting in a more stable functionalization of PEI. %0 journal article %@ 1759-9954 %A De Leon, A.S.,Malhotra, S.,Molina, M.,Calderon, M.,Munoz-Bonilla, A.,Rodriguez-Hernandez, J. %D 2016 %J Polymer Chemistry %N 24 %P 4112-4120 %R doi:10.1039/C6PY00601A %T Fabrication of honeycomb films from highly functional dendritic structures: electrostatic force driven immobilization of biomolecules %U https://doi.org/10.1039/C6PY00601A 24 %X Herein we report the preparation of honeycomb porous films for selective immobilization of biomolecules via the breath figure technique, a water-assisted micropatterning method. In particular, porous films are obtained from polymeric blends composed of high molecular weight polystyrene as the major component and an oligoglycerol based dendron covalently bonded to a hydrophobic polystyrene chain as the minor constituent. The multivalent dendritic architecture presents a well-defined molecular structure with controlled glycine arrays on their surfaces. Due to the mechanism of the breath figure formation, the resulting films exhibit an especial chemical distribution at the surfaces, in which the dendritic functional polymer is located preferentially in the interior of the pores while the rest of the polymer surface is mainly formed by the high molecular weight polystyrene. The high amount of amine functional groups inside the pores allowed the specific immobilization of biomolecules into the cavities by electrostatic interactions. In particular, the protein bovine serum albumin (BSA) and a DNA sequence were attached onto the films as a proof of concept. Besides, it was demonstrated that the density of biomolecules immobilized can be easily tuned by varying the content of the dendritic functional polymer in the film. These unique characteristics open new alternatives for the use of these platforms in biorelated applications including bio-recognition processes, or the understanding of cell–protein and even cell–DNA interactions on biofunctional microstructured polymeric supports. %0 journal article %@ 0168-3659 %A Du, F.,Hoenzke, S.,Neumann, F.,Keilitz, J.,Chen, W.,Ma, N.,Hedtrich, S.,Haag, R. %D 2016 %J Journal of Controlled Release %N %P 42-49 %R doi:10.1016/j.jconrel.2016.06.048 %T Development of biodegradable hyperbranched core-multishell nanocarriers for efficient topical drug delivery %U https://doi.org/10.1016/j.jconrel.2016.06.048 %X The topical application of drugs allows for a local application in skin disease and can reduce side effects. Here we present biodegradable core-multishell (CMS) nanocarriers which are composed of a hyperbranched polyglycerol core functionalized with diblock copolymers consisting of polycaprolactone (PCL) and poly(ethylene glycol) (mPEG) as the outer shell. The anti-inflammatory drug Dexamethasone (Dexa) was loaded into these CMS nanocarriers. DLS results suggested that Dexa loaded nanoparticles mostly act as a unimolecular carrier system. With longer PCL segments, a better transport capacity is observed. In vitro skin permeation studies showed that CMS nanocarriers could improve the Nile red penetration through the skin by up to 7 times, compared to a conventional cream formulation. Interestingly, covalently FITC-labeled CMS nanocarriers remain in the stratum corneum layer. This suggests the enhancement is due to the release of cargo after being transported into the stratum corneum by the CMS nanocarriers. In addition, the hPG-PCL-mPEG CMS nanocarriers exhibited good stability, low cytotoxicity, and their production can easily be scaled up, which makes them promising nanocarriers for topical drug delivery. %0 journal article %@ 1838-7640 %A Tondera, C.,Hauser, S.,Krueger-Genge, A.,Jung, F.,Neffe, A.T.,Lendlein, A.,Klopfleisch, R.,Steinbach, J.,Neuber, C.,Pietzsch, J. %D 2016 %J Theranostics %N 12 %P 2114-2128 %R doi:10.7150/thno.16614 %T Gelatin-based Hydrogel Degradation and Tissue Interaction in vivo: Insights from Multimodal Preclinical Imaging in Immunocompetent Nude Mice %U https://doi.org/10.7150/thno.16614 12 %X Hydrogels based on gelatin have evolved as promising multifunctional biomaterials. Gelatin is crosslinked with lysine diisocyanate ethyl ester (LDI) and the molar ratio of gelatin and LDI in the starting material mixture determines elastic properties of the resulting hydrogel. In order to investigate the clinical potential of these biopolymers, hydrogels with different ratios of gelatin and diisocyanate (3-fold (G10_LNCO3) and 8-fold (G10_LNCO8) molar excess of isocyanate groups) were subcutaneously implanted in mice (uni- or bilateral implantation). Degradation and biomaterial-tissue-interaction were investigated in vivo (MRI, optical imaging, PET) and ex vivo (autoradiography, histology, serum analysis). Multimodal imaging revealed that the number of covalent net points correlates well with degradation time, which allows for targeted modification of hydrogels based on properties of the tissue to be replaced. Importantly, the degradation time was also dependent on the number of implants per animal. Despite local mechanisms of tissue remodeling no adverse tissue responses could be observed neither locally nor systemically. Finally, this preclinical investigation in immunocompetent mice clearly demonstrated a complete restoration of the original healthy tissue. %0 journal article %@ 2059-8521 %A Balk, M.,Behl, M.,Noechel, U.,Lendlein, A. %D 2016 %J MRS Advances %N 27 %P 2011-2017 %R doi:10.1557/adv.2016.414 %T Architectured Shape-Memory Hydrogels with Switching Segments Based on Oligo(Epsilon-caprolactone) %U https://doi.org/10.1557/adv.2016.414 27 %X Shape-memory hydrogels (SMHs) are potential candidate materials for biomedical applications as they can mimic the elastic properties of soft tissue and exhibit shape transformations at body temperature. Here we explored, whether architectured SMHs can be designed by incorporating oligo(ε-caprolactone) (OCL, = 4500 g·mol-1, T m = 54 °C) side chains as switching segment into hydrophilic polymer networks based on N-vinylpyrrolidone as backbone forming component and oligo(ethylene glycol)divinylether (OEGDVE, = 250 g·mol-1) as crosslinker. By utilizing NaCl and NaHCO3 as porogene during thermal crosslinking architectured hydrogels having pore diameters between 30 and 500 µm and wall thicknesses ranging from 10 to 190 µm in the swollen state were synthesized. According to the porous microstructure, a macroscopic form stability was obtained when the polymer networks were swollen until equilibrium in water. Material properties were investigated as function of the OCL content, which was varied between 20 and 40 wt%. In compression experiments the architectured hydrogels exhibited strain fixity and strain recovery ratios above 80%. These architectured SMHs might enable biomaterial applications as smart implants with the recovery of bulky structures from compact shapes. %0 journal article %@ 1386-0291 %A Schulz, C.,Vukicevic, R.,Krueger-Genge, A.,Neffe, A.T.,Lendlein, A.,Jung, F. %D 2016 %J Clinical Hemorheology and Microcirculation %N 4 %P 699-710 %R doi:10.3233/CH-168007 %T Monolayer formation and shear-resistance of human umbilical vein endothelial cells on gelatin-based hydrogels with tailorable elsticity and degradability %U https://doi.org/10.3233/CH-168007 4 %X The formation of a functionally-confluent and shear-resistant endothelial cell monolayer on cardiovascular implants is a promising strategy to prevent thrombogenic processes after implantation. On the basis of existing studies with arterial endothelial cells adhering after two hours on gelatin-based hydrogels in marked higher numbers compared to tissue culture plates, we hypothesize that also venous endothelial cells (HUVEC) should be able to adhere and form an endothelial monolayer on these hydrogels after days. Furthermore, variation of the hydrogel composition, which slightly influences the materials elasticity and even more the degradation behaviour, should have no considerable effect on HUVEC. Therefore, the monolayer formation and shear resistance of HUVEC were explored on two gelatin-based hydrogels differing in their elasticity (Young’s moduli between 35 and 55 kPa) in comparison to a positive control (HUVEC on glass cover slips) and a negative control (HUVEC on glass cover slips activated with interleukin-1β) after 9 days of culturing. HUVEC density after 9 days of culturing under static conditions was lower on the hydrogels compared to both controls (p < 0.05 each). On G10_LNCO8 slightly more EC adhered than on G10_LNCO5. Staining of the actin cytoskeleton and VE-cadherin revealed a pronounced cell-substrate interaction while the cell-cell interaction was comparable to the controls (HUVEC on glass). The secretion of vasoactive and inflammatory mediators did not differ between the hydrogels and the controls. Adherent HUVEC seeded on the hydrogels were able to resist physiological shear forces and the release of cyto- and chemokines in response to the shear forces did not differ from controls (HUVEC on glass). Therefore, both gelatin-based hydrogels are a suitable substrate for EC and a promising candidate for cardiovascular applications. %0 journal article %@ 1386-0291 %A Krueger-Genge, A.,Jung, F.,Fuhrmann, R.,Franke, R.-P. %D 2016 %J Clinical Hemorheology and Microcirculation %N 4 %P 867-874 %R doi:10.3233/CH-168051 %T Effects of different components of the extracellular matrix on endothelialization %U https://doi.org/10.3233/CH-168051 4 %X The endothelialization of cardiovascular prostheses is known to improve their haemocompatibility. As such body-foreign materials often do not endothelialize spontaneously. A lot of in vitro studies are ongoing how endothelialization of biomaterials can be improved. In this study the influence of different components of a tissue-typical extracellular matrix (ECM) like laminin, fibronectin or gelatin on the formation of an endothelial cell monolayer and on the shear resistance of adherent cells on these substrates was studied.The study revealed that the density of human venous endothelial cells (HUVEC) monolayers differed markedly between cells grown on a natural ECM and cells grown on singularized components of an ECM (p < 0.001). Only HUVEC grown on laminin showed similar densities and a stress fiber pattern comparable to HUVEC grown on the ECM. HUVEC grown on gelatin- or fibronectin-coated coverslips were less firmly attached to the substrate; frequently individual HUVEC and even groups of cells detached.Concluding it seems that coating of implants with laminin supports the formation of shear resistant endothelial cell (EC) monolayer - superior to other ECM components. %0 journal article %@ 0955-2219 %A Zehbe, R.,Mochales, C.,Radzik, D.,Mueller, W.-D.,Fleck, C. %D 2016 %J Journal of the European Ceramic Society %N 2 %P 357-364 %R doi:10.1016/j.jeurceramsoc.2015.08.022 %T Electrophoretic deposition of multilayered (cubic and tetragonal stabilized) zirconia ceramics for adapted crack deflection %U https://doi.org/10.1016/j.jeurceramsoc.2015.08.022 2 %X The electrophoretic deposition process was used to produce multi-layered ceramics consisting of alternating layers of fully stabilized cubic zirconia and partially stabilized tetragonal zirconia to make use of their different mechanical behaviour, investigating the possibility to deflect advancing cracks at the interfaces of the different layers. This crack deflection is apparently impacted by a toughening mechanism only found in the tetragonal stabilized zirconia polymorph and is characterized by the stress induced transformation of the metastable tetragonal phase into the monoclinic one, which is accompanied by a volume increase resulting in a closing mechanism for advancing cracks.,While improving the electrophoretic deposition process, we investigated the transformation toughening mechanism at the layer interfaces and their effect on crack propagation. Investigations involved a combination of different imaging methods, including light microscopy, white light interferometry, atomic force microscopy, scanning electron microscopy, energy dispersive X-ray spectroscopy and Raman spectroscopy. %0 journal article %@ 0032-3861 %A Peng, X.,Behl, M.,Zhang, P.,Mazurek-Budzynska, M.,Razzaq, M.Y.,Lendlein, A. %D 2016 %J Polymer %N %P 318-326 %R doi:10.1016/j.polymer.2016.10.033 %T Hexyl-modified morpholine-2,5-dione-based oligodepsipeptides with relatively low glass transition temperature %U https://doi.org/10.1016/j.polymer.2016.10.033 %X Oligodepsipeptides (oDPs), alternating copolymers of an α-amino acid and an α-hydroxy acid, are typically created by ring-opening polymerization (ROP) of morpholine-2,5-dione derivatives (MDs). In general, oDPs exhibit relatively high glass transition temperatures (Tgs) caused by the strong intermolecular H-bonding between amide and ester bonds. So far, it was not reported that variation at α-amino acid moieties in MDs monomers lead to lower Tg. Here we explored whether the thermal properties of the oDPs can be adjusted by introducing a hexyl side chain in the α-hydroxy acid part of the MDs. By synthesizing a MD with an atactic pendant hexyl group at position 3, the influence of a modification at position 6 compared to a modification at position 3 towards ROP was investigated. In both cases the atactic bulky side groups hindered the H-bonding between chain segments resulting in a significant reduction of the Tgs to a temperature around human body temperature (32 and 36 °C) in contrast to ROP of a MD providing a methyl group at position 3 and a Tg ≈ 65 °C. Such oDPs could be interesting candidate materials for biomedical applications such as degradable implants. %0 journal article %@ 2059-8521 %A Jiang, Y.,Fang, L.,Kratz, K.,Lendlein, A. %D 2016 %J MRS Advances %N 27 %P 1985-1993 %R doi:10.1557/adv.2016.389 %T Influence of Compression Direction on the Shape-Memory Effect of Micro-Cylinder Arrays Prepared from Semi-Crystalline Polymer Networks %U https://doi.org/10.1557/adv.2016.389 27 %X Microstructured polymeric surfaces capable of a thermally-induced shape-memory effect (SME) can perform on demand changes of surface properties such as wettability or adhesion.,In this study, we explored the influence of the applied compression direction during programming, i.e. vertical compression and tilted compression, on the SME of microstructured crosslinked poly[ethylene-co-(vinyl acetate)] (cPEVA) films comprising arrays of micro-cylinders with a height of 10 µm and different diameters of 10 µm, 25 µm, and 50 µm. The shape recovery of the microstructures during heating was visualized online by optical microscopy, while atomic force microscopy (AFM) was utilized to investigate the temperature-induced shape change of single micro-cylinders. Here, the changes in micro-cylinder height and the characteristic angle θ were followed and analyzed for quantification of the shape-memory performance. Both compression modes resulted in almost flat programmed surfaces as indicated by high shape fixity ratios of R f ≥ 93±1%. A nearly complete recovery of the micro-cylinders was obtained for all investigated cPEVA samples documented by high shape recovery values of R r ≥ 97±1%, while the obtained shape change of the micro-cylinders during recovery almost reversely recalled the applied deformation during programming. The presented capability of SMP microstructured substrates to memorize the way of deformation during programming could be a new tool for controlling particular shape changes of microstructures during recovery and in such a way the generated local recovery forces can be adjusted. %0 journal article %@ 1022-1336 %A Zhang, P.,Behl, M.,Peng, X.,Razzaq, M.,Lendlein, A. %D 2016 %J Macromolecular Rapid Communications %N 23 %P 1897-1903 %R doi:10.1002/marc.201600439 %T Ultrasonic Cavitation Induced Shape-Memory Effect in Porous Polymer Networks %U https://doi.org/10.1002/marc.201600439 23 %X Inspired by the application of ultrasonic cavitation based mechanical force (CMF) to open small channels in natural soft materials (skin or tissue), it is explored whether an artificial polymer network can be created, in which shape-changes can be induced by CMF. This concept comprises an interconnected macroporous rhodium-phosphine (Rh-P) coordination polymer network, in which a CMF can reversibly dissociate the Rh-P microphases. In this way, the ligand exchange of Rh-P coordination bonds in the polymer network is accelerated, resulting in a topological rearrangement of molecular switches. This rearrangement of molecular switches enables the polymer network to release internal tension under ultrasound exposure, resulting in a CMF-induced shape-memory capability. The interconnected macroporous structure with thin pore walls is essential for allowing the CMF to effectively permeate throughout the polymer network. Potential applications of this CMF-induced shape-memory polymer can be mechanosensors or ultrasound controlled switches. %0 journal article %@ 1386-0291 %A Kumar, R.K.,Basu, S.,Lemke, H.-D.,Jankowski, J.,Kratz, K.,Lendlein, A.,Tetali, S.D. %D 2016 %J Clinical Hemorheology and Microcirculation %N 4 %P 931-940 %R doi:10.3233/CH-168046 %T Influence of nanoporous poly(ether imide) particle extracts on human aortic endothelial cells (HAECs) %U https://doi.org/10.3233/CH-168046 4 %X Accumulated uremic toxins like indoxyl sulphate, hippuric acid and p-cresyl sulphates in renal failure patients stimulate proinflammatory effects, and consequently kidney and cardiovascular diseases. Low clearance rate of these uremic toxins from the blood of uremic patients by conventional techniques like hemodialysis is due to their strong covalent albumin binding (greater than 95%) and hydrophobic nature, which led to alternatives like usage of hydrophobic adsorber’s in removing these toxins from the plasma of kidney patients. Polymers like polyethylene, polyurethane, polymethylmethacrylate, cellophane and polytetrafluoroethylene were already in use as substitutes for metal devices as dialysis membranes. Among new synthetic polymers, one such ideal adsorber material are highly porous microparticles of poly(ether imide) (PEI) with diameters in the range from 50–180μm and a porosity around 88±2% prepared by a spraying and coagulation process.,It is essential to make sure that these synthetic polymers should not evoke any inflammatory or apoptotic response during dialysis. Therefore in our study we evaluated in vitro effect of PEI microparticle extracts in human aortic endothelial cells (HEACs) concerning toxicity, inflammation and apoptosis. No cell toxicity was observed when HAECs were treated with PEI extracts and inflammatory/apoptotic markers were not upregulated in presence of PEI extracts. Our results ensure biocompatibility of PEI particles and further hemocompatibility of particles will be tested. %0 journal article %@ 0168-3659 %A Wang, W.,Balk, M.,Deng, Z.,Wischke, C.,Gossen, M.,Behl, M.,Ma, N.,Lendlein, A. %D 2016 %J Journal of Controlled Release %N %P 71-79 %R doi:10.1016/j.jconrel.2016.08.004 %T Engineering biodegradable micelles of polyethylenimine-based amphiphilic block copolymers for efficient DNA and siRNA delivery %U https://doi.org/10.1016/j.jconrel.2016.08.004 %X Polycationic micelles have shown advantageous properties as nucleic acid delivery vectors both in vitro and in vivo. In contrast to polycationic micelles reported so far, we designed particles integrating a sufficient nucleic acid condensation capability by polycationic polyethylenimine (PEI) segments as well as only a mild cytotoxic behavior. The micelles composed of a hydrophobic oligoester core with glycolide units resulting in fast degradation after cellular internalization in combination with PEG moieties acting as shielding agents. By grafting branched 25 kDa polyethylenimine (PEI25) and poly(ethylene glycol) (PEG) on poly[(ε-caprolactone)-co-glycolide] (CG), amphiphilic PEI-CG-PEI and PEG-CG block copolymers were used to form a series of micelles via self-assembly of PEI-CG-PEI or co-assembly of both copolymers for DNA and siRNA delivery. This modular system enabled a systematic investigation of different parameters and their synergetic effects as different functions were introduced. The polyplex formation and serum stability, cytotoxicity, and transfection activity could be tailored by changing the CG chain length in PEI-based copolymer, incorporating PEG-CG, and varying the N/P ratio. All micelle-based polyplex compositions showed high DNA transfection activity according to reporter gene-expression and an exceptionally high knockdown in siRNA delivery experiments. Remarkably, the GFP expression of > 99% cells was successfully knocked down by micelle-mediated siRNA interference, resulting in a decrease of two orders of magnitude in fluorescence intensity. Incorporation of PEG-CG in the micelles reduced the PEI-related cytotoxicity, and markedly enhanced the serum stability of both DNA and siRNA polyplexes. Compared with homo-PEI25, these micelles showed several advantages including the lower toxicity, higher siRNA transfection efficiency and higher polyplex stability in the presence of serum. This study therefore provides an effective approach to tune the structure, property and function of polycationic micelles for efficient DNA and siRNA delivery, which could contribute to the design and development of novel non-viral transfection vectors with superb functionality. %0 journal article %@ 0066-4219 %A Stein, C. %D 2016 %J Annual Review of Medicine %N %P 433-451 %R doi:10.1146/annurev-med-062613-093100 %T Opioid Receptors %U https://doi.org/10.1146/annurev-med-062613-093100 %X Opioids are the oldest and most potent drugs for the treatment of severe pain. Their clinical application is undisputed in acute (e.g., postoperative) and cancer pain, but their long-term use in chronic pain has met increasing scrutiny. This article reviews mechanisms underlying opioid analgesia and other opioid actions. It discusses the structure, function, and plasticity of opioid receptors; the central and peripheral sites of analgesic actions and side effects; endogenous and exogenous opioid receptor ligands; and conventional and novel opioid compounds. Challenging clinical situations, such as the tension between chronic pain and addiction, are also illustrated. %0 journal article %@ 1616-5187 %A Tschiche, A.,Thota, B.N.S.,Neumann, F.,Schaefer, A.,Ma, N.,Haag, R. %D 2016 %J Macromolecular Bioscience %N 6 %P 811-823 %R doi:10.1002/mabi.201500363 %T Crosslinked Redox-Responsive Micelles Based on Lipoic Acid-Derived Amphiphiles for Enhanced siRNA Delivery %U https://doi.org/10.1002/mabi.201500363 6 %X Successful application of gene silencing approaches critically depends on systems that are able to safely and efficiently deliver genetic material such as small interfering RNA (siRNA). Due to their beneficial well-defined dendritic nanostructure, self-assembling dendrimers are emerging as promising nanovectors for siRNA delivery. However, these kinds of vectors are plagued with stability issues, especially when considered for in vivo applications. Therefore, in the present study, disulfide-based temporarily fixed micelles are developed that can degrade upon reductive conditions, and thus lead to efficient cargo release. In detail, lipoic acid-derived crosslinked micelles are synthesized based on small polymerizable dendritic amphiphiles. Particularly, one candidate out of this series is able to efficiently release siRNA due to its redox-responsive biodegradable profile when exposed to simulated intracellular environments. As a result, the reduction-triggered disassembly leads to potent gene silencing. In contrast, noncrosslinkable, structurally related constructs fails under the tested assay conditions, thereby confirming the applied rational design approach and demonstrating its large potential for future in vivo applications. %0 journal article %@ 1005-281X %A Liu, W.,Zhang, L.,Yang, J.,Xuefang, H.,Li, Q.,Feng, Y. %D 2016 %J Progress in Chemistry %N 6 %P 954-960 %R doi:10.7536/PC151218 %T Targeting carrier/gene complexes to promote the proliferation of endothelial cells %U https://doi.org/10.7536/PC151218 6 %X Due to the lack of a living functional layer of endothelial cells( ECs) on the surface of artificial vascular scaffolds, especially small-diameter artificial vascular scaffolds, usually encounter long-term low patency and restenosis, limiting their clinical application. Nevertheless, it has been proved that reendothelialization of artificial vascular scaffolds can be aquired rapidly via gene transfection tow ards endothelial cells,which is mediated by gene complexes. At present,gene carriers modified with targeting peptides provide a useful approach to promote transfection efficiency as well as decrease cytotoxicity. We introduce the desired genes and gene carriers applied in gene transfection detailedly. Based on polycationic gene carriers,the recent developments of gene carriers with targeting peptides for promoting the proliferation of ECs and endothelialization are highlighted in this review. Combined with the progress of small diameter artificial blood vessels,some perspectives on accomplishing rapid endothelialization via gene transfection are also presented. %0 journal article %@ 1873-5061 %A Hildebrand, L.,Rossbach, B.,Kuehnen, P.,Gossen, M.,Kurtz, A.,Reinke, P.,Seemann, P.,Stachelscheid, H. %D 2016 %J Stem Cell Research %N 1 %P 54-58 %R doi:10.1016/j.scr.2015.11.017 %T Generation of integration free induced pluripotent stem cells from fibrodysplasia ossificans progressiva (FOP) patients from urine samples %U https://doi.org/10.1016/j.scr.2015.11.017 1 %X Fibrodysplasia ossificans progressiva (FOP) is an extremely rare, autosomal dominant transmitted genetic disease. Patients experience progressive bone formation replacing tendons, ligaments, muscle and soft tissue. Cause of FOP are gain-of-function mutations in the Bone Morphogenetic Protein (BMP) receptor Activin A receptor type 1 (ACVR1) (Kaplan et al., 2008). The most common mutation is R206H, which leads to the substitution of codon 206 from arginine to histidine (Shore et al., 2006).,Here, we describe the derivation and characterization of two hiPSC lines from two FOP patients, both carrying the mutation R206H. Cells were isolated from urine and reprogrammed using integration free Sendai virus vectors under defined conditions. %0 journal article %@ 2041-1723 %A Fuhrmann, A.,Goestl, R.,Wendt, R.,Koetteritzsch, J.,Hager, M.D.,Schubert, U.S.,Brademann-Jock, K.,Thuenemann, A.F.,Noechel, U.,Behl, M.,Hecht, S. %D 2016 %J Nature Communications %N %P 13623 %R doi:10.1038/ncomms13623 %T Conditional repair by locally switching the thermal healing capability of dynamic covalent polymers with light %U https://doi.org/10.1038/ncomms13623 %X Healable materials could play an important role in reducing the environmental footprint of our modern technological society through extending the life cycles of consumer products and constructions. However, as most healing processes are carried out by heat alone, the ability to heal damage generally kills the parent material’s thermal and mechanical properties. Here we present a dynamic covalent polymer network whose thermal healing ability can be switched ‘on’ and ‘off’ on demand by light, thereby providing local control over repair while retaining the advantageous macroscopic properties of static polymer networks. We employ a photoswitchable furan-based crosslinker, which reacts with short and mobile maleimide-substituted poly(lauryl methacrylate) chains forming strong covalent bonds while simultaneously allowing the reversible, spatiotemporally resolved control over thermally induced de- and re-crosslinking. We reason that our system can be adapted to more complex materials and has the potential to impact applications in responsive coatings, photolithography and microfabrication. %0 journal article %@ 2059-8521 %A Vukicevic, R.,Neffe, A.T.,Gebauer, T.,Frank, O.,Schossig, M.,Lendlein, A. %D 2016 %J MRS Advances %N 27 %P 1995-2001 %R doi:10.1557/adv.2016.416 %T Mechanical Properties of Architectured Gelatin-Based Hydrogels on Different Hierarchical Levels %U https://doi.org/10.1557/adv.2016.416 27 %X Preparation of three-dimensionally architectured porous biomaterials can be achieved in a one-step process by stabilizing gelatin with L-lysine diisocyanate ethyl ester (LDI) in water. The reaction of gelatin with LDI in presence of water leads to the formation of oligourea bridges between gelatin molecules and oligourea chains grafted on gelatin. The number and the length of the bridges, as well as of the grafted chains strongly depend on the concentration of the LDI used for the stabilization, and this has huge influence on the mechanical properties of the material on different hierarchical levels. Higher LDI concentrations yield materials with increased deformation resistance in tensile tests due to the higher number of covalent and physical netpoints in the material. However, mechanical properties determined on the micro-level by AFM indentation showed the opposite trend, i.e. a decrease of Young’s modulus with increasing LDI content. This was interpreted by a decreasing number of shorter oligourea bridges between gelatin chains with decreasing LDI content. %0 journal article %@ 0024-9297 %A Bilici, C.,Can, V.,Noechel, U.,Behl, M.,Lendlein, A.,Okay, O. %D 2016 %J Macromolecules %N 19 %P 7442-7449 %R doi:10.1021/acs.macromol.6b01539 %T Melt-Processable Shape-Memory Hydrogels with Self-Healing Ability of High Mechanical Strength %U https://doi.org/10.1021/acs.macromol.6b01539 19 %X We present here a synthetic strategy for the preparation of melt-processable shape-memory hydrogels with self-healing ability. The supramolecular hydrogel with a water content of 60–80 wt % consists of poly(acrylic acid) chains containing 20–50 mol % crystallizable n-octadecyl acrylate (C18A) segments together with surfactant micelles. The key of our approach to render the hydrogel melt-processable is the absence of chemical cross-links and the presence of surfactant micelles. At temperatures above the melting temperature Tm of the crystalline domains of alkyl side chains, the hydrogel liquefies due to the presence of surfactant micelles effective for solubilizing the hydrophobic C18A segments. At this stage, it can easily be shaped into any desired form by pouring into molds. Cooling below Tm and removing the surfactant from the gel network results in a hydrogel of any permanent shape with a particularly high compressive strength of 90 MPa and a Young’s modulus of 26 MPa. If the hydrogel was damaged on purpose e.g. by cutting into two pieces, the extraordinary mechanical properties can completely be recovered via temperature-induced healing process. The hydrogel also exhibits a complete shape fixity ratio and a shape recovery ratio of 97 ± 2%. %0 journal article %@ 2470-1343 %A Wyss, P.P.,Herrera, L.C.,Bouteghmes, N.S.,Sarem, M.,Reichardt, W.,Leupold, J.,Hennig, J.,Shastri, V.P. %D 2016 %J ACS Omega %N 2 %P 182-192 %R doi:10.1021/acsomega.6b00088 %T Nanoprobes for Multimodal Visualization of Bone Mineral Phase in Magnetic Resonance and Near-Infrared Optical Imaging %U https://doi.org/10.1021/acsomega.6b00088 2 %X Imaging agents with affinity for bone can enable early detection of changes to bone mineral density, which is a hallmark of many bone-associated pathologies such as Paget’s disease and osteoporosis. Here, we report the development of a polymer nanoparticle (NP)-based multimodal imaging probe that enables visualization of bone mineral phase in near-infrared (NIR) optical tomography and detection in T2-weighted magnetic resonance imaging (MRI). Ultrasmall superparamagnetic iron oxide was first encapsulated in NPs derived by blending poly(dl-lactic-co-glycolic acid)–poly(ethylene glycol) (PLGA–PEG) with N-hydroxysuccinimide functionalized-PLGA (NHS–PLGA). Postmodification of NHS surface functionality on the NPs with alendronic acid (Aln), a bone-targeting ligand, yielded stable ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) containing NPs that exhibit good serum stability and favorable cytocompatibility. These post-Aln-modified NPs exhibit 8- to 10-fold higher affinity for synthetic and biogenic hydroxyapatite in comparison to NPs where Aln was introduced before NP formation and shorten the T2 relaxation times in both agarose phantoms and fresh spongy bone, thus enabling the interrogation of bone mineral phase in T2-MRI. Finally, by introducing an NIR-dye-modified PLGA during the NP formation step, NP probes that enable the visualization of bone mineral phase in both NIR optical tomography and MRI have been realized. The system presented herein meets many of the criteria for clinical translation and therefore opens new opportunities for bone imaging and targeted therapeutics. %0 journal article %@ 1525-7797 %A Forget, A.,Arya, N.,Randriantsilefisoa, R.,Miessmer, F.,Buck, M.,Ahmadi, V.,Jonas, D.,Blencowe, A.,Shastri, V.P. %D 2016 %J Biomacromolecules %N 12 %P 4021-4026 %R doi:10.1021/acs.biomac.6b01401 %T Nonwoven Carboxylated Agarose-Based Fiber Meshes with Antimicrobial Properties %U https://doi.org/10.1021/acs.biomac.6b01401 12 %X Hydrogel forming polysaccharides, such as the seaweed derived agarose, are well suited for wound dressing applications as they have excellent cell and soft tissue compatibility. For wound dressings, fibrous structure is desirable as the high surface area can favor adsorption of wound exudate and promote drug delivery. Although electrospinning offers a straightforward means to produce nonwoven fibrous polymeric structures, processing agarose and its derivatives into fibers through electrospinning is challenging as it has limited solubility in solvents other than water. In this study we describe the processing of carboxylated agarose (CA) fibers with antibacterial properties by electrospinning from a solution of the ionic liquid (IL) 1-butyl-3-methylimidazolium chloride ([Bmim]+Cl–) possessing antimicrobial properties. The extent of carboxylation was found to impact fiber diameter, mesh elastic modulus, fiber swelling, and the loading and release of IL. IL-bearing CA fibers inhibited the growth of Staphylococcus aureus and Pseudomonas aeruginosa, bacteria commonly found in wound exudate. In sum, nonwoven CA fibers processed from IL are promising as biomaterials for wound dressing applications. %0 journal article %@ 1862-8338 %A Di Lorenzo, F.,Seiffert, S. %D 2016 %J Macromolecular Reaction Engineering %N 3 %P 201-205 %R doi:10.1002/mren.201500061 %T Effect of Droplet Size in Acrylamide-Based Microgel Formation by Microfluidics %U https://doi.org/10.1002/mren.201500061 3 %X Polymer microgels with sizes of some tens to hundreds of micrometers can be formed with exquisite control by droplet-based microfluidic templating. This study presents a systematic assessment of the effect of the premicrogel droplet size on the ability of production of such microgels. The focus is on two popular acrylamide-derivatives at a fixed monomer concentration and external polymerization temperature. An exponential dependence of the success of droplet gelation on the droplet size is found, which can be rationalized in view of the balance between production and transfer of heat within and from the droplets on basis of a simple Arrhenius argument. %0 journal article %@ 2050-750X %A Lv, J.,Yang, J.,Hao, X.,Ren, X.,Feng, Y.,Zhang, W. %D 2016 %J Journal of Materials Chemistry B %N 5 %P 997-1008 %R doi:10.1039/c5tb02310f %T Biodegradable PEI modified complex micelles as gene carriers with tunable gene transfection efficiency for ECs %U https://doi.org/10.1039/c5tb02310f 5 %X In recent years, gene therapy has evoked an increasing interest in clinical treatments of coronary diseases because it is a potential strategy to realize rapid endothelialization of artificial vascular grafts. The balance of high transfection efficiency and low cytotoxicity of nonviral gene carriers is an important issue to be solved. In this study, we aim to establish a gene delivery system offering an elegant way to tune the transfection activity and cytotoxicity. Biodegradable complex micelles were prepared from polyethylenimine-b-poly(lactide-co-3(S)-methyl-morpholine-2,5-dione)-b-polyethylenimine (PEI-b-PLMD-b-PEI) and methoxy-poly(ethylene glycol)-b-poly(lactide-co-3(S)-methyl-morpholine-2,5-dione) (mPEG-b-PLMD) copolymers by a co-assembly method. Then the ZNF580 gene plasmid (pDNA) was encapsulated into the complex micelles. The hydrodynamic size and zeta potential of these complex micelles and micelles/pDNA complexes indicated that they were feasible for use in cellular uptake and gene transfection. As expected, the transfection efficiency and cytotoxicity of these micelles/pDNA complexes could be conveniently tuned by changing the mass ratio of mPEG-b-PLMD to PEI-b-PLMD-b-PEI (3/1, 2/2, 1/3 and 0/4) in the mixed mPEG/PEI shell. The transfection efficiency increased as the mass ratio of mPEG-b-PLMD/PEI-b-PLMD-b-PEI decreased from 3/1 to 0/4, while the cytotoxicity showed an opposite tendency. Moreover, ZNF580 protein expression determined by Western blot analysis and the migration of transfected endothelial cells (ECs) by wound healing assay were consistent with the result of transfection efficiency. All these results indicated that the co-assembled complex micelles could act as suitable gene carriers with tunable gene transfection efficiency and cytotoxicity, which should have great potential for the transfection of vascular ECs. %0 journal article %@ 2050-750X %A Yang, J.,Liu, W.,Lv, J.,Feng, Y.,Ren, X.,Zhang, W. %D 2016 %J Journal of Materials Chemistry B %N 19 %P 3365-3376 %R doi:10.1039/C6TB00686H %T REDV–polyethyleneimine complexes for selectively enhancing gene delivery in endothelial cells %U https://doi.org/10.1039/C6TB00686H 19 %X Gene therapy provides a new strategy for promoting endothelialization, and rapid endothelialization has attracted increasing attention for inhibiting thrombosis and restenosis in artificial vascular implants. However, the low transfection efficiency and high cytotoxicity of gene delivery systems prevent their in vivo application. In this study, an endothelial cell (EC)-specific gene carrier with relatively high transfection efficiency and low cytotoxicity was prepared successfully. Using bifunctional hydroxylsuccinimide–poly(ethylene glycol)–maleimide (NHS–PEG–MAL) as the linker, an EC-specific REDV peptide was conveniently grafted onto polyethyleneimine-b-poly(lactide-co-3(S)-methyl-morpholine-2,5-dione)-b-polyethyleneimine (PEI–PLMD–PEI). By varying the molar ratios of REDV to PEI, a series of REDV modified copolymers REDV–PEG-g-PEI–PLMD–PEI-g-PEG–REDV (REDV–PPP) were prepared. Then these copolymers were self-assembled into nanoparticles (NPs) as gene carriers. These NPs could easily condense the EGFP-ZNF580 plasmid (pZNF580) to form REDV peptide functionalized NP/pZNF580 complexes with low cytotoxicity. The fluorescence images, Western blot analysis, and quantitative real-time RT-PCR results verified that the effective transfection of REDV peptide functionalized NP/pZNF580 complexes in ECs was comparable with the positive control of PEI (25000 Da)/pZNF580 complexes. The high transfection efficiency was attributed to the enhanced cell uptake by the REDV peptide and relied on the quantity of the peptide. Furthermore, the rapid migration of the transfected ECs showed the active function of the expressed ZNF580 protein and further demonstrated that the REDV peptide functionalized NP/pZNF580 complexes could improve the transfection of pZNF580 in ECs. These results provided a useful platform to design EC-specific gene carriers and use gene therapy to enhance endothelialization. %0 journal article %@ 0141-3910 %A Schoene, A.-C.,Kratz, K.,Schulz, B.,Lendlein, A. %D 2016 %J Polymer Degradation and Stability %N %P 114-121 %R doi:10.1016/j.polymdegradstab.2016.07.010 %T Polymer architecture versus chemical structure as adjusting tools for the enzymatic degradation of oligo(Epsilon-caprolactone) based films at the air-water interface %U https://doi.org/10.1016/j.polymdegradstab.2016.07.010 %X The enzymatic degradation of oligo(ε-caprolactone) (OCL) based films at the air-water interface is investigated by Langmuir monolayer degradation (LMD) experiments to elucidate the influence of the molecular architecture and of the chemical structure on the chain scission process. For that purpose, the interactions of 2D monolayers of two star-shaped poly(ε-caprolactone)s (PCLs) and three linear OCL based copolyesterurethanes (P(OCL-U)) with the lipase from Pseudomonas cepacia are evaluated in comparison to linear OCL. While the architecture of star-shaped PCL Langmuir layers slightly influences their degradability compared to OCL films, significantly retarded degradations are observed for P(OCL-U) films containing urethane junction units derived from 2, 2 (4), 4-trimethyl hexamethylene diisocyanate (TMDI), hexamethylene diisocyanate (HDI) or lysine ethyl ester diisocyanate (LDI). The enzymatic degradation of the OCL based 2D structures is related to the presence of hydrophilic groups within the macromolecules rather than to the packing density of the film or to the molecular weight. The results reveal that the LMD technique allows the parallel analysis of both the film/enzyme interactions and the degradation process on the molecular level. %0 journal article %@ 2059-8521 %A Neffe, A.T.,Federico, S.,Lendlein, A. %D 2016 %J MRS Advances %N 27 %P 1965-1970 %R doi:10.1557/adv.2016.266 %T Secondary Structure of Decorin-Derived Peptides in Solution %U https://doi.org/10.1557/adv.2016.266 27 %X Decorin is a small leucine-rich repeat proteoglycan supporting collagen fibril formation by controlling the rate of collagen fibrillogenesis and fibril dimensions. Peptides derived from the inner surface of decorin have been shown to bind to collagen, while peptides derived from the outer surface do not display such binding affinity. As typical secondary structural elements such as β-sheets and α-helical regions were found in the decorin X-ray crystal structure, here it was investigated by Circular Dichroism (CD) spectroscopy in solution, whether the same structural elements can be found in the derived peptides. Here it is shown that the peptide derived from decorin’s outer surface has the propensity to adopt helical conformation, as it was found in the crystal structure. The results were more pronounced in 80 vol% TFE solution, which led to an increase in the number as well as the length of helices. In contrast, peptides derived from the inner surface had a higher tendency to adopt β-sheet conformation, also in TFE, which corresponds to the conformation of the original sequence in the crystal structure of decorin. This suggests that the peptides derived from decorin adopt the structures present in the native protein. %0 journal article %@ 0168-3659 %A Vogt, A.,Wischke, C.,Neffe, A.T.,Ma, N.,Alexiev, U.,Lendlein, A. %D 2016 %J Journal of Controlled Release %N %P 3-15 %R doi:10.1016/j.jconrel.2016.07.027 %T Nanocarriers for drug delivery into and through the skin - Do existing technologies match clinical challenges? %U https://doi.org/10.1016/j.jconrel.2016.07.027 %X The topical application of drug-loaded particles has been explored extensively aiming at a dermal, follicular or transdermal drug delivery. This review summarizes the present state of the field of polymeric nanocarriers for skin application, also covering methodologies to clinically characterize their interaction and penetration in skin in vivo. Furthermore, with a focus on a clinical perspective, a number of questions are addressed: How well are existing nanoparticle systems penetrating the skin? Which functions of new carrier concepts may meet the clinical requirements? To which extend will instrumental imaging techniques provide information on the biological functions of nanocarriers? Which issues have to be addressed for translating experimental concepts into a future clinical application? %0 journal article %@ 0032-3861 %A Fang, L.,Yan, W.,Noechel, U.,Kratz, K.,Lendlein, A. %D 2016 %J Polymer %N %P 54-62 %R doi:10.1016/j.polymer.2016.08.105 %T Programming structural functions in phase-segregated polymers by implementing a defined thermomechanical history %U https://doi.org/10.1016/j.polymer.2016.08.105 %X Unwanted shrinkage behaviors or failure in structural functions such as mechanical strength or deformability of polymeric products related to their thermomechanical history are a major challenge in production of plastics. Here, we address the question whether we can turn this challenge into an opportunity by creating defined thermomechanical histories in polymers, represented by a specific morphology and nanostructure, to equip polymeric shaped bodies with desired functions, e.g. a temperature-memory, by hot, warm or cold deformation into multiblock copolymers having two partially overlapping melting transitions. A copolyesterurethane named PDLCL, consisting of poly(ε-caprolactone) (PCL) and poly(ω-pentadecalactone) (PPDL) crystalline domains, exhibiting a pronounced phase-segregated morphology and partially overlapping melting transitions was selected for this study. Different types of PCL and PPDL crystals as well as distinct degrees of orientation in both amorphous and crystalline domains were obtained after deformation at 20 or 40 °C and to a lower extent at 60 °C. The generated non-isotropic structures were stable at ambient temperature and represent the different stresses stored. Stress-free heating experiments showed that the relaxation in both amorphous and crystalline phases occurred predominantly with melting of PCL crystals. When the switching temperature, which was similar to the applied deformation temperature (temperature-memory), was exceeded in stress-free heating experiments, the implemented thermomechanical history could be reversed. In contrast, during constant-strain heating to 60 °C the generated structural features remained almost unchanged.,These findings provide insights about the structure function relation in multiblock copolymers with two crystalline phases exhibiting a temperature-memory effect by implementation of specific thermomechanical histories, which might be a general principle for tailoring other functions like mechanical strength or deformability in polymers. %0 journal article %@ 0032-3861 %A Schoene, A.-C.,Kratz, K.,Schulz, B.,Lendlein, A. %D 2016 %J Polymer %N %P 92-98 %R doi:10.1016/j.polymer.2016.09.001 %T The relevance of hydrophobic segments in multiblock copolyesterurethanes for their enzymatic degradation at the air-water interface %U https://doi.org/10.1016/j.polymer.2016.09.001 %X The interplay of an enzyme with a multiblock copolymer PDLCL containing two segments of different hydrophilicity and degradability is explored in thin films at the air-water interface. The enzymatic degradation was studied in homogenous Langmuir monolayers, which are formed when containing more than 40 wt% oligo(ε-caprolactone) (OCL). Enzymatic degradation rates were significantly reduced with increasing content of hydrophobic oligo(ω-pentadecalactone) (OPDL). The apparent deceleration of the enzymatic process is caused by smaller portion of water-soluble degradation fragments formed from degradable OCL fragments. Beside the film degradation, a second competing process occurs after adding lipase from Pseudomonas cepacia into the subphase, namely the enrichment of the lipase molecules in the polymeric monolayer. The incorporation of the lipase into the Langmuir film is experimentally revealed by concurrent surface area enlargement and by Brewster angle microscopy (BAM). Aside from the ability to provide information about the degradation behavior of polymers, the Langmuir monolayer degradation (LMD) approach enables to investigate polymer-enzyme interactions for non-degradable polymers. %0 journal article %@ 0169-409X %A Balk, M.,Behl, M.,Wischke, C.,Zotzmann, J.,Lendlein, A. %D 2016 %J Advanced Drug Delivery Reviews %N %P 136-152 %R doi:10.1016/j.addr.2016.05.012 %T Recent advances in degradable lactide-based shape-memory polymers %U https://doi.org/10.1016/j.addr.2016.05.012 %X Biodegradable polymers are versatile polymeric materials that have a high potential in biomedical applications avoiding subsequent surgeries to remove, for example, an implanted device. In the past decade, significant advances have been achieved with poly(lactide acid) (PLA)-based materials, as they can be equipped with an additional functionality, that is, a shape-memory effect (SME). Shape-memory polymers (SMPs) can switch their shape in a predefined manner upon application of a specific external stimulus. Accordingly, SMPs have a high potential for applications ranging from electronic engineering, textiles, aerospace, and energy to biomedical and drug delivery fields based on the perspectives of new capabilities arising with such materials in biomedicine. This study summarizes the progress in SMPs with a particular focus on PLA, illustrates the design of suitable homo- and copolymer structures as well as the link between the (co)polymer structure and switching functionality, and describes recent advantages in the implementation of novel switching phenomena into SMP technology. %0 journal article %@ 2190-4286 %A Rottke, F.O.,Schulz, B.,Richau, K.,Kratz, K.,Lendlein, A. %D 2016 %J Beilstein Journal of Nanotechnology %N %P 1156-1165 %R doi:10.3762/bjnano.7.107 %T An ellipsometric approach towards the description of inhomogeneous polymer-based Langmuir layers %U https://doi.org/10.3762/bjnano.7.107 %X The applicability of nulling-based ellipsometric mapping as a complementary method next to Brewster angle microscopy (BAM) and imaging ellipsometry (IE) is presented for the characterization of ultrathin films at the air–water interface. First, the methodology is demonstrated for a vertically nonmoving Langmuir layer of star-shaped, 4-arm poly(ω-pentadecalactone) (PPDL-D4). Using nulling-based ellipsometric mapping, PPDL-D4-based inhomogeneously structured morphologies with a vertical dimension in the lower nm range could be mapped. In addition to the identification of these structures, the differentiation between a monolayer and bare water was possible. Second, the potential and limitations of this method were verified by applying it to more versatile Langmuir layers of telechelic poly[(rac-lactide)-co-glycolide]-diol (PLGA). All ellipsometric maps were converted into thickness maps by introduction of the refractive index that was derived from independent ellipsometric experiments, and the result was additionally evaluated in terms of the root mean square roughness, Rq. Thereby, a three-dimensional view into the layers was enabled and morphological inhomogeneity could be quantified. %0 journal article %@ 2192-2640 %A Dong, C.,Liu, Z.,Liu, J.,Wu, C.,Neumann, F.,Wang, H.,Schaefer-Korting, M.,Kleuser, B.,Chang, J.,Li, W.,Ma, N.,Haag, R. %D 2016 %J Advanced Healthcare Materials %N 17 %P 2214-2226 %R doi:10.1002/adhm.201600212 %T A Highly Photostable Hyperbranched Polyglycerol-Based NIR Fluorescence Nanoplatform for Mitochondria-Specific Cell Imaging %U https://doi.org/10.1002/adhm.201600212 17 %X Considering the critical role of mitochondria in the life and death of cells, non-invasive long-term tracking of mitochondria has attracted considerable interest. However, a high-performance mitochondria-specific labeling probe with high photostability is still lacking. Herein a highly photostable hyperbranched polyglycerol (hPG)-based near-infrared (NIR) quantum dots (QDs) nanoplatform is reported for mitochondria-specific cell imaging. Comprising NIR Zn-Cu-In-S/ZnS QDs as extremely photostable fluorescent labels and alkyl chain (C12)/triphenylphosphonium (TPP)-functionalized hPG derivatives as protective shell, the tailored QDs@hPG-C12/TPP nanoprobe with a hydrodynamic diameter of about 65 nm exhibits NIR fluorescence, excellent biocompatibility, good stability, and mitochondria-targeted ability. Cell uptake experiments demonstrate that QDs@hPG-C12/TPP displays a significantly enhanced uptake in HeLa cells compared to nontargeted QDs@hPG-C12. Further co-localization study indicates that the probe selectively targets mitochondria. Importantly, compared with commercial deep-red mitochondria dyes, QDs@hPG-C12/TPP possesses superior photostability under continuous laser irradiation, indicating great potential for long-term mitochondria labeling and tracking. Moreover, drug-loaded QDs@hPG-C12/TPP display an enhanced tumor cell killing efficacy compared to nontargeted drugs. This work could open the door to the construction of organelle-targeted multifunctional nanoplatforms for precise diagnosis and high-efficient tumor therapy. %0 journal article %@ 1386-0291 %A Braune, S.,Zhou, S.,Groth, B.,Jung, F. %D 2015 %J Clinical Hemorheology and Microcirculation %N 2 %P 225-236 %R doi:10.3233/CH-151995 %T Quantification of adherent platelets on polymer-based biomaterials. Comparison of colorimetric and microscopic assessment %U https://doi.org/10.3233/CH-151995 2 %X BACKGROUND: Platelet adhesion to artificial surfaces is one of the most important indicators for the thrombogenicity of implant materials. Currently, a variety of enzyme activity-based colorimetric assays or microscopy-based techniques are commonly in use to assess this characteristic. Studies about how data of colorimetric assays correlate with the image-based quantification of adherent platelets are scarce. To address this question, the present study compared two colorimetric assays (lactate dehydrogenase (LDH) and acid phosphatase (ACP)) with an image-based quantification of the density of platelets adhering on polymer-based biomaterial surfaces.,MATERIALS AND METHODS: Tri-sodium citrated whole blood was collected from apparently healthy subjects and platelet rich plasma (PRP) was prepared according to a standardized protocol. An in vitro static thrombogenicity test was applied to study platelet adhesion from PRP adjusted to 50,000 platelets per μL on three different polymers: medical grade polytetrafluoroethylene (PTFE), silicone and polyethylene terephthalate (PET). For the direct image-based approach, surface adherent platelets were fixed, fluorescently labelled and microscopically visualized. The image-based determination of platelet densities provided reference values for the comparison with data of the colorimetric assays. Correlation between standard platelet concentrations and ACP/LDH absorbance measurements were analysed to estimate accuracy and association of both parameters. ACP and LDH release from resting and ADP-stimulated platelets was studied to estimate how platelet activation influences colorimetric assay results.,RESULTS: The density of adherent platelets ranged from 15,693 ± 2,487 platelets·mm–2 (PTFE) to 423 ± 99 platelets·mm–2 (silicone) and 4,621 ± 1,427 platelets·mm–2 (PET) and differed significantly between the three polymers (ANOVA: p <  0.05). Correlation coefficients between microscopic and colorimetric determination of platelet densities ranged between r = 0.93 (LDH, p <  0.001) and r = 0.94 (ACP, p <  0.001). ACP absorbance measurements of platelet standards with different concentrations corresponded well to an ideal linear regression, while LDH data either deceeded or exceeded the expected values. The LDH release during ADP-induced platelet activation was significantly higher compared to the release of ACP.,CONCLUSION: For an adjusted platelet concentration of 50,000 platelets· μL–1, both colorimetric assays (ACP and LDH) allowed a similar accurate quantification of the mean platelet density compared to the microscopic evaluation. Better linearity of the assay standards, less variability of the results and a lower influence of platelet activation on the measurements mark the ACP assay as more suitable for the assessment of material surface adherent platelets compared to the LDH assay, particularly, if near physiological platelet concentrations are applied. %0 journal article %@ 1742-7061 %A Khan, M.,Yang, J.,Shi, C.,Lv, J.,Feng, Y.,Zhang, W. %D 2015 %J Acta Biomaterialia %N %P 69-81 %R doi:10.1016/j.actbio.2015.03.032 %T Surface tailoring for selective endothelialization and platelet inhibition via a combination of SI-ATRP and click chemistry using Cys–Ala–Gly-peptide %U https://doi.org/10.1016/j.actbio.2015.03.032 %X Surface tailoring is an attractive approach to enhancing selective endothelialization, which is a prerequisite for current vascular prosthesis applications. Here, we modified polycarbonate urethane (PCU) surface with both poly(ethylene glycol) and Cys–Ala–Gly-peptide (CAG) for the purpose of creating a hydrophilic surface with targeting adhesion of endothelial cells (ECs). In the first step, PCU-film surface was grafted with poly(ethylene glycol) methacrylate (PEGMA) to covalently tether hydrophilic polymer brushes via surface initiated atom transfer radical polymerization (SI-ATRP), followed by grafting of an active monomer pentafluorophenyl methacrylate (PFMA) by a second ATRP. The postpolymerization modification of the terminal reactive groups with allyl amine molecules created pendant allyl groups, which were subsequently functionalized with cysteine terminated CAG-peptide via photo-initiated thiol-ene click chemistry. The functionalized surfaces were characterized by water contact angle and XPS analysis. The growth and proliferation of human ECs or human umbilical arterial smooth muscle cells on the functionalized surfaces were investigated for 1, 3 and 7 day/s. The results indicated that these peptide functionalized surfaces exhibited enhanced EC adhesion, growth and proliferation. Furthermore, they suppressed platelet adhesion in contact with platelet-rich plasma for 2 h. Therefore, these surfaces with EC targeting ligand could be an effective anti-thrombogenic platform for vascular tissue engineering application. %0 journal article %@ 1386-0291 %A Krueger, A.,Fuhrmann, R.,Jung, F.,Franke, R.P. %D 2015 %J Clinical Hemorheology and Microcirculation %N 2 %P 151-156 %R doi:10.3233/CH-151992 %T Morphology of primary human venous endothelial cell cultures before and after culture medium exchange %U https://doi.org/10.3233/CH-151992 2 %X BACKGROUND: Platelet adhesion to artificial surfaces is one of the most important indicators for the thrombogenicity of implant materials. Currently, a variety of enzyme activity-based colorimetric assays or microscopy-based techniques are commonly in use to assess this characteristic. Studies about how data of colorimetric assays correlate with the image-based quantification of adherent platelets are scarce. To address this question, the present study compared two colorimetric assays (lactate dehydrogenase (LDH) and acid phosphatase (ACP)) with an image-based quantification of the density of platelets adhering on polymer-based biomaterial surfaces.,MATERIALS AND METHODS: Tri-sodium citrated whole blood was collected from apparently healthy subjects and platelet rich plasma (PRP) was prepared according to a standardized protocol. An in vitro static thrombogenicity test was applied to study platelet adhesion from PRP adjusted to 50,000 platelets per μL on three different polymers: medical grade polytetrafluoroethylene (PTFE), silicone and polyethylene terephthalate (PET). For the direct image-based approach, surface adherent platelets were fixed, fluorescently labelled and microscopically visualized. The image-based determination of platelet densities provided reference values for the comparison with data of the colorimetric assays. Correlation between standard platelet concentrations and ACP/LDH absorbance measurements were analysed to estimate accuracy and association of both parameters. ACP and LDH release from resting and ADP-stimulated platelets was studied to estimate how platelet activation influences colorimetric assay results.,RESULTS: The density of adherent platelets ranged from 15,693 ± 2,487 platelets·mm–2 (PTFE) to 423 ± 99 platelets·mm–2 (silicone) and 4,621 ± 1,427 platelets·mm–2 (PET) and differed significantly between the three polymers (ANOVA: p <  0.05). Correlation coefficients between microscopic and colorimetric determination of platelet densities ranged between r = 0.93 (LDH, p <  0.001) and r = 0.94 (ACP, p <  0.001). ACP absorbance measurements of platelet standards with different concentrations corresponded well to an ideal linear regression, while LDH data either deceeded or exceeded the expected values. The LDH release during ADP-induced platelet activation was significantly higher compared to the release of ACP.,CONCLUSION: For an adjusted platelet concentration of 50,000 platelets· μL–1, both colorimetric assays (ACP and LDH) allowed a similar accurate quantification of the mean platelet density compared to the microscopic evaluation. Better linearity of the assay standards, less variability of the results and a lower influence of platelet activation on the measurements mark the ACP assay as more suitable for the assessment of material surface adherent platelets compared to the LDH assay, particularly, if near physiological platelet concentrations are applied. %0 journal article %@ 1465-3249 %A Schwerk, A.,Altschueler, J.,Roch, M.,Gossen, M.,Winter, C.,Berg, J.,Kurtz, A.,Steiner, B. %D 2015 %J Cytotherapy %N 2 %P 199-214 %R doi:10.1016/j.jcyt.2014.09.005 %T Human adipose-derived mesenchymal stromal cells increase endogenous neurogenesis in the rat subventricular zone acutely after 6-hydroxydopamine lesioning %U https://doi.org/10.1016/j.jcyt.2014.09.005 2 %X Background aims,In Parkinson's disease (PD), neurogenesis in the subventricular zone (SVZ)–olfactory bulb (OB) axis is affected as the result of the lack of dopaminergic innervations reaching the SVZ. This aberrant network has been related to the hyposmia of PD patients, which is an early diagnostic marker of the disease. Consequently, much interest arose in finding mechanisms to modulate the SVZ-OB axis. Direct modulation of this axis could be achieved by transplantation of mesenchymal stromal cells (MSC), as it has been shown in rat and mouse PD models. However, the neurogenic effect of MSC in PD was thus far only analyzed weeks after transplantation, and little is known about effects immediately after transplantation.,Methods,We assessed the acute neuroprotective and neurogenic effects of adipose-derived MSC transplanted into the rat substantia nigra in the 6-hydroxydopamine model of PD.,Results,Three days after transplantation, subventricular neurogenesis was significantly increased in MSC-transplanted versus non-transplanted animals. Most MSC were found in the region of the substantia nigra and the surrounding arachnoid mater, expressing S100β and brain-derived neurotrophic factor, whereas some MSC showed an endothelial phenotype and localized around blood vessels.,Conclusions,The acute neurogenic effects and neurotrophic factor expression of MSC could help to restore the SVZ-OB axis in PD. %0 journal article %@ 1386-0291 %A Julich-Gruner, K.K.,Roch, T.,Ma, N.,Neffe, A.T.,Lendlein, A. %D 2015 %J Clinical Hemorheology and Microcirculation %N 1 %P 13-23 %R doi:10.3233/CH-151938 %T Synthesis and characterization of star-shaped oligo(ethylene glycol) with tyrosine derived moieties under variation of their molecular weight %U https://doi.org/10.3233/CH-151938 1 %X Desamino tyrosine (DAT) and desamino tyrosyl tyrosine (DATT) can be used to functionalize the end groups of water soluble polymers. The phenolic groups may enable physical interactions by π– π interaction and hydrogen bonds, which might lead to the formation of a hydrogel by physical crosslinking. However, using star-shaped oligo(ethylene glycols) (sOEG) with a molecular weight of 5 kDa for functionalization with DAT or DATT resulted in the formation of surfactants and not in hydrogels.,As the molecular weight of the sOEG polymer chain can have an influence on forming physical cross links, DAT(T)-fuctionalization of sOEGs with higher molecular weight was investigated, the polymers were structurally characterized and for their mechanical properties were evaluated by rheological measurements.,Aqueous solutions of DAT(T)-sOEGs with 10 and 20 kDa showed lower storage and loss moduli compared to unfunctionalized sOEGs indicating also the formation of surfactants. Cell-based assays showed that all sOEG solutions did not impair cell viability and were free of endotoxins, which could otherwise induce uncontrolled immune responses.,Conclusively, our data suggested that the sOEG solutions have surface active properties without inducing unwanted cellular responses, which is required e.g. in pharmaceutical applications to solubilize hydophobic substances. %0 journal article %@ 1944-8244 %A Hao, X.,Li, Q.,Lv, J.,Yu, L.,Ren, X.,Zhang, L.,Feng, Y.,Zhang, W. %D 2015 %J ACS Applied Materials and Interfaces %N 22 %P 12128-12140 %R doi:10.1021/acsami.5b02399 %T CREDVW-Linked Polymeric Micelles As a Targeting Gene Transfer Vector for Selective Transfection and Proliferation of Endothelial Cells %U https://doi.org/10.1021/acsami.5b02399 22 %X Nowadays, gene transfer technology has been widely used to promote endothelialization of artificial vascular grafts. However, the lack of gene vectors with low cytotoxicity and targeting function still remains a pressing challenge. Herein, polyethylenimine (PEI, 1.8 kDa or 10 kDa) was conjugated to an amphiphilic and biodegradable diblock copolymer poly(ethylene glycol)-b-poly(lactide-co-glycolide) (mPEG-b-PLGA) to prepare mPEG-b-PLGA-g-PEI copolymers with the aim to develop gene vectors with low cytotoxicity while high transfection efficiency. The micelles were prepared from mPEG-b-PLGA-g-PEI copolymers by self-assembly method. Furthermore, Cys-Arg-Glu-Asp-Val-Trp (CREDVW) peptide was linked to micelle surface to enable the micelles with special recognition for endothelial cells (ECs). In addition, pEGFP-ZNF580 plasmids were condensed into these CREDVW-linked micelles to enhance the proliferation of ECs. These CREDVW-linked micelle/pEGFP-ZNF580 complexes exhibited low cytotoxicity by MTT assay. The cell transfection results demonstrated that pEGFP-ZNF580 could be transferred into ECs efficiently by these micelles. The results of Western blot analysis showed that the relative ZNF580 protein level in transfected ECs increased to 76.9%. The rapid migration of transfected ECs can be verified by wound healing assay. These results indicated that CREDVW-linked micelles could be a suitable gene transfer vector with low cytotoxicity and high transfection efficiency, which has great potential for rapid endothelialization of artificial blood vessels. %0 journal article %@ 1438-7492 %A Khan, M.,Yang, J.,Shi, C.,Feng, Y.,Zhang, W.,Gibney, K.,Tew, G.N. %D 2015 %J Macromolecular Materials and Engineering %N 8 %P 802-809 %R doi:10.1002/mame.201500038 %T Surface Modification of Polycarbonate Urethane with Zwitterionic Polynorbornene via Thiol-ene Click-Reaction to Facilitate Cell Growth and Proliferation %U https://doi.org/10.1002/mame.201500038 8 %X Herein, we grafted the zwitterionic polynorbornene onto polycarbonate urethane (PCU) film surface by a convenient route of thiol-ene click-chemistry. The PCU film surface was first treated with hexamethylene-1,6-diisocynate and subsequently with two different thiol agents (l-cysteine and β-marcaptoethanol) in the presence of di-n-butyltin dilaurate (DBTDL) to immobilize sulfhydryl groups onto the surface. Here, DBTDL acted as selective catalyst for the reaction between surface-tethered isocyanates and amine/hydroxyl groups in thiol agents over that of free thiol groups. In the next step, zwitterionic polynorbornene (poly(NSulfoZI)) having functionalizable double bonds was grafted onto these surfaces by photo-initiated thiol-ene click-reaction. The modified surfaces were characterized by water contact angle and XPS analysis. Moreover, the cytocompatibility of these surfaces was investigated by model endothelial cells, EA.hy926, for 1, 3, and 7 d culture times, which showed enhanced cell adhesion and growth. Therefore, the poly(NSulfoZI) functionalized PCU surface using l-cysteine as thiol agent could be a good candidate for tissue engineering material application. %0 journal article %@ 0957-4530 %A Zhou, W.,Feng, Y.,Yang, J.,Fan, J.,Lv, J.,Zhang, L.,Guo, J.,Ren, X.,Zhang, W. %D 2015 %J Journal of Materials Science: Materials in Medicine %N 1 %P 56 %R doi:10.1007/s10856-015-5386-6 %T Electrospun scaffolds of silk fibroin and poly(lactide-co-glycolide) for endothelial cell growth %U https://doi.org/10.1007/s10856-015-5386-6 1 %X Electrospun scaffolds of silk fibroin (SF) and poly(lactide-co-glycolide) (PLGA) were prepared to mimic the morphology and chemistry of the extracellular matrix. The SF/PLGA scaffolds were treated with ethanol to improve their usability. After ethanol treatment the scaffolds exhibited a smooth surface and uniform fibers. SF transformed from random coil conformation to β-sheet structure after ethanol treatment, so that the SF/PLGA scaffolds showed low hydrophilicity and dissolving rate in water. The mechanical properties and the hydrophilicity of the blended fibrous scaffolds were affected by the weight ratio of SF and PLGA. During degradation of ethanol-treated SF/PLGA scaffolds in vitro, the fibers became thin along with the degradation time. Human umbilical vein endothelial cells (HUVECs) were seeded onto the ethanol-treated nanofibrous scaffolds for cell viability, attachment and morphogenesis studies. These SF/PLGA scaffolds could enhance the viability, spreading and attachment of HUVECs. Based on these results, these ethanol-treated scaffolds are proposed to be a good candidate for endothelial cell growth. %0 journal article %@ 2046-2069 %A Khan, M.,Yang, J.,Shi, C.,Feng, Y.,Zhang, W.,Gibney, K.,Tew, G.N. %D 2015 %J RSC Advances %N 15 %P 11284-11292 %R doi:10.1039/c4ra14608e %T Manipulation of polycarbonate urethane bulk properties via incorporated zwitterionic polynorbornene for tissue engineering applications %U https://doi.org/10.1039/c4ra14608e 15 %X Elastomeric crosslinked materials based on polycarbonate urethane (PCU) and zwitterionic polynorbornene were designed by thiol–ene click-chemistry and crosslinking reaction. The zwitterionic polynorbornene poly(NSulfoZI) with functionalisable double bonds was first treated with L-cysteine via thiol–ene click-reaction and subsequently formed a crosslinked structure upon treatment with PCU in the presence of a small amount of hexamethylene-1,6-diisocyanate as a crosslinking agent. The obtained materials possessed improved tensile strength (14–20 MPa) and initial modulus (8–14 MPa). All of these materials showed high breaking strain (εb 740–900%) except the material with a high poly(NSulfoZI) content of 28% (εb 470 ± 80%). The biodegradability of these materials was enhanced compared to blank PCU, as demonstrated by testing in PBS for five weeks. Moreover, the cytocompatibility was studied by MTT assay. The adhesion and proliferation of endothelial cells (EA.hy926) over a one-week period indicated that cell growth on these designed material surfaces was enhanced. Therefore, these zwitterionic polynorbornene-modified PCU-based materials could be suitable candidates for tissue engineering applications. %0 journal article %@ 1944-8244 %A Shi, C.,Li, Q.,Zhang, W.,Feng, Y.,Ren, X. %D 2015 %J ACS Applied Materials and Interfaces %N 36 %P 20389-20399 %R doi:10.1021/acsami.5b06286 %T REDV Peptide Conjugated Nanoparticles/pZNF580 Complexes for Actively Targeting Human Vascular Endothelial Cells %U https://doi.org/10.1021/acsami.5b06286 36 %X Herein, we demonstrate that the REDV peptide modified nanoparticles (NPs) can serve as a kind of active targeting gene carrier to condensate pZNF580 for specific promotion of the proliferation of endothelial cells (ECs). First, we synthesized a series of biodegradable amphiphilic copolymers by ring-opening polymerization reaction and graft modification with REDV peptide. Second, we prepared active targeting NPs via self-assembly of the amphiphilic copolymers using nanoprecipitation technology. After condensation with negatively charged pZNF580, the REDV peptide modified NPs/pZNF580 complexes were formed finally. Due to the binding affinity toward ECs of the specific peptide, these REDV peptide modified NPs/pZNF580 complexes could be recognized and adhered specifically by ECs in the coculture system of ECs and human artery smooth muscle cells (SMCs) in vitro. After expression of ZNF580, as the key protein to promote the proliferation of ECs, the relative ZNF580 protein level increased from 15.7% to 34.8%. The specificity in actively targeting ECs of the REDV peptide conjugated NPs/pZNF580 complexes was still retained in the coculture system. These findings in the present study could facilitate the development of actively targeting gene carriers for the endothelialization of artificial blood vessels. %0 journal article %@ 2050-750X %A Wang, H.,Feng, Y.,Yang, J.,Guo, J.,Zhang, W. %D 2015 %J Journal of Materials Chemistry B %N 16 %P 3379-3391 %R doi:10.1039/c4tb02019g %T Targeting REDV peptide functionalized polycationic gene carrier for enhancing the transfection and migration capability of human endothelial cells %U https://doi.org/10.1039/c4tb02019g 16 %X Targeting gene engineering should be considered as an effective method for promoting endothelialization of vascular grafts. Herein, we developed a targeting REDV peptide functionalized polycationic gene carrier for carrying the pEGFP-ZNF580 plasmid with the aim of enhancing the transfection and migration capability of human endothelial cells. This polycationic gene carrier with the REDV peptide (mPEG-P(LA-co-CL)-PEI-REDV) was prepared by the conjugation of the Cys-Arg-Glu-Asp-Val-Trp (CREDVW) peptide with the amphiphilic block copolymer methoxy poly(ethylene glycol) ether-poly(L-lactide-co-ε-caprolactone)-poly(ethyleneimine) (mPEG-P(LA-co-CL)-PEI). mPEG-P(LA-co-CL)-PEI nanoparticles (NP) and mPEG-P(LA-co-CL)-PEI-REDV nanoparticles (REDV-NP) were formed by the self-assembly of the corresponding polycationic polymers, and then their pEGFP-ZNF580 complexes were prepared via the electrostatic interaction with pEGFP-ZNF580 plasmids, respectively. Gel electrophoresis results show that the targeted REDV-NPs could compress pEGFP-ZNF580 plasmids into stable complexes and protect the plasmids against desoxyribonuclease degradation. MTT assay indicates that these targeted REDV-NP/pEGFP-ZNF580 complexes exhibit better cyto-compatibility than the non-targeted NP/pEGFP-ZNF580 complexes and the control PEI 1800 Da/pEGFP-ZNF580 complexes. In vitro transfection experiments and western blot analysis of EA.hy926 endothelial cells show that the pEGFP-ZNF580 plasmid expression and the relative protein level transfected by targeted REDV-NP/pEGFP-ZNF580 complexes are roughly consistent with that transfected by PEI 25 kDa/pEGFP-ZNF580 complexes. More importantly, the scratch wound assay results demonstrate that the migration capability of EA.hy926 cells has been improved significantly by the expression of the pEGFP-ZNF580 plasmid. Our results indicate that the polycationic polymer with functional REDV peptides can be a potential candidate as a pEGFP-ZNF580 plasmid delivery carrier and may be used in the endothelialization of vascular grafts. %0 journal article %@ 1381-5148 %A Yu, L.,Feng, Y.,Li, Q.,Hao, X.,Liu, W.,Zhou, W.,Shi, C.,Ren, X.,Zhang, W. %D 2015 %J Reactive and Functional Polymers %N %P 19-27 %R doi:10.1016/j.reactfunctpolym.2015.04.003 %T PLGA/SF blend scaffolds modified with plasmid complexes for enhancing proliferation of endothelial cells %U https://doi.org/10.1016/j.reactfunctpolym.2015.04.003 %X Biomimetic scaffolds have been investigated for vascular tissue engineering for many years. However, the design of an ideal biodegradable vascular scaffold is still in progress. The optimization of poly(lactide-co-glycolide)/silk fibroin (PLGA/SF) blend composition was performed to provide the designed scaffolds with adequate mechanical properties and favorable biocompatibility for the intended application. By systematically varying the weight ratio of PLGA and SF, we could control fiber diameter and hydrophilicity as well as mechanical properties of the fibrous scaffolds. These scaffolds with a weight ratio of PLGA/SF at 70/30 exhibited excellent performance, such as tensile strength of 1.5 ± 0.1 MPa, and elongation at break of 77.4 ± 6.4%. Therefore, PLGA/SF scaffold with a weight ratio of 70/30 was chose as the matrix because it matches at best the mechanical demands for application in vascular tissue engineering. In order to promote the endothelialization of electrospun scaffolds, we used pEGFP-ZNF580 plasmid (pZNF580) complexes to modify the electrospun scaffolds by electrospraying technique. pZNF580 complexes were prepared from pZNF580 and microparticles (MPs) of amphiphilic copolymer methoxy-poly(ethylene glycol)-block-poly(3(S)-methyl-2,5-morpholinedione-co-glycolide)-graft-polyethyleneimine. Negatively charged PLGA/SF fibers adsorbed the positively charged MPs via physical deposition and electrostatic force. Scanning electron microscope image indicated the forming of composite scaffold and MPs did not change fiber’s shape and 3-D structure. Cell culture experiments demonstrated that the scaffolds modified with MPs/pZNF580 complexes could promote human umbilical vein endothelial cell growth and inhibit human umbilical artery smooth muscle cell proliferation. Our results indicated that the composite scaffolds with MPs/pZNF580 complexes could be used as a potential scaffold for vascular tissue engineering. %0 journal article %@ 2352-3697 %A Franke, R.P.,Fuhrmann, R.,Krueger, A.,Jung, F. %D 2015 %J Journal of Cellular Biotechnology %N 1 %P 119-130 %R doi:10.3233/JCB-15012 %T Reaction of arterial endothelial cells to stent impression: In vitro study using a model of the human artery wall %U https://doi.org/10.3233/JCB-15012 1 %X Stenoses in arterial blood vessels by artherosclerotic processes can decrease the supply of downstream tissue dramatically. The implantation of stents by percutaneous coronary intervention is one method of choice to restore the physiological blood flow. In some cases in-stent re-stenoses by thrombotic events, vascular wall hyperplasia or endothelial dysfunction occur. Causes and nature underlying this processes are not fully understood.,Aim of the present study was to study the re-stenotic processes after stent impress on a cellular and molecular level in vitro. Therefore, human arterial endothelial cells (HUAEC) were seeded on a model vascular wall intima consisting of extracellular matrix secreted by bovine corneal endothelial cells. Subsequently, a pre-mounted balloon-expendable tubular stent made of 316 L was impressed through the HUAEC layer leading to an impairment of the vessel wall intima. After stent removal the wound healing process, HUAEC membrane integrity, vitality, proliferation and function were assessed.,Immediately after stent impress an increased level of lactate dehydrogenase (LDH) was observed indicating an impairment of the cell membrane integrity. After 24 h baseline LDH values presented again. HUAEC vitality adjacent to the stent impress induced wound was normal (investigated by inverted microscopy). The proliferation of HUAEC was the highest in the direct vicinity of the stent impress induced wound. Prostacyclin and nitric oxide decreased significantly indicating a temporary loss of cell function.,These results could imply that the healing process of the endothelial cell lesion is superior to the maintenance of vascular tonicity and downregulation of platelet aggregation. %0 journal article %@ 1616-5187 %A Bergueiro, J.,Calderon, M. %D 2015 %J Macromolecular Bioscience %N 2 %P 183-199 %R doi:10.1002/mabi.201400362 %T Thermoresponsive Nanodevices in Biomedical Applications %U https://doi.org/10.1002/mabi.201400362 2 %X In the last couple of decades several drug carriers have been tailored on the nanometric scale by taking advantage of new stimuli responsive materials. Thermoresponsive polymers in particular have been extensively employed as stimuli-responsive building blocks that in combination with other environmental-responsive materials allowed the birth of smarter systems that can respond to more than one stimulus. Examples that highlight the different polymers for thermally triggered drug delivery will be described. A special emphasis will be given to the description of novel theranostic nanodevices that combine more than one responsive modality in order to create a local hyperthermia that leads to the polymer phase transition and triggered drug release, cell recognition, and/or appearance of an imaging signal. %0 journal article %@ 0021-9606 %A Yigit, C.,Heyda, J.,Ballauff, M.,Dzubiella, J. %D 2015 %J The Journal of Chemical Physics %N 6 %P 064905 %R doi:10.1063/1.4928078 %T Like-charged protein-polyelectrolyte complexation driven by charge patches %U https://doi.org/10.1063/1.4928078 6 %X We study the pair complexation of a single, highly charged polyelectrolyte (PE) chain (of 25 or 50 monomers) with like-charged patchy protein models (CPPMs) by means of implicit-solvent, explicit-salt Langevin dynamics computer simulations. Our previously introduced set of CPPMs embraces well-defined zero-, one-, and two-patched spherical globules each of the same net charge and (nanometer) size with mono- and multipole moments comparable to those of globular proteins with similar size. We observe large binding affinities between the CPPM and the like-charged PE in the tens of the thermal energy, kBT, that are favored by decreasing salt concentration and increasing charge of the patch(es). Our systematic analysis shows a clear correlation between the distance-resolved potentials of mean force, the number of ions released from the PE, and CPPM orientation effects. In particular, we find a novel two-site binding behavior for PEs in the case of two-patched CPPMs, where intermediate metastable complex structures are formed. In order to describe the salt-dependence of the binding affinity for mainly dipolar (one-patched) CPPMs, we introduce a combined counterion-release/Debye-Hückel model that quantitatively captures the essential physics of electrostatic complexation in our systems. %0 journal article %@ 1744-683X %A Yu, S.,Xu, X.,Yigit, C.,Giet, M.van der,Zidek, W.,Jankowski, J.,Dzubiella, J.,Ballauff, M. %D 2015 %J Soft Matter %N 23 %P 4630-4639 %R doi:10.1039/c5sm00687b %T Interaction of human serum albumin with short polyelectrolytes: A study by calorimetry and computer simulations %U https://doi.org/10.1039/c5sm00687b 23 %X We present a comprehensive study of the interaction of human serum albumin (HSA) with poly(acrylic acid) (PAA; number average degree of polymerization: 25) in aqueous solution. The interaction of HSA with PAA is studied in dilute solution as a function of the concentration of added salt (20–100 mM) and temperature (25–37 °C). Isothermal titration calorimetry (ITC) is used to analyze the interaction and to determine the binding constant and related thermodynamic data. It is found that only one PAA chain is bound per HSA molecule. The free energy of binding ΔGb increases with temperature significantly. ΔGb decreases with increasing salt concentration and is dominated by entropic contributions due to the release of bound counterions. Coarse-grained Langevin computer simulations treating the counterions in an explicit manner are used to study the process of binding in detail. These simulations demonstrate that the PAA chains are bound in the Sudlow II site of HSA. Moreover, ΔGb is calculated from the simulations and found to be in very good agreement with the measured data. The simulations demonstrate clearly that the driving force of binding is the release of counterions in full agreement with the ITC-data. %0 journal article %@ 1520-6106 %A Oberle, M.,Yigit, C.,Angioletti-Uberti, S.,Dzubiella, J.,Ballauff, M. %D 2015 %J The Journal of Physical Chemistry B %N 7 %P 3250-3258 %R doi:10.1021/jp5119986 %T Competitive Protein Adsorption to Soft Polymeric Layers: Binary Mixtures and Comparison to Theory %U https://doi.org/10.1021/jp5119986 7 %X Nanoparticles immersed in biological fluids readily adsorb proteins. The protein corona thus generated on the surface of the particles largely determines their biological fate. Since biological fluids, e.g., blood plasma, contain a large number of proteins, competitive adsorption must be considered. We study the competitive adsorption of lysozyme, cytochrome c, papain, and RNase A onto a soft charged polymeric layer. The experimental data of binary protein mixtures are compared to a theoretical model taking into account electrostatic and hydrophobic interactions between the proteins and the network. The interactions between bound proteins are modeled within a second virial approximation. The model possesses full generality and can be applied to the adsorption of an arbitrary number of protein types. The parameters describing the adsorption of a single protein type are obtained by isothermal titration calorimetry (ITC), while the competitive adsorption of a binary mixture is studied by fluorescence spectroscopy. The competitive adsorption can be predicted from the data related to the adsorption of the single types without adjustable parameters. %0 journal article %@ 1058-2916 %A Boehringer, F.,Jankowski, V.,Gajjala, P.R.,Zidek, W.,Jankowski, J. %D 2015 %J ASAIO Journal %N 1 %P 55-60 %R doi:10.1097/MAT.0000000000000166 %T Release of Uremic Retention Solutes from Protein Binding by Hypertonic Predilution Hemodiafiltration %U https://doi.org/10.1097/MAT.0000000000000166 1 %X Protein-bound uremic retention solutes accumulate in patients suffering from chronic kidney disease, and the removal of these solutes by hemodialysis is hampered. Therefore, we developed a dialysis technique where the protein-bound uremic retention solutes are removed more efficiently under high ionic strength. Protein-bound uremic solutes such as phenylacetic acid, indoxyl sulfate, and p-cresyl sulfate were combined with plasma in the presence of increased ionic strength. The protein integrity of proteins and enzymatic activities were analyzed. In vitro dialysis of albumin solution was performed to investigate the clearance of the bound uremic retention solutes. In vitro hemodiafiltrations of human blood were performed to investigate the influence of increased ionic strength on blood cell survival. The protein-bound fraction of phenylacetic acid, indoxyl sulfate, and p-cresyl sulfate was significantly decreased from 59.4% ± 3.4%, 95.7% ± 0.6%, 96.9% ± 1.5% to 36.4% ± 3.7%, 87.8% ± 0.6%, and 90.8% ± 1.3%, respectively. The percentage of phenylacetic acid, indoxyl sulfate, and p-cresyl sulfate released from protein was 23.0% ± 5.7%, 7.9% ± 1.1%, and 6.1% ± 0.2%, respectively. The clearance during in vitro dialysis was increased by 13.1% ± 3.6%, 68.8% ± 15.1%, and 53.6% ± 10.2%, respectively. There was no difference in NaCl concentrations at the outlet of the dialyzer using isotonic and hypertonic solutions. In conclusion, this study forms the basis for establishing a novel therapeutic approach to remove protein-bound retention solutes. %0 journal article %@ 1420-682X %A Hildebrand, L.,Seemann, P.,Kurtz, A.,Hecht, J.,Contzen, J.,Gossen, M.,Stachelscheid, H. %D 2015 %J Cellular and Molecular Life Sciences %N 23 %P 4671-4680 %R doi:10.1007/s00018-015-1957-4 %T Selective cell targeting and lineage tracing of human induced pluripotent stem cells using recombinant avian retroviruses %U https://doi.org/10.1007/s00018-015-1957-4 23 %X Human induced pluripotent stem cells (hiPSC) differentiate into multiple cell types. Selective cell targeting is often needed for analyzing gene function by overexpressing proteins in a distinct population of hiPSC-derived cell types and for monitoring cell fate in response to stimuli. However, to date, this has not been possible, as commonly used viruses enter the hiPSC via ubiquitously expressed receptors. Here, we report for the first time the application of a heterologous avian receptor, the tumor virus receptor A (TVA), to selectively transduce TVA+ cells in a mixed cell population. Expression of the TVA surface receptor via genetic engineering renders cells susceptible for infection by avian leucosis virus (ALV). We generated hiPSC lines with this stably integrated, ectopic TVA receptor gene that expressed the receptor while retaining pluripotency. The undifferentiated hiPSCTVA+ as well as their differentiating progeny could be infected by recombinant ALV (so-called RCAS virus) with high efficiency. Due to incomplete receptor blocking, even sequential infection of differentiating or undifferentiated TVA+ cells was possible. In conclusion, the TVA/RCAS system provides an efficient and gentle gene transfer system for hiPSC and extends our possibilities for selective cell targeting and lineage tracing studies. %0 journal article %@ 1042-7147 %A Sauter, T.,Geiger, B.,Kratz, K.,Lendlein, A. %D 2015 %J Polymers for Advanced Technologies %N 10 %P 1209-1216 %R doi:10.1002/pat.3583 %T Encasement of metallic cardiovascular stents with endothelial cell-selective copolyetheresterurethane microfibers %U https://doi.org/10.1002/pat.3583 10 %X Cardiovascular metallic stents established in clinical application are typically coated by a thin polymeric layer on the stent struts to improve hemocompatibility, whereby often a drug is added to the coating to inhibit neointimal hyperplasia. Besides such thin film coatings recently nano/microfiber coated stents are investigated, whereby the fibrous coating was applied circumferential on stents. Here, we explored whether a thin fibrous encasement of metallic stents with preferentially longitudinal aligned fibers and different local fiber densities can be achieved by electrospinning. An elastic degradable copolyetheresterurethane, which is reported to selectively enhance the adhesion of endothelial cells, while simultaneously rejecting smooth muscle cells, was utilized for stent coating. The fibrous stent encasements were microscopically assessed regarding their single fiber diameters, fiber covered area and fiber alignment at three characteristic stent regions before and after stent expansion. Stent coatings with thicknesses in the range from 30 to 50 µm were achieved via electrospinning with 1,1,1,3,3,3-hexafluoro-2-propanol (HFP)-based polymer solution, while a mixture of HFP and formic acid as solvent resulted in encasements with a thickness below 5 µm comprising submicron sized single fibers. All polymeric encasements were mechanically stable during expansion, whereby the fibers deposited on the struts remained their position. The observed changes in fiber density and diameter indicated diverse local deformation mechanisms of the microfibers at the different regions between the struts. Based on these results it can be anticipated that the presented fibrous encasement of stents might be a promising alternative to stents with polymeric strut coatings releasing anti-proliferative drugs. %0 journal article %@ 1022-1336 %A Schoene, A.-C.,Richau, K.,Kratz, K.,Schulz, B.,Lendlein, A. %D 2015 %J Macromolecular Rapid Communications %N 21 %P 1910-1915 %R doi:10.1002/marc.201500316 %T Influence of Diurethane Linkers on the Langmuir Layer Behavior of Oligo[(rac-lactide)-co-glycolide]-based Polyesterurethanes %U https://doi.org/10.1002/marc.201500316 21 %X Three oligo[(rac-lactide)-co-glycolide] based polyesterurethanes (OLGA-PUs) containing different diurethane linkers are investigated by the Langmuir monolayer technique and compared to poly[(rac-lactide)-co-glycolide] (PLGA) to elucidate the influence of the diurethane junction units on hydrophilicity and packing motifs of these polymers at the air–water interface. The presence of diurethane linkers does not manifest itself in the Langmuir layer behavior both in compression and expansion experiments when monomolecular films of OLGA-PUs are spread on the water surface. However, the linker retard the evolution of morphological structures at intermediate compression level under isobaric conditions (with a surface pressure greater than 11 mN m−1) compared to the PLGA, independent on the chemical structure of the diurethane moiety. The layer thicknesses of both OLGA-PU and PLGA films decrease in the high compression state with decreasing surface pressure, as deduced from ellipsometric data. All films must be described with the effective medium approximation as water swollen layers. %0 journal article %@ 0021-9797 %A Seiffert, S.,Friess, F.,Lendlein, A.,Wischke, C. %D 2015 %J Journal of Colloid and Interface Science %N %P 38-42 %R doi:10.1016/j.jcis.2015.04.017 %T Faster Droplet Production by Delayed Surfactant-Addition in Two-Phase Microfluidics to form Thermo-Sensitive Microgels %U https://doi.org/10.1016/j.jcis.2015.04.017 %X Microfluidic droplet templating produces monodisperse particles of well controllable sizes, but this is limited by the necessity to operate microfluidic devices at low flow rates in the dripping regime. Here, the per-channel rate of droplet production could be substantially increased by delayed surfactant addition as applied and verified for microfluidic production of N-isopropylacrylamide based microgels. %0 journal article %@ 2050-7488 %A Noechel, U.,Reddy, C.S.,Wang, K.,Cui, J.,Zizak, I.,Behl, M.,Kratz, K.,Lendlein, A. %D 2015 %J Journal of Materials Chemistry A %N 16 %P 8284-8293 %R doi:10.1039/C4TA06586G %T Nanostructural changes in crystallizable controlling units determine the temperature-memory of polymers %U https://doi.org/10.1039/C4TA06586G 16 %X Temperature-memory polymers remember the temperature, where they were deformed recently, enabled by broad thermal transitions. In this study, we explored a series of crosslinked poly[ethylene-co-(vinyl acetate)] networks (cPEVAs) comprising crystallizable polyethylene (PE) controlling units exhibiting a pronounced temperature-memory effect (TME) between 16 and 99 °C related to a broad melting transition ([similar]100 °C). The nanostructural changes in such cPEVAs during programming and activation of the TME were analyzed via in situ X-ray scattering and specific annealing experiments. Different contributions to the mechanism of memorizing high or low deformation temperatures (Tdeform) were observed in cPEVA, which can be associated to the average PE crystal sizes. At high deformation temperatures (>50 °C), newly formed PE crystals, which are established during cooling when fixing the temporary shape, dominated the TME mechanism. In contrast, at low Tdeform (<50 °C), corresponding to a cold drawing scenario, the deformation led preferably to a disruption of existing large crystals into smaller ones, which then fix the temporary shape upon cooling. The observed mechanism of memorizing a deformation temperature might enable the prediction of the TME behavior and the knowledge based design of other TMPs with crystallizable controlling units. %0 journal article %@ 1022-1336 %A Saatchi, M.,Behl, M.,Noechel, U.,Lendlein, A. %D 2015 %J Macromolecular Rapid Communications %N 10 %P 880-884 %R doi:10.1002/marc.201400729 %T Copolymer Networks From Oligo(Epsilon-caprolactone) and n-Butyl Acrylate Enable a Reversible Bidirectional Shape-Memory Effect at Human Body Temperature %U https://doi.org/10.1002/marc.201400729 10 %X Exploiting the tremendous potential of the recently discovered reversible bidirectional shape-memory effect (rbSME) for biomedical applications requires switching temperatures in the physiological range. The recent strategy is based on the reduction of the melting temperature range (ΔT m) of the actuating oligo(ε-caprolactone) (OCL) domains in copolymer networks from OCL and n-butyl acrylate (BA), where the reversible effect can be adjusted to the human body temperature. In addition, it is investigated whether an rbSME in the temperature range close or even above Tm,offset (end of the melting transition) can be obtained. Two series of networks having mixtures of OCLs reveal broad ΔTms from 2 °C to 50 °C and from −10 °C to 37 °C, respectively. In cyclic, thermomechanical experiments the rbSME can be tailored to display pronounced actuation in a temperature interval between 20 °C and 37 °C. In this way, the application spectrum of the rbSME can be extended to biomedical applications. %0 journal article %@ 0378-5173 %A Staufenbiel, S.,Merino, M.,Li, W.,Huang, M.-D.,Baudis, S.,Lendlein, A.,Mueller, R.H.,Wischke, C. %D 2015 %J International Journal of Pharmaceutics %N 1-2 %P 87-96 %R doi:10.1016/j.ijpharm.2015.02.072 %T Surface characterization and protein interaction of a series of model poly[acrylonitrile-co-(N-vinyl pyrrolidone)] nanocarriers for drug targeting %U https://doi.org/10.1016/j.ijpharm.2015.02.072 1-2 %X The surface properties of intravenously injected nanoparticles determine the acquired blood protein adsorption pattern and subsequently the organ distribution and cellular recognition. A series of poly[acrylonitrile-co-(N-vinyl pyrrolidone)] (PANcoNVP) model nanoparticles (133–181 nm) was synthesized, in which the surface properties were altered by changing the molar content of NVP (0–33.8 mol%) as the more hydrophilic repeating unit. The extent of achieved surface property variation was comprehensively characterized. The residual sodium dodecyl sulfate (SDS) content from the synthesis was in the range 0.3–1.6 μg ml−1, potentially contributing to the surface properties. Surface hydrophobicity was determined by Rose Bengal dye adsorption, hydrophobic interaction chromatography (HIC) and aqueous two-phase partitioning (TPP). Particle charge was quantified by zeta potential (ZP) measurements including ZP–pH profiles. The interaction with proteins was analyzed by ZP measurements in serum and by adsorption studies with single proteins. Compared to hydrophobic polystyrene model nanoparticles, all PANcoNVP particles were very hydrophilic. Differences in surface hydrophobicity could be detected, which did not linearly correlate with the systematically altered bulk composition of the PANcoNVP nanoparticles. This proves the high importance of a thorough surface characterization applying a full spectrum of methods, complementing predictions solely based on bulk polymer composition. %0 journal article %@ 1751-6161 %A Guglielmi, P.O.,Herbert, E.G.,Tartivel, L.,Behl, M.,Lendlein, A.,Huber, N.,Lilleodden, E.T. %D 2015 %J Journal of the Mechanical Behavior of Biomedical Materials %N %P 1-10 %R doi:10.1016/j.jmbbm.2015.02.009 %T Mechanical characterization of oligo(ethylene glycol)-based hydrogels by dynamic nanoindentation experiments %U https://doi.org/10.1016/j.jmbbm.2015.02.009 %X Oligo(ethylene glycol)-based (OEG) hydrogel samples of varying cross-link densities and degrees of swelling were characterized through dynamic nanoindentation testing. Experiments were performed using a non-standard nanoindentation method, which was validated on a standard polystyrene sample. This method maximizes the capability of the instrument to measure the stiffness and damping of highly compliant, viscoelastic materials. Experiments were performed over the frequency range of 1 to 50 Hz, using a 1 mm diameter flat punch indenter. A hydration method was adopted to avoid sample dehydration during testing. Values of storage modulus (E′)(E′) ranged from 3.5 to 8.9 MPa for the different OEG-hydrogel samples investigated. Samples with higher OEG concentrations showed greater scatter in the modulus measurements and it is attributed to inhomogeneities in these materials. The (E′)(E′) values did not show a strong variation over frequency for any of the samples. Values of loss modulus (E″)(E″) were two orders of magnitude lower than the storage modulus, resulting in very low values of loss factor (E″/E′E″/E′<0.1). These are characteristics of strong gels, which present negligible viscous properties. %0 journal article %@ 1386-0291 %A Yan, W.,Fang, L.,Heuchel, M.,Kratz, K.,Lendlein, A. %D 2015 %J Clinical Hemorheology and Microcirculation %N 1 %P 109-120 %R doi:10.3233/CH-151940 %T Modeling of stress relaxation of a semi-crystalline multiblock copolymer and its deformation behavior %U https://doi.org/10.3233/CH-151940 1 %X Stress relaxation can strongly influence the shape-memory capability of polymers. Recently a modified Maxwell-Wiechert model comprising two Maxwell units and single spring unit in parallel has been introduced to successfully describe the shape recovery characteristics of amorphous polyether urethanes. In this work we explored whether such a modified Maxwell-Wiechert model is capable to describe the stress relaxation behavior of a semi-crystalline multiblock copolymer named PCL-PIBMD, which consists of crystallizable poly(ε-caprolactone) (PCL) segments and crystallizable poly(3S-isobutylmorpholine-2,5-dione) (PIBMD) segments. The stress relaxation behavior of PCL-PIBMD was explored after uniaxial deformation to different strains ranging from 50 to 900% with various strain rates of 1 or 10 or 50 mm·min−1. The modeling results indicated that under the assumption that in PCL-PIBMD both PCL and PIBMD blocks have narrow molecular weight distributions and are arranged in sequence, the two relaxation processes can be related to the amorphous PCL and PIBMD domains and the spring element can be associated to the PIBMD crystalline domains. The first Maxwell unit representing the faster relaxation process characterized by the modulus E1 and the relaxation time τ1 is related to the amorphous PCL domains (which are in the rubbery state), while the second Maxwell unit (E2 ;τ2) represents the behavior of the amorphous PIBMD domains, which are in the glassy state at 50°C. Increasing strain rates resulted in an increase of E1 and a significantly reduction in τ1, whereas the elastic modulus as well as the relaxation time related to the amorphous PIBMD domains remained almost constant. When a higher deformation was applied (ε ≥ 200%) lower values for the elastic moduli of the three model elements were obtained. In general the applied model was also capable to describe the relaxation behavior of PCL-PIBMD at a deformation temperature of 20°C, where additional crystalline PCL domains are existent. The presented approach using a modified Maxwell-Wiechert model to analyze the stress relaxation behavior can be useful to understand the changes in structure-function relation of amorphous as well as semi-crystalline polymers occurring during its uniaxial deformation. %0 journal article %@ 1386-0291 %A Roch, T.,Ma, N.,Kratz, K.,Lendlein, A. %D 2015 %J Clinical Hemorheology and Microcirculation %N 1 %P 51-63 %R doi:10.3233/CH-151939 %T Cell-based detection of microbial biomaterial contaminations %U https://doi.org/10.3233/CH-151939 1 %X A major challenge in biomaterial synthesis and functionalization is the prevention of microbial contaminations such as endotoxins (lipopolysaccharides (LPS)). In addition to LPS, which are exclusively expressed by Gram negative bacteria, also other microbial products derived from fungi or Gram positive bacteria can be found as contaminations in research laboratories. Typically, the Limulus amebocyte lysate (LAL)-test is used to determine the endotoxin levels of medical devices. However, this test fails to detect material-bound LPS and other microbial contaminations and, as demonstrated in this study, detects LPS from various bacterial species with different sensitivities. In this study a cell-based assay using genetically engineered RAW macrophages, which detect not only soluble but also material-bound microbial contaminations is introduced. The sensitivity of this cell-line towards different LPS species and different heat-inactivated microbes was investigated. As proof of principle a soft hydrophobic poly(n-butyl acrylate) network (cPnBA), which may due to adhesive properties strongly bind microbes, was deliberately contaminated with heat-inactivated bacteria. While the LAL-test failed to detect the microbial contamination, the cell-based assay clearly detected material-bound microbial contaminations. Our data demonstrate that a cell-based detection system should routinely be used as supplement to the LAL-test to determine microbial contaminations of biomaterials. %0 journal article %@ 0032-3861 %A Heuchel, M.,Razzaq, M.Y.,Kratz, K.,Behl, M.,Lendlein, A. %D 2015 %J Polymer %N %P 215-222 %R doi:10.1016/j.polymer.2015.03.063 %T Modeling the heat transfer in magneto-sensitive shape-memory polymer nanocomposites with dynamically changing surface area to volume ratios %U https://doi.org/10.1016/j.polymer.2015.03.063 %X Magneto-sensitive shape-memory polymer nanocomposites (SMPNCs) enable non-contact actuation of a shape-memory effect (SME) by inductive heating in an alternating magnetic field (AMF). Hereby, the achievable temperature (Tmax) at fixed magnetic field strength (H) and frequency is depending on the amount and type of incorporated magnetic fillers as well as on surface area to volume (S/V) ratio of the test specimen.,Here we present a heat transfer model for predicting Tmax of SMPNCs samples with different S/V ratios when exposed to an AMF. The obtained temperature difference between sample and surrounding in an AMF of constant magnetic field strength decreases at uni-axial deformation with the square root of the stretching ratio. The model was validated with magnetically heating experiments of two different SMPNC systems (comprising crystallizable or amorphous switching segments) containing the same magnetic nanoparticles, while H was varied from 7 to 27 kA m−1 at a fixed frequency of 258 kHz. The experimentally achieved temperatures at deformations up to 50% could be predicted with a divergence below 6%. Finally the model was applied in a principle design study of a device consisting of a rolled SMPNC stripe, which was stepwise opened by increasing H. The modeling approach might be helpful to predict the temperature profiles of SMPNCs which were heated by other mechanisms, e.g., radiofrequency or near IR. %0 journal article %@ 1753-9447 %A Gori, T.,Wild, P.S.,Schnabel, R.,Schulz, A.,Pfeiffer, N.,Blettner, M.,Beutel, M.E.,Forconi, S.,Jung, F.,Lackner, K.J.,Blankenberg, S.,Muenzel, T. %D 2015 %J Therapeutic Advances in Cardiovascular Disease %N 6 %P 354-365 %R doi:10.1177/1753944715589887 %T The distribution of whole blood viscosity, its determinants and relationship with arterial blood pressure in the community: cross-sectional analysis from the Gutenberg Health Study %U https://doi.org/10.1177/1753944715589887 6 %X Background: Blood viscosity has a role in modulating cardiovascular homeostasis; changes in this parameter have been associated with cardiovascular mortality and morbidity. However, it remains unclear whether these changes are (1) involved in the pathophysiology of disease, (2) an epiphenomenon, or (3) the expression of counterregulatory mechanisms. We report data on the normal values of blood viscosity and its association with cardiovascular risk factors, prevalent cardiovascular disease, and blood pressure in a large population-based cohort study.,Methods and results: Viscosity was calculated using validated formulae and its associations were explored in 15,010 participants (mean 55.0, min–max: 35–74 years old; 49.5% women) from the Gutenberg Health Study as well as in a subgroup of 3223 subjects (61.1% women, mean age 49.2, min–max 35–74 years old) without risk factors or self-reported cardiovascular disease. Age- and gender-adjusted mean values for viscosity were defined. Regression models showed a relationship between classical risk factors and blood viscosity measures; the overall R 2 of the multiple linear regression model was however as low as 0.067 and 0.049 for high and low shear stress viscosity, respectively. After correction for cardiovascular risk factors, there was a very mild association between viscosity and prevalent coronary artery disease and heart failure. Systolic, mean and diastolic blood pressure increased with increasing blood viscosity after correction for age and gender.,Conclusions: We provide reference values for viscosity in a population-based cohort. Blood viscosity decreases in older subjects and shows a very mild association with cardiovascular risk factors and prevalent disease in our cohort. There is a linear positive association between viscosity and blood pressure. %0 journal article %@ 0935-9648 %A Neffe, A.T.,Pierce, B.F.,Tronci, G.,Ma, N.,Pittermann, E.,Gebauer, T.,Frank, O.,Schossig, M.,Xu, X.,Willie, B.M.,Forner, M.,Ellinghaus, A.,Lienau, J.,Duda, G.N.,Lendlein, A. %D 2015 %J Advanced Materials %N 10 %P 1738-1744 %R doi:10.1002/adma.201404787 %T One Step Creation of Multifunctional 3D Architectured Hydrogels Inducing Bone Regeneration %U https://doi.org/10.1002/adma.201404787 10 %X Structured hydrogels showing form stability and elastic properties individually tailorable on different length scales are accessible in a one-step process. They support cell adhesion and differentiation and display growing pore size during degradation. In vivo experiments demonstrate their efficacy in biomaterial-induced bone regeneration, not requiring addition of cells or growth factors. %0 journal article %@ 1438-7492 %A Zhang, Q.,Sauter, T.,Fang, L.,Kratz, K.,Lendlein, A. %D 2015 %J Macromolecular Materials and Engineering %N 5 %P 522-530 %R doi:10.1002/mame.201400267 %T Shape-Memory Capability of Copolyetheresterurethane Microparticles Prepared via Electrospraying %U https://doi.org/10.1002/mame.201400267 5 %X Multifunctional thermo-responsive and degradable microparticles exhibiting a shape-memory effect (SME) have attracted widespread interest in biomedicine as switchable delivery vehicles or microactuators. In this work almost spherical solid microparticles with an average diameter of 3.9 ± 0.9 μm are prepared via electrospraying of a copolyetheresterurethane named PDC, which is composed of crystallizable oligo(p-dioxanone) (OPDO) hard and oligo(ε-caprolactone) (OCL) switching segments. The PDC microparticles are programmed via compression at different pressures and their shape-memory capability is explored by off-line and online heating experiments. When a low programming pressure of 0.2 MPa is applied a pronounced thermally-induced shape-memory effect is achieved with a shape recovery ratio about 80%, while a high programming pressure of 100 MPa resulted in a weak shape-memory performance. Finally, it is demonstrated that an array of PDC microparticles deposited on a polypropylene (PP) substrate can be successfully programmed into a smart temporary film, which disintegrates upon heating to 60 °C. %0 journal article %@ 1386-0291 %A Krueger, A.,Fuhrmann, R.,Jung, F.,Franke, R.-P. %D 2015 %J Clinical Hemorheology and Microcirculation %N 1 %P 153-161 %R doi:10.3233/CH-151943 %T Influence of the coating with extracellular matrix and the number of cell passages on the endothelialization of a polystyrene surface %U https://doi.org/10.3233/CH-151943 1 %X The proper morphology and function of the vascular endothelium are prerequisites for a sufficient supply of the tissues. Endothelial cell (EC) dysfunction can lead to circulatory disorders and the development of cardiovascular diseases. The endothelialization of cardiovascular implants is a sophisticated task since EC miss their natural environment and physiological stimuli in vitro. In addition, different studies revealed that the EC behavior and morphology depended on the substrate and the passage number of the EC. Therefore, the comparison of endothelialization studies is very difficult, when passage and substrate are unknown. The aim of this study was to investigate the growth potential and cell morphology of human venous endothelial cells (HUVEC) as a function of different cell passages and different substrates (pristine polystyrene, tissue-typical ECM-coated polystyrene). The study revealed that HUVEC morphology and growth potential were significantly different on pristine polystyrene compared to the basal lamina-like ECM-coated polystyrene surface. Furthermore, it became obvious that the passage of the cells affected the endothelialization of the polystyrene surface significantly. In conclusion, this study emphasized the need for a critical consideration of EC data whereas a simple comparison of results is not possible if EC age and passage is unknown. %0 journal article %@ 0306-0012 %A Ren, X.,Feng, Y.,Guo, J.,Wang, H.,Li, Q.,Yang, J.,Hao, X.,Lv, J.,Ma, N.,Li, W. %D 2015 %J Chemical Society Reviews %N 15 %P 5680-5742 %R doi:10.1039/c4cs00483c %T Surface modification and endothelialization of biomaterials as potential scaffolds for vascular tissue engineering applications %U https://doi.org/10.1039/c4cs00483c 15 %X Surface modification and endothelialization of vascular biomaterials are common approaches that are used to both resist the nonspecific adhesion of proteins and improve the hemocompatibility and long-term patency of artificial vascular grafts. Surface modification of vascular grafts using hydrophilic poly(ethylene glycol), zwitterionic polymers, heparin or other bioactive molecules can efficiently enhance hemocompatibility, and consequently prevent thrombosis on artificial vascular grafts. However, these modified surfaces may be excessively hydrophilic, which limits initial vascular endothelial cell adhesion and formation of a confluent endothelial lining. Therefore, the improvement of endothelialization on these grafts by chemical modification with specific peptides and genes is now arousing more and more interest. Several active peptides, such as RGD, CAG, REDV and YIGSR, can be specifically recognized by endothelial cells. Consequently, graft surfaces that are modified by these peptides can exhibit targeting selectivity for the adhesion of endothelial cells, and genes can be delivered by targeting carriers to specific tissues to enhance the promotion and regeneration of blood vessels. These methods could effectively accelerate selective endothelial cell recruitment and functional endothelialization. In this review, recent developments in the surface modification and endothelialization of biomaterials in vascular tissue engineering are summarized. Both gene engineering and targeting ligand immobilization are promising methods to improve the clinical outcome of artificial vascular grafts. %0 journal article %@ 1946-4274 %A Stoermann, F.,Wischke, C.,Lendlein, A. %D 2015 %J MRS Online Proceedings Library %N %P 95-100 %R doi:10.1557/opl.2015.494 %T Photo-Reversibility of Cinnamylidene Acetic Acid Derived Crosslinks in Poly(ε-caprolactone) Networks %U https://doi.org/10.1557/opl.2015.494 %X Photoswitchable polymeric materials comprise moieties that undergo light-induced chemical reactions or conformational alteration. The reversibility of photo-responsive molecular switches has an influence on material functions observed on the macroscopic level such as reversibility of shape switching, especially with regard to the number of cycles. Cinnamylidene acetic acid (CAA) has received attention due to its reversible dimerization by [2+2] cycloaddition reactions. In the present study, possible side-reactions during photo-scission of the CAA dimers as netpoints in poly(ε-caprolactone) based materials were studied by fluorescence spectroscopy, HPLC and 1H,1H-COSY. Liberation of fluorescent fragments, which have their origin in the various dimer structures, could only be found in small amounts, while a non-identified species seems to be generated during dimerization and photo-scission. The results furthermore suggest that CAA-based switches in PCL-networks do not provide full reversibility of netpoint formation under the examined conditions, due to non-selective side-reactions, which could lead to an attenuation of the macroscopic effect in multiple photo-cycles. In perspective, the design of CAA derivatives with enhanced photo-reversibility should be targeted. %0 journal article %@ 1022-1336 %A Vukicevic, R.,Neffe, A.T.,Luetzow, K.,Pierce, B.F.,Lendlein, A. %D 2015 %J Macromolecular Rapid Communications %N 21 %P 1891-1896 %R doi:10.1002/marc.201500311 %T Conditional Ultrasound Sensitivity of Poly[(N-isopropylacrylamide)-co-(vinyl imidazole)] Microgels for Controlled Lipase Release %U https://doi.org/10.1002/marc.201500311 21 %X Triggering the release of cargo from a polymer network by ultrasonication as an external, noninvasive stimulus can be an interesting concept for on-demand release. Here, it is shown that, in pH- and thermosensitive microgels, the ultrasound sensitivity of the polymer network depends on the external conditions. Crosslinked poly[(N-isopropylacrylamide)-co-(vinyl imidazole)] microgels showed a volume phase transition temperature (VPTT) of 25–50 °C, which increases with decreasing pH. Above the VPTT the polymer chains are collapsed, while below VPTT they are extended. Only in the case of maximum observed swelling, where the polymer chains are expanded, the microgels are mechanically fragmented through ultrasonication. In contrast, when the polymer chains are partially collapsed it is not possible to manipulate the microgels by ultrasound. Additionally, the ultrasound-induced on-demand release of wheat germ lipase from the microgels could be demonstrated successfully. The principle of conditional ultrasound sensitivity is likely to be general and can be used for selection of matrix–cargo combinations. %0 journal article %@ 0044-8249 %A Federico, S.,Pierce, B.F.,Piluso, S.,Lendlein, A.,Neffe, A.T. %D 2015 %J Angewandte Chemie %N 37 %P 11131-11135 %R doi:10.1002/ange.201505227 %T Design von Decorin-basierten Peptiden, die an Kollagen I binden, und ihr Potenzial als Adhaesionssequenzen in Biomaterialien %U https://doi.org/10.1002/ange.201505227 37 %X Das Nachbilden der Bindungsepitope von Protein-Protein-Wechselwirkungen mithilfe kleiner Peptide ist wichtig bei der Entwicklung modularer biomimetischer Systeme. Hier beschreiben wir eine Strategie zum Design solcher bioaktiver Peptide, ohne dass Strukturdaten des Proteinkomplexes benötigt werden, und weisen den Effekt der Inkorporierung solcher Adhäsionssequenzen in komplexen Biomaterialsystemen nach. Dazu wurde die hochrepetitive Struktur von Decorin analysiert. Für dessen innere sowie äußere Oberfläche wurden repräsentative Peptide identifiziert und synthetisiert. Nur Peptide auf Basis der inneren Oberfläche binden an Kollagen. Das Peptid mit der höchsten Bindungsaffinität für Kollagen I führte zu einer geringeren Diffusionsgeschwindigkeit eines gekuppelten Farbstoffs in einem Kollagengel. Dimere des Peptids ermöglichten eine physikalische Vernetzung von Kollagen, wodurch der Speichermodul eines Gels stark erhöht werden konnte. Dies belegt das Potenzial der Peptide für das Design von Biomaterialien für die regenerative Medizin. %0 journal article %@ 1788-618X %A Yan, W.,Fang, L.,Noechel, U.,Kratz, K.,Lendlein, A. %D 2015 %J eXPRESS Polymer Letters %N 7 %P 624-635 %R doi:10.3144/expresspolymlett.2015.58 %T Influence of deformation temperature on structural variation and shape-memory effect of a thermoplastic semi-crystalline multiblock copolymer %U https://doi.org/10.3144/expresspolymlett.2015.58 7 %X A multiblock copolymer termed as PCL-PIBMD, consisting of crystallizable poly(!-caprolactone) (PCL) segments,and crystallizable poly(3S-isobutyl-morpholine-2,5-dione) (PIBMD) segments, has been reported as a material,showing a thermally-induced shape-memory effect. While PIBMD crystalline domains act as netpoints to determine the,permanent shape, both PCL crystalline domains and PIBMD amorphous domains, which have similar transition temperatures,(Ttrans) can act as switching domains. In this work, the influence of the deformation temperature (Tdeform = 50 or 20°C),,which was above or below Ttrans, on the structural changes of PCL-PIBMD during uniaxial deformation and the shapememory,properties were investigated. Furthermore, the relative contribution of crystalline PCL and PIBMD amorphous,phases to the fixation of the temporary shape were distinguished by a toluene vapor treatment approach. The results indicated,that at 50°C, both PCL and PIBMD amorphous phases can be orientated during deformation, resulting in thermallyinduced,crystals of PCL domains and joint contribution to the switching domains. In contrast at 20°C, the temporary shape,was mainly fixed by PCL crystals generated via strain-induced crystallization. %0 journal article %@ 2161-1653 %A Di Lorenzo, F.,Hellwig, J.,Klitzing, R.von,Seiffert, S. %D 2015 %J ACS Macro Letters %N 7 %P 698-703 %R doi:10.1021/acsmacrolett.5b00228 %T Macroscopic and Microscopic Elasticity of Heterogeneous Polymer Gels %U https://doi.org/10.1021/acsmacrolett.5b00228 7 %X Polymer-network gels often exhibit local defects and spatial heterogeneity of their cross-linking density, which may differently affect their elasticity on microscopic and macroscopic scales. To appraise this effect, we prepare polymeric gels with defined extents of nanostructural heterogeneity and use atomic force microscopy to probe their local microscopic Young’s moduli in comparison to their macroscopic elastic moduli measured by shear rheology. In this comparison, the moduli of the heterogeneous gels are found to be progressively smaller if the length scale of the probed gel region exceeds the size of the purposely imparted polymer-network heterogeneities. This finding can be explained with a conceptual picture of nonaffine deformation of the densely cross-linked polymer network domains in the heterogeneous gels. %0 journal article %@ 0939-6411 %A Mathew, S.,Baudis, S.,Neffe, A.T.,Behl, M.,Wischke, C.,Lendlein, A. %D 2015 %J European Journal of Pharmaceutics and Biopharmaceutics A %N %P 18-26 %R doi:10.1016/j.ejpb.2015.03.025 %T Effect of diisocyanate linkers on the degradation characteristics of copolyester urethanes as potential drug carrier matrices %U https://doi.org/10.1016/j.ejpb.2015.03.025 %X In this study, the effect of three aliphatic diisocyanate linkers, L-lysine diisocyanate ethyl ester (LDI), hexamethylene diisocyanate (HDI), and racemic 2,2,4-/2,4,4-trimethyl hexamethylene diisocyanate (TMDI), on the degradation of oligo[(rac-lactide)-co-glycolide] (64:36 mol%) based polyester urethanes (PEU) was examined. Samples were characterized for their molecular weight, mass loss, water uptake, sequence structure, and thermal and mechanical properties. Compared to non-segmented PLGA, the PEU showed higher water uptake and generally degraded faster. Interestingly, the rate of degradation was not directly correlating with the hydrophilicity of the diisocyanate moieties; instead, competing intra-/intermolecular hydrogen bonds in between urethane moieties appear to substantially decrease the rate of degradation for LDI-derived PEU. By comparing microparticles (μm) and films (mm) as matrices of different dimensions, it was shown that autocatalysis remains a contributor to degradation of the larger-sized PEU matrices as it is typical for non-segmented lactide/glycolide copolymers. The shown capacity of lactide/glycolide-based multiblock copolymers to degrade faster than PLGA and exhibit improved elastic properties could be of interest for medical implants and drug release systems. %0 journal article %@ 1386-0291 %A Fang, L.,Wischke, C.,Kratz, K.,Lendlein, A. %D 2015 %J Clinical Hemorheology and Microcirculation %N 1 %P 77-87 %R doi:10.3233/CH-151934 %T Influence of film thickness on the crystalline morphology of a copolyesterurethane comprising crystallizable poly(Epsilon-caprolactone) soft segments %U https://doi.org/10.3233/CH-151934 1 %X BACKGROUND: In this work a model approach to investigate changes in crystalline morphology during heating/cooling procedures in the context of programming and induction of the shape-memory effect is presented. OBJECTIVE AND METHOD: Atomic-force microscopy (AFM) was performed to investigate the variations in poly(ε-caprolactone) (PCL) crystalline morphology in nm thin films on a silicon substrate and a film with 20 μm thickness, prepared from a copolyesterurethane (named PDLCL) consisting of crystallizable poly(ω-pentadecalactone) (PPDL) hard segments and crystallizable PCL segments forming switching domains. RESULTS: PCL crystals in switching domains melted/recrystallized repeatedly during heating/cooling cycles between 20 and 70°C, while evident variation in PPDL crystals forming hard domains remained was not observed. When film thickness was 20 nm, PCL edge-on lamellae were observed, confined in the phase-separated morphology, while flat-on PCL lamellae, which broke out from the previous phase-separated morphology, were obtained at a film thickness of 170 nm. In contrast, large PCL spherulites were observed in the 20 μm thick film. CONCLUSION: PCL crystalline morphology in PDLCL as well as the competition between crystallization and phase separation can be tailored by the film thickness and the substrate. Such AFM investigations on thin films can be a helpful approach for predicting the crystal morphology in micro-/nanoscaled objects. %0 journal article %@ 0928-4931 %A Shi, C.,Yuan, W.,Khan, M.,Li, Q.,Feng, Y.,Yao, F.,Zhang, W. %D 2015 %J Materials Science and Engineering C %N %P 201-209 %R doi:10.1016/j.msec.2015.02.015 %T Hydrophilic PCU scaffolds prepared by grafting PEGMA and immobilizing gelatin to enhance cell adhesion and proliferation %U https://doi.org/10.1016/j.msec.2015.02.015 %X Gelatin contains many functional motifs which can modulate cell specific adhesion, so we modified polycarbonate urethane (PCU) scaffold surface by immobilization of gelatin. PCU-g-gelatin scaffolds were prepared by direct immobilizing gelatins onto the surface of aminated PCU scaffolds. To increase the immobilization amount of gelatin, poly(ethylene glycol) methacrylate (PEGMA) was grafted onto PCU scaffolds by surface initiated atom transfer radical polymerization. Then, following amination and immobilization, PCU-g-PEGMA-g-gelatin scaffolds were obtained.,Both modified scaffolds were characterized by chemical and biological methods. After immobilization of gelatin, the microfiber surface became rough, but the original morphology of scaffolds was maintained successfully. PCU-g-PEGMA-g-gelatin scaffolds were more hydrophilic than PCU-g-gelatin scaffolds. Because hydrophilic PEGMA and gelatin were grafted and immobilized onto the surface, the PCU-g-PEGMA-g-gelatin scaffolds showed low platelet adhesion, perfect anti-hemolytic activity and excellent cell growth and proliferation capacity. It could be envisioned that PCU-g-PEGMA-g-gelatin scaffolds might have potential applications in tissue engineering artificial scaffolds. %0 journal article %@ 2050-750X %A Yang, J.,Khan, M.,Zhang, L.,Ren, X.,Guo, J.,Feng, Y.,Wei, S.,Zhang, W. %D 2015 %J Journal of Materials Chemistry B %N 39 %P 7682-7697 %R doi:10.1039/c5tb01155h %T Antimicrobial surfaces grafted random copolymers with REDV peptide beneficial for endothelialization %U https://doi.org/10.1039/c5tb01155h 39 %X Polycarbonate urethane (PCU) elastomeric materials have been developed for vascular prosthesis applications, because of their excellent mechanical and physical properties. However, thrombosis and inflammation often limit their usage as small-diameter vascular grafts. Herein, we focused on the design and functionalization of a PCU elastomer with enhanced hemocompatibility, rapid endothelialization and antimicrobial properties. An atom transfer radical polymerization (ATRP) technique was utilized to graft random copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA) and eugenyl methacrylate (EgMA) onto a PCU surface, and subsequently the cysteine-terminated CREDV peptide sequence was directly linked onto the surface by a thiol–ene click reaction to prepare a series of REDV peptide functionalized surfaces. The chemical compositions of the modified surfaces were quantified by X-ray photoelectron spectroscopy (XPS), and the hydrophilicity was evaluated by water contact analysis and water uptake. The surface hemocompatibility was verified by platelet adhesion assays, and the results demonstrated that platelet adhesion was significantly reduced on the modified surface. More importantly, the functionalized surfaces with high hydrophilicity and cell specific adhesive REDV peptide could selectively enhance the adhesion and proliferation of human umbilical vein endothelial cells (HUVECs) but they suppressed these behaviors in human arterial smooth muscle cells (HASMCs). Moreover, these surfaces showed excellent antibacterial properties, which originate from the EgMA moieties of the copolymers. The successful fabrication of multifunctional surfaces with excellent hemocompatibility, rapid endothelialization, and good antimicrobial activity through a feasible route could be an attractive platform for tissue engineering applications. %0 journal article %@ 1946-4274 %A Baudis, S.,Lendlein, A.,Behl, M. %D 2015 %J MRS Online Proceedings Library %N %P 109-115 %R doi:10.1557/opl.2015.493 %T Robot Assisted Synthesis and Characterization of Polyester-based Polyurethanes %U https://doi.org/10.1557/opl.2015.493 %X Dihydroxy telechelics are precursors for the synthesis of multiblock copolymers. In order to synthesize high molecular weight polymers with good elastic properties it is necessary to gain detailed knowledge of the reaction behavior of these precursors. Therefore it was explored whether the polyaddition reaction of polyester-diols can be established in a robotic synthesizer platform to facilitate the elucidation of reaction characteristics. A series of 16 reactions was performed using a telechelic polyester and trimethylhexamethylene diisocyanate. The chain extension behavior of the building block was compared with respect to the Carothers equation. It was found, that the chain extension behavior follows the expected trend. The molecular weight of the polymers increased when the optimal ratio of reactive groups was approached. %0 journal article %@ 0168-3659 %A Hao, X.,Lv, J.,Li, Q.,Fan, J.,Feng, Y.,Behl, M.,Lendlein, A. %D 2015 %J Journal of Controlled Release %N %P e 123 %R doi:10.1016/j.jconrel.2015.05.207 %T REDV-linked biodegradable polymeric micelles as the transfer vector of ZNF580 for the proliferation of endothelial cells %U https://doi.org/10.1016/j.jconrel.2015.05.207 %X No abstract %0 journal article %@ 1386-0291 %A Wang, W.,Kratz, K.,Behl, M.,Yan, W.,Liu, Y.,Xu, X.,Baudis, S.,Li, Z.,Kurtz, A.,Lendlein, A.,Ma, N. %D 2015 %J Clinical Hemorheology and Microcirculation %N 2 %P 301-321 %R doi:10.3233/CH-152001 %T The interaction of adipose-derived human mesenchymal stem cells and polyether ether ketone %U https://doi.org/10.3233/CH-152001 2 %X Polyether ether ketone (PEEK) as a high-performance, thermoplastic implant material entered the field of medical applications due to its structural function and commercial availability. In bone tissue engineering, the combination of mesenchymal stem cells (MSCs) with PEEK implants may accelerate the bone formation and promote the osseointegration between the implant and the adjacent bone tissue. In this concept the question how PEEK influences the behaviour and functions of MSCs is of great interest. Here the cellular response of human adipose-derived MSCs to PEEK was evaluated and compared to tissue culture plate (TCP) as the reference material. Viability and morphology of cells were not altered when cultured on the PEEK film. The cells on PEEK presented a high proliferation activity in spite of a relatively lower initial cell adhesion rate. There was no significant difference on cell apoptosis and senescence between the cells on PEEK and TCP. The inflammatory cytokines and VEGF secreted by the cells on these two surfaces were at similar levels. The cells on PEEK showed up-regulated BMP2 and down-regulated BMP4 and BMP6 gene expression, whereas no conspicuous differences were observed in the committed osteoblast markers (BGLAP, COL1A1 and Runx2). With osteoinduction the cells on PEEK and TCP exhibited a similar osteogenic differentiation potential. Our results demonstrate the biofunctionality of PEEK for human MSC cultivation and differentiation. Its clinical benefits in bone tissue engineering may be achieved by combining MSCs with PEEK implants. These data may also provide useful information for further modification of PEEK with chemical or physical methods to regulate the cellular processes of MSCs and to consequently improve the efficacy of MSC-PEEK based therapies. %0 journal article %@ 1746-0751 %A Schwerk, A.,Altschueler, J.,Roch, M.,Gossen, M.,Winter, C.,Berg, J.,Kurtz, A.,Akyuez, L.,Steiner, B. %D 2015 %J Regenerative Medicine %N 4 %P 431-446 %R doi:10.2217/RME.15.17 %T Adipose-derived human mesenchymal stem cells induce long-term neurogenic and anti-inflammatory effects and improve cognitive but not motor performance in a rat model of Parkinson's disease %U https://doi.org/10.2217/RME.15.17 4 %X Background: Mesenchymal stem cells (MSC) are easily harvested, and possess anti-inflammatory and trophic properties. Furthermore, MSC promote neuroprotection and neurogenesis, which could greatly benefit neurodegenerative disorders, such as Parkinson's disease. Methods: MSC were transplanted one week after 6-hydroxydopamine lesioning and effects were evaluated after 6 months. Results: MSC localized around the substantia nigra and the arachnoid mater, expressing pericyte and endothelial markers. MSC protected dopamine levels and upregulated peripheral anti-inflammatory cytokines. Furthermore, adipose-derived MSC increased neurogenesis in hippocampal and subventricular regions, and boosted memory functioning. Conclusion: Considering that hyposmia and loss of memory function are two major nonmotor symptoms in Parkinson's disease, transplants with modulatory effects on the hippocampus and subventricular zone could provide a disease-modifying therapy. %0 journal article %@ 0885-3282 %A Ivashchenko, S.,Escobar Ivirico, J.L.,Garcia Cruz, D.M.,Campillo-Fernandez, A.,Gallego Ferrer, G.,Monleon Pradas, M. %D 2015 %J Journal of Biomaterials Applications %N 8 %P 1096-1108 %R doi:10.1177/0885328214554816 %T Bioactive organic–inorganic poly(CLMA-co-HEA)/silica nanocomposites %U https://doi.org/10.1177/0885328214554816 8 %X A series of novel poly(CLMA-co-HEA)/silica nanocomposites is synthesized from caprolactone 2-(methacryloyloxy)ethyl ester (CLMA) and 2-hydroxyethyl acrylate (HEA) as organic comonomers and the simultaneous sol-gel polymerization of tetraethyloxysilane (TEOS) as silica precursor, in different mass ratios up to a 30 wt% of silica. The nanocomposites are characterized as to their mechanical and thermal properties, water sorption, bioactivity and biocompatibility, reflecting the effect on the organic matrix provided by the silica network formation. The nanocomposites nucleate the growth of hydroxyapatite (HAp) on their surfaces when immersed in the simulated body fluid of the composition used in this work. Proliferation of the MC3T3 osteoblast-like cells on the materials was assessed with the MTS assay showing their biocompatibility. Immunocytochemistry reveals osteocalcin and type I collagen production, indicating that osteoblast differentiation was promoted by the materials, and calcium deposition was confirmed by von Kossa staining. The results indicate that these poly(CLMA-co-HEA)/silica nanocomposites could be a promising biomaterial for bone tissue engineering. %0 journal article %@ 1386-0291 %A Hiebl, B.,Nennig, E.,Schiestel, S.,Kovacs, A.,Jung, F.,Fischer, H. %D 2015 %J Clinical Hemorheology and Microcirculation %N 2 %P 205-211 %R doi:10.3233/CH-151983 %T Biocompatibility of a novel zinc stent with a closed-cell-design %U https://doi.org/10.3233/CH-151983 2 %X Biomaterials made of zinc have been widely described to be antioxidative, hypothrombogenic, antiinflammatory and antiproliferative. Additionally in vivo zinc is toxic only in high concentrations and can completely be metabolized in vivo. Due to these properties zinc based vascular stents might be able to reduce the rate of restenosis in comparison to bare metal stents and zinc stents might be also able to limit the foreign body reaction. In the presented study we tested the biocompatibility and degradability of a stent made of zinc and characterized by a closed-cell-design to achieve high opening force and to increase stent stiffness. After 100 days of enzymatic and hydrolytic degradation in 15 ml blood serum (fetal calf serum) a significant loss of weight (1.72 wt% ) was measured. Zinc was compared to other metals in terms of degradation rates. After six weeks of incubation in physiologic sodium chloride solution zinc showed the slowest degradation time, 6 times less than stainless steel and 4 times less than magnesium. In the tests for cytotoxic effects the degraded zinc stent caused no changes in the LDH-release and cell membrane integrity (3T3 cells, mouse fibroblasts) respectively, in the cell activity/proliferation (MTS assay) and in the morphological characteristics of the cells and cell layers in comparison to the control material (polystyrene). Based on these results the tested zinc stent proved to be non-cytotoxic and to be characterized by degradation characteristics which might be advantageous in comparison to magnesium and stainless steel. %0 journal article %@ 1946-4274 %A Noechel, U.,Kratz, K.,Behl, M.,Lendlein, A. %D 2015 %J MRS Online Proceedings Library %N %P 41-48 %R doi:10.1557/opl.2015.427 %T Relation -between Nanostructural Changes and Macroscopic Effects during Reversible Temperature-Memory Effect under Stress-Free Conditions in Semicrystalline Polymer Networks %U https://doi.org/10.1557/opl.2015.427 %X Temperature-memory effects in polymers under stress-free conditions are typically limited to one way effects. Recently, crosslinked polymer networks comprising crystallizable domains, which were capable of a reversible temperature-memory effect (rTME) under stress-free conditions, were introduced. The utilization of crystallizable actuator domains (AD) and shape determining domains (SD) where related to two different temperature ranges of a single broad melting temperature transition in case of rTME. In this study we investigated the nanostructure of crosslinked poly[ethylene-co-(vinyl acetate)] cPEVA capable of rTME in situ during actuation cycles utilizing X-ray scattering techniques and related the changes on the nanoscale to effects on the macroscopic scale. It was observed that 23% of SD obtained at a separation temperature of 75 °C gave the highest reversible strain and when exceeding 80 °C only isotropic crystallization occurred and no rTME was observed. Furthermore, distances between oriented crystalline lamellae correlated to the macroscopic actuation during heating-cooling cycles, exhibiting long-periods from 14 to 17 nm as function of temperature. %0 journal article %@ 1946-4274 %A Razzaq, M.Y.,Behl, M.,Lendlein, A. %D 2015 %J MRS Online Proceedings Library %N %P 71-76 %R doi:10.1557/opl.2015.495 %T Thermally Controlled Shape-Memory Investigations of Nanocomposites Based on Oligo(ω-pentadecalactone) and Magnetic Nanoparticles Acting as Crosslinks %U https://doi.org/10.1557/opl.2015.495 %X Covalent integration of inorganic nanoparticles into polymer matrices leads to a homogenization of their distribution and enhances the structural properties. Here, we report on a thermally-controlled reversible shape-memory effect (R-SME) of magnetic nanocomposites under stress-controlled conditions. The magnetic nanocomposites consisted of an oligo(ω-pentadecalactone) (OPDL) matrix with covalently integrated or physically added magnetic nanoparticles (MNP). The R-SME of these materials was based on crystallization-induced elongation (CIE) and melting-induced contraction (MIC) under a constant stress in thermomechanical experiments. Furthermore, the adjustability of the recovery stress in magnetic nanocomposites as a function of MNP content was investigated. A slight increase in the recovery stress from 0.9 MPa for pure OPDL network to 1.2 MPa for H-NC containing 9 wt% of covalently integrated MNP was observed. %0 journal article %@ 1946-4274 %A Racheva, M.,Romero, O.,Julich-Gruner, K.K.,Ulrich, A.S.,Wischke, C.,Lendlein, A. %D 2015 %J MRS Online Proceedings Library %N %P 36-41 %R doi:10.1557/opl.2015.260 %T Purity of mushroom tyrosinase as a biocatalyst for biomaterial synthesis affects the stability of therapeutic peptides %U https://doi.org/10.1557/opl.2015.260 %X The formation of injectable implants in the presence of cells or solutes has previously been conceptualized to be based on the selectivity of bioorthogonal chemical reactions. As an alternative approach, hydrogel network synthesis by enzymatic reactions with a typically high inherent substrate specificity and low toxicity have been repeatedly proposed, e.g. using commercial mushroom tyrosinase (MTyr), which specifically catalyzes phenol oxidation. In this study, it should be explored whether MTyr is compatible with therapeutic peptides that may be delivered from such hydrogels in the future. Based on the specificity of MTyr to phenol residues, no modification of peptides lacking the amino acid tyrosine would be expected. One example of such peptides is gramicidin S (GS), a potent antimicrobial peptide. However, when GS was incubated with commercial MTyr, peptide degradation occurred as observed by HPLC analysis. Several fragments of the peptide were detected by MALDI-TOF. Contamination of MTyr with peptidases was proven as the source of undesired peptide cleavage, which needs to be considered when preparing enzymatically crosslinked hydrogels for biomedical applications. %0 journal article %@ 0033-4545 %A Wang, L.,Baudis, S.,Kratz, K.,Lendlein, A. %D 2015 %J Pure and Applied Chemistry %N 11-12 %P 1085-1097 %R doi:10.1515/pac-2015-0607 %T Characterization of bi-layered magnetic nanoparticles synthesized via two-step surface-initiated ring-opening polymerization %U https://doi.org/10.1515/pac-2015-0607 11-12 %X A versatile strategy to integrate multiple functions in a polymer based material is the formation of polymer networks with defined nanostructures. Here, we present synthesis and comprehensive characterization of covalently surface functionalized magnetic nanoparticles (MNPs) comprising a bi-layer oligomeric shell, using Sn(Oct)2 as catalyst for a two-step functionalization. These hydroxy-terminated precursors for degradable magneto- and thermo-sensitive polymer networks were prepared via two subsequent surface-initiated ring-opening polymerizations (ROPs) with ω-pentadecalactone and ε-caprolactone. A two-step mass loss obtained in thermogravimetric analysis and two distinct melting transitions around 50 and 85°C observed in differential scanning calorimetry experiments, which are attributed to the melting of OPDL and OCL crystallites, confirmed a successful preparation of the modified MNPs. The oligomeric coating of the nanoparticles could be visualized by transmission electron microscopy. The investigation of degrafted oligomeric coatings by gel permeation chromatography and 1H-NMR spectroscopy showed an increase in number average molecular weight as well as the presence of signals related to both of oligo(ω-pentadecalactone) (OPDL) and oligo(ε-caprolactone) (OCL) after the second ROP. A more detailed analysis of the NMR results revealed that only a few ω-pentadecalactone repeating units are present in the degrafted oligomeric bi-layers, whereby a considerable degree of transesterification could be observed when OPDL was polymerized in the 2nd ROP step. These findings are supported by a low degree of crystallinity for OPDL in the degrafted oligomeric bi-layers obtained in wide angle X-ray scattering experiments. Based on these findings it can be concluded that Sn(Oct)2 was suitable as catalyst for the preparation of nanosized bi-layered coated MNP precursors by a two-step ROP. %0 journal article %@ 2041-7314 %A Lakhkar, N.J.,Day, R.M.,Kim, H.-W.,Ludka, K.,Mordan, N.J.,Salih, V.,Knowles, J.C. %D 2015 %J Journal of Tissue Engineering %N %P 2041731415617741 %R doi:10.1177/2041731415617741 %T Titanium phosphate glass microcarriers induce enhanced osteogenic cell proliferation and human mesenchymal stem cell protein expression %U https://doi.org/10.1177/2041731415617741 %X In this study, we have developed 50- to 100-µm-sized titanium phosphate glass microcarriers (denoted as Ti5) that show enhanced proliferation of human mesenchymal stem cells and MG63 osteosarcoma cells, as well as enhanced human mesenchymal stem cell expression of bone differentiation markers, in comparison with commercially available glass microspheres at all time points. We also demonstrate that these microcarriers provide superior human mesenchymal stem cell proliferation with conventional Dulbecco's Modified Eagle medium than with a specially developed commercial stem cell medium. The microcarrier proliferative capacity is revealed by a 24-fold increase in MG63 cell numbers in spinner flask bioreactor studies performed over a 7-day period, versus only a 6-fold increase in control microspheres under the same conditions; the corresponding values of Ti5 and control microspheres under static culture are 8-fold and 7-fold, respectively. The capability of guided osteogenic differentiation is confirmed by ELISAs for bone morphogenetic protein-2 and osteopontin, which reveal significantly greater expression of these markers, especially osteopontin, by human mesenchymal stem cells on the Ti5 microspheres than on the control. Scanning electron microscopy and confocal laser scanning microscopy images reveal favorable MG63 and human mesenchymal stem cell adhesion on the Ti5 microsphere surfaces. Thus, the results demonstrate the suitability of the developed microspheres for use as microcarriers in bone tissue engineering applications. %0 journal article %@ 1946-4274 %A Roch, T.,Julich-Gruner, K.K.,Neffe, A.T.,Ma, N.,Leindlein, A. %D 2015 %J MRS Online Proceedings Library %N %P %R doi:10.1557/opl.2015.327 %T Immuno-compatibility of desaminotyrosine and desaminotyrosyl tyrosine functionalized star-shaped oligo(ethylene glycol)s with different molecular weights %U https://doi.org/10.1557/opl.2015.327 %X Polymer-based therapeutic strategies require biomaterials with properties and functions tailored to the demands of specific applications leading to an increasing number of newly designed polymers. For the evaluation of those new materials, comprehensive biocompatibility studies including cyto-, tissue-, and immunocompatibility are essential. Recently, it could be demonstrated that star-shaped amino oligo(ethylene glycol)s (sOEG) with a number average molecular weight of 5 kDa and functionalized with the phenol-derived moieties desaminotyrosine (DAT) or desaminotyrosyl tyrosine (DATT) behave in aqueous solution like surfactants without inducing a substantial cytotoxicity, which may qualify them as solubilizer for hydrophobic drugs in aqueous solution. However, for biomedical applications the polymer solutions need to be free of immunogenic contaminations, which could result from inadequate laboratory environment or contaminated starting material. Furthermore, the materials should not induce uncontrolled or undesired immunological effects arising from material intrinsic properties. Therefore, a comprehensive immunological evaluation as perquisite for application of each biomaterial batch is required. This study investigated the immunological properties of sOEG-DAT(T) solutions, which were prepared using sOEG with number average molecular weights of 5 kDa, 10 kDa, and 20 kDa allowing analyzing the influence of the sOEG chain lengths on innate immune mechanisms. A macrophage-based assay was used to first demonstrate that all DAT(T)-sOEG solutions are free of endotoxins and other microbial contaminations such as fungal products. In the next step, the capacity of the different DAT(T)-functionalized sOEG solutions to induce cytokine secretion and generation of reactive oxygen species (ROS) was investigated using whole human blood. It was observed that low levels of the pro-inflammatory cytokines interleukin(IL)-1β and IL-6 were detected for all sOEG solutions but only when used at concentrations above 250 µg·mL-1. Furthermore, only the 20 kDa sOEG-DAT induced low amounts of ROS-producing monocytes. Conclusively, the data indicate that the materials were not contaminated with microbial products and do not induce substantial immunological adverse effects in vitro, which is a prerequisite for future biological applications. %0 journal article %@ 0121-6651 %A Molina, M.,Bergueiro, J.,Sousa-Herves, A.,Calderon, M %D 2015 %J Revista Iberoamericana de Polimeros %N 3 %P 164-172 %T Aplicaciones biomedicas de nanogeles dendriticos termosensibles %U 3 %X Los nanogeles son redes entrecruzadas de tamaño nanométrico compuestas por cadenas poliméricas hidrófilas o anfifílicas capaces de absorber y liberar grandes cantidades de agua. Comúnmente son desarrollados como vehículos para transportar fármacos o biomacromoléculas. Por otro lado, los polímeros termosensibles experimentan una transición de fase en agua a una determinada temperatura conocida como temperatura de transición de fase (Tf). Como consecuencia cambian su estado de agregación, exhiben un cambio conformacional y experimentan un colapso, hinchamiento o micelización bajo un estímulo térmico. Por lo tanto, una combinación de las propiedades de los nanogeles con la de los polímeros termosensibles representa un enfoque prometedor para el desarrollo de sistemas de liberación controlada de fármacos que revelan altas capacidades de carga y mejoran la estabilidad in vivo de los fármacos encapsulados. En el presente documento, se hace una revisión del desarrollo de nanogeles dendríticos (dNGs) termosensibles para aplicaciones biomédicas, usando diferentes polímeros lineales termosensibles y poliglicerol dendrítico como agente entrecruzante.,Nanogels are nanosized crosslinked networks composed of hydrophilic or amphiphilic polymer chains that are capable of absorbing and releasing large quantities of water. They are developed as carriers to transport drugs or biomacromolecules. Thermoresponsive polymers undergo a phase transition at a certain temperature in aqueous media known as phase transition (Tp). As a consequence, they can change their aggregation state, exhibit conformational change and undergo shrinking, swelling, or micellization upon a thermal trigger. The combination of the nanogel properties and thermo-responsiveness represents a promising approach for the development of stimuli-controlled release systems, which reveals high loading capacity and improves the in vivo drug stability. Herein, the engineering of thermoresponsive dendritic nanogels (dNGs) using different thermoresponsive linear polymers and dendritic polyglycerol as macro-crosslinker for biomedical applications is reviewed. %0 journal article %@ 0883-7694 %A Sarem, M.,Luedeke, S. %D 2015 %J MRS Bulletin %N 6 %P 490-498 %R doi:10.1557/mrs.2015.116 %T Circular dichroism: A powerful tool for studying biomineralization promoter proteins %U https://doi.org/10.1557/mrs.2015.116 6 %X Biomineralization is the matrix-directed calcification of tissue in living organisms. The deposition of different polymorphs of calcium phosphate or calcium carbonate is a highly regulated process. It may involve cell-controlled mechanisms with vesicular delivery of inorganic material to the extracellular matrix and cell-independent processes mediated by dedicated matrix proteins. These proteins promote the formation of microscopic crystals of defined size and shape, which combine to form bio-inorganic materials with unique properties. Successful biomineralization is correlated with structural elements, such as matrix proteins involved in the nucleation process. Circular dichroism (CD) is a spectroscopic technique for the determination of a secondary structure of proteins and has therefore been applied for studying numerous biomineralization promoter proteins. This article reviews and compares CD data on matrix proteins from different contexts, such as eggs, seashells, and teeth. It highlights the potential of CD for secondary structure determination and quantification and points out pitfalls that may lead to misinterpretation of CD spectra. The data suggest that most biomineralization promoter proteins contain domains of different secondary structure with predominantly unordered conformation. However, they may acquire a higher degree of order initiated by environmental factors such as pH, presence of cations, or charged surfaces. %0 journal article %@ 2051-6347 %A Wei, Q.,Haag, R. %D 2015 %J Materials Horizons %N 6 %P 567-577 %R doi:10.1039/c5mh00089k %T Universal polymer coatings and their representative biomedical applications %U https://doi.org/10.1039/c5mh00089k 6 %X Universal polymer coatings have excellent potential for biomedical applications, because of their substrate-independent properties and versatile surface functionalization methods. The goal of this review is to summarize the state-of-art research on universal polymer coatings and their biomedical applications, as well as to present their common features including some general rules for their further development. %0 journal article %@ 1525-7797 %A Psarra, E.,Foster, E.,Koenig, U.,You, J.,Ueda, Y.,Eichhorn, K.-J.,Mueller, M.,Stamm, M.,Revzin, A.,Uhlmann, P. %D 2015 %J Biomacromolecules %N 11 %P 3530-3542 %R doi:10.1021/acs.biomac.5b00967 %T Growth Factor-Bearing Polymer Brushes - Versatile Bioactive Substrates Influencing Cell Response %U https://doi.org/10.1021/acs.biomac.5b00967 11 %X In this study we present the development of responsive nanoscale substrates exhibiting cell-guiding properties based on incorporated bioactive signaling cues. The investigative approach considered the effect of two different surface-bound growth factors (GFs) on cell behavior and response: hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF). Two surface biofunctionalization strategies were explored in order to conceive versatile, bioactive thin polymer brush films. Polymer brushes made of tethered poly(acrylic)acid (PAA) polymer layers with a high grafting density of polymer chains were biofunctionalized with GFs either by physisorption or chemisorption. Both GFs showed high binding efficiencies to PAA brushes based on their initial loading concentrations. The GF release kinetics can be distinguished depending on the applied biofunctionalization method. Specifically, a high initial burst followed by a constant slow release was observed in the case of both physisorbed HGF and bFGF. In contrast, the release kinetics of chemisorbed GFs were quite different. Remarkably, chemisorbed HGF remained bound to the brush surface for over 1 week, whereas 50% of chemisorbed bFGF was released slowly. Furthermore, the effect of these GF-biofunctionalized PAA brushes on different cells was investigated. A human hepatoma cell line (HepG2) was used to analyze the bioactivity of HGF-modified PAA brushes by measuring cell growth inhibition and scattering effects. Additionally, the differentiation of mouse embryonic stem cells (mESCs) toward endoderm was studied on bFGF-modified PAA brush surfaces. Finally, the results illustrate that PAA brushes, particularly those biofunctionalized with chemisorbed GFs, produce an expected measurable effect on both cell types. Therefore, PAA polymer brushes biofunctionalized with GFs can be used as bioactive cell culture substrates with tuned efficiency. %0 journal article %@ 0391-3988 %A Braune, S.,Zhou, S.,Groth, B.,Lendlein, A.,Jung, F. %D 2015 %J The International Journal of Artificial Organs %N 7 %P 345-418 %R doi:10.5301/ijao.5000417 %T Quantification of adherent platelets on biomaterials. Comparison of colorimetric and microscopic assessment %U https://doi.org/10.5301/ijao.5000417 7 %X No abstract %0 journal article %@ 1946-4274 %A Heuchel, M.,Al-Qaisi, L.,Kratz, K.,Noechel, U.,Behl, M.,Lendlein, A. %D 2015 %J MRS Online Proceedings Library %N %P 127-134 %R doi:10.1557/opl.2015.527 %T Thermomechanical Characterization of a Series of Crosslinked Poly[ethylene-co-(vinyl acetate)] (PEVA) Copolymers %U https://doi.org/10.1557/opl.2015.527 %X Crosslinked poly[ethylene-co-(vinyl acetate)] (cPEVA) has been recently introduced as a polymer material, which can be functionalized with various shape-memory effects by solely altering the thermomechanical treatment called programming.,In this study two series of cPEVAs with different vinyl acetate contents of 18 wt% (cPEVA18) and 28 wt% (cPEVA28) comprising different crosslink densities were investigated by differential scanning calorimetry (DSC) and dynamic mechanical thermal analysis (DMTA) in the temperature range of -130 °C to 120 °C. DMTA tests were performed in torsion mode, because such movements are highly relevant in the context of complex shape changes in shape-memory polymer based devices. Finally, the obtained DMTA results were compared with DMTA conducted in tension mode. Swelling experiments revealed a gel content in the range from 81% to 90% for cPEVA18 samples while for cPEVA28s a complete conversion was observed. The degree of swelling was found to decrease substantially with increasing crosslink density for both cPEVA series.,The influence of VA content and extent of crosslinking on the appearance of the respective melting (Tm) and glass transition (Tg) as well as the thermomechanical properties of cPEVA systems could be demonstrated by discussing both DSC and DMTA results. The temperature range of mechanical stability correlates with the VA content and is determined by decreasing Tm values. The cross links do barely alter the stiffness of a PEVA up to the Tm rang, but lead to constant mechanical rigidity in the rubbery range above Tm. %0 journal article %@ 1946-4274 %A Wischke, C.,Weigel, J.,Lendlein, A. %D 2015 %J MRS Online Proceedings Library %N %P 30-35 %R doi:10.1557/opl.2015.60 %T Poly(n-butylcyanoacrylate) Nanoparticles as Carriers for Adenosine triphosphate %U https://doi.org/10.1557/opl.2015.60 %X Adenosine triphosphate (ATP) has numerous biological functions both intra- and extracellularly, including effects on the directed migration of cells with a regenerative potential in brain tissue. Therefore, carrier systems would be of interest that would be capable to be loaded with ATP and release it in a controlled manner. In the present study, poly(n-butylcyanoacrylate) (PBCA) nanoparticles as a potential carrier system were prepared by anionic polymerization using different polymerization media, which resulted in different zeta potential values and in some cases aggregation of nanoparticles. By decorating the particle surface with positively charged diethylaminoethyl dextran, multivalent ionic interaction allowed to load ATP to the nanoparticles by adsorption. In release experiments, an ATP release over 6 hours was observed. ATP-loaded nanoparticles may thus be suitable to explore biological effects of short-term ATP delivery for biomedical applications. %0 journal article %@ 1042-7147 %A Yang, J.,Feng, Y.,Zhang, L. %D 2015 %J Polymers for Advanced Technologies %N 12 %P 1370-1377 %R doi:10.1002/pat.3636 %T Biodegradable carrier/gene complexes to mediate the transfection and proliferation of human vascular endothelial cells %U https://doi.org/10.1002/pat.3636 12 %X Artificial vascular scaffolds have been developed and used clinically for many years, but the lack of a living functional layer of human umbilical vein endothelial cells (HUVECs) remains a significant challenge, especially for small diameter artificial blood vessels. Endothelialization of artificial vascular scaffolds has been proved as one of the most potential approaches to improve their hemocompatibility and long-term patency. A variety of non-viral gene carriers have been investigated to mediate the transfection and proliferation of HUVECs. In this mini-review, we will summarize the recent development of the non-viral gene carriers for transfecting HUVECs. The gene transfection with targeting ligand immobilized carriers is a promising approach to enhance endothelialization of artificial vascular scaffolds. %0 journal article %@ 1042-7147 %A Zhang, Q.,Kratz, K.,Lendlein, A. %D 2015 %J Polymers for Advanced Technologies %N 12 %P 1468-1475 %R doi:10.1002/pat.3630 %T Shape-memory properties of degradable electrospun scaffolds based on hollow microfibers %U https://doi.org/10.1002/pat.3630 12 %X Multifunctional thermo-responsive and degradable porous materials exhibiting a shape-memory effect are explored in biomedicine as actively moving scaffolds or switchable substrates. One example are electrospun shape-memory polymer-based scaffolds comprising solid microfibers or nanofibers. In this work, we explored whether fibrous scaffolds composed of hollow microfibers can be prepared from a degradable shape-memory copolyetheresterurethane named PDC, which is composed of crystallizable oligo(p-dioxanone) (OPDO) hard and oligo(ε-caprolactone) (OCL) switching segments. Scaffolds based on PDC microfibers with identical outer diameter around 1.4 ± 0.3 µm and different hollowness of 0%, 13%, and 33% related to the outer diameter (determined by scanning electron microscopy) were prepared by coaxial electrospinning using poly(ethylene glycol) (PEG) as sacrificial core. Thermal characterization of the scaffolds by differential scanning calorimetry (DSC) and thermogravimetric analysis confirmed a successful removal of PEG. DSC results revealed that the degree of crystallinity increased with increasing microfiber hollowness. The Young's modulus and the failure stress of the prepared scaffolds determined by tensile tests at ambient temperature and 50 °C were found to increase with rising hollowness, while the elongation at break decreased. Cyclic, thermomechanical uniaxial tensile tests showed a pronounced dual-shape effect for all tested materials. Scaffolds comprising microfibers with a hollowness of 33% exhibited the highest shape recovery ratio. Here, we could demonstrate that the degree of hollowness of microfibers, which alters the degree of macromolecular chain orientation, is a suitable design parameter to tailor the mechanical properties as well as the shape-memory performance of electrospun shape-memory polymer fibrous scaffolds. %0 journal article %@ 1042-7147 %A Vijaya Bhaskar, T.B.,Roch, T.,Romero, O.,Ma, N.,Kratz, K.,Lendlein, A. %D 2015 %J Polymers for Advanced Technologies %N 12 %P 1387-1393 %R doi:10.1002/pat.3639 %T Single and competitive protein adsorption on polymeric surfaces %U https://doi.org/10.1002/pat.3639 12 %X The biological response to material surfaces is often influenced by protein layers formed at the bio-interface. Understanding this protein layer is of paramount importance for biomedical materials and cell culture devices, which often require protein coating for optimal cell growth. An insert system fitting exactly into standard tissue culture plates was developed and can be used for biological investigations without the influence of the cell culture material. Inserts prepared from polystyrene (PS), polycarbonate (PC), poly(styrene-co-acrylonitrile) (PSAN) and poly(ether imide) (PEI) exhibit a similar surface roughness and wettability so that only the chemistry is varied. Previously, stem cell adhesion responses were found to be different for these inserts, possibly because of their different protein adsorption profiles. This work investigated if the surface functional groups of these inserts influence their protein binding ability. Single and competitive adsorption of two most abundant blood proteins, human serum albumin (HSA) and immunoglobulin G (IgG) on these polymers was investigated by labeling both proteins with different near-infrared (IR) dyes. PEI showed the highest protein adsorption propensity in single and competitive adsorption of IgG and HSA while PS exhibited the least adsorption capability, whereas PSAN and PC showed an intermediate protein adsorption profile. Chemical inertness of PS could be the reason for this low protein binding ability and limited cell growth. Conclusively, a novel method to efficiently detect protein adsorption on polymer surfaces was established, and using this method the high relevance of the chemical composition of polymeric substrates on their protein adsorption profile could be proven. %0 journal article %@ 1042-7147 %A Schoene, A.-C.,Kratz, K.,Schulz, B.,Reiche, J.,Santer, S.,Lendlein, A. %D 2015 %J Polymers for Advanced Technologies %N 12 %P 1411-1420 %R doi:10.1002/pat.3638 %T Surface pressure-induced isothermal 2D- to 3D-transitions in Langmuir films of poly(Epsilon-caprolactone)s and oligo(Epsilon-caprolactone) based polyesterurethanes %U https://doi.org/10.1002/pat.3638 12 %X Surface pressure-induced isothermal 2D- to 3D-transitions in Langmuir films of biodegradable poly(ε-caprolactone) (PCL) and oligo(ε-caprolactone) based polyester-urethanes P(OCL-U)s are investigated in order to gain deeper insights into the influence of the linker species on the crystallization and aggregation behavior of macromolecules in a biomimetic aqueous environment. The presence of three urethane linkers derived from 2, 2 (4), 4-trimethyl-hexamethylene-diisocyanate (TMDI), hexamethylene diisocyanate (HDI) and lysine ethylester diisocyanate (LDI) induces remarkable changes in the mesoscopic structure compared to PCL Langmuir films. The pronounced changes in the morphology of the 3D structures co-existing with the Langmuir film above a collapse surface pressure are visualized by Brewster angle microscopy (BAM). Hysteresis of the compression–expansion isotherm in the surface pressure range of the 2D- to 3D-transition indicates the influence of the urethane linkers on the diffusion-limited kinetics and on the reversibility of this phase transition. %0 journal article %@ 1042-7147 %A Schoene, A.-C.,Falkenhagen, S.,Travkova, O.,Schulz, B.,Kratz, K.,Lendlein, A. %D 2015 %J Polymers for Advanced Technologies %N 12 %P 1402-1410 %R doi:10.1002/pat.3701 %T Influence of intermediate degradation products on the hydrolytic degradation of poly[(rac-lactide)-co-glycolide] at the air–water interface %U https://doi.org/10.1002/pat.3701 12 %X The influence of intermediate degradation products on the hydrolytic degradation of poly[(rac-lactide)-co-glycolide] (PLGA, 50 mol% lactide) at the air–water interface is investigated using the Langmuir film balance. For that purpose, PLGA bulk samples were degraded in aqueous solution for different time periods to generate different sized fragments with varying water solubility. After dissolution in chloroform the water-insoluble degradation products are able to form Langmuir monolayers with an increased elasticity modulus by decreasing molecular weights. Water-soluble degradation products of PLGA were found to be surface active and form an adsorption layer at the air–water interface, which can be further compressed, and revealing a different adsorption behavior in dependence on their composition. The obtained results imply that measured surface area reduction as it is determined in Langmuir monolayer degradation (LMD) experiment is restricted by the effect of the surface activity of adsorbed oligomer fragments during the degradation process. The surface activity of the formed degradation products makes it difficult to derive degradation mechanism from a common LMD experiment. To elucidate the mechanism in detail, dimers, trimers and longer oligomers with known composition and end-groups have to be investigated. %0 journal article %@ 1386-0291 %A Roch, T.,Kratz, K.,Ma, N.,Lendlein, A. %D 2015 %J Clinical Hemorheology and Microcirculation %N 2 %P 347-357 %R doi:10.3233/CH-152004 %T Polymeric inserts differing in their chemical composition as substrates for dendritic cell cultivation %U https://doi.org/10.3233/CH-152004 2 %X Dendritic cells (DC) contribute to immunity by presenting antigens to T cells and shape the immune response by the secretion of cytokines. Due to their immune stimulatory potential DC-based therapies are promising approaches to overcome tolerance e.g. against tumors. In order to enforce the immunogenicity of DCs, they have to be matured and activated in vitro , which requires an appropriate cell culture substrate, supporting their survival expansion and activation. Since most cell culture devices are not optimized for DC growth, it is hypothesized that polymers with certain physicochemical properties can positively influence the DC cultures. With the aim to evaluate the effects that polymers with different chemical compositions have on the survival, the activation status, and the cytokine/chemokine secretion profile of DC, their interaction with polystyrene (PS), polycarbonate (PC), poly(ether imide) (PEI), and poly(styrene-co -acrylonitrile) (PSAN)-based cell culture inserts was investigated. By using this insert system, which fits exactly into 24 well cell culture plates, effects induced from the culture dish material can be excluded. The viability of untreated DC after incubation with the different inserts was not influenced by the different inserts, whereas LPS-activated DC showed an increased survival after cultivation on PC, PS, and PSAN compared to tissue culture polystyrene (TCP). The activation status of DC estimated by the expression of CD40, CD80, CD83, CD86 and HLA-DR expression was not altered by the different inserts in untreated DC but slightly reduced when LPS-activated DC were cultivated on PC, PS, PSAN, and PEI compared to TCP. For each polymeric cell culture insert a distinct cytokine profile could be observed. Since inserts with different chemical compositions of the inserts did not substantially alter the behavior of DC all insert systems could be considered as alternative substrate. The observed increased survival on some polymers, which showed in contrast to TCP a hydrophobic surface, could be beneficial for certain applications such as T cell expansion and activation. %0 journal article %@ 1042-7147 %A Basu, S.,Heuchel, M.,Weigel, T.,Kratz, K.,Lendlein, A. %D 2015 %J Polymers for Advanced Technologies %N 12 %P 1447-1455 %R doi:10.1002/pat.3684 %T Integrated process for preparing porous, surface functionalized polyetherimide microparticles %U https://doi.org/10.1002/pat.3684 12 %X Highly porous polyetherimide (PEI) microparticles achieved by a spraying/coagulation process are candidate absorber materials for apheresis applications. Hydrophobic PEI surfaces tend to be rapidly coated with proteins when in contact with blood. Therefore, a hydrophilic modification of such particles is required. In this study, we explored the formation of porous, surface functionalized PEI microparticles by low molecular weight polyethyleneimine (Pei) or potassium hydroxide (KOH) in an integrated process combining chemical modification and particle formation. The integrated process resulted in smaller microparticles with diameters of 70 to 80 µm compared to the chemical two-step process. All particles exhibited similar bulk densities, ranging from 0.09 to 0.015 g cm−3, and average pore sizes around 180–250 nm. A successful modification of the particles' surface by both processing approaches could be confirmed by X-ray photoelectron spectroscopy measurements and microwetting experiments, where hydrophilic advancing contact angles of 57° to 64° were determined. Integrated particle processing further resulted in changes of the bulk properties, i.e. molecular weight, thermal decomposition behavior or glass transition temperature. Hydrophilic modified PEI microparticles have been successfully prepared by different approaches. In a next step their absorption capacity for uremic toxins will be investigated with regard to a potential application in blood detoxification. %0 journal article %@ 1042-7147 %A Goers, J.,Roch, T.,Tartivel, L.,Behl, M.,Ma, N.,Lendlein, A. %D 2015 %J Polymers for Advanced Technologies %N 12 %P 1378-1386 %R doi:10.1002/pat.3676 %T Immuno-compatibility of amphiphilic ABA triblock copolymer-based hydrogel films for biomedical applications %U https://doi.org/10.1002/pat.3676 12 %X The protein adsorption and immuno-compatibility of hydrogels largely influence the clinical outcome in biomedical application scenarios. In this study photo-crosslinked 2-isocyanate ethyl methacrylate–functionalized oligo(ethylene glycol)–oligo(propylene glycol)–oligo(ethylene glycol) (IEMA–OEG–OPG–OEG–IEMA)-based polymer hydrogel films were explored with respect to endotoxin contaminations, intrinsic immuno-modulatory features, and protein adsorption of human fibronectin as well as serum albumin. Therefore three different hydrogel films were prepared from aqueous solutions of dimethacrylated OEG–OPG–OEG triblock copolymers (Mn = 12,700 g mol−1, 70 mol% OEG content) with varying wt% of the macromonomer (10 to 30%) resulting in polymeric networks, which differ in their crosslinking density and accordingly their physical properties. It could be shown that all three hydrogel film compositions do not cause complement and immune cell activation. The films were protein repellent, but reversible protein diffusion in and out of the hydrogel network, depending on the mesh size of the network, could be observed. In conclusion, the hydrogels can be considered as immuno-compatible, which qualifies them for biomedical applications such as drug release systems. %0 journal article %@ 1042-7147 %A Farhan, M.,Chaganti, S.R.,Noechel, U.,Kratz, K.,Lendlein, A. %D 2015 %J Polymers for Advanced Technologies %N 12 %P 1421-1427 %R doi:10.1002/pat.3702 %T Reversible shape-memory properties of surface functionalizable, crystallizable crosslinked terpolymers %U https://doi.org/10.1002/pat.3702 12 %X There is a high demand for polymer actuators comprising reactive groups at their surface in biotechnological or bioanalytical devices especially in microfluidics. In this work, we explored whether a thermoplastic poly[ethylene-co-(ethyl acylate)-co-(maleic anhydride)] (PEEAMA) terpolymer can be converted to a multifunctional shape-memory actuator by introducing covalent netpoints. In crosslinked PEEAMA (cPEEAMA) crystalline polyethylene (PE) domains with melting temperatures below 70°C should serve as actuation domains, responsible for the reversible shape change during cyclic heating and cooling, while higher melting PE crystals act as skeleton forming domains; finally maleic anhydride (MAH) groups enable surface modification of the polymeric substrate. cPEEAMAs with a fixed composition and various crosslink densities were prepared by thermally crosslinking of PEEAMA using different dicumyl peroxide (DCP) concentrations in the starting reaction mixture. A broad melting transition in the range of 50 to 90°C with a melting temperature interval of ∆Tm = 40°C, related to the crystalline PE domains, was observed for all polymer networks in differential scanning calorimetric experiments. Cyclic, thermomechanical uniaxial tensile tests revealed high reversible strains up to 17 ± 2%. A reversible change in long period during repetitive heating and cooling was observed in in situ small angle X-ray scattering experiments. Finally, a successful functionalization of the MAH groups at the cPEEAMA surface by reaction with ethylene diamine was confirmed by infrared spectroscopy analysis. The presented amino functionalized cPEEAMA substrates could be a candidate material for the preparation of adaptive microfluidic devices. %0 journal article %@ 0306-0012 %A Molina, M.,Asadian-Birjand, M.,Balach, J.,Bergueiro, J.,Miceli, E.,Calderon, M. %D 2015 %J Chemical Society Reviews %N 17 %P 6161-6186 %R doi:10.1039/C5CS00199D %T Stimuli-responsive nanogel composites and their application in nanomedicine %U https://doi.org/10.1039/C5CS00199D 17 %X Nanogels are nanosized crosslinked polymer networks capable of absorbing large quantities of water. Specifically, smart nanogels are interesting because of their ability to respond to biomedically relevant changes like pH, temperature, etc. In the last few decades, hybrid nanogels or composites have been developed to overcome the ever increasing demand for new materials in this field. In this context, a hybrid refers to nanogels combined with different polymers and/or with nanoparticles such as plasmonic, magnetic, and carbonaceous nanoparticles, among others. Research activities are focused nowadays on using multifunctional hybrid nanogels in nanomedicine, not only as drug carriers but also as imaging and theranostic agents. In this review, we will describe nanogels, particularly in the form of composites or hybrids applied in nanomedicine. %0 journal article %@ 2192-2640 %A Li, Q.,Shi, C.,Zhang, W.,Behl, M.,Lendlein, A.,Feng, Y. %D 2015 %J Advanced Healthcare Materials %N 8 %P 1225-1235 %R doi:10.1002/adhm.201400817 %T Nanoparticles Complexed with Gene Vectors to Promote Proliferation of Human Vascular Endothelial Cells %U https://doi.org/10.1002/adhm.201400817 8 %X Amphiphilic block copolymers containing biodegradable hydrophobic segments of depsipeptide based copolymers have been synthesized and explored as gene carriers for enhancing proliferation of endothelial cells in vitro. These polymers form nanoparticles (NPs) with positive charges on their surface, which could condense recombinant plasmids of enhanced green fluorescent protein plasmid and ZNF580 gene (pEGFP-ZNF580) and protect them against DNase I. ZNF580 gene is efficiently transported into EA.hy926 cells to promote their proliferation, whereby the transfection efficiency of NPs/pEGFP-ZNF580 is approximately similar to that of Lipofectamine 2000. These results indicate that the NPs might have potential as a carrier for pEGFP-ZNF580, which could support endothelialization of cardiovascular implants. %0 journal article %@ 1946-4274 %A Julich-Gruner, K.K.,Lendlein, A.,Boccaccini, A.R.,Neffe, A.T. %D 2015 %J MRS Online Proceedings Library %N %P 82-87 %R doi:10.1557/opl.2015.492 %T Anisotropic Composites of Desaminotyrosine and Desaminotyrosyl Tyrosine Functionalized Gelatin and Bioactive Glass Microparticles %U https://doi.org/10.1557/opl.2015.492 %X Functionalization of gelatin with desaminotyrosine (DAT) and desamino tyrosyl tyrosine (DATT) has been demonstrated to allow network formation based on non-covalent interactions of the aromatic moieties. Based on the observation that the DAT(T) groups furthermore could interact with hydroxyapatite fillers, here it was investigated whether such interactions of DAT(T) could also be employed to stabilize composites formed by functionalized gelatins and bioactive glass (BG) particles. Because of sedimentation of the BG microparticles during the gelification, anisotropic composites with two distinct layers were formed. The characterization of mechanical properties by tensile tests and rheology showed that all composites of non-functionalized and DAT(T) functionalized gelatins with BG microparticles showed an increased Young’s modulus (E) up to 3 MPa, an increased storage modulus (G’) up to 100 kPa, increased tensile strength (σmax) up to 3.4 MPa, and increased loss modulus (G’’) compared to the pure matrices. As the observed effects were more pronounced in the DAT(T) functionalized gelatins compared to non-functionalized gelatins, and a much increased thermal stability of these composites was found, it is likely that there are binding interactions between the aromatic moieties and the BG microparticles. This effect open opportunities for the further development of this type of gelatin-based composites for bone regeneration applications. %0 journal article %@ 2192-2640 %A Neffe, A.T.,Lendlein, A. %D 2015 %J Advanced Healthcare Materials %N 5 %P 642-645 %R doi:10.1002/adhm.201400724 %T Going Beyond Compromises in Multifunctionality of Biomaterials %U https://doi.org/10.1002/adhm.201400724 5 %X Prioritizing one function in biomaterial and biomedical device design goes hand in hand with compromises with respect to other functions. Strategies to overcome the limitations of such an approach for realizing novel fields of biomaterial application are critically evaluated to promote interdisciplinary and integrative research. %0 journal article %@ 1946-4274 %A Loewenberg, C.,Julich-Gruner, K.K.,Neffe, A.T.Lendlein, A. %D 2015 %J MRS Online Proceedings Library %N %P 76-81 %R doi:10.1557/opl.2015.491 %T Influence of glycidylmethacrylate functional groups attached to gelatin on the formation and properties of hydrogels %U https://doi.org/10.1557/opl.2015.491 %X Gelatin functionalized with glycidyl methacrylate (GMA) has been shown to allow crosslinking by photopolymerization and metathesis reaction. However, side chain functionalization of gelatin might reduce triple helicalization, which influences mechanical properties of gelatin-based polymer networks. Here, the influence of glycidylmethycrylation of gelatin on the chain organization, swelling, and mechanical properties is investigated by comparing among each other physical gels prepared from GMA-gelatin solutions of different concentrations (5-20 wt.-%) by drying and rehydration. An increase of GMA-gelatin concentration from 5 wt.-% to 20 wt.-% led to an increased density of produced gelatin films and a decreasing water uptake of the films from 1160 wt.-% to 730 wt.-%, while the storage modulus was increasing about one order of magnitude from 440 Pa to 4090 Pa. The relative single and triple helix content was not influenced by the variation of polymer concentration. %0 journal article %@ 1386-0291 %A Vijaya Bhaskar, T.B.,Ma, N.,Lendlein, A.,Roch, T. %D 2015 %J Clinical Hemorheology and Microcirculation %N 2 %P 119-133 %R doi:10.3233/CH-151991 %T The interaction of human macrophage subsets with silicone as a biomaterial %U https://doi.org/10.3233/CH-151991 2 %X Silicones are widely used as biomaterials for medical devices such as extracorporeal equipments. However, there is often conflicting evidence about their supposed cell- and histocompatibility. Macrophages could mediate silicone-induced adverse responses such as foreign body reaction and fibrous encapsulation. The polarization behaviour of macrophages could determine the clinical outcome after implantation of biomaterials. Induction of classically activated macrophages (CAM) may induce and support uncontrolled inflammatory responses and undesired material degradation. In contrast, polarization into alternatively activated macrophages (AAM) is assumed to support healing processes and implant integration.,This study compared the interaction of non-polarized macrophages (M0), CAM, and AAM with commercially available tissue culture polystyrene (TCP) and a medical grade silicone-based biomaterial, regarding the secretion of inflammatory mediators such as cytokines and chemokines. Firstly, by using the Limulus amoebocyte lysate (LAL) test the silicone films were shown to be free of soluble endotoxins, which is the prerequisite to investigate their interaction with primary immune cells. Primary human monocyte-derived macrophages (M0) were polarized into CAM and AAM by addition of suitable differentiation factors. These macrophage subsets were incubated on the materials for 24 hours and their viability and cytokine secretion was assessed. In comparison to TCP, cell adhesion was lower on silicone after 24 hours for all three macrophage subsets. However, compared to TCP, silicone induced higher levels of certain inflammatory and chemotactic cytokines in M0, CAM, and AAM macrophage subsets.,Conclusively, it was shown that silicone has the ability to induce a pro-inflammatory state to different magnitudes dependent on the macrophage subsets. This priming of the macrophage phenotype by silicone could explain the incidence of severe foreign body complications observed in vivo. %0 journal article %@ 0168-3659 %A Lv, J.,Hao, X.,Yang, J.,Feng, Y.,Behl, M.,Lendlein, A. %D 2015 %J Journal of Controlled Release %N %P e 60 %R doi:10.1016/j.jconrel.2015.05.099 %T PEI modified biodegradable complex micelles as gene transfer vector for proliferation of ECs %U https://doi.org/10.1016/j.jconrel.2015.05.099 %X No abstract %0 journal article %@ 2192-2659 %A Friess, F.,Noechel, U.,Lendlein, A.,Wischke, C. %D 2014 %J Advanced Healthcare Materials %N 12 %P 1986-1990 %R doi:10.1002/adhm.201400433 %T Polymer Micronetworks with Shape-Memory as Future Platform to Explore Shape-Dependent Biological Effects %U https://doi.org/10.1002/adhm.201400433 12 %X Polymer micronetworks allowing stimuli-induced, predefined, and spatially directed shape shifts. The temperature-induced on-demand switching of shape is introduced as a function of polyester carriers. With their adjustable ­switching temperature, micronetworks may serve as a model system to explore static and dynamic shape effects in biological systems. %0 journal article %@ 2050-750X %A Shi, C.,Yao, F.,Huang, J.,Han, G.,Li, Q.,Khan, M.,Feng, Y.,Zhang, W. %D 2014 %J Journal of Materials Chemistry B %N 13 %P 1825-1837 %R doi:10.1039/c3tb21601b %T Proliferation and migration of human vascular endothelial cells mediated by ZNF580 gene complexed with mPEG-b-P(MMD-co-GA)-g-PEI microparticles %U https://doi.org/10.1039/c3tb21601b 13 %X Herein, we developed a novel biodegradable gene carrier for rapid endothelialization of endothelial cells (ECs) in vitro. Three triblock amphiphilic copolymers, methoxy-poly(ethylene glycol)-block-poly(3(S)-methyl-2,5-morpholinedione-co-glycolide)-graft-polyethyleneimine (mPEG-b-P(MMD-co-GA)-g-PEI) with different 3(S)-methyl-2,5-morpholinedione and glycolide contents were synthesized. Microparticles (MPs) were obtained via self-assembly of these copolymers. The hydrophobic core composed of P(MMD-co-GA) segments provide crosslinking points for numbers of PEG and short PEI chains to form a highly hydrophilic and positively charged corona/shell of MPs. Using these MPs, potential genes (ZNF580) for rapid endothelialization were efficiently transported into EA.hy926 cells. Because of the hydrophilic PEG chains and low molecular weight PEI in the triblock copolymers, the cytotoxicity of these MPs and their complexes with pEGFP–ZNF580 was decreased significantly. The transfection efficacy of MPs/pEGFP–ZNF580 complexes was as high as Lipofectamine™ 2000 reagent to EA.hy926 cells in vitro. The proliferation and migration of EA.hy926 cells were improved greatly by the expression of pEGFP–ZNF580 after 60 hours. Our results indicated that the mPEG-b-P(MMD-co-GA)-g-PEI based MPs could be a suitable non-viral gene carrier for ZNF580 gene to enhance rapid endothelialization. %0 journal article %@ 1525-7797 %A Schoenwaelder, S.M.S.,Bally, F.,Heinke, L.,Azucena, C.,Bulut, Oe.D.,Heissler, S.,Kirschhoefer, F.,Gebauer, T.P.,Neffe, A.T.,Lendlein, A.,Brenner-Weiss, G.,Lahann, J.,Welle, A.,Overhage, J.,Woell, C. %D 2014 %J Biomacromolecules %N 7 %P 2398-2406 %R doi:10.1021/bm500750v %T Interaction of Human Plasma Proteins with Thin Gelatin-Based Hydrogel Films: A QCM-D and ToF-SIMS Study %U https://doi.org/10.1021/bm500750v 7 %X In the fields of surgery and regenerative medicine, it is crucial to understand the interactions of proteins with the biomaterials used as implants. Protein adsorption directly influences cell-material interactions in vivo and, as a result, regulates, for example, cell adhesion on the surface of the implant. Therefore, the development of suitable analytical techniques together with well-defined model systems allowing for the detection, characterization, and quantification of protein adsorbates is essential. In this study, a protocol for the deposition of highly stable, thin gelatin-based films on various substrates has been developed. The hydrogel films were characterized morphologically and chemically. Due to the obtained low thickness of the hydrogel layer, this setup allowed for a quantitative study on the interaction of human proteins (albumin and fibrinogen) with the hydrogel by Quartz Crystal Microbalance with Dissipation Monitoring (QCM-D). This technique enables the determination of adsorbant mass and changes in the shear modulus of the hydrogel layer upon adsorption of human proteins. Furthermore, Secondary Ion Mass Spectrometry and principal component analysis was applied to monitor the changed composition of the topmost adsorbate layer. This approach opens interesting perspectives for a sensitive screening of viscoelastic biomaterials that could be used for regenerative medicine. %0 journal article %@ 0142-9612 %A Ullm, S.,Krueger, A.,Tondera, C.,Gebauer, T.P.,Neffe, A.T.,Lendlein, A.,Jung, F.,Pietzsch, J. %D 2014 %J Biomaterials %N 37 %P 9755-9766 %R doi:10.1016/j.biomaterials.2014.08.023 %T Biocompatibility and inflammatory response in vitro and in vivo to gelatin-based biomaterials with tailorable elastic properties %U https://doi.org/10.1016/j.biomaterials.2014.08.023 37 %X Hydrogels prepared from gelatin and lysine diisocyanate ethyl ester provide tailorable elastic properties and degradation behavior. Their interaction with human aortic endothelial cells (HAEC) as well as human macrophages (Mɸ) and granulocytes (Gɸ) were explored. The experiments revealed a good biocompatibility, appropriate cell adhesion, and cell infiltration. Direct contact to hydrogels, but not contact to hydrolytic or enzymatic hydrogel degradation products, resulted in enhanced cyclooxygenase-2 (COX-2) expression in all cell types, indicating a weak inflammatory activation in vitro. Only Mɸ altered their cytokine secretion profile after direct hydrogel contact, indicating a comparably pronounced inflammatory activation. On the other hand, in HAEC the expression of tight junction proteins, as well as cytokine and matrix metalloproteinase secretion were not influenced by the hydrogels, suggesting a maintained endothelial cell function. This was in line with the finding that in HAEC increased thrombomodulin synthesis but no thrombomodulin membrane shedding occurred. First in vivo data obtained after subcutaneous implantation of the materials in immunocompetent mice revealed good integration of implants in the surrounding tissue, no progredient fibrous capsule formation, and no inflammatory tissue reaction in vivo. Overall, the study demonstrates the potential of gelatin-based hydrogels for temporal replacement and functional regeneration of damaged soft tissue. %0 journal article %@ 0168-3659 %A Alnasif, N.,Zoschke, C.,Fleige, E.,Brodwolf, R.,Boreham, A.,Ruehl, E.,Eckl, K.-M.,Merk, H.-F.,Hennies, H.C.,Alexiev, U.,Haag, R.,Kuechler, S.,Schaefer-Korting, M. %D 2014 %J Journal of Controlled Release %N %P 45-50 %R doi:10.1016/j.jconrel.2014.04.006 %T Penetration of normal, damaged and diseased skin - An in vitro study on dendritic core-multishell nanotransporters %U https://doi.org/10.1016/j.jconrel.2014.04.006 %X A growing intended or accidental exposure to nanoparticles asks for the elucidation of potential toxicity linked to the penetration of normal and lesional skin.,We studied the skin penetration of dye-tagged dendritic core–multishell (CMS) nanotransporters and of Nile red loaded CMS nanotransporters using fluorescence microscopy. Normal and stripped human skin ex vivo as well as normal reconstructed human skin and in vitro skin disease models served as test platforms. Nile red was delivered rapidly into the viable epidermis and dermis of normal skin, whereas the highly flexible CMS nanotransporters remained solely in the stratum corneum after 6 h but penetrated into deeper skin layers after 24 h exposure. Fluorescence lifetime imaging microscopy proved a stable dye-tag and revealed striking nanotransporter–skin interactions. The viable layers of stripped skin were penetrated more efficiently by dye-tagged CMS nanotransporters and the cargo compared to normal skin. Normal reconstructed human skin reflected the penetration of Nile red and CMS nanotransporters in human skin and both, the non-hyperkeratotic non-melanoma skin cancer and hyperkeratotic peeling skin disease models come along with altered absorption in the skin diseases. %0 journal article %@ 0044-8249 %A Wei, Q.,Becherer, T.,Angioletti-Uberti, S.,Dzubiella, J.,Wischke, C.,Neffe, A.T.,Lendlein, A.,Ballauff, M.,Haag, R. %D 2014 %J Angewandte Chemie %N 31 %P 8138-8169 %R doi:10.1002/ange.201400546 %T Wechselwirkungen von Proteinen mit Polymerbeschichtungen und Biomaterialien %U https://doi.org/10.1002/ange.201400546 31 %X Die Proteinadsorption gilt als der wichtigste Faktor der Wechselwirkung zwischen polymeren Biomaterialien und Körperflüssigkeiten oder -gewebe. Die Haupteinflussfaktoren auf die Proteinadsorption sind wasservermittelte hydrophobe und Hydratationskräfte sowie elektrostatische Wechselwirkungen. Eine systematische Analyse verschiedener Monolagen führte zur Aufstellung allgemeiner Leitsätze, den sogenannten “Whitesides-Regeln”. Diese Konzepte wurden erfolgreich auf die Entwicklung verschiedener proteinresistenter Oberflächen angewendet und werden kontinuierlich weiterentwickelt, um das Verständnis von Protein-Material-Wechselwirkungen über die bisherigen Grenzen hinaus zu erweitern. Ebenso werden die Theorien zu Proteinadsorptionsmechanismen aufgrund der sich schnell entwickelnden analytischen Technologien fortlaufend verbessert. Ziel dieses Aufsatzes ist die Verbesserung der aufgestellten empirischen Leitlinien im Hinblick auf die theoretischen und analytischen Fortschritte. Dabei werden die aktuellen analytischen Methoden zur Untersuchung mechanistischer Hypothesen und Theorien zu Protein-Oberflächen-Wechselwirkungen besprochen. Ein besonderes Augenmerk liegt auf aktuellen Technologien im Bereich bioinerter und biospezifischer Beschichtungen und ihrer Anwendungen in der Biomedizin. %0 journal article %@ 0168-3659 %A Wischke, C.,Weigel, J.,Bulavina, L.,Lendlein, A. %D 2014 %J Journal of Controlled Release %N %P 86-91 %R doi:10.1016/j.jconrel.2014.07.047 %T Sustained release carrier for adenosine triphosphate as signaling molecule %U https://doi.org/10.1016/j.jconrel.2014.07.047 %X Adenosine triphosphate (ATP) is a molecule with a fascinating variety of intracellular and extracellular biological functions that go far beyond energy metabolism. Due to its limited passive diffusion through biological membranes, controlled release systems may allow to interact with ATP-mediated extracellular processes. In this study, two release systems were explored to evaluate the capacity for either long-term or short-term release: (i) Poly[(rac-lactide)-co-glycolide] (PLGA) implant rods were capable of ATP release over days to weeks, depending on the PLGA molecular weight and end-group capping, but were also associated with partial hydrolytic degradation of ATP to ADP and AMP, but not adenosine. (ii) Thermosensitive methylcellulose hydrogels with a gelation occurring at body temperature allowed combining adjustable loading levels and the capacity for injection, with injection forces less than 50 N even for small 27G needles. Finally, a first in vitro study illustrated purinergic-triggered response of primary murine microglia to ATP released from hydrogels, demonstrating the potential relevance for biomedical applications. %0 journal article %@ 1386-0291 %A Gerk, U.,Krueger, A.,Franke, R.P.,Jung, F. %D 2014 %J Clinical Hemorheology and Microcirculation %N 1 %P 171-174 %R doi:10.3233/CH-141879 %T Effect of radiographic contrast media (Iodixanol, Iopromide) on hemolysis %U https://doi.org/10.3233/CH-141879 1 %X Radiographic contrast media can lead to drastic changes of the morphology of erythrocytes. The change of the erythrocyte morphology is associated with a decreased deformability possibly resulting from distinctions in the loss of constituents of the membrane cytoskeleton. However, it is unclear whether there is an intravascular hemolysis as a consequence of the disintegration of the erythrocyte membrane. The results of this study showed, that free haemoglobin increased from 16.8 ± 10.0 mg/dl to 21.6 ± 12.6 mg/dl after Iopromide application (p = 0.240), while it slightly decreased from 20.5 ± 10.3 mg/dl to 19.5 ± 12.2 mg/dl after Iodixanol application (p = 0.547). The slight decrease of free haemoglobin after application of Iodixanol differed significantly compared to the increase of free haemoglobin after Iopromide application (p < 0.05). This different response is thought to give evidence to the assumption that the erythrocyte membrane integrity was compromised leading to the release of free haemoglobin as an indicator of hemolysis as well. %0 journal article %@ 2046-2069 %A Filice, M.,Romero, O.,Abian, O.,de las Rivas, B.,Polomo, J.M. %D 2014 %J RSC Advances %N 90 %P 49115-49122 %R doi:10.1039/C4RA07625G %T Low ionic liquid concentration in water: A green and simple approach to improve activity and selectivity of lipases %U https://doi.org/10.1039/C4RA07625G 90 %X The activity of several commercial and genetically engineered lipases, already immobilized on octyl-Sepharose, in aqueous solutions containing ionic liquids (ILs) in a molar concentration of 0.01 mol L−1 was investigated. Strong variations in the hydrolytic activity values were found depending on the lipase, the ionic liquid and the substrate used. The most interesting results were found in the engineered variants of Geobacillus thermocatenolatus lipase (GTL). The activity of GTLσ-L230C variant in the monodeacetylation of per-acetylated glucal increased seven fold when using 1-ethyl-3-methylimidazoliumhexafluorophosphate [emim[PF6] and fivefold when using 1-ethyl-3-methylimidazolium methyl sulphate [emim][MeSO3]. In general, ILs containing BF4− had a very negative effect on the enzyme activity. Moreover, improvements in the enantio and regioselectivity of the immobilized lipases were obtained by adding ILs to the reaction medium. The regioselectivity of Candida rugosa lipase in the hydrolysis of peracetylated thymidine improved (from 72% to 81% yield of C-5 monodeprotected product) in the presence of [emim][PF6]. More interestingly, the addition of 1-butyl-2,3-dimethylimidazolium hexafluorophosphate [bdmim][PF6] improved the regioselectivity of immobilized GTLσ-L230C variant in the hydrolysis of peracetylated glucal, from 78% to 96% yield of the C-3 monodeprotected product. Circular dichroism and fluorescence experiments revealed conformational changes in the tertiary structure of the enzyme induced by the ionic liquid which could explain these phenomena. %0 journal article %@ 1386-0291 %A Braune, S.,Walter, M.,Schulze, F.,Lendlein, A.,Jung, F. %D 2014 %J Clinical Hemorheology and Microcirculation %N 1 %P 159-170 %R doi:10.3233/CH-141876 %T Changes in platelet morphology and function during 24 hours of storage %U https://doi.org/10.3233/CH-141876 1 %X For in vitro studies assessing the interaction of platelets with implant materials, common and standardized protocols for the preparation of platelet rich plasma (PRP) are lacking, which may lead to non-matching results due to the diversity of applied protocols. Particularly, the aging of platelets during prolonged preparation and storage times is discussed to lead to an underestimation of the material thrombogenicity. Here, we study the influence of whole blood- and PRP-storage times on changes in platelet morphology and function. Blood from apparently healthy subjects was collected according to a standardized protocol and examined immediately after blood collection, four hours and twenty four hours later. The capability of platelets to adhere and form stable aggregates (PFA100, closure time) was examined in sodium citrate anticoagulated whole blood (WB) using the agonists equine type I collagen and epinephrine bitartrate (collagen/epinephrine) as well as equine type I collagen and adenosine-5′-diphosphate (collagen/ADP). Circulating platelets were quantified at each time point. Morphology of platelets and platelet aggregates were visualized microscopically and measured using an electric field multi-channel counting system (CASY). The percentage of activated platelets was assessed by means of P-selectin (CD62P) expression of circulating platelets. Furthermore, platelet factor 4 (PF4) release was measured in platelet poor plasma (PPP) at each time point. Whole blood PFA100 closure times increased after stimulation with collagen/ADP and collagen/epinephrine. Twenty four hours after blood collection, both parameters were prolonged pathologically above the upper limit of the reference range. Numbers of circulating platelets, measured in PRP, decreased after four hours, but no longer after twenty four hours. Mean platelet volumes (MPV) and platelet large cell ratios (P-LCR, 12 fL – 40 fL) decreased over time. Immediately after blood collection, no debris or platelet aggregates could be visualized microscopically. After four hours, first debris and very small aggregates occurred. After 24 hours, platelet aggregates and also debris progressively increased. In accordance to this, the CASY system revealed an increase of platelet aggregates (up to 90 μm diameter) with increasing storage time. The percentage of CD62P positive platelets and PF4 increased significantly with storage time in resting PRP. When soluble ADP was added to stored PRP samples, the number of activatable platelets decreased significantly over storage time. The present study reveals the importance of a consequent standardization in the preparation of WB and PRP. Platelet morphology and function, particularly platelet reactivity to adherent or soluble agonists in their surrounding milieu, changed rapidly outside the vascular system. This knowledge is of crucial interest, particularly in the field of biomaterial development for cardiovascular applications, and may help to define common standards in the in vitro hemocompatibility testing of biomaterials. %0 journal article %@ 0167-577X %A Wong, T.W.,Wahit, M.U.,Kadir, M.R.A.,Soheilmoghaddam, M.,Balakrishnan, H. %D 2014 %J Materials Letters %N %P 105-108 %R doi:10.1016/j.matlet.2014.04.020 %T A novel poly(xylitol-co-dodecanedioate)/hydroxyapatite composite with shape-memory behaviour %U https://doi.org/10.1016/j.matlet.2014.04.020 %X A novel shape-memory polymer, poly(xylitol-co-dodecanedioate) (PXDD) was developed and the effect of hydroxyapatite (HA) in PXDD/HA composites on the chemical interactions, shape-memory and crystallization behaviours was studied. FTIR confirmed the formation of PXDD and also showed that the chemical structure did not change with the addition of HA. DSC and XRD revealed that the degree of crystallinity (Xc) of PXDD/HA composites improved in parallel to increasing HA content. The permanent shape is recovered with a precision of almost 100% as soon as the recovery temperature (Trec=48 °C) is reached. The findings of the study showed that PXDD/HA composites have great potential as shape-memory implant in minimal invasive surgeries. %0 journal article %@ 1549-9634 %A Ostrowski, A.,Nordmeyer, D.,Boreham, A.,Brodwolf, R.,Mundhenk, L.,Fluhr, J.W.,Lademann, J.,Graf, C.,Ruehl, E.,Alexiev, U.,Gruber, A.D. %D 2014 %J Nanomedicine: Nanotechnology, Biology and Medicine %N 7 %P 1571-1581 %R doi:10.1016/j.nano.2014.04.004 %T Skin barrier disruptions in tape stripped and allergic dermatitis models have no effect on dermal penetration and systemic distribution of AHAPS-functionalized silica nanoparticles %U https://doi.org/10.1016/j.nano.2014.04.004 7 %X The skin is a potential site of entry for nanoparticles (NP) but the role of disease-associated barrier disturbances on the path and extent of skin penetration of NP remains to be characterized. Silica nanoparticles (SiO2-NP) possess promising potential for various medical applications. Here,,effects of different skin barrier disruptions on the penetration of N-(6-aminohexyl)-aminopropyltrimethoxysilane (AHAPS) functionalized SiO2-NP,were studied. AHAPS-SiO2-NP (55 ± 6 nm diameter)were topically applied on intact, tape stripped or on inflamed skin of SKH1 mice with induced allergic contact dermatitis for one or five consecutive days, respectively. Penetration of AHAPS-SiO2-NP through the skin was not observed regardless of the kind of barrier disruption. However, only after subcutaneous injection, AHAPS-SiO2-NP were incorporated by macrophages and transported to the regional lymph node only. Adverse effects on cells or tissues were not observed. In conclusion, AHAPS-SiO2-NP seemto not cross the normal or perturbed mouse skin. %0 journal article %@ 1042-7147 %A Boreham, A.,Brodwolf, R.,Pfaff, M.,Kim, T.-Y.,Schlieter, T.,Mundhenk, L.,Gruber, A.D,Groeger, D.,Licha, K.,Haag, R.,Alexiev, U. %D 2014 %J Polymers for Advanced Technologies %N 11 %P 1329-1336 %R doi:10.1002/pat.3355 %T Temperature and environment dependent dynamic properties of a dendritic polyglycerol sulfate %U https://doi.org/10.1002/pat.3355 11 %X Structural changes within dendritic polymer scaffolds may influence the polymer's behavior in biological relevant systems such as tissues and cells. A dendritic polyglycerol sulfate (dPGS) was recently found to act as an inhibitor of inflammatory processes. Here, we investigated the molecular dynamics and environmental sensitivity of dPGS using an indocarbocyanine (ICC) labeled variant (dPGS-ICC). The environmental sensitivity was demonstrated by UV/Vis and fluorescence spectroscopic characterization of dPGS-ICC in different solvents. In particular, fluorescence lifetime measurements revealed additional information on the local dye environment that manifest themselves in characteristic fluorescence lifetime signatures depending on the solvent. Furthermore, the interaction of dPGS-ICC with a model cell system—giant unilamellar vesicles (GUVs)—was studied with fluorescence lifetime imaging microscopy. We observed that dPGS-ICC is enriched in the membrane but does not penetrate into the lumen of the GUV. The characteristic lifetime signature of dPGS-ICC within the lipid membrane (τmean = 1.6 ns) was clearly different from that obtained for dPGS-ICC in aqueous solution (τmean = 0.42 ns) and can thus be employed to dissect differential interactions of dPGS in tissue. By using time-resolved fluorescence depolarization, we further showed that the size of dPGS shrinks by nearly 50% above 30 °C. These results contribute to a further understanding of dPGS structure and dynamics and may help to provide tailor-made polymer architectures for biomedical applications. %0 journal article %@ 1381-5148 %A Lv, J.,Zhang, L.,Khan, M.,Ren, X.,Guo, J.,Feng, Y. %D 2014 %J Reactive and Functional Polymers %N %P 89-97 %R doi:10.1016/j.reactfunctpolym.2014.06.005 %T Biodegradable depsipeptide–PDO–PEG-based block copolymer micelles as nanocarriers for controlled release of doxorubicin %U https://doi.org/10.1016/j.reactfunctpolym.2014.06.005 %X Nowadays, biodegradable amphiphilic block copolymers with stable performance and adjustable structure have attracted the interests of researchers in the field of drug delivery. In this work, the triblock copolymer, P(SBMD-co-PDO)-b-PEG-b-P(SBMD-co-PDO), was successfully synthesized by ring-opening polymerization of 3(S)-sec-butyl-morpholine-2,5-dione (SBMD) and p-dioxanone (PDO) with poly(ethylene glycol) (PEG) as the initiator. In phosphate buffered solution (PBS), these copolymers could self-assemble into nano-sized micelles that have a hydrophobic P(SBMD-co-PDO) core surrounded by a hydrophilic PEG shell. Because of the strong hydrogen bonding and hydrophobic interactions, doxorubicin (DOX) was loaded into the micelles with high loading capacity (LC, up to 28.4%) and encapsulation efficiency (EE, up to 62.5%). %0 journal article %@ 1433-7851 %A Wei, Q.,Becherer, T.,Angioletti-Uberti, S.,Dzubiella, J.,Wischke, C.,neffe, A.T.,Lendlein, A.,Ballauff, M.,Haag, R. %D 2014 %J Angewandte Chemie - International Edition %N 31 %P 8004-8031 %R doi:10.1002/anie.201400546 %T Protein Interactions with Polymer Coatings and Biomaterials %U https://doi.org/10.1002/anie.201400546 31 %X Protein adsorption is considered to be the most important factor of the interaction between polymeric biomaterials and body fluids or tissues. Water-mediated hydrophobic and hydration forces as well as electrostatic interactions are believed to be the major factors of protein adsorption. A systematic analysis of various monolayer systems has resulted in general guidelines, the so-called “Whitesides rules”. These concepts have been successfully applied for designing various protein-resistant surfaces and are being studied to expand the understanding of protein–material interactions beyond existing limitations. Theories on the mechanisms of protein adsorption are constantly being improved due to the fast-developing analytical technologies. This Review is aimed at improving these empirical guidelines with regard to present theoretical and analytical advances. Current analytical methods to test mechanistic hypotheses and theories of protein–surface interactions will be discussed. Special focus will be given to state-of-the-art bioinert and biospecific coatings and their applications in biomedicine. %0 journal article %@ 1042-7147 %A Neffe, A.T.,Chua, K.,Luetzow, K.,Pierce, B.F.,Lendlein, A.,Abell, A.D. %D 2014 %J Polymers for Advanced Technologies %N 11 %P 1371-1375 %R doi:10.1002/pat.3359 %T Crosslinking of gelatin by ring opening metathesis under aqueous conditions - An exploratory study %U https://doi.org/10.1002/pat.3359 11 %X Ring-opening metathesis catalysis has received little attention as a means to functionalize or crosslink biopolymers in water since the required catalysts are usually not stable under these conditions. However, biopolymer solubility suggests such a procedure. We show that Grubbs first and second generation catalysts (in emulsion) as well as a water-soluble Hoveyda-Grubbs catalyst can be applied to crosslink glycidyl methacrylated gelatin with norbornene dicarboxylic acid in water by a cross metathesis-ring opening metathesis approach. A mechanistic study suggests that cross metathesis between the functionalized polymer and the cyclic olefin acts as an initiating step for the crosslinking reaction. %0 journal article %@ 1386-0291 %A Franke, R.P.,Scharnweber, T.,Fuhrmann, R.,Mrowietz, C.,Wenzel, F.,Krueger, A.,Jung, F. %D 2014 %J Clinical Hemorheology and Microcirculation %N 1 %P 49-63 %R doi:10.3233/CH-141894 %T Radiographic contrast media alterate the localization of actin/band4.9 in the membrane cytoskeleton of human erythrocytes %U https://doi.org/10.3233/CH-141894 1 %X Different radiographic contrast media (RCM) were shown to induce morphological changes of blood cells (e.g. erythrocytes or thrombocytes) and endothelial cells. The echinocytic shape change of erythrocytes, particularly, affords alterations of the membrane cytoskeleton. The cytoskeleton plays a crucial role for the shape and deformability of the red blood cell. Disruption of the interaction between components of the red blood cell membrane cytoskeleton may cause a loss of structural and functional integrity of the membrane. In this study band4.9 and actin as components of the cytoskeletal junctional complex were examined in human erythrocytes after suspension in autologous plasma or in plasma RCM mixtures (30% v/v Iodixanol-320 or Iopromide-370) followed by a successive double staining with TRITC-/FITC-coupled monoclonal antibodies. After adding Iopromide-370 to the plasma in practically none of the cells the rounded conformation of the membrane cytoskeleton – as it appeared in cells suspended in autologous plasma – was found. In addition, Iopromide-370 induced thin lines and coarse knob-like structures of band4.9 at the cell periphery while most cell centers were devoid of band4.9, and a box-like arrangement of bands of band4.9. A dissociation between colours red (actin) and green (band4.9) occurred as well. In contrast, erythrocytes suspended in a plasma/Iodixanol-320 mixture showed a membrane cytoskeleton comparable to cells suspended in autologous plasma, Similar results were found with respect to the distribution of actin. This study revealed for the first time RCM-dependent differences in band4.9 activities as possible pathophysiological mechanism for the chemotoxicity of radiographic contrast media. %0 journal article %@ 1386-0291 %A Roch, T.,Schulz, C.,Jung, F.,Ma, N.,Lendlein, A. %D 2014 %J Clinical Hemorheology and Microcirculation %N 2 %P 203-212 %R doi:10.3233/CH-141831 %T Interaction of poly(ether imide) films with early immune mechanisms %U https://doi.org/10.3233/CH-141831 2 %X With the worldwide increase of atherosclerosis, the need for new engineered patient specific implants such as stents or vascular grafts is still emerging. Recently, very smooth poly(ether imide) (PEI) films were, based on their excellent hemocompatibility and compatibility with endothelial cells, suggested as potential biomaterial for cardiovascular applications. In atherosclerosis, immune mechanisms such as complement activation, but also cellular responses such as monocytes and neutrophils activation, can mediate the inflammatory response. Therefore, it is important that the implant material itself does not trigger the inflammatory response. Early immune mechanisms - e.g. macrophage activation, complement induction, generation of reactive oxygen species (ROS), and the secretion of inflammatory cytokines by leukocytes - could potentiate the inflammatory responses, and may thereby alter endothelial cells behaviour or facilitate platelet activation. Therefore, it is important to evaluate the immuno-compatibility of PEI-films. The PEI-films were fabricated from commercially available PEI, which was dissolved in dichloromethane and pulled out on a cleaned, smooth glass surface and subsequently, solvent residues were removed during the drying procedure. Using a murine macrophage reporter cell line possible material bound microbial contaminations and material intrinsic immuno-stimulatory properties were investigated. The macrophages were viable after adhering on the PEI-films and did not show signs of activation, indicating that the used PEI-film was free of microbial contaminations. To determine whether PEI-films induced complement activation, the release of C5a in pooled human plasma was analyzed. The detected C5a levels did not differ between PEI-films and tissue culture plates (TCP), which served as control material. Furthermore, in whole human blood, the generation of ROS as well as the cytokine production were investigated by flow cytometry and by multiplex bead arrays, respectively. The production of IL-6 and TNF-α as well as the generation of ROS by immune cells of the whole blood was not induced upon contact with PEI-films. The immunological evaluation of PEI-films revealed that no substantial activation of the investigated early immune mechanisms occurred. Altogether, this data demonstrate that PEI is immuno-compatible and from that perspective may be a suitable biomaterial for cardiovascular applications. %0 journal article %@ 0939-6411 %A Mathew, S.,Lendlein, A.,Wischke, C. %D 2014 %J European Journal of Pharmaceutics and Biopharmaceutics %N 2 %P 403-407 %R doi:10.1016/j.ejpb.2014.04.003 %T Characterization of protein-adjuvant coencapsulation in microparticles for vaccine delivery %U https://doi.org/10.1016/j.ejpb.2014.04.003 2 %X Protein antigens encapsulated as vaccines in poly[(rac-lactide)-co-glycolide] (PLGA) microparticle carriers can induce immune responses. The intensity and directions of this response can be controlled by coloading the microparticles with immunomodulatory adjuvants, e.g., muramyl dipeptide (MDP) as adjuvant combined with ovalbumin (Ova) as protein antigen. In this study, methodologies for an individual quantification of both encapsulated substances should be reported, which comprise (i) a separation process to isolate and determine MDP as intact molecule and (ii) a simultaneous degradation of both analytes with subsequent specific quantification of Ova fragments. It was shown that coloading of both substances resulted in a substantially reduced encapsulation efficiency of MDP. This illustrates that correct conclusions on dose–response relationships in future vaccination studies can only be drawn, if a selective method for adjuvant and protein quantification will be applied. %0 journal article %@ 0028-0836 %A Shen, P.,Roch, T.,Lampropoulou, V.,O´Connor, R.A.,Stervbo, U.,Hilgenberg, E.,Ries, S.,Dang, V.D.,Jaimes, Y.,Daridon, C.,Li, R.,Jouneau, L.,Boudinot, P.,Wilantri, S.,Sakwa, I.,Miyazaki, Y.,Leech, M.D.,McPherson, R.C.,Wirtz, S.,Neurath, M.,Hoehlig, K.,Meinl, E.,Gruetzkau, A.,Gruen, J.R.,Horn, K.,Kuehl, A.A.,Doerner, T.,Bar-Or, A.,Kaufmann, A.H.E.,Anderton, S.M.,Fillatreau, S. %D 2014 %J Nature %N 7492 %P 366-370 %R doi:10.1038/nature12979 %T IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases %U https://doi.org/10.1038/nature12979 7492 %X B lymphocytes have critical roles as positive and negative regulators of immunity. Their inhibitory function has been associated primarily with interleukin 10 (IL-10) because B-cell-derived IL-10 can protect against autoimmune disease and increase susceptibility to pathogens1, 2. Here we identify IL-35-producing B cells as key players in the negative regulation of immunity. Mice in which only B cells did not express IL-35 lost their ability to recover from the T-cell-mediated demyelinating autoimmune disease experimental autoimmune encephalomyelitis (EAE). In contrast, these mice displayed a markedly improved resistance to infection with the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium as shown by their superior containment of the bacterial growth and their prolonged survival after primary infection, and upon secondary challenge, compared to control mice. The increased immunity found in mice lacking IL-35 production by B cells was associated with a higher activation of macrophages and inflammatory T cells, as well as an increased function of B cells as antigen-presenting cells (APCs). During Salmonella infection, IL-35- and IL-10-producing B cells corresponded to two largely distinct sets of surface-IgM+CD138hiTACI+CXCR4+CD1dintTim1int plasma cells expressing the transcription factor Blimp1 (also known as Prdm1). During EAE, CD138+ plasma cells were also the main source of B-cell-derived IL-35 and IL-10. Collectively, our data show the importance of IL-35-producing B cells in regulation of immunity and highlight IL-35 production by B cells as a potential therapeutic target for autoimmune and infectious diseases. This study reveals the central role of activated B cells, particularly plasma cells, and their production of cytokines in the regulation of immune responses in health and disease. %0 journal article %@ 1613-6810 %A Wischke, C.,Schossig, M.,Lendlein, A. %D 2014 %J Small %N 1 %P 83-87 %R doi:10.1002/smll.201202213 %T Shape-Memory Effect of Micro-/Nanoparticles from Thermoplastic Multiblock Copolymers %U https://doi.org/10.1002/smll.201202213 1 %X The miniaturization and retained full shape-memory functionality with particle switching to different predefined shapes is reported for semi-crystalline multiblock copolymer matrices with all dimensions in the low micrometer-range. A matrix size-induced reduction of crystallinity suggests limitations of functionality in the low nanometer range. Applications as actuators in microdevices or as microcarriers with switchable shapes for modulated biorecognition are suggested. %0 journal article %@ 1022-1352 %A Ghobadi, E.,Heuchel, M.,Kratz, K.,Lendlein, A. %D 2014 %J Macromolecular Chemistry and Physics %N 1 %P 65-75 %R doi:10.1002/macp.201300507 %T Atomistic Simulation of the Shape-Memory Effect in Dry and Water Swollen Poly[(rac-lactide)-co-glycolide] and Copolyester Urethanes Thereof %U https://doi.org/10.1002/macp.201300507 1 %X An atomistic molecular dynamics simulation approach is applied to model the influence of urethane linker units as well as the addition of water molecules on the simulated shape-memory properties of poly[(rac-lactide)-co-glycolide] (PLGA) and PLGA-based copolyester urethanes comprising different urethane linkers. The shape-memory performance of these amorphous packing models is explored in a simulated heating–deformation–cooling–heating procedure. Depending on the type of incorporated urethane linker, the mechanical properties of the dry copolyester urethanes are found to be significantly improved compared with PLGA, which can be attributed to the number of intermolecular hydrogen bonds between the urethane units. Good shape-memory properties are observed for all the modeled systems. In the dry state, the shape fixation is found to be improved by implementation of urethane units. After swelling of the copolymer models with water, which results in a reduction of their glass transition temperatures, the relaxation kinetics during unloading and shape recovery are found to be substantially accelerated. %0 journal article %@ 1932-6203 %A Franke, R.-P.,Scharnweber, T.,Fuhrmann, R.,Wenzel, F.,Krueger, A.,Mrowietz, C.,Jung, F. %D 2014 %J PLoS One %N 2 %P e89512 %R doi:10.1371/journal.pone.0089512 %T Effect of Radiographic Contrast Media on the Spectrin/Band3-Network of the Membrane Skeleton of Erythrocytes %U https://doi.org/10.1371/journal.pone.0089512 2 %X The membrane of red blood cells consists of a phospholipid bilayer with embedded membrane proteins and is associated on the cytoplasmatic side with a network of proteins, the membrane skeleton. Band3 has an important role as centre of the functional complexes e.g. gas exchange complex and as element of attachment for the membrane skeleton maintaining membrane stability and flexibility. Up to now it is unclear if band3 is involved in the morphology change of red blood cells after contact with radiographic contrast media. The study revealed for the first time that Iopromide induced markedly more severe alterations of the membrane skeleton compared to Iodixanol whose effects were similar to erythrocytes suspended in autologous plasma. A remarkable clustering of band3 was found associated with an accumulation of band3 in spicules and also a sequestration of band3 to the extracellular space. This was evidently accompanied by a gross reduction of functional band3 complexes combined with a dissociation of spectrin from band3 leading to a loss of homogeneity of the spectrin network. It could be demonstrated for the first time that RCM not only induced echinocyte formation but also exocytosis of particles at least coated with band3. %0 journal article %@ 1525-7797 %A Wei, Q.,Becherer, T.,Mutihac, R.-C.,Noeske, P.-L.M.,Paulus, F.,Haag, R.,Grunwald, I. %D 2014 %J Biomacromolecules %N 8 %P 3061-3071 %R doi:10.1021/bm500673u %T Multivalent Anchoring and Cross-Linking of Mussel-Inspired Antifouling Surface Coatings %U https://doi.org/10.1021/bm500673u 8 %X In this work, we combine nature’s amazing bioadhesive catechol with the excellent bioinert synthetic macromolecule hyperbranched polyglycerol (hPG) to prepare antifouling surfaces. hPG can be functionalized by different amounts of catechol groups for multivalent anchoring and cross-linking because of its highly branched architecture. The catecholic hPGs can be immobilized on various surfaces including metal oxides, noble metals, ceramics, and polymers via simple incubation procedures. The effect of the catechol amount on the immobilization, surface morphology, stability, and antifouling performance of the coatings was studied. Both anchoring and cross-linking interactions provided by catechols can enhance the stability of the coatings. When the catechol groups on the hPG are underrepresented, the tethering of the coating is not effective; while an overrepresentation of catechol groups leads to protein adsorption and cell adhesion. Thus, only a well-balanced amount of catechols as optimized and described in this work can supply the coatings with both good stability and antifouling ability. %0 journal article %@ 1022-1352 %A Di Lorenzo, F.,Seiffert, S. %D 2014 %J Macromolecular Chemistry and Physics %N 21 %P 2097-2111 %R doi:10.1002/macp.201400317 %T Tracer Diffusion in Heterogeneous Polymer Networks %U https://doi.org/10.1002/macp.201400317 21 %X The diffusion of linear polymer chains in swollen polymer networks is studied with different extents of spatial heterogeneity of their crosslinking density. Structural heterogeneity is imparted to these gels by photo-crosslinking of polymer precursor chains in semidilute solution, which comprise either just one batch of precursors, yielding gels with just a little spatial heterogeneity, or mixtures of two different batches of precursors, one with high and one with low degree of functionalization with crosslinkable moieties, yielding gels with more pronounced heterogeneity. In addition, heterogeneous gels are also prepared from crosslinkable precursor chains and defined fractions of pre-crosslinked microgel particles that serve as doped-in nanometer-scale domains of high local crosslinking density. The resulting gels are probed by static light scattering and shear rheology, and the self-diffusion of fluorescent linear tracer chains within the gels is studied by fluorescence recovery after photobleaching. The outcome of these investigations is that spatial heterogeneity of a given crosslinking density in swollen polymer networks decreases their ability to store mechanical deformation energy, but has no marked impact on the above-micrometer-scale diffusivity of linear tracer chains. %0 journal article %@ 2046-2069 %A Schmidt, C.,Behl, M.,Lendlein, A.,Beuermann, S. %D 2014 %J RSC Advances %N 66 %P 35099-35105 %R doi:10.1039/c4ra06815g %T Synthesis of high molecular weight polyglycolide in supercritical carbon dioxide %U https://doi.org/10.1039/c4ra06815g 66 %X Polyglycolide (PGA) is a biodegradable polymer with multiple applications in the medical sector. Here the synthesis of high molecular weight polyglycolide by ring-opening polymerization of diglycolide is reported. For the first time stabilizer free supercritical carbon dioxide (scCO2) was used as a reaction medium. scCO2 allowed for a reduction in reaction temperature compared to conventional processes. Together with the lowering of monomer concentration and consequently reduced heat generation compared to bulk reactions thermal decomposition of the product occurring already during polymerization is strongly reduced. The reaction temperatures and pressures were varied between 120 and 150 °C and 145 to 1400 bar. Tin(II) ethyl hexanoate and 1-dodecanol were used as catalyst and initiator, respectively. The highest number average molecular weight of 31200 g mol−1 was obtained in 5 hours from polymerization at 120 °C and 530 bar. In all cases the products were obtained as a dry white powder. Remarkably, independent of molecular weight the melting temperatures were always at (219 ± 2) °C. %0 journal article %@ 1386-0291 %A Schulz, C.,Ruesten-Lange, M.v.,Krueger, A.,Lendlein, A.,Jung, F. %D 2014 %J Clinical Hemorheology and Microcirculation %N 2 %P 147-158 %R doi:10.3233/CH-141826 %T Adherence and shear-resistance of primary human endothelial cells on smooth poly(ether imide) films %U https://doi.org/10.3233/CH-141826 2 %X BACKGROUND: Occlusions of artificial small-diameter cardiovascular grafts are frequent events after implantation, often caused by clot formations. A main factor is the insufficient hemocompatibility of the inner artificial graft surface, which could be improved by endothelialization. Therefore, one challenge in cardiovascular graft engineering is the establishment of a shear-resistant endothelial cell layer to prevent cell detachment by shear forces after implantation. MATERIALS AND METHODS: Recently, very smooth (Rq = 2.37 ± 1.40 nm) poly(ether imide) (PEI) films were introduced as a biocompatible candidate material for cardiovascular devices. In this study the stability of primary human umbilical vein endothelial cell (HUVEC) monolayer was investigated after long-term seeding (9 days) on PEI-films and subsequent exposure to a venous shear stress of 3 dyn/cm2 for up to 6 hours using the cone-and-plate shearing technique. Cell density, growth pattern and morphology of HUVEC were determined prior and after shearing compared to glass as control substrate. HUVEC adhering to the substrate after shear stress were counted and analyzed by fluorescent staining. Supernatants were collected and secretion profile analysis of vasoactive and inflammatory mediators was performed. RESULTS: The cell density on PEI-films compared to the controls was slightly higher after long-term seeding and exposure to shear stress (glass: 71,656 ± 8,830 cells/cm2 and 42,239 ± 5,607 cells/cm2; PEI-film: 64,056 ± 2,829 cells/cm2 and 45,422 ± 2,507 cells/cm2 before and after shear stress, respectively). Actin- and vinculin-staining revealed a scattered re-organization of the cytoskeleton as well as a formation of stress fibers and focal adhesion points. Secretion of prostacyclin and thromboxane A2 was increased after application of shear stress, but no significant differences were detectable between cells growing on PEI-films or glass. Amounts of secreted inflammatory cytokines IL-6 and IL-8 in the supernatant were significantly lower for HUVEC seeded on PEI-films compared to glass before as well as after stress. CONCLUSION: The study demonstrated that HUVEC were able to resist exposure to venous shear stress when seeded on smooth PEI-films with typical morphology and adhesion behavior. However, HUVEC adherence on PEI was not yet sufficient to retain a complete cell monolayer after shear stress exposure. Occasionally, single cells or cell plaques were disrupted resulting in cell free areas in the confluent HUVEC layer. Apart from this our data suggest that PEI is a suitable substrate for HUVEC under static and dynamic conditions and therefore a promising candidate material for cardiovascular applications. The next objective is a surface functionalization of the PEI-films in a cell specific manner to reach a functionally confluent, shear resistant HUVEC monolayer. %0 journal article %@ 2050-750X %A Neffe, A.T.,Ruesten-Lange, M.v.,Braune, S.,Luetzow, K.,Roch, T.,Richau, K.,Krueger, A.,Becherer, T.,Thuenemann, A.F.,Jung, F.,Haag, R.,Lendlein, A. %D 2014 %J Journal of Materials Chemistry B %N 23 %P 3626-3635 %R doi:10.1039/C4TB00184B %T Multivalent grafting of hyperbranched oligo- and polyglycerols shielding rough membranes to mediate hemocompatibility %U https://doi.org/10.1039/C4TB00184B 23 %X Hemocompatible materials are needed for internal and extracorporeal biomedical applications, which should be realizable by reducing protein and thrombocyte adhesion to such materials. Polyethers have been demonstrated to be highly efficient in this respect on smooth surfaces. Here, we investigate the grafting of oligo- and polyglycerols to rough poly(ether imide) membranes as a polymer relevant to biomedical applications and show the reduction of protein and thrombocyte adhesion as well as thrombocyte activation. It could be demonstrated that, by performing surface grafting with oligo- and polyglycerols of relatively high polydispersity (>1.5) and several reactive groups for surface anchoring, full surface shielding can be reached, which leads to reduced protein adsorption of albumin and fibrinogen. In addition, adherent thrombocytes were not activated. This could be clearly shown by immunostaining adherent proteins and analyzing the thrombocyte covered area. The presented work provides an important strategy for the development of application relevant hemocompatible 3D structured materials. %0 journal article %@ 1042-7147 %A Lendlein, A.,Domb, A.J.,Baudis, S.,Behl, M. %D 2014 %J Polymers for Advanced Technologies %N 11 %P 1187-1188 %R doi:10.1002/pat.3377 %T From macromolecules to materials to systems %U https://doi.org/10.1002/pat.3377 11 %X No abstract %0 journal article %@ 0032-3861 %A Razzaq, M.Y.,Behl, M.,Noechel, U.,Lendlein, A. %D 2014 %J Polymer %N 23 %P 5953-5960 %R doi:10.1016/j.polymer.2014.07.025 %T Magnetically controlled shape-memory effects of hybrid nanocomposites from oligo(Omega-pentadecalactone) and covalently integrated magnetite nanoparticles %U https://doi.org/10.1016/j.polymer.2014.07.025 23 %X The covalent integration of inorganic nanoparticles in polymer matrices has gained significance for improving the structural properties of polymer-based materials. Here we report on the performance of poly(ω-pentadecalactone) networks with magnetite nanoparticles as netpoints in their magnetically-controlled shape-memory capability. Hybrid nanocomposites with magnetite nanoparticle content ranging from 5 to 11 wt% were prepared by reacting two types of oligo(ω-pentadecalactone) (OPDL) based precursors with terminal hydroxy groups, a three arm OPDL (3AOPDL, Mn = 6000 g mol−1) and an OPDL (Mn = 3300 g mol−1) coated magnetite nanoparticle (∅ = 10 nm), with a diisocyanate. Homogenous hybrid nanocomposites were obtained independent from the weight content of the OPDL decorated nanoparticles in the samples. At 100 °C (T > Tm-OPDL) the covalent integration of the nanoparticles increased the mechanical strength with increasing weight content whereby the elasticity remained almost constant. In magnetically-controlled one-way dual-shape experiments the shape fixity decreased from 95% to 90% but the shape recovery increased slightly from 95% to 97% when the nanoparticle content was increased. In magnetically-controlled reversible dual-shape experiments the nanoparticles had a restraining effect and the maximum shape-change of 65% for hybrid nanocomposites with 5 wt% magnetite nanoparticles was reduced to 36% when the particle content was increased to 11 wt%. These results show that the performance of hybrid nanocomposites can be tailored by nanoparticle content, however in terms of their applicability either mechanical strength or actuation capability should be focussed in the material selection. %0 journal article %@ 1422-0067 %A Franke, R.-P.,Krueger, A.,Scharnweber, T.,Wenzel, F.,Jung, F. %D 2014 %J International Journal of Molecular Sciences %N 9 %P 16134-16152 %R doi:10.3390/ijms150916134 %T Effects of Radiographic Contrast Media on the Micromorphology of the Junctional Complex of Erythrocytes Visualized by Immunocytology %U https://doi.org/10.3390/ijms150916134 9 %X Effects of radiographic contrast media (RCM) application were demonstrated in vitro and in vivo where the injection of RCM into the A. axillaris of patients with coronary artery disease was followed by a significant and RCM-dependent decrease of erythrocyte velocity in downstream skin capillaries. Another study in pigs revealed that the deceleration of erythrocytes coincided with a significant reduction of the oxygen partial pressure in the myocardium—supplied by the left coronary artery—after the administration of RCM into this artery. Further reports showed RCM dependent alterations of erythrocytes like echinocyte formation and exocytosis, sequestration of actin or band 3 and the buckling of endothelial cells coinciding with a formation of interendothelial fenestrations leading to areas devoid of endothelial cells. Key to morphological alterations of erythrocytes is the membrane cytoskeleton, which is linked to the band 3 in the erythrocyte membrane via the junctional complex. Fundamental observations regarding the cell biological and biochemical aspects of the structure and function of the cell membrane and the membrane cytoskeleton of erythrocytes have been reported. This review focuses on recent results gained, e.g., by advanced confocal laser scanning microscopy of different double-stained structural elements of the erythrocyte membrane cytoskeleton. %0 journal article %@ 1042-7147 %A Friess, F.,Lendlein, A.,Wischke, C. %D 2014 %J Polymers for Advanced Technologies %N 11 %P 1285-1292 %R doi:10.1002/pat.3313 %T Photoinduced synthesis of polyester networks from methacrylate functionalized precursors: analysis of side reactions %U https://doi.org/10.1002/pat.3313 11 %X Polyester networks can be prepared by ultraviolet (UV)-light-induced radical polymerization of methacrylate functionalized oligo(ε-caprolactone)s. The properties and functions of the obtained materials depend on defined network structures and may be altered, if crosslinking would occur by side reactions in other positions than the methacrylate endgroups. In order to explore whether and to which extent such side reactions occur, network synthesis as well as related model reactions were performed in the absence of photoinitiator. Hereby precursor structures (linear and four-arm star-shaped) and reaction conditions (in solution and in the melt) were varied. Unspecific side reactions were found only upon extensive UV irradiation for 60 min (26 mW cm-2) with minor but detectable alterations of physicochemical properties of the networks. The analysis of model reactions suggested minor photolytic cleavage of ester bonds during polymer network synthesis. However, the effect of these side reactions on network properties and functions appeared to be less relevant than an incomplete precursor integration because of a too short UV irradiation for crosslinking. %0 journal article %@ 0006-355X %A Hardeman, M.,Alexy, T.,Brouwer, B.,Connes, P.,Jung, F.,Kuipers, H.,Baskurt, O.K. %D 2014 %J Biorheology %N 2-3 %P 83-90 %R doi:10.3233/BIR-140655 %T EPO or PlacEPO? Science versus Practical Experience Panel discussion on efficacy of erythropoetin in improving performance %U https://doi.org/10.3233/BIR-140655 2-3 %X Recombinant human erythropoietin (rHuEPO) is an agent commonly used by athletes with the aim to improve performance in endurance sports. However, the scientific community continues to debate the risks, benefits and its mechanism of action when used as a doping agent. This paper provides a brief overview on the pros and cons of rHuEPO use, as discussed by a group of scientist with diverse background, at the 17th Conference of the European Society for Clinical Hemorheology and Microcirculation in Pecs, Hungary. Among multiple topics, panel members challenged the common belief that the increased circulating hemoglobin concentration is the simple key to the improved sporting performance. Rather, hemorheologists developed the concept of optimal hematocrit (Hct), a Hct value that represents the optimal balance between the oxygen transport capacity of blood and blood viscosity. While guideline-directed transfusion therapy is advantageous under pathological conditions, such as severe anemia related to chronic kidney disease, its beneficial effects on endurance in healthy athletes remains questionable. Further studies are warranted in the field evaluating the effects of rHuEPO that are independent of increasing hemoglobin concentration, such as peripheral vasodilation and tissue metabolic changes. %0 journal article %@ 0006-355X %A Jung, F.,Krueger, A.,Pindur, G.,Sternitzky, R.,Franke, R.P.,Gori, T. %D 2014 %J Biorheology %N 2-3 %P 207-214 %R doi:10.3233/BIR-140651 %T Tissue oxygen partial pressure in the tibialis anterior muscle in patients with claudication before, during and after a two-stage treadmill stress test %U https://doi.org/10.3233/BIR-140651 2-3 %X BACKGROUND: The role of the microcirculation in the pathophysiology and symptoms of peripheral arterial obliterative disease (PAOD) has been progressively emphasized during the past decades. Under resting conditions, already, the tissue oxygen partial pressure in the m. tibialis anterior (pO2im) is reduced to about 50% compared to healthy subjects.,METHODS: In the framework of this study the pO2im of patients with PAOD stage II according to Fontaine (n=16) in the m. tibialis anterior was measured under resting conditions and during walking on a treadmill in comparison to healthy subjects (n=10).,RESULTS: Under resting conditions the pO2im only marginally differed between PAOD patients and healthy subjects. But during exercise the pO2im dropped significantly more severely in PAOD patients and a return to baseline values could only be reached when the treadmill was stopped and the patients stood still. The pO2im minima correlated clearly with the clinical symptom of calf pain.,CONCLUSION: The data revealed that the pO2im values were lower in PAOD patients and dropped significantly faster during walking compared to the pO2im values in healthy subjects. The pO2im decrease correlated with the calf pain occurring when the pO2im values approached or fell below 10 mmHg. %0 journal article %@ 1042-7147 %A Karimi, M.,Heuchel, M.,Weigel, T.,Kratz, K.,Lendlein, A. %D 2014 %J Polymers for Advanced Technologies %N 11 %P 1349-1355 %R doi:10.1002/pat.3371 %T Influence of expansion cooling regime on morphology of poly(Epsilon-caprolactone) foams prepared by pressure quenching using supercritical CO2 %U https://doi.org/10.1002/pat.3371 11 %X Creation of foam structures from hydrolytically degradable poly(ε-caprolactone) (PCL) is a current task in biomaterial research. One example are degradable scaffolds. The thermodynamic and kinetic conditions in a supercritical CO2 (scCO2) supported foaming process of PCL can influence the resulting morphology of the foam. PCL foaming with scCO2 was systematically investigated in the pressure range from 78 to 200 bar at temperatures between 25°C and 50°C with the help of a view cell. PCL foams could be obtained at both conditions above the pressure dependent melting temperature as well as below this temperature, i.e. from supercooled melt states. Differential scanning calorimetry investigations of the PCL foam samples were used for the analysis of the relationship between pore morphology and foaming conditions. Three characteristic regions could be distinguished in the PCL/CO2 phase diagram. Only when the foaming was conducted above the critical temperature of CO2, a significant influence of the depressurization rate could be observed. Here, an increase in the quenching rate resulted in a decreasing pore size while the pore density was found to increase. %0 journal article %@ 0020-7225 %A Kazakeviciute-Makovska, R.,Heuchel, M.,Kratz, K.,Steeb, H. %D 2014 %J International Journal of Engineering Science %N %P 140-158 %R doi:10.1016/j.ijengsci.2014.05.009 %T Universal relations in linear thermoelastic theories of thermally-responsive shape memory polymers %U https://doi.org/10.1016/j.ijengsci.2014.05.009 %X In this paper we formulate a one-dimensional linear thermo-elastic (LTE) model in integral form for describing the behavior of thermally-responsive shape memory polymers (SMPs), which unifies and slightly generalizes numerous theories proposed in the literature starting with the seminal approach proposed by Liu et al. (2006). The presented model in its most general form requires the calibration of three response functions. Detailed analysis of four types of shape memory cycles (SMCs) used to quantify the shape memory effect in thermally-responsive SMPs and the corresponding forms of constitutive relations derived within LTE model display a number of critical properties. In particular, two of three response functions may be determined in many different ways from strain and stress storage/recovery profiles measured in SMCs (the third response function may be determined from an independent test). As implication of this fact, we show that the LTE model predicts a number of inter-relations between the measured strain and stress storage/recovery profiles. All these relations are universal in the sense that for any shape memory polymer, which may be correctly described by LTE model, the strain/stress storage/recovery profiles measured in SMCs must satisfy (at least approximately) these relations. Their role within the LTE model is analogous to the role of universal relations in the theory of finite deformation elasticity. In particular, these universal relationships provide a theoretical basis for the validation of any model within the LTE class. The basic theoretical results derived in this paper are illustrated using data obtained by Liu et al. (2006). %0 journal article %@ 1386-0291 %A Krueger, A.,Mayer, A.,Roch, T.,Schulz, C.,Lendlein, A. %D 2014 %J Clinical Hemorheology and Microcirculation %N 1 %P 229-240 %R doi:10.3233/CH-141875 %T Angiogenically stimulated alternative monocytes maintain their pro-angiogenic and non-inflammatory phenotype in long-term co-cultures with HUVEC %U https://doi.org/10.3233/CH-141875 1 %X Angiogenically stimulated alternative monocytes (aMO2) could be established as cellular release system accelerating the endothelialization of polymers rendering their surfaces hemocompatible in a short-term study. However, for their clinical application it is essential that aMO2 do not switch back to the MO1 state sustaining their capability as cellular release system over an extended period of time. We explored whether aMO2 can maintain their differentiation state over 21 days in a mono- and in a co-culture with HUVEC. In comparison, the influence of recombinant VEGF-A165 on the endothelialization of biomaterials was assessed including endothelial cell (HUVEC) density, organisation of the endothelial cytoskeleton, cytokine secretion profile and release of prostacyclin, thromboxaneA2 and matrix metalloproteinases. In mono-culture aMO2 secreted high amounts of VEGF and other growth factors/cytokines. Co-cultured with HUVEC, aMO2 accelerated the formation of a confluent HUVEC monolayer. Furthermore, no pro-inflammatory cytokines were found, neither in aMO2-mono, nor in co-cultures with HUVEC indicating that the majority of the aMO2 remained stable in their aMO2 state during the 21 days of cultivation. In contrast, the addition of recombinant VEGF-A165 instead of the co-culture with aMO2 resulted in the formation of stress fibres, dissociated marginal filament bands, and a detachment of HUVEC. In addition, the profile of bioactive agents of HUVEC (e.g. prostacyclin, thromboxaneA2, matrix metalloproteinases, IFN-γ and TNF-α) was influenced by the VEGF-A165 treatment inducing the detachment of HUVEC. In conclusion, in co-culture with HUVEC aMO2 remained stable in their type 2 state over 21 days confirming the suitability of aMO2 as biological release system for the endothelialization of biomaterial surfaces with constant release of angiogenic factors but without secretion of pro-inflammatory cytokines over three weeks. Therefore, this endothelialization approach seems to be appropriate to improve the hemocompatibility of cardiovascular implant materials in vitro, and proved to be superior to the use of recombinant VEGF-A165. %0 journal article %@ 1022-1352 %A Lv, J.,Hao, X.,Yang, J.,Feng, Y.,Behl, M.,Lendlein, A. %D 2014 %J Macromolecular Chemistry and Physics %N 24 %P 2463-2472 %R doi:10.1002/macp.201400345 %T Self-Assembly of Polyethylenimine-Modified Biodegradable Complex Micelles as Gene Transfer Vector for Proliferation of Endothelial Cells %U https://doi.org/10.1002/macp.201400345 24 %X Polyethylenimine (PEI) can perfectly condense with DNA and sufficiently transfer genes, but its high toxicity limits its application. Here, complex micelles are prepared as low-toxicity gene vectors by self-assembly of two block copolymers in aqueous solution. The complex micelles consist of a biodegradable poly(lactide-co-glycolide) (PLGA) core and a mixed poly(ethylene glycol) (PEG)/PEI shell. The ZNF580 gene plasmid (pEGFP-ZNF580), which has the ability of enhancing the proliferation of vascular endothelial cells, is encapsulated into the complex micelles. Using dynamic light scattering, the degradation behavior of the micelles is investigated in vitro. The hydrodynamic size and zeta potential of blank and DNA-loaded micelles are feasible to cellular uptake and gene transfection. 3-(4,5-Dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay shows that the cytotoxicity of the complex micelles is very low when the PEG/PEI ratio is 3/1. The DNA-loaded micelles are found to be able to enhance the proliferation of endothelial cells. %0 journal article %@ 1386-0291 %A Wang, W.,Xu, X.,Li, Z.,Lendlein, A.,Ma, N. %D 2014 %J Clinical Hemorheology and Microcirculation %N 1 %P 19-48 %R doi:10.3233/CH-141883 %T Genetic engineering of mesenchymal stem cells by non-viral gene delivery %U https://doi.org/10.3233/CH-141883 1 %X Mesenchymal stem cells (MSCs) are an ideal cell source for tissue engineering and regenerative medicine as they possess self-renewal properties and multilineage differentiation potential. They can be isolated from various tissues and expanded easily through normal cell culture techniques. Genetic modifications of MSCs to further improve their therapeutic efficacy have been widely studied and extensively researched. Compared to viral gene delivery methods, non-viral methods generate less toxicity and immunogenicity and thus represent a promising and effective tool for the genetic engineering of MSCs. In the last decades, various non-viral gene delivery strategies have been developed and some of them have been applied for MSC transfection. This paper gives an overview of the techniques, influencing factors and potential applications of non-viral methods used for the genetic engineering of MSCs. %0 journal article %@ 1022-1360 %A Wang, L.,Noechel, U.,Fang, L.,Kratz, K.,Lendlein, A. %D 2014 %J Macromolecular Symposia %N 1 %P 82-90 %R doi:10.1002/masy.201400141 %T Impact of Molecular Architectures on the Thermal and Mechanical Properties of Multi-Phase Polymer Networks %U https://doi.org/10.1002/masy.201400141 1 %X Multiphase copolymer networks (CLEG) composed of crystallizable poly(ε-caprolactone) (PCL) and crystallizable poly(ethylene glycol) (PEG) segments can exhibit a pronounced triple-shape effect in the dry state or a dual-shape effect in the water swollen, hydrogel state. We hypothesize that by adjusting the network architecture of CLEG copolymers networks the swelling behavior, the thermal and mechanical properties, as well as the crystal structure of PEG and PCL domains can be tailored. Here, we studied CLEG materials with a fixed PCL/PEG weight ratio but different polymer network architectures, whereby the PEG segments were incorporated as grafted side chains or as network chains connecting two netpoints. The prepared CLEGs were analyzed regarding their gel contents, swelling behavior, thermal and mechanical properties and finally the crystallinity of the polymer networks were determined by differential scanning calorimetry (DSC) and wide angle X-ray scattering (WAXS) measurements. High gel content values of G  ≥ 98% were achieved for all copolymer network samples, indicating an almost complete conversion of the reaction precursors. The degree of swelling (Q) determined with water increased from Q ≈ 150% to 223% with increasing poly(ethylene glycol) monomethyl monomethacrylate (PEGMMA) content to create more PEG grafted side chains. Only when PEGMMA moieties were present in the CLEG networks two separated melting transitions related to the PCL and PEG segments were obtained, whereby Tm,PEG was found to increase with increasing the PEGMMA weight fraction. Based on this observation it can be assumed that the incorporated poly(ε-caprolactone) diisocyanoethyl methacrylate PEGDIMA segments forming the main network were not able to form crystallites in CLEG networks. An almost two-fold decrease in the Younǵs modulus was observed with increasing amounts of grafted PEG side chains, while the elongation at break increased significantly. Based on Mooney-Rivlin Equations, the crosslinking density increased from 0.10% to 0.21% when PEG segments switched from grafted chains to the network. WAXS and DSC investigations revealed an increase in the degree of crystallinity (DOC) of PEG segments with increasing PEGMMA moieties, while the DOC related to the crystalline PCL domains remained almost constant. The obtained results clearly demonstrated the importance of the molecular architecture in designing polymer networks. %0 journal article %@ 1743-5889 %A Delyagina, E.,Schade, A.,Scharfenberg, D.,Skorska, A.,Lux, C.,Li, W.,Steinhoff, G. %D 2014 %J Nanomedicine %N 7 %P 999-1017 %R doi:10.2217/nnm.13.71 %T Improved transfection in human mesenchymal stem cells: effective intracellular release of pDNA by magnetic polyplexes %U https://doi.org/10.2217/nnm.13.71 7 %X Magnetically guided transfection has been shown as a promising approach for the genetic modification of cells. We observed that polyethylenimine (PEI)-condensed pDNA, combined with magnetic nanoparticles (MNPs) via biotin–streptavidin interactions could provide higher transfection efficiency than pDNA/PEI alone, even without the application of a magnetic force. Therefore, we intended to investigate the beneficial properties of MNP-based transfection. Materials & methods: We performed three-color fluorescent labeling of magnetic transfection complexes and traced them inside human mesenchymal stem cells over time using confocal microscopy in order to study pDNA release kinetics by colocalization studies. Results: We demonstrated that MNP-combined pDNA/PEI complexes provide more rapid and efficient release of pDNA than pDNA/PEI alone, which could be explained by the retention of PEI on the surface of the MNPs due to strong biotin–streptavidin interactions. Conclusion: The process of pDNA liberation may significantly influence the efficiency of the transfection vector. Therefore, it should be carefully considered when creating novel gene delivery agents. %0 journal article %@ 0304-3959 %A Jagla, C.,Martus, P.,Stein, C. %D 2014 %J Pain %N 10 %P 2056-2062 %R doi:10.1016/j.pain.2014.07.011 %T Peripheral opioid receptor blockade increases postoperative morphine demands—A randomized, double-blind, placebo-controlled trial %U https://doi.org/10.1016/j.pain.2014.07.011 10 %X Experimental studies suggest that a large proportion of opioid analgesia can be mediated by peripheral opioid receptors. This trial examined the contribution of such receptors to clinical analgesia induced by intravenous morphine. We hypothesized that the selective blockade of peripheral opioid receptors by methylnaltrexone (MNX) would increase the patients’ demand for morphine to achieve satisfactory postoperative pain relief. In a double‐blind, placebo‐controlled, sequential 2‐center trial, 50 patients undergoing knee replacement surgery were randomized (1:1) to receive either subcutaneous MNX (0.9 mg/kg) (hospital I: n = 14; hospital II: n = 11) or saline (hospital I: n = 13; hospital II: n = 12) at the end of surgery. The primary endpoint was the cumulative amount of intravenous morphine administered during the first 8 hours. Secondary endpoints were pain scores at rest and during movement (by numerical rating scale and McGill Questionnaire), vital signs, adverse side effects, and withdrawal symptoms. After MNX, demands for morphine were strongly (by about 40%) increased (hospital I: 35.31 ± 12.99 mg vs 25.51 ± 7.92 mg, P = 0.03; hospital II: 35.42 ± 11.73 mg vs 24.80 ± 7.84 mg, P = 0.02; pooled data: P < .001; means ± SD). Secondary endpoints were similar in all groups (P > .05). Thus, a significant proportion of analgesia produced by systemically administered morphine is mediated by peripheral opioid receptors. Drugs that selectively activate such receptors should have the potential to produce powerful clinical pain relief. %0 journal article %@ 1022-1360 %A Zhang, Q.,Sauter, T.,Wang, L.,Fang, L.,Kratz, K.,Lendlein, A. %D 2014 %J Macromolecular Symposia %N 1 %P 66-74 %R doi:10.1002/masy.201400140 %T Preparation of Magneto-Sensitive Polymer Nanocomposite Microparticles from Copolyesterurethanes via Electrospraying %U https://doi.org/10.1002/masy.201400140 1 %X Small stimuli-responsive magneto-sensitive microparticles (<5 μm) have attracted broad interest for biomedical applications, since they can be delivered minimal-invasively (e.g. via injection) and guided to a specific site or organ, while using their magnetic properties. In addition, such particles can be remotely heated, e.g., for hyperthermia therapy approaches. In this study, we prepared magneto-sensitive polymer-based nanocomposite microparticles by electrospraying of a 1,1,1,3,3,3 hexafluoro-2-propanol solution containing a mixture of a copolyetheresterurethane (PDC) and magnetic Fe3O4 nanoparticles (MNPs). Thermal gravimetric analysis (TGA) revealed a weight content of 23 ± 0.5 wt-% MNPs in the PDC magneto-sensitive nanocomposite microparticles, which was identical with the initial starting composition. Scanning electron microscopy (SEM) results indicated a bimodal particle size distribution for the prepared magneto-sensitive nanocomposite microparticles around 1.2 ± 0.3 μm and 400 ± 100 nm, respectively. Decreasing the size of the magneto-sensitive nanocomposite microparticles resulted in an increase in their reduced modulus, which was obtained via nanoindentation testing. The PDC magneto-sensitive nanocomposite microparticles could be successfully manipulated in dispersion medium suspension with a permanent magnet, demonstrating their magneto-sensitivity. In addition, the inductive heating capability of the microparticulate nanocomposites could be demonstrated for a thin compression molded test specimen, which could be heated to 44 °C in an alternating magnetic field. The results indicated that such magneto-sensitive nanocomposite microparticles can be potentially used as magneto-responsive shape-memory microparticles for on-demand and remotely controlled drug delivery. %0 journal article %@ 1386-0291 %A Roch, T.,Akymenko, O.,Krueger, A.,Jung, F.,Ma, N.,Lendlein, A. %D 2014 %J Clinical Hemorheology and Microcirculation %N 1 %P 147-158 %R doi:10.3233/CH-141885 %T Expression pattern analysis and activity determination of matrix metalloproteinase derived from human macrophage subsets %U https://doi.org/10.3233/CH-141885 1 %X The polarization behavior of macrophages determines the clinical outcome after implantation of biomaterials. Formation of classically activated macrophages (CAM) may result in cell fusion to form foreign body giant cells, which induce and support uncontrolled inflammatory responses and can cause undesired material degradation. In contrast, polarization into alternatively activated macrophages (AAM) is assumed to support healing processes and implant integration. The expression of matrix metalloproteinases (MMP) by the different macrophage subsets might play a crucial role for inflammatory and wound healing processes and may subsequently influence the implant integration. Therefore, it is of importance to characterize the MMP expression pattern by the different macrophage subsets. This knowledge could support the design of biomaterials in which specific MMP cleavage sites are incorporated allowing a controlled cell-mediated degradation of the material. However, it needs to be considered that the pure expression levels may not correlate with the enzymatic activity of the MMP, which depends on a variety of different parameters such as additional co-factors. For this reason, the differential MMP expression levels and the overall enzymatic activity of in vitro generated human non-polarized macrophages (M0), CAM, and AAM are analyzed in this study. While MMP-1, MMP-3, and MMP-10 showed the highest expression levels in CAM, MMP-12 was most strongly expressed by AAM. Interestingly, although various MMP were expressed at high levels in CAM, the enzymatic MMP activity was increased in supernatants of AAM cultures. The data presented here illustrate the importance to combine the measurement of MMP expression levels with the analysis of the enzymatic activity. The observed MMP-12 expression in combination with the higher enzymatic activity detected in AAM supernatants might motivate the design of biomaterials, whose structure could be modified by MMP-12 catalyzed reactions leading to interactive polymers. %0 journal article %@ 0743-7463 %A Wischke, C.,Lendlein, A. %D 2014 %J Langmuir %N 10 %P 2820-2827 %R doi:10.1021/la4025926 %T Method for Preparation, Programming, and Characterization of Miniaturized Particulate Shape-Memory Polymer Matrices %U https://doi.org/10.1021/la4025926 10 %X Their capability to change their shape on demand has created significant interest for shape-memory polymers (SMPs) in minimally invasive surgery. To evaluate the miniaturization of SMP matrices for small-sized implants or controlled release systems, a strategy to prepare and evaluate microsized SMP model particles is required. This methodological study reports the emulsion-based preparation of ∼30 μm microparticles (MPs) from a phase-segregated SMP, poly(ε-caprolactone) [PCL] and poly(ω-pentadecalactone) [PPDL], with a particular focus on the effects of process parameters such as polymer solvents or stabilizer type/concentration on formation and size distribution of SMP MPs. Processes for the preparation of SMP MP-loaded water-soluble polymer films with tailored mechanical properties were developed and applied for programming the SMP MP to a temporary ellipsoid shape by film stretching. For the functional evaluation of shape recovery of MPs, a light microscopy-based setup with temperature control is proposed by which the stimuli-induced switching of the microsized SMP matrices could be confirmed. Overall, by applying this methodological strategy to various thermoplastic SMPs, a routine to identify and characterize the microscale functionality of SMPs in miniaturized applications will be broadly accessible. %0 journal article %@ 1022-1360 %A Neffe, A.T.,Santan, H.D.,Kamlage, S.,Gottschalk, B.,Lendlein, A. %D 2014 %J Macromolecular Symposia %N 1 %P 91-97 %R doi:10.1002/masy.201400145 %T Micellization of Aminoterminated Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) in the Presence of Hyaluronic Acid %U https://doi.org/10.1002/masy.201400145 1 %X At concentrations above 15 wt-%, aqueous solutions of mixtures of aminoterminated poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) block copolymers (PEPE) and hyaluronic acid show a reversible sol-gel-transition upon change of temperature. For non-aminoterminated PEPEs, this gel transition could be related to micellization and subsequent colloidal jamming of the micelles. Here, the mechanism of gelation for the aminoterminated compound is investigated by fluorescence spectroscopy and 1H-NMR spectroscopy. The aminoterminated PEPE also form micelles. The onset of micellization is temperature and concentration dependent, and can be tuned to 20–40 °C. Interestingly, with increasing molecular weight of the hyaluronic acid component, the micellization is observed at lower concentrations. %0 journal article %@ 1549-3296 %A Reddy, C.S.,Venugopal, J.R.,Ramakrishna, S.,Zussman, E. %D 2014 %J Journal of Biomedical Materials Research A %N 10 %P 3713-3725 %R doi:10.1002/jbm.a.35045 %T Polycaprolactone/oligomer compound scaffolds for cardiac tissue engineering %U https://doi.org/10.1002/jbm.a.35045 10 %X Polycaprolactone (PCL), a synthetic biocompatible and biodegradable polymer generally used as a scaffold material for tissue engineering applications. The high stiffness and hydrophobicity of the PCL fiber mesh does not provide significant cell attachment and proliferation in cardiac tissue engineering. Towards this goal, the study focused on a compound of PCL and oligomer hydrogel [Bisphenol A ethoxylated dimethacrylate (BPAEDMA)] processed into electrospun nanofibrous scaffolds. The composition, morphology and mechanical properties of the compound scaffolds, composed of varying ratios of PCL and hydrogel were characterized by scanning electron microscopy, infrared spectroscopy and dynamic mechanical analyzer. The elastic modulus of PCL/BPAEDMA nanofibrous scaffolds was shown to be varying the BPAEDMA weight fraction and was decreased by increasing the BPAEDMA weight fraction. Compound fiber meshes containing 75 wt % BPAEDMA oligomer hydrogel exhibited lower modulus (3.55 MPa) and contact angle of 25o. Rabbit cardiac cells cultured for 10 days on these PCL/BPAEDMA compound nanofibrous scaffolds remained viable and expressed cardiac troponin and alpha-actinin proteins for the normal functioning of myocardium. Cell adhesion and proliferations were significantly increased on compound fiber meshes containing 75 wt % BPAEDMA, when compared with other nanofibrous scaffolds. The results observed that the produced PCL/BPAEDMA compound nanofibrous scaffolds promote cell adhesion, proliferation and normal functioning of cardiac cells to clinically beneficial levels, relevant for cardiac tissue engineering. %0 journal article %@ 0927-7765 %A Wei, Q.,Krysiak, S.,Achazi, K.,Becherer, T.,Noeske, P.-L.M.,Paulus, F.,Liebe, H.,Grunwald, I.,Dernedde, J.,Hartwig, A.,Hugel, T.,Haag, R. %D 2014 %J Colloids and Surfaces B %N %P 684-692 %R doi:10.1016/j.colsurfb.2014.08.001 %T Multivalent anchored and crosslinked hyperbranched polyglycerol monolayers as antifouling coating for titanium oxide surfaces %U https://doi.org/10.1016/j.colsurfb.2014.08.001 %X A set of new catecholic monolayer coatings was developed to improve the antifouling performance of TiO2 surfaces. To solve the problem of the weak charge-transfer interaction between a single catechol anchor and TiO2, multiple catechol groups were combined with hyperbranched polyglycerol (hPG) which is a distinct dendritic scaffold that exposes its multivalent anchor groups on the surface. Thus, multivalent catecholic hPGs can be easily prepared for surface modification. The immobilization of the compounds was monitored by quartz crystal microbalance with dissipation monitoring. Surface properties of the coatings were analyzed by water contact angle, X-ray photoelectron spectroscopy, and atomic force microscopy. The antifouling ability and stability were investigated by protein adsorption and cell adhesion. By increasing the number of catechol groups on the hPG scaffold, the stability and surface coverage could be significantly enhanced. Moreover, the inner-layer crosslinking of the coatings by grafting and initiating vinyl groups clearly improved their long-term stability. As a result, hPG with a catecholic functional degree of 10% (hPG-Cat10) and hPG with both catecholic and vinylic functional degree of 5% (hPG-Cat5-V5) were identified as the best catecholic hPGs to prepare bioinert and stable monolayer coatings on TiO2. %0 journal article %@ 0935-9648 %A Wei, Q.,Becherer, T.,Noeske, P.-L.M.,Grunwald, I.,Haag, R. %D 2014 %J Advanced Materials %N 17 %P 2688-2693 %R doi:10.1002/adma.201304737 %T A Universal Approach to Crosslinked Hierarchical Polymer Multilayers as Stable and Highly Effective Antifouling Coatings %U https://doi.org/10.1002/adma.201304737 17 %X Material-independent and bioinert hierarchical polymer multilayer coatings are presented. Chemically active catecholic hyperbranched polyglycerols (hPGs) form a foundation layer on a versatile surface via multivalent anchoring and crosslinking, the activity of which is shielded by the bioinert catecholic hPGs. Mono-catecholic hPGs finally terminate all of the free catechols to build a flexible bioinert top layer. These coatings perfectly prevent protein and cell adhesion. %0 journal article %@ 1022-1360 %A Baudis, S.,Lendlein, A.,Behl, M. %D 2014 %J Macromolecular Symposia %N 1 %P 105-111 %R doi:10.1002/masy.201400159 %T High-Throughput Synthesis as a Technology Platform for Copolymer Libraries %U https://doi.org/10.1002/masy.201400159 1 %X Quantitative structure-property relationships are of utmost importance for the rational design of materials. A systematic variation of one structure parameter in a series of polymers requires a large number of syntheses. Here combinatorial techniques are the method of choice. In this study high-throughput methods were applied for the synthesis and characterization of polymer libraries with stepwise changed composition to build up such material libraries. A high-throughput workflow was established, in which 112 different copolymerizations were performed. The polymers were characterized by means of NMR and FTIR (composition), GPC (number average molecular weight, inline imageand DSC (glass transition temperature, Tg). The gradually changed composition of the copolymers with number average molecular weights of around 150 kg ∙ mol-1 was confirmed and structure-property relationships between composition and Tgs ranging between 102 and 126 °C were proposed, rendering the polymer libraries now as a technology platform for further studies. %0 journal article %@ 1022-1360 %A Saatchi, M.,Behl, M.,Lendlein, A. %D 2014 %J Macromolecular Symposia %N 1 %P 100-107 %R doi:10.1002/masy.201400158 %T Double Layer Porous Structures by an Injection Molding/Particulate Leaching Approach %U https://doi.org/10.1002/masy.201400158 1 %X Scaffolds as a temporary substitute for the extracellular matrix should provide interconnected pores and often require a multilayer design to mimic the geometry and biomechanics of the target tissue. Here, it was explored whether bilayer porous structures can be obtained by a process free of organic solvents and how the individual layers contribute to the overall elastic properties. Porous layers were obtained from polyurethane (PU) blends with polyvinyl alcohol (PVA), which were immersed in water after sequential injection molding. Pore sizes in both layers ranged from 1 μm to 100 μm with an average of 22 ± 1 μm at a porosity of 50 ± 5% in combination with a high interconnectivity. The pore sizes were tailored by applying an annealing treatment, while the porosity was kept constant. Mechanical properties of the individual layers and the double layer constructs as determined by tensile tests suggested that the overall elasticity of the compact bilayer construct and porous bilayer construct was in agreement with the predicted overall elasticity according to the rule of mixtures. The porous bilayer model system will serve as a basis for determining structure-property relationships with respect to pore size, porosity as well as mechanical properties of individual layers and in this way enable a knowledge-based design of layered scaffolds. %0 journal article %@ 1022-1360 %A Rijckaert, B.,Neffe, A.T.,Roch, T.,Gebauer, T.,Pierce, B.F.,Goers, J.,Smink, J.J.,Gossen, M.,Lendlein, A.,Leutz, A. %D 2014 %J Macromolecular Symposia %N 1 %P 91-99 %R doi:10.1002/masy.201400147 %T A High Content Screening Assay for Evaluation of Biomaterial-Mediated Cell Fusion Processes %U https://doi.org/10.1002/masy.201400147 1 %X Biomaterials are of increasing importance in regenerative medicine and entail delivery systems in somatic cell therapies, matrices for tissue engineering or tissue regeneration. The evaluation of biomaterial induced biological effects remains a key issue in clinical application. Cell-based assays for potential cytotoxic and immunological responses have been developed but are often inadequate to address cell-type specific responses to biomaterials. To quantitatively monitor attachment, survival, proliferation and fusion-controlled differentiation of osteoclasts (bone resorbing cells), a High Content Screening (HCS) assay has been developed based on osteoclast differentiation of the murine monocytic cell line RAW 264.7. This assay was applied to investigate the influence of degradation products of polymers from gelatin and lysine diisocyanate, which display tailorable mechanical properties and have potential as biomaterials. The data show that the degradation products inhibit formation of multinuclear osteoclasts and suggest a potential support of bone regeneration by suppression of bone resorption. %0 journal article %@ 1433-7851 %A Wei, Q.,Achazi, K.,Liebe, H.,Schulz, A.,Noeske, P.-L.M.,Grunwald, I.,Haag, R. %D 2014 %J Angewandte Chemie - International Edition %N 43 %P 11650-11655 %R doi:10.1002/anie.201407113 %T Mussel-Inspired Dendritic Polymers as Universal Multifunctional Coatings %U https://doi.org/10.1002/anie.201407113 43 %X A rapid and universal approach for multifunctional material coatings was developed based on a mussel-inspired dendritic polymer. This new kind of polymer mimics not only the functional groups of mussel foot proteins (mfps) but also their molecular weight and molecular structure. The large number of catechol and amine groups set the basis for heteromultivalent anchoring and crosslinking. The molecular weight reaches 10 kDa, which is similar to the most adhesive mussel foot protein mfp-5. Also, the dendritic structure exposes its functional groups on the surface like the folded proteins. As a result, a very stable coating can be prepared on virtually any type of material surface within 10 min by a simple dip-coating method, which is as fast as the formation of mussel byssal threads in nature. %0 journal article %@ 0305-1048 %A Werner, J.,Gossen, M. %D 2014 %J Nucleic Acids Research %N 21 %P 13061-13073 %R doi:10.1093/nar/gku1124 %T Modes of TAL effector-mediated repression %U https://doi.org/10.1093/nar/gku1124 21 %X Engineered transcription activator-like effectors, or TALEs, have emerged as a new class of designer DNA-binding proteins. Their DNA recognition sites can be specified with great flexibility. When fused to appropriate transcriptional regulatory domains, they can serve as designer transcription factors, modulating the activity of targeted promoters. We created tet operator (tetO)-specific TALEs (tetTALEs), with an identical DNA-binding site as the Tet repressor (TetR) and the TetR-based transcription factors that are extensively used in eukaryotic transcriptional control systems. Different constellations of tetTALEs and tetO modified chromosomal transcription units were analyzed for their efficacy in mammalian cells. We find that tetTALE-silencers can entirely abrogate expression from the strong human EF1α promoter when binding upstream of the transcriptional control sequence. Remarkably, the DNA-binding domain of tetTALE alone can effectively counteract trans-activation mediated by the potent tettrans-activator and also directly interfere with RNA polymerase II transcription initiation from the strong CMV promoter. Our results demonstrate that TALEs can act as highly versatile tools in genetic engineering, serving as trans-activators, trans-silencers and also competitive repressors. %0 journal article %@ 1022-1360 %A Balk, M.,Behl, M.,Noechel, U.,Lendlein, A. %D 2014 %J Macromolecular Symposia %N 1 %P 8-13 %R doi:10.1002/masy.201400043 %T Shape-Memory Hydrogels with Crystallizable Oligotetrahydrofuran Side Chains %U https://doi.org/10.1002/masy.201400043 1 %X Stimuli-sensitive materials, such as shape-memory polymers (SMP) have attracted tremendous interest in the field of biomedical applications and Regenerative Therapies. In case of implants intended for soft tissue, adequate elastic properties can be mimicked by water swollen hydrophilic polymer networks (i.e. hydrogels) and can be equipped with a shape-memory capability. Shape-memory hydrogels (SMHs) having body compatible transition temperatures (Ttrans) have not been reported so far. Here we explored, whether SMHs with Ttrans ≤ 37 °C could be created consisting of the hydrophilic poly(N-vinyl pyrrolidone) segment, the crosslinker oligo(ethylene glycol) dimethacrylate (OEGDMA, Mn = 370 g · mol−1), and grafted crystallizable oligotetrahydrofuran (OTHF, Mn = 7.100 g · mol−1, Tm = 31 °C) segments as switching domains. As function of the OTHF content (30–75 wt%), the hydrogels had a degree of swelling between 450 and 3200%, a Ttrans about 26 °C, and soft mechanical properties in the kPa range. Therefore, these SMHs might be interesting biomaterial candidates e.g. as smart implants. %0 journal article %@ 0142-9612 %A Shi, C.,Yao, F.,Li, Q.,Khan, M.,Ren, X.,Feng, Y.,Huang, J.,Zhang, W. %D 2014 %J Biomaterials %N 25 %P 7133-7145 %R doi:10.1016/j.biomaterials.2014.04.110 %T Regulation of the endothelialization by human vascular endothelial cells by ZNF580 gene complexed with biodegradable microparticles %U https://doi.org/10.1016/j.biomaterials.2014.04.110 25 %X The lack of living endothelial cells (ECs) functional layer is one of the major reasons which account for thrombosis of synthetic vascular vessels. To overcome this obstacle, we employed ZNF580 gene complexed with biodegradable microparticles (MPs) to promote the rapid endothelialization by ECs. In order to realize the controlled release of ZNF580 gene from MPs/gene complexes, a series of amphiphilic triblock copolymers with different degradation rate, namely, methoxy-poly(ethylene glycol)-block-poly(3(S)-methyl-morpholine-2,5-dione)-graft-polyethyleneimine (mPEG-b-PMMD-g-PEI), methoxy-poly(ethylene glycol)-block-poly(3(S)-methyl-morpholine-2,5-dione-co-lactide)-graft-polyethyleneimine (mPEG-b-P(MMD-co-LA)-g-PEI) and methoxy-poly(ethylene glycol)-block-poly(3(S)-methyl-morpholine-2,5-dione-co-lactide-co-glycolide)-graft-polyethyleneimine (mPEG-b-P(MMD-co-LA-co-GA)-g-PEI), were synthesized. Then, MPs were formed by self-assembly. The hydrophobic cores of these MPs were composed of PMMD, P(MMD-LA) or P(MMD-co-LA-co-GA) segments, and provided crosslinking points for numbers of PEG and short PEI chains to form a high hydrophilic and positive charged corona/shell structure.,Based on their positive charged surface, MPs can compact pEGFP-ZNF580 into MPs/pEGFP-ZNF580 complexes. The cell transfection result demonstrated that pEGFP-ZNF580 could be transported efficiently into ECs by these complexes. The result of western blot showed that the relative ZNF580 protein level can increase to 35.74%–46.11% by the overexpression of ZNF580 gene. Furthermore, the release of pEGFP-ZNF580 could be sustained at least 25 days due to the controllable degradation ability of the hydrophobic MPs' core. The MPs and MPs/pEGFP-ZNF580 complexes showed low cytotoxicity because of the introduction of PEG chains and low molecular weight PEI on the surface of these MPs. Notably, at the low concentration (20 μg/mL), the MPs and their complexes were non-cytotoxicity. The rapid endothelialization was promoted significantly by the expression of pEGFP-ZNF580. %0 journal article %@ 1022-1360 %A Kusmierczuk, M.,Noechel, U.,Baudis, S.,Behl, M.,Kratz, K.,Lendlein, A. %D 2014 %J Macromolecular Symposia %N 1 %P 98-104 %R doi:10.1002/masy.201400150 %T Shape-Memory Polymer Networks Prepared from Star-Shaped Poly[(L-lactide)-co-glycolide] Precursors %U https://doi.org/10.1002/masy.201400150 1 %X Amorphous degradable copolymer networks such as poly[(L-lactide)-co-glycolide] (PLGA) are promising multifunctional polymers with tailorable degradation profiles and capable of a thermally-induced shape-memory effect. Currently, the shape-memory performance for covalently crosslinked networks based on linear PLGA dimethacrylate precursors (cPLGA) is limited. In this study we explored the shape-memory properties of cPLGA networks prepared from three-armed 2-isocyanatoethyl methacrylate functionalized precursors via photopolymerization. cPLGA exhibited excellent dual-shape properties characterized by an almost complete fixation of the temporary shape as well as an almost perfect recovery of the original shape. In the dry state cPLGA exhibited a switching temperature (Tsw) of 60 °C with a narrow recovery temperature interval of ΔTrec = 5 °C, while a significant lower Tsw of 40 °C with a ΔTrec = 15 °C was obtained when the polymer network was investigated in an aqueous environment. A concomitant decrease in the glass transition temperature could be observed in differential scanning calorimetry heating curves for copolymer networks after storage in aqueous buffer solution at 37 °C for 7 days, which can be attributed to the up-take of water molecules (1.5 wt%). The shape-memory properties achieved for cPLGA, in particular the shape recovery ratio and ΔTrec were superior to those of analogous polymer networks based on linear PLGA dimethacrylates. %0 journal article %@ 2192-2659 %A Xu, X.,Wang, W.,Kratz, K.,Fang, L.,Li, Z.,Kurtz, A.,Ma, N.,Lendlein, A. %D 2014 %J Advanced Healthcare Materials %N 12 %P 1933 %R doi:10.1002/adhm.201470060 %T Cover Picture - Stem Cells: Controlling Major Cellular Processes of Human Mesenchymal Stem Cells using Microwell Structures %U https://doi.org/10.1002/adhm.201470060 12 %X The geometry of polymeric matrices is a powerful tool to control cell behavior. On page 1991 N. Ma, A. Lendlein, and co-workers demonstrate human adipose-derived stem cells that show ROCK pathway-mediated differences in their response to square- and round-shaped microwells with respect to their morphology, proliferation, migration, and differentiation. Phagocytes react differently to spherical and ellipsoid microparticles, which now can shift their shape upon stimulation due to an internal polymer micronetwork structure. %0 journal article %@ 2095-0179 %A Yang, J.,Lv, J.,Gao, B.,Zhang, L.,Yang, D.,Shi, C.,Guo, J.,Li, W.,Feng, Y. %D 2014 %J Frontiers of Chemical Science and Engineering %N 2 %P 188-196 %R doi:10.1007/s11705-014-1414-1 %T Modification of polycarbonateurethane surface with poly (ethylene glycol) monoacrylate and phosphorylcholine glyceraldehyde for anti-platelet adhesion %U https://doi.org/10.1007/s11705-014-1414-1 2 %X Poly(ethylene glycol) monoacrylate (PEGMA) is grafted onto polycarbonateurethane (PCU) surface via ultraviolet initiated photopolymerization. The hydroxyl groups of poly(PEGMA) on the surface react with one NCO group of isophorone diisocyanate (IPDI) and another NCO group of IPDI is then hydrolyzed to form amino terminal group, which is further grafted with phosphorylcholine glyceraldehyde to establish a biocompatible hydrophilic structure on the surface. Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy confirm the successful grafting of both PEG and phosphorylcholine functional groups on the surface. The decrease of the water contact angle for the modified film is caused by synergic effect of PEG and phosphorylcholine, which both have the high hydrophilicity. Furthermore, the number of platelets adhered is relative low on the synergetically modified PCU film compared with the PCU film modified only by poly(PEGMA). Our synergic modification method using both PEG and phosphorylcholine may be applied in surface modification of blood-contacting biomaterials and some relevant devices. %0 journal article %@ 1022-1352 %A Molina, M.,Guilbudagian, M.,Calderon, M. %D 2014 %J Macromolecular Chemistry and Physics %N 24 %P 2414-2419 %R doi:10.1002/macp.201400286 %T Positively Charged Thermoresponsive Nanogels for Anticancer Drug Delivery %U https://doi.org/10.1002/macp.201400286 24 %X Thermoresponsive nanogels (NGs) are often used as smart nanocarriers for delivering bioactive molecules. Copolymerization of monomers with different functionalities is a well-known technique that enables the tuning of their properties. Here, the synthesis of positively charged thermoresponsive NGs is reported, based on (N-isopropylacrylamide) (NIPAM) as a thermoresponsive monomer, 2-dimethyl(aminoethyl) methacrylate (DMAEM) as a charged comonomer, and dendritic acrylated polyglycerol (dPG) as a macro-crosslinker. The NGs are characterized in terms of size, Z potential, and transition temperature. In order to evaluate its potential for anticancer therapy, the encapsulation and release of anticancer drugs such as doxorubicin (DOXO) and methotrexate (MTX) are tested. A high drug loading capacity and release rate make these NGs promising nanocarriers for biomedical applications. %0 journal article %@ 1438-7492 %A Baudis, S.,Lendlein, A.,Behl, M. %D 2014 %J Macromolecular Materials and Engineering %N 11 %P 1292-1297 %R doi:10.1002/mame.201400073 %T High Throughput Characterization of Polymer Libraries by Diffuse Reflectance Infrared Spectroscopy %U https://doi.org/10.1002/mame.201400073 11 %X Diffuse reflectance FTIR (DRIFT) was established as a high throughput characterization method for classic copolymer systems. Four different methyl methacrylate-based polymer libraries with styrene, N-vinylpyrrolidone, 4-vinylpyridine, or 2-carboxyethyl acrylate as comonomers were synthesized using an automated/robotic synthesizer platform, and analyzed by 1H NMR and DRIFT. By multivariate data analysis both data sets were compared and correlations with R2 between 0.9373 and 0.9971 could be achieved. By this means high throughput screening of comonomer contents of these polymer libraries was enabled. %0 journal article %@ 1022-1352 %A Noechel, U.,Kumar, U.N.,Wang, K.,Kratz, K.,Behl, M.,Lendlein, A. %D 2014 %J Macromolecular Chemistry and Physics %N 24 %P 2446-2456 %R doi:10.1002/macp.201400445 %T Triple-Shape Effect with Adjustable Switching Temperatures in Crosslinked Poly[ethylene-co-(vinyl acetate)] %U https://doi.org/10.1002/macp.201400445 24 %X A triple-shape capability of copolymer networks enabling a variation of the two switching temperatures Tsws by purely physical functionalization is introduced. The polymer networks obtained by covalently crosslinking of poly[ethylene-co-(vinyl acetate)] exhibit a broad melting transition. The influence of the two deformation temperatures Tdeforms applied during programming of the triple-shape effect (TSE) on the two Tsws is explored. Interestingly, it turns out that the deformation geometry plays an important role in the realizability of this concept. Tensile deformations allow adjusting only one Tsw in the lower melting temperature range of 45 to 60 °C, whereas in bending tests, both Tsws can be varied. Finally, two independent TSEs associated to four different Tsws between 45 and 90 °C can be realized in the same specimen. Shape fixity and shape recovery ratios generally exceed 90%, demonstrating an excellent performance of the triple-shape function. %0 journal article %@ 1022-1352 %A Baudis, S.,Behl, M.,Lendlein, A. %D 2014 %J Macromolecular Chemistry and Physics %N 24 %P 2399-2402 %R doi:10.1002/macp.201400561 %T Smart Polymers for Biomedical Applications %U https://doi.org/10.1002/macp.201400561 24 %X Smart materials have the ability to respond to changes in their environment by variations in their,molecular structure or in their physicochemical properties. Shape-memory and shape-changing,polymers are examples for this class of materials, whose capability to perform stimuli-induced,active movements has inspired engineers to develop heat-shrinkable packing materials, smart,textiles or morphing structures for aerospace vehicles. In the last 15 years these materials have,created significant interest in the field of biomedicine, e.g. in minimally invasive surgery for the,insertion of self-inflating bulky medical devices. The progress in material chemistry,,physicochemical characterization techniques, assessment of biomaterial interaction with cells,and tissues, and computer-assisted modelling motivates the exploration of knowledge-based,approaches for the design of active polymer systems. However, these active polymers are not,restricted to actively moving materials. They can offer a wide-spread spectrum of functions,,including controlled release, swellability, and degradability, that may be controlled by suitable,stimuli. The concepts for the design of smart polymers with the associated processes can be,categorized by the targeted device (e.g. coating, particles) and the nature of the function. Beside,shape-memory polymers[3] material systems of interest are stimuli-sensitive hydrogels[4] and,nanocarriers for the targeted administration of drugs or genes. %0 journal article %@ 0167-5273 %A Park, J.-W.,Sherif, M.A.,Zintl, K.,Lam, Y.-Y.,Goedde, M.,Scharnweber, T.,Jung, F.,Franke, R.P.,Brachmann, J. %D 2014 %J International Journal of Cardiology %N 3 %P 957-963 %R doi:10.1016/j.ijcard.2014.09.194 %T Percutaneous left atrial appendage closure with a novel self-modelizing device: A pre-clinical feasibility study %U https://doi.org/10.1016/j.ijcard.2014.09.194 3 %X The aim of the study is to evaluate the feasibility and safety of a new left atrial appendage (LAA) occluder.,Twelve pigs were included. In 2 pigs the implantation process failed due to pericardial tamponade in 1 pig and device embolization in the other pig. The placement of the devices was controlled via TEE and fluoroscopy. After 6 weeks of implantation the hearts were explanted.,The devices were found to be easy to deploy and showed a very good adaptation to the LAA tissue. Eight out of 10 pigs had full closure of the LAA directly after implantation.,After six weeks, due to the self-modelizing properties of the device, all pigs had a full closure of the LAA. The macroscopic evaluation of the explanted hearts showed that all devices were securely integrated in LAA tissues.,There was one case of mild pericarditis but no macroscopic signs of inflammation on the device surrounding endocardium. The explantation revealed that device loops had penetrated the LAA tissue in three pigs. However, no signs of bleeding, pericardial effusion, or other damage to the LAA wall could be detected and the pigs were in good condition with normal weight gain and no clinical symptoms.,The Occlutech® LAA occluder achieved complete closure of the LAA in all pigs, and remained in the LAA, with benign healing and no evidence of new thrombus or damage to surrounding structures. Moreover, the uncompromised survival of all implanted pigs demonstrates the feasibility and safety of the device. %0 journal article %@ 1386-0291 %A Hiebl, B.,Hopperdietzel, C.,Hueningen, H.,Dietze, K.,Jung, F.,Niehues, S.M. %D 2014 %J Clinical Hemorheology and Microcirculation %N 1 %P 107-113 %R doi:10.3233/CH-141881 %T Tissue reaction induced by implanted venous access ports in adult patients after infection of the implantation site %U https://doi.org/10.3233/CH-141881 1 %X Implantable long-term central venous port systems (CVPS) are widely used as a permanent means of accessing the vascular system for intravenous delivery of drugs, parenteral nutrition, blood transfusion, and blood sampling. These systems allow easy and repetitive puncture without causing much damage to the vessels. However, the body foreign surface of CVPS induces an inflammatory response with varying intensity (depending on the implant materials) that leads to formation of a fibrous tissue capsule around the implant. This study was designed to investigate the influence of bacterial infection on the tissue reaction induced by implanted CVPS in adult patients. 20 patients (9 women, 11 men, 58 ± 14 yrs of age) were included in this study. These patients received explantation of a polysulfone based CVPS (ChemoSite™, Covidien, Mansfield, USA) due to port related infections (patients with bacterial infections at the implantation site: group A, 5 men, 1 women) or to other reasons such as termination of treatment, thrombosis, or CVPS dysfunction (patients without bacterial infections, group B, 6 men, 8 women) 299.9 ± 261.2 days after CVPS implantation. A sample of the encapsulating tissue covering the CVPS together with surrounding tissue (at least 1 × 1 cm2) was placed in a small container with fixing agent, a buffered neutral 4% formalin solution (pH 7). Histological sections of the samples were prepared for light microscopic analysis after paraffin embedding. Sections of 3 μm were cut and stained with haematoxylin and eosin, Weigert's elastic stain, and Heidenhain's azan stain. There was no difference in thickness, collagen and elastin content, or cell and capillary density of the fibrous capsule between both groups. Due to the wound healing reaction involving angiogenesis and fibroblast activation cell density and number of capillaries in the capsule tissue of all patients showed a positive correlation (r = 0.45, p < 0.05). However, the study demonstrated that at the end of the foreign body reaction the artificial tissue layer which covers the CVPS after implantation due to foreign body reaction shows only low reactivity towards infections. %0 journal article %@ 0935-9648 %A Wei, Q.,Schlaich, C.,Prevost, S.,Schulz, A.,Boettcher, C.,Gradzielski, M.,Qi, Z.,Haag, R.,Schalley, C.A. %D 2014 %J Advanced Materials %N 43 %P 7358-7364 %R doi:10.1002/adma.201401366 %T Supramolecular Polymers as Surface Coatings: Rapid Fabrication of Healable Superhydrophobic and Slippery Surface %U https://doi.org/10.1002/adma.201401366 43 %X Supramolecular polymerization for non-wetting surface coatings is described. The self-assembly of low-molecular-weight gelators (LMWGs) with perfluorinated side chains can be utilized to rapidly construct superhydrophobic, as well as liquid-infused slippery surfaces within minutes. The lubricated slippery surface exhibits impressive repellency to biological li­quids, such as human serum and blood, and very fast self-healing. %0 journal article %@ 1433-7851 %A Hommes, P.,Fischer, C.,Lindner, C.,Zipse, H.,Reissig, H. %D 2014 %J Angewandte Chemie - International Edition %N 29 %P 7347-7651 %R doi:10.1002/anie.201403403 %T Unprecedented Strong Lewis Bases - Synthesis and Methyl Cation Affinities of Dimethylamino-Substituted Terpyridines† %U https://doi.org/10.1002/anie.201403403 29 %X A versatile method for the synthesis of functionalized 2,2′:6′,2′′-terpyridines by assembly of the terminal pyridine rings is presented. The cyclization precursors—bis-β-ketoenamides—are prepared from 4-substituted 2,6-pyridinedicarboxylic acids and acetylacetone or its corresponding enamino ketone. Treatment with trimethylsilyl trifluoromethanesulfonate induces a twofold intramolecular condensation providing an efficient access to 4,4′′-di- and 4,4′,4′′-trifunctionalized 6,6′′-dimethyl-2,2′:6′,2′′-terpyridines. Using this method, hitherto unknown 4,4′′-bis(dimethylamino)- and 4,4′,4′′-tris(dimethylamino)terpyridines have been prepared that show remarkably high calculated Lewis basicities. %0 journal article %@ 1022-1360 %A Lendlein, A.,Behl, M.,Domb, A.J. %D 2014 %J Macromolecular Symposia %N 1 %P 7 %R doi:10.1002/masy.201470041 %T Preface %U https://doi.org/10.1002/masy.201470041 1 %X No abstract %0 journal article %@ 1022-1352 %A Schoene, A.-C.,Schulz, B.,Richau, K.,Kratz, K.,Lendlein, A. %D 2014 %J Macromolecular Chemistry and Physics %N 24 %P 2437-2445 %R doi:10.1002/macp.201400377 %T Characterization of Langmuir Films Prepared from Copolyesterurethanes Based on Oligo(Ômega-pentadecalactone) and Oligo(Epsilon-caprolactone) Segments %U https://doi.org/10.1002/macp.201400377 24 %X A series of multiblock copolymers (PDLCL) synthesized from oligo(ω-pentadecalactone)diol (OPDL) and oligo(ε-caprolactone)diol (OCL), which are linked by 2,2(4),4-trimethyl-hexa­methylene diisocyanate (TMDI), is investigated by the Langmuir monolayer technique at the air–water interface. Brewster angle microscopy (BAM) and spectroscopic ellipsometry are employed to characterize the polymer film morphologies in situ. PDLCL containing ≥40 wt% OCL segments form homogeneous Langmuir monofilms after spreading. The film elasticity modulus decreases with increasing amounts of OPDL segments in the copolymer. In contrast, the OCL-free polyesterurethane OPDL-TMDI cannot be spread to monomolecular films on the water surface properly, and movable slabs are observed by BAM even at low surface pressures. The results of the in situ morphological characterization clearly show that essential information concerning the reliability of Langmuir monolayer degradation (LMD) experiments cannot be obtained from the evaluation of the π–A isotherms only. Consequently, in situ morphological characterization turns out to be indispensable for characterization of Langmuir layers before LMD experiments. %0 journal article %@ 2192-2659 %A Xu, X.,Wang, W.,Kratz, K.,Fang, L.,Li, Z.,Kurtz, A.,Ma, N.,Lendlein, A. %D 2014 %J Advanced Healthcare Materials %N 12 %P 1991-2003 %R doi:10.1002/adhm.201400415 %T Controlling Major Cellular Processes of Human Mesenchymal Stem Cells using Microwell Structures %U https://doi.org/10.1002/adhm.201400415 12 %X Directing stem cells towards a desired location and function by utilizing the structural cues of biomaterials is a promising approach for inducing effective tissue regeneration. Here, the cellular response of human adipose-derived mesenchymal stem cells (hADSCs) to structural signals from microstructured substrates comprising arrays of square-shaped or round-shaped microwells is explored as a transitional model between 2D and 3D systems. Microwells with a side length/diameter of 50 μm show advantages over 10 μm and 25 μm microwells for accommodating hADSCs within single microwells rather than in the inter-microwell area. The cell morphologies are three-dimensionally modulated by the microwell structure due to differences in focal adhesion and consequent alterations of the cytoskeleton. In contrast to the substrate with 50 μm round-shaped microwells, the substrate with 50 μm square-shaped microwells promotes the proliferation and osteogenic differentiation potential of hADSCs but reduces the cell migration velocity and distance. Such microwell shape-dependent modulatory effects are highly associated with Rho/ROCK signaling. Following ROCK inhibition, the differences in migration, proliferation, and osteogenesis between cells on different substrates are diminished. These results highlight the possibility to control stem cell functions through the use of structured microwells combined with the manipulation of Rho/ROCK signaling. %0 journal article %@ 1022-1360 %A Fang, L.,Yan, W.,Zierke, M.,Richau, K.,Behl, M.,Kratz, K.,Lendlein, A. %D 2014 %J Macromolecular Symposia %N 1 %P 83-90 %R doi:10.1002/masy.201400143 %T Crystallization and Phase Segregation of Multifunctional Multiblock Copolymers in Spin Coated Thin Films Altered by Diurethane Junction Units %U https://doi.org/10.1002/masy.201400143 1 %X A multiblock copolymer named PDC is composed of crystallizable oligo(p-dioxanone) (OPDO) and oligo(ε-caprolactone) (OCL) as hard and switching segments. PDC has been synthesized via connecting two oligomeric macrodiols using a diisocyanate linker such as 2,2(4), 4-trimethyl-hexamethylene diisocyanate (TMDI) or 1,6-hexamethylene diisocyanate (HDI). In this work, the surface morphologies of spin coated thin films from two PDCs (PDC-HDI and PDC-TMDI) were investigated via in-situ atomic force microscopy (AFM) to examine how the diisocyanate linkers affect the balance between crystallization and phase segregation behavior. The results demonstrated that in PDC-HDI, the crystallization of poly(ε-caprolactone) (PCL) crystals provoked a “break out” from the phase segregated morphology. On contrary, the crystallization of PCL crystals in PDC-TMDI was strictly confined in the phase segregated morphology. %0 journal article %@ 1022-1360 %A Jiang, Y.,Fang, L.,Kratz, K.,Lendlein, A. %D 2014 %J Macromolecular Symposia %N 1 %P 59-65 %R doi:10.1002/masy.201400138 %T Crystallization Behavior of Copolyesterurethanes Containing Different Weight Contents of Crystallizable Poly(Epsilon-caprolactone) Segments %U https://doi.org/10.1002/masy.201400138 1 %X Multiblock copolymers composed of crystallizable poly(ω-pentadecalactone) (PPDL) and poly(ε-caprolactone) (PCL) segments, which are linked via an aliphatic urethane unit, named PDLCL, have been recently introduced as temperature-memory materials. In this work, we studied the effect of different PCL weight content on the crystallization behavior of both PCL and PPDL domains in PDLCLs by differential scanning calorimetry (DSC), optical microscopy (OM) and atomic force microscopy (AFM). The results demonstrated that the nucleation mechanism of PCL crystals, the crystallization and melting temperatures of PCL domains, as well as their crystal morphology and size were found to change with varying composition, i.e., PCL weight content. %0 journal article %@ 1022-1360 %A Jiang, Y.,Fang, L.,Kratz, K.,Lendlein, A. %D 2014 %J Macromolecular Symposia %N 1 %P 75-82 %R doi:10.1002/masy.201400142 %T Effect of the Fixation Temperature Tlow on the Crystallization Behavior and Shape-Memory Performance of Crystallizable Copolyesterurethanes %U https://doi.org/10.1002/masy.201400142 1 %X Multiblock copolymers (PDLCL) composed of crystallizable poly(ω-pentadecalactone) (PPDL) segments forming hard domains and crystallizable poly(ε-caprolactone) (PCL) segments forming switching domains, have been recently introduced as multifunctional shape-memory material. The shape-memory properties of PDLCL are related to the crystallization and melting behavior of PCL switching domains, which enable the temporary fixation of an applied deformation via crystallization as well as the recovery of the original shape by melting of the PCL crystals upon heating. In this work, we explored the effect of different fixation temperatures (Tlow = 0, 10, 20 and 25 °C) on the crystallization behavior of PCL domains in compression-molded films prepared from PDLCL with identical weight contents of PCL and PPDL segments in the starting composition by atomic force microscopy (AFM) and differential scanning calorimetry (DSC). The results demonstrated that lower Tlows ≤ 10 °C supported the nucleation of PCL domains, while a Tlow ≥ 20 °C facilitated the growth of PCL crystals. Reducing Tlow, on one hand, increased the degree of crystallinity of PCL domains, which resultantly improved the shape fixation ratio (Rf) from 83% at 25 °C to 89% at 0 °C. Furthermore, the onset temperature of the recovery process (Ts) related to the crystalline PCL domains, was shifted from Ts = 29 °C to 14 °C when Tlow decreased from 25 to 0 °C, causing an increase in the width of the shape-memory transition. In contrast, the shape recovery ratio, with constant high values of Rr ≥ 96% and the almost identical characteristic switching temperature at Tsw ≈ 42 °C, were found to be independent from the applied Tlow. The obtained results confirmed that the shape-memory performance of multiblock copolymers with crystallizable switching domains can be tailored by altering the fixation temperature during programming. %0 journal article %@ 1759-9954 %A Giulbudagian, M.,Asadian-Birjand, M.,Steinhilber, D.,Achazi, K.,Molina, M.,Calderon, M. %D 2014 %J Polymer Chemistry %N 24 %P 6909-6913 %R doi:10.1039/c4py01186d %T Fabrication of thermoresponsive nanogels by thermo-nanoprecipitation and in situ encapsulation of bioactives %U https://doi.org/10.1039/c4py01186d 24 %X A synthetic method for thermoresponsive, glycerol based nanogels has been developed. The nanogels were synthesized by nanoprecipitation of the orthogonally functionalized macromonomers and their gelation in water. The crosslinking points were generated by strain promoted azide–alkyne cycloaddition which enabled the in situ encapsulation of Doxorubicin HCl. The mild and surfactant free reaction conditions make these nanogels ideal candidates for biomedical applications. %0 journal article %@ 1433-7851 %A Steinhilber, D.,Rossow, T.,Wedepohl, S.,Paulus, F.,Seiffert, S.,Haag, R. %D 2013 %J Angewandte Chemie - International Edition %N 51 %P 13538-13543 %R doi:10.1002/anie.201308005 %T A Microgel Construction Kit for Bioorthogonal Encapsulation and pH-Controlled Release of Living Cells %U https://doi.org/10.1002/anie.201308005 51 %X pH-Cleavable cell-laden microgels with excellent long-term viabilities were fabricated by combining bioorthogonal strain-promoted azide–alkyne cycloaddition (SPAAC) and droplet-based microfluidics. Poly(ethylene glycol)dicyclooctyne and dendritic poly(glycerol azide) served as bioinert hydrogel precursors. Azide conjugation was performed using different substituted acid-labile benzacetal linkers that allowed precise control of the microgel degradation kinetics in the interesting pH range between 4.5 and 7.4. By this means, a pH-controlled release of the encapsulated cells was achieved upon demand with no effect on cell viability and spreading. As a result, the microgel particles can be used for temporary cell encapsulation, allowing the cells to be studied and manipulated during the encapsulation and then be isolated and harvested by decomposition of the microgel scaffolds. %0 journal article %@ 0003-2700 %A Krueger, K.,Terne, C.,Werner, C.,Freudenberg, U.,Jankowski, V.,Zidek, W.,Jankowski, J. %D 2013 %J Analytical Chemistry %N 10 %P 4998-5004 %R doi:10.1021/ac4002063 %T Characterization of Polymer Membranes by MALDI Mass-Spectrometric Imaging Techniques %U https://doi.org/10.1021/ac4002063 10 %X For physical and chemical characterization of polymers, a wide range of analytical methods is available. Techniques like NMR and X-ray are often combined for a detailed characterization of polymers used in medical applications. Over the past few years, MALDI mass-spectrometry has been developed as a powerful tool for space-resolved analysis, not least because of its mass accuracy and high sensitivity. MALDI imaging techniques combine the potential of mass-spectrometric analysis with imaging as additional spatial information. MALDI imaging enables the visualization of localization and distribution of biomolecules, chemical compounds, and other molecules on different surfaces. In this study, surfaces of polymeric dialyzer membranes, consisting of polysulfone (PS) and polyvinylpyrrolidone (PVP), were investigated, regarding chemical structure and the compound’s distribution. Flat membranes as well as hollow fiber membranes were analyzed by MALDI imaging. First, analysis parameters like laser intensity and laser raster step size (spatial resolution in resulting image) were established in accordance with polymer’s characteristics. According to the manufacturing process, luminal and abluminal membrane surfaces are characterized by differences in chemical composition and physical characteristics. The MALDI imaging demonstrated that the abluminal membrane surface consists more of polysulfone than polyvinylpyrrolidone, and the luminal membrane surface displayed more PVP than PS. The addition of PVP as hydrophilic modifier to polysulfone-based membranes increases the biocompatibility of the dialysis membranes. The analysis of polymer distribution is a relevant feature for characterization of dialysis membranes. In conclusion, MALDI imaging is a powerful technique for polymer membrane analysis, regarding not only detection and identification of polymers but also localization and distribution in membrane surfaces. %0 journal article %@ 1558-3724 %A Sauter, T.,Heuchel, M.,Kratz, K.,Lendlein, A. %D 2013 %J Polymer Reviews %N 1 %P 6-40 %R doi:10.1080/15583724.2012.756519 %T Quantifying the Shape-Memory Effect of Polymers by Cyclic Thermomechanical Tests %U https://doi.org/10.1080/15583724.2012.756519 1 %X Shape-memory polymers (SMPs) can be deformed and fixed in defined temporary shapes, which significantly differ from their original shape and remain unchanged until exposed to heat or other stimuli. The shape-memory effect (SME) of polymers is generally quantified in cyclic thermomechanical experiments, which allow to simultaneously control stress or strain and temperature during programming and recovery. Characteristic shape-memory quantities such as the shape-fixity ratio R f and shape-recovery ratio R r as well as the specific response temperatures can be determined from the obtained stress-temperature-strain curves. This review reports on the most common cyclic testing methods utilizing tensile, bending, and compression experiments for examination of dual-shape polymers. Furthermore, recently developed testing protocols for triple- and multi-shape polymers as well as materials that exhibit a temperature-memory effect or can show a two-way SME under constant stress are discussed. %0 journal article %@ 0032-3861 %A Welsch, N.,Lu, Y.,Dzubiella, J.,Ballauff, M. %D 2013 %J Polymer %N 12 %P 2835-2849 %R doi:10.1016/j.polymer.2013.03.027 %T Adsorption of proteins to functional polymeric nanoparticles %U https://doi.org/10.1016/j.polymer.2013.03.027 12 %X We review recent work on the adsorption of proteins on two types of well-defined colloidal particles, namely on i) spherical polyelectrolytes that consist of a solid core onto which long chains of a polyelectrolyte are attached, and ii) core–shell microgels that have a shell of crosslinked poly(N-isopropylacrylamide) (pNiPAm) chains. The latter system may bear charges as well by copolymerization with acrylic acid. The surface layers of both systems that have a thickness of ca. 50 nm create a microenvironment in which the salt concentration and the pH differ from the outside solution. Adsorption of various proteins to these particles is monitored by various methods including calorimetry, fluorescence spectroscopy and small-angle X-ray scattering. These investigations also include studies of the kinetics of adsorption. The secondary structure of the proteins can be analyzed in these systems by FT-IR spectroscopy. Their tertiary structure can be checked by measurements of the enzymatic activity. In some cases the adsorbed enzymes exhibit an even higher activity as compared to the free protein in solution. We review the application of these techniques to monitor adsorption of proteins to these particles. All data demonstrate that both types of particles present model systems that help us to explore the main driving forces of protein adsorption. %0 journal article %@ 1386-0291 %A Braune, S.,Ruesten-Lange, M.v.,Mrowietz, C.,Luetzow, K.,Roch, T.,Neffe, A.T.,Lendlein, A.,Jung, F. %D 2013 %J Clinical Hemorheology and Microcirculation %N 3 %P 235-248 %R doi:10.3233/CH-131729 %T Dynamic in vitro hemocompatibility testing of poly(ether imide) membranes functionalized with linear, methylated oligoglycerol and oligo(ethylene glycol) %U https://doi.org/10.3233/CH-131729 3 %X Linear, side-chain methylated oligoglycerols (OGMe) were recently reported as potential surface passivating molecules for improving the protein resistance of cardiovascular application relevant poly(ether imide) (PEI) membranes. A previously reported in vitro screening under static test conditions allowed an end-point evaluation of the adhesion and activation of adherent thrombocytes performed on the material surfaces and revealed similar levels of thrombogenicity on PEI membranes, functionalized with OGMe and oligo(ethylene glycol) (OEG) of similar molecular weight (Mn = 1,300 g·mol−1 - 1,800 g·mol−1). In the present study, we investigated the hemocompatibility of these materials in a dynamic closed loop system, in order to study time-dependent thrombocyte material interactions also of the circulating thrombocytes by mimicking in vivo relevant flow conditions in a dynamic test system with multiple material contacts. Activation and aggregation of circulating thrombocytes as well as complement activation and plasmatic coagulation were evaluated after 40 circulations of thrombocyte rich plasma in the closed loop system. The results of the dynamic tests revealed no differences between the OGMe and OEG functionalized PEI membranes. Furthermore, no differences were observed between the latter and a PEI membrane treated under the conditions of functionalization at pH 11 (PEI-pH11) without an oligoether being present. Blood plasma protein adsorption, as well as activation, and adherence of circulating thrombocytes occurred in a comparable, but minor manner on all investigated PEI membranes. From this we conclude that the OGMe and OEG surface functionalization did not lead to an improvement of the already good hemocompatibility of the PEI-pH11 membrane. %0 journal article %@ 1386-0291 %A Franke, R.P.,Scharnweber, T.,Fuhrmann, R.,Mrowietz, C.,Jung, F. %D 2013 %J Clinical Hemorheology and Microcirculation %N 3 %P 273-285 %R doi:10.3233/CH-131733 %T Effect of radiographic contrast media (Iodixanol, Iopromide) on the spectrin/actin-network of the membranous cytoskeleton of erythrocytes %U https://doi.org/10.3233/CH-131733 3 %X Red blood cells demonstrate a unique ability for repeated large deformation. Under the influence of a variety of agents, shapes other than the discocyte – e.g. stomatocytes or echinocytes - can be observed. Some radiographic agents induce shape changes from discocytic to echinocytic cells. Especially the echinocyte formation is associated with a rigidification of the cells bearing the risk of a hindered capillary passage of the echinocytes. The mechanisms leading to the formation of echinocytes are not well understood assuming that the membrane cytoskeleton is a key player. That is why this examination was focused on the participation of components of the membrane cytoskeleton in the formation of echinocytes and the protrusions accompanying the formation of echinocytes. Two radiographic contrast media approved for intra-arterial application were used to study echinocyte formation (Iodixanol320; Iopromide370). In the in vitro study serious changes in the membrane cytoskeleton were only found in those erythrocytes incubated in plasma supplemented with Iopromide370 (30%v/v). The shape of the spectrin net was completely altered; from the more homogeneous distribution - typical of cells in autologous plasma and also of cells in plasma supplemented with Iodixanol320 – to a distribution of spectrin concentrated in the membrane-near regions with the appearance of spectrin-actin co-localization. Co-localized spectrin with actin was also found around the membranous roots of protrusions which resemble exocytotic processes. In central parts of the cells there was a pronounced dissociation of spectrin and actin; green coloured condensed spectrin bundles originating from the cell membrane reached up to the root of the protrusions. Separate from this there were also fine long actin fibres passing through the whole cell. The incubation of erythrocytes in plasma supplemented with Iopromide370 induced rounded bubble-like protrusions from the cell membrane containing almost completely long bundles of actin fibres. The examination confirmed earlier studies showing that some radiographic contrast media are able to induce echinocyte formation. Furthermore, subcellular mechanisms were revealed explaining the different effects of Iodixanol in comparison to Iopromide. %0 journal article %@ 0006-355X %A Jung, F.,Pindur, G.,Ohlmann, P.,Spitzer, G.,Sternitzky, R.,Franke, R.P.,Leithäuser, B.,Wolf, S.,Park, J.-W. %D 2013 %J Biorheology %N 5-6 %P 241-255 %R doi:10.3233/BIR-130645 %T Microcirculation in hypertensive patients %U https://doi.org/10.3233/BIR-130645 5-6 %X Regardless of the mechanisms that initiate the increase in blood pressure, functional and structural changes in the systemic vasculature are the final result of long-standing hypertension. These changes can occur in the macro- but also in the microvasculature. The supply of the tissues with oxygen, nutrients, and metabolites occurs almost exclusively in the microcirculation (which comprises resistance arterioles, capillaries and venules), and an adequate perfusion via the microcirculatory network is essential for the integrity of tissue and organ function. This review focuses on results from clinical studies in hypertensive patients, which have been performed in close cooperation with different clinical groups over the last three decades. Intravital microscopy was used to study skin microcirculation, microcatheters for the analysis of skeletal muscle microcirculation, the slit lamp for conjunctival microcirculation and the laser scanning ophthalmoscope for the measurement of the retinal capillary network. The first changes of the normal microcirculation can be found in about 93% of patients with essential hypertension, long before organ dysfunctions become clinically manifest. The earliest disorders were found in skin capillaries and thereafter in the retina and the skeletal muscle. In general, the disorders in the different areas were clearly correlated. While capillary rarefaction occurred mainly in the retina and the conjunctiva bulbi, in skin capillaries morphological changes were rare. A significant decrease of capillary erythrocyte velocities under resting conditions together with a marked damping of the postischemic hyperemia was found, both correlating with the duration of hypertension or WHO stage or the fundus hypertonicus stage. Also the mean oxygen tension in the skeletal muscle was correlated with the state of the disease. These data show that the microcirculatory disorders in hypertension are systemic and are hallmarks of the long-term complications of hypertension. There is now a large body of evidence that microvascular changes occur very early and may be important in their pathogenesis and progression. %0 journal article %@ 1022-1360 %A Racheva, M.,Julich-Gruner, K.K.,Nöchel, U.,Neffe, A.T.,Wischke, C.,Lendlein, A. %D 2013 %J Macromolecular Symposia %N 1 %P 24-32 %R doi:10.1002/masy.201300112 %T Influence of Drying Procedures on Network Formation and Properties of Hydrogels from Functionalized Gelatin %U https://doi.org/10.1002/masy.201300112 1 %X Side chain functionalization of gelatin with tyrosine-derived moieties, desaminotyrosine (DAT) or desaminotyrosyl tyrosine (DATT), has been reported to lead to physical networks stabilized by aromatic interactions and hydrogen bonds, while the inherent ability of gelatin chains to organize in helices is suppressed. Here, the treatment of DAT and DATT gelatin films at defined temperatures (drying at 5 °C, freeze-drying, and freeze-thawing) were explored for the potential to additionally stabilize the hydrogels by increasing the content of helical domains as additional physical netpoints. The influence of the drying procedures on the hydrogel properties such as network morphology and mechanical properties were analyzed by WAXS, swelling, and rheological measurements. The triple helix content had a stabilizing effect on gelatin-based hydrogels at temperatures below the helix-to-coil transition. However, this effect was less pronounced at physiological conditions above the transition temperature, resulting in rapid dissolution of the physical gelatin networks. %0 journal article %@ 0887-6266 %A Heuchel, M.,Sauter, T.,Kratz, K.,Lendlein, A. %D 2013 %J Journal of Polymer Science B %N 8 %P 621-637 %R doi:10.1002/polb.23251 %T Thermally induced shape-memory effects in polymers: Quantification and related modeling approaches %U https://doi.org/10.1002/polb.23251 8 %X Thermo-sensitive polymers, which are capable to exhibit a dual-, triple-, or multi-shape effect or a temperature-memory effect (TME), characterized by a controlled shape change in a predefined way, are of current technological interest for designing and realization of actively moving intelligent devices. Here, the methods for the quantitative characterization of shape-memory effects in polymers and recently developed thermomechanical modeling approaches for the simulation of dual-, triple-, and multi-shape polymers as well as materials that exhibit a TME are discussed and some application oriented models are presented. Standardized methods for comprehensive quantification of the different effects and reliable modeling approaches form the basis for a successful translation of the extraordinary achievements of fundamental research into technological applications. %0 journal article %@ 1022-1360 %A Saatchi, M.,Behl, M.,Lendlein, A. %D 2013 %J Macromolecular Symposia %N 1 %P 33-39 %R doi:10.1002/masy.201300151 %T Manufacturing and Characterization of Controlled Foaming of Single Layers in Bilayer Constructs Differing in Pore Morphology %U https://doi.org/10.1002/masy.201300151 1 %X Bilayer porous constructs from degradable polymers are considered as scaffold materials with beneficial elastic properties for cell culture application in tissue engineering. Here, we explored whether such bilayer constructs, in which only one layer was porous while the other layer enhanced the compressive mechanical properties, could be created by specific foaming of one layer with supercritical carbon dioxide (scCO2). The bilayer constructs of a poly(L-lactide) (PLLA) and a poly(ϵ-caprolactone) (PCL) layer were prepared by sequential injection molding and subsequent specific foaming with scCO2. Foaming conditions of T = 45 °C and P = 100 bar resulted in the formation of a porous PCL layer and a non-porous PLLA layer. When the time intervals of the foaming process were increased the pore size was increased and the shape of the pores was changed from a circular to an unidirectional lamellar shape, which reduced the compressive elastic modulus of the porous PCL layer. Furthermore, the foaming process increased the adhesion force between the PLLA and PCL layers, which was attributed to a higher degree of diffusion of molten PCL into the PLLA layer. In summary, it was demonstrated that scCO2 foaming is a suitable method for the creation of layered scaffolds with only one foamed layer, in which the compressive elastic modulus and pore morphology of single porous layers can be controlled by the time interval of scCO2 process. %0 journal article %@ 1743-4440 %A Neffe, A.T.,Wischke, C.,Racheva, M.,Lendlein, A. %D 2013 %J Expert Review of Medical Devices %N 6 %P 813-833 %R doi:10.1586/17434440.2013.839209 %T Progress in biopolymer-based biomaterials and their application in controlled drug delivery %U https://doi.org/10.1586/17434440.2013.839209 6 %X Biopolymer-based materials are based on re-growing resources and are attractive for biomedical applications, as they can inherently combine degradability in vivo, can offer sites of adhesion for cells and proteins, often show good biocompatibility and may additionally be used to release embedded bioactive molecules. However, their selection and efficient use for specific applications require an understanding of molecular principles and relationships between the molecular and macroscopic level to establish distinct properties and functions. Here, synthetic routes are described, which allow tailoring properties and functions of biopolymer-based materials. The biological evaluation of such materials is discussed, with a special emphasis on their application in controlled release systems such as hydrogels and particulate carriers. %0 journal article %@ 1946-4274 %A Ekinci, D.,Sisson, A.L.,Lendlein, A. %D 2013 %J MRS Online Proceedings Library %N %P 79-84 %R doi:10.1557/opl.2013.962 %T Quantification of Protein Adsorption on Polyglycerol-based Polymer Network Films %U https://doi.org/10.1557/opl.2013.962 %X Neutral, hydrophilic, polymer-based architectures are widely investigated for a wide range of biomedical applications from drug-conjugates to delivery systems and scaffolds for regenerative therapies. In most cases, it is crucial that biomaterials provide a blank, inert background in order to hinder unspecific cell-material interactions so that protein mediated biological events leading to foreign body reactions are prevented. Hydrophilic polyglycerol-based polymer network films are a recently developed class of amorphous macroscopic materials, which offer great versatility in design and control of resultant properties. In this study, protein adsorption on polyglycerol-based polymer network films is investigated by using Micro BCA protein assay for three types of proteins having critical roles in the human body, and various copolymer networks with differing sidechains and crosslink densities. %0 journal article %@ 0008-6215 %A Tripodo, G.,Wischke, C.,Neffe, A.T.,Lendlein, A. %D 2013 %J Carbohydrate Research %N %P 59-63 %R doi:10.1016/j.carres.2013.08.018 %T Efficient synthesis of pure monotosylated beta-cyclodextrin and its dimers %U https://doi.org/10.1016/j.carres.2013.08.018 %X 6-O-Monotosyl-β-cyclodextrin (mono-Ts-βCD) is one of the most important intermediates in the production of substituted βCD. So far, performing the monotosylation reaction and, in particular, the purification steps was challenging, relied on toxic solvents, and resulted in long and expensive procedures at, importantly, low yields. Here, the reaction of cyclodextrin with p-toluenesulfonyl chloride in aqueous environment is described to obtain a highly pure mono-Ts-βCD, for which a single-step purification with a cation exchange resin was applied. With this synthetic route and purification, yields could be increased from typically <10–15% to 35%, and organic solvents could be avoided. As characterized by FTIR, mass spectrometry, elemental analysis, and NMR, mono-Ts-βCD was obtained with a molar purity of >98 mol %. From mono-Ts-βCD, β-cyclodextrin dimers linked by ethylenediamine (bis-Et-βCD) were successfully prepared (yield 93%, purity 96 mol %) in a one-step approach using an anion exchange resin to trap leaving groups that typically interfere in the reaction. This synthesis procedure with a direct collection of side-products may be a general strategy applicable for nucleophilic substitution of tosylated cyclodextrins. %0 journal article %@ 0014-3057 %A Noechel, U.,Reddy, C.S.,Uttamchand, N.K.,Kratz, K.,Behl, M.,Lendlein, A. %D 2013 %J European Polymer Journal %N 9 %P 2457-2466 %R doi:10.1016/j.eurpolymj.2013.01.022 %T Shape-memory properties of hydrogels having a poly(Epsilon-caprolactone) crosslinker and switching segment in an aqueous environment %U https://doi.org/10.1016/j.eurpolymj.2013.01.022 9 %X Multiphase copolymer networks are of great relevance as their thermal and mechanical as well as shape-memory properties can be adjusted by the variation of the composition and crosslink density. In this context recently grafted copolymer networks (named CLEG), prepared by thermal free-radical polymerization with different ratios of the hydrophobic telechelic crosslinker poly(ε-caprolactone) diisocyanoethyl methacrylate (PCLDIMA, Tm,PCL = 55 °C) and hydrophilic poly(ethylene glycol) monomethyl ether monomethacrylate (PEGMA, Tm,PEG = 38 °C) as co-monomer, were introduced, which additionally allow the alteration of the overall elastic properties via controlled water uptake.,Here we study the thermomechanical properties as well as the shape-memory behavior of a series of CLEG copolymer networks in an aqueous environment. The mechanical properties of the networks at 25 °C in aqueous environment were found to increase from 4 MPa to 77 MPa with increasing crosslink density. The shape-memory properties of the copolymer networks were examined in an aqueous environment by both bending as well as uniaxial elongation experiments. Excellent dual-shape properties with high shape fixity ratios around Rf = 79–100% and shape recovery ratios in the range of Rr = 59% to Rr = 100% were obtained for copolymers with a PCLDIMA weight fraction ⩾50 wt% in the starting composition. The swelling of CLEG in H2O resulted in a reduction of the switching temperature. Furthermore the structural changes during programming of CLEG were assessed in situ by small and wide angle X-ray scattering (SAXS, WAXS) experiments, which confirmed that the overall degree of crystallinity as well as the orientation of the crystalline domains controlled the dual-shape performance. We have found that an appropriate switching segment should result in a degree of crystallinity higher than 10–20% to enable high strain fixity ratios. Furthermore, hydrogels having dual shape-memory capability could be created by using semi-crystalline crosslinker simultaneously acting as the switching segment. %0 journal article %@ 0168-3659 %A Wischke, C.,Schneider, C.,Neffe, A.T.,Lendlein, A. %D 2013 %J Journal of Controlled Release %N 3 %P 321-328 %R doi:10.1016/j.jconrel.2013.02.013 %T Polyalkylcyanoacrylates as in situ formed diffusion barriers in multimaterial drug carriers %U https://doi.org/10.1016/j.jconrel.2013.02.013 3 %X Polymeric hydrogels typically release their drug payload rapidly due to their high water content and the diffusivity for drug molecules. This study proposes a multimaterial system to sustain the release by covering the hydrogel with a poly(alkyl-2-cyanoacrylate) [PACA]-based film, which should be formed by an in situ polymerization on the hydrogel surface initiated upon contact with water. A series of PACA-hydrogel hybrid systems with increasing PACA side chain hydrophobicity was prepared using physically crosslinked alginate films and hydrophilic diclofenac sodium as model hydrogel/drug system. Successful synthesis of PACA at the hydrogel surface was confirmed and the PACA layer was identified to be most homogeneous for poly(n-butyl-2-cyanoacrylate) on both the micro- and nanolevel. At the same time, the diclofenac release from the hybrid systems was substantially sustained from ~ 1 day for unmodified hydrogels up to > 14 days depending on the type of PACA employed as diffusion barrier. Overall, in situ polymerized PACA films on hydrogels may be widely applicable to various hydrogel matrices, different matrix sizes as well as more complex shaped hydrogel carriers. %0 journal article %@ 1552-4973 %A Trajkovski, B.,Petersen, A.,Perka, C.,Scharnagl, N.,Wischke, C.,Wagermaier, W.,Lendlein, A.,Duda, G.N. %D 2013 %J Journal of Biomedical Materials Research B %N 6 %P 950-963 %R doi:10.1002/jbm.b.32900 %T Local drug delivery by personalized, intraoperative custom-made implant coating %U https://doi.org/10.1002/jbm.b.32900 6 %X Local administration of drugs can enhance regeneration, prevent infection, or treat postsurgical pain. If used in conjunction with implants, coating strategies should allow the choice of a drug or combination of drugs, their doses, localization, and release due to intraoperative considerations. Current coating technologies lack the ability for personalized medicine strategies. Here, we describe a new intraoperative strategy for drug delivery that allows a personalized approach as local drug delivery by implant coating. A polyvinylalcohol (PVA) patch provides rapid attachment to implant surfaces by cyanoacrylate (CA) adhesives. The CA polymerization was initiated by water uptake of the patch due to exposure to a humid environment. The coating strength depended on the type of the CA, the time of external pressing load and humidification, the properties of the patch and the implant surface. The CA adhesive penetrated and polymerized within the patch without impeding the bioactivity of the embedded molecules or strongly altering the protein release pattern after attachment to the implant surface. The use of CA in combination with the PVA patch proved to be noncytotoxic in vitro. This technology platform opens the possibility for personalized medicine to locally administer drugs due to intraoperative requirements. %0 journal article %@ 1946-4274 %A Julich-Gruner, K.K.,Roch, T.,Ma, N.,Neffe, A.T.,Lendlein, A. %D 2013 %J MRS Online Proceedings Library %N %P 9-14 %R doi:10.1557/opl.2013.831 %T Immunological investigations of oligoethylene glycols functionalized with desaminotyrosine and desaminotyrosyltyrosine %U https://doi.org/10.1557/opl.2013.831 %X Biomaterials require thorough in vitro testing before being applied in vivo. Unwanted contaminations of biomaterials but also their intrinsic properties can cause uncontrolled immune response leading to severe consequences for the patient. Therefore, immunological evaluation of materials for biomedical applications is mandatory before entering clinical application. In order to introduce physical netpoints, the aromatic compounds desaminotyrosine (DAT) and desaminotyrosyl-tyrosine (DATT) were successfully used to functionalize linear and star-shaped oligoethylene glycol (lOEG and sOEG) as previously described. The materials showed properties of surfactants and have potential to be used for solubilization of lipophilic drugs in water. Furthermore, the materials are susceptible for H2O2 degradation as determined by MALDI-ToF MS analyses. This is important for potential in vivo applications, as macrophages can release reactive oxygen species (ROS) under inflammatory conditions. As it is known that surfactant solutions of high concentration can lead to cell lysis, the effects of OEG-DAT(T) solutions on murine RAW macrophages were investigated. Even at highest OEG-DAT(T) concentration of 1000 µg·mL-1 the viability of the RAW cells was not significantly impaired. Additionally, the polymers were incubated with whole human blood and the production of inflammatory cytokines such as the tumor necrosis factor (TNF)-α and interleukin (IL)-6 was determined. Only at high concentrations, the OEG-DAT(T) solution induced low levels of TNF-α and IL-6, indicating that a mild inflammatory reaction could be expected when such high OEG-DAT(T) concentrations are applied in vivo. Similarly, the OEG-DAT(T) solution did not induce ROS in monocytes and neutrophils after incubation with whole human blood. Conclusively, the data presented here demonstrate that OEG-DAT(T) do not lead to a substantial activation of the innate immune mechanisms and could therefore be investigated for solubilizing pharmaceutical agents. %0 journal article %@ 0884-2914 %A Pehlivanova, V.,Krasteva, V.,Seifert, B.,Luetzow, K.,Tsoneva, I.,Becker, T.,Richau, K.,Lendlein, A.,Tzoneva, R. %D 2013 %J Journal of Materials Research %N 16 %P 2180-2186 %R doi:10.1557/jmr.2013.193 %T The role of alternating current electric field for cell adhesion on 2D and 3D biomimetic scaffolds based on polymer materials and adhesive proteins %U https://doi.org/10.1557/jmr.2013.193 16 %X Tissue engineering principles suggest the formation of 3D scaffolds based on polymer fibers and adhesive proteins. These scaffolds aim to mimic the native extracellular matrix and thus providing a favorable environment for cell attachment and proliferation. The application of an electric field (EF) can influence the quantity and the spatial orientation/conformation of adsorbed proteins, which could lead to changes in their functions. We study the influence of alternating current (AC) EF on the adsorption of fibronectin onto poly(etherimide) (PEI) electrospun fiber materials in 3D structures and subsequent cell adhesion. The results are compared with 2D PEI material and glass surface. 3D scaffolds adsorbed a lower amount of fibronectin than 2D film or glass. Application of AC EF with a frequency of 1 Hz decreased the adsorption of fibronectin. Cell adhesion on 3D materials was reduced compared with 2D film and glass. The application of EF with frequencies between 1 and 10 Hz improved cell adhesion on both 2D and 3D materials. %0 journal article %@ 1389-2010 %A Wang, W.,Li, W.,Ma. N.,Steinhoff, G. %D 2013 %J Current Pharmaceutical Biotechnology %N 1 %P 46-60 %R doi:10.2174/1389201011314010008 %T Non-Viral Gene Delivery Methods %U https://doi.org/10.2174/1389201011314010008 1 %X Gene delivery has attracted increasing interest as a highly promising therapeutic method to treat various diseases, including both genetic and acquired disorders. Viral-vectors based gene delivery can achieve higher transduction efficiency and long-term gene expression, but they may be associated with some shortcomings, such as immunogenicity, carcinogenicity, poor target cell specificity, inability to transfer large size genes and high costs. Non-viral approaches show high potential due to advantages of relative safety, ability to transfer large size gene, less toxicity and easiness for preparation etc. However, the clinical application of non-viral methods is still restricted by some limitations including low transfection efficiency and poor transgene expression. In order to improve gene transfer efficacy, a lot of efforts have been made in the past years, and numerous gene carriers and techniques have been developed. In this review, we summarized the features, drawbacks and prospects of existing and emerging non-viral gene delivery methods. %0 journal article %@ 1386-0291 %A König, J.,Kohl, B.,Kratz, K.,Jung, F.,Lendlein, A.,Ertel, W.,Schulze-Tanzil, G. %D 2013 %J Clinical Hemorheology and Microcirculation %N 4 %P 523-533 %R doi:10.3233/CH-131788 %T Effect of polystyrene and polyether imide cell culture inserts with different roughness on chondrocyte metabolic activity and gene expression profiles of aggrecan and collagen %U https://doi.org/10.3233/CH-131788 4 %X In vitro cultured autologous chondrocytes can be used for implantation to support cartilage repair. For this purpose, a very small number of autologous cells harvested from a biopsy have to be expanded in monolayer culture. Commercially available polymer surfaces lead to chondrocyte dedifferentiation. Hence, the demanding need for optimized polymers and surface topologies supporting chondrocytes' differentiated phenotypes in vitro arises. In this study we explored the effect of tailored cell culture plate inserts prepared from polystyrene (PS) and polyether imide (PEI) exhibiting three different roughness levels (R0, RI, RII) on chondrocyte morphology, metabolism and gene expression profile. As a control, commercially available tissue culture plastic (TCP) dishes were included. Primary porcine articular chondrocytes were seeded on tailored PS and PEI inserts with three different roughness levels. The metabolic activity of the chondrocytes was determined after 24 hours using alamar blue assay. Chondrocyte gene expression profiles (aggrecan, type I and type II collagen) were monitored after 48 hours using Real Time Detection (RTD)-PCR. Chondrocytes cultured on PS and PEI surfaces formed cell clusters after 24 and 48 hours, which was not observed on TCP. The metabolic activity of chondrocytes cultured on PS was lower than of chondrocytes cultured on PEI, but also lower than on TCP. Gene expression analyses revealed an elevated expression of cartilage-specific aggrecan and an impaired expression of both collagen types by chondrocytes on PS and PEI compared with TCP. In summary, PEI is a biocompatible biomaterial suitable for chondrocyte culturing, which can be further chemically functionalized for generating specific surface interactions or covalent binding of biomolecules. %0 journal article %@ 0939-6411 %A Wischke, C.,Krueger, A.,Roch, T.,Pierce, B.F.,Li, W.,Jung, F.,Lendlein, A. %D 2013 %J European Journal of Pharmaceutics and Biopharmaceutics %N 2 %P 288-296 %R doi:10.1016/j.ejpb.2013.01.025 %T Endothelial cell response to (co)polymer nanoparticles depending on the inflammatory environment and comonomer ratio %U https://doi.org/10.1016/j.ejpb.2013.01.025 2 %X Endothelial cells lining the lumen of blood vessels serve as a physiological barrier controlling nanoparticle movement from the vasculature into the tissue. For exploring the effect of polymer hydrophilicity on nanoparticle interactions with human umbilical vein endothelial cells (HUVECs) in vitro, a series of monomodal poly[acrylonitrile-co-(N-vinylpyrrolidone)] model nanoparticles with increasing hydrophilicity as related to their increasing content (0–30 mol.%) of N-vinylpyrrolidone (NVP) were synthesized by miniemulsion polymerization. Nanoparticles with a low NVP content were rapidly endocytized into all cells independent from the particle dose with toxic effects only observed at high particle concentrations, while only 10–30% of the cells incorporated particles with ⩾20 mol.% NVP. Since pathologies are often related to inflammation, an inflammatory HUVEC culture condition with IL-1β stimulation has been introduced and suggested to be widely applied for studying nanocarriers, since cellular uptake in this assay was clearly increased for NVP contents ⩾20 mol.%. Importantly, the secretion of functional biological mediators by HUVECs was not relevantly influenced by the nanoparticles for both homeostatic and inflammatory conditions. These findings may motivate concepts for nanocarriers specifically targeted to pathologic regions. Additionally, rapidly endocytized Rhodamin B loaded particles with low NVP content may be explored for cell labeling and tracking. %0 journal article %@ 1742-5247 %A Wischke, C.,Behl, M.,Lendlein, A. %D 2013 %J Expert Opinion on Drug Delivery %N 9 %P 1193-1205 %R doi:10.1517/17425247.2013.797406 %T Drug-releasing shape-memory polymers – The role of morphology, processing effects, and matrix degradation %U https://doi.org/10.1517/17425247.2013.797406 9 %X Introduction: Shape-memory polymers (SMPs) have gained interest for temporary drug-release systems that should be anchored in the body by self-sufficient active movements of the polymeric matrix.,Areas covered: Based on the so far published scientific literature, this review highlights three aspects that require particular attention when combining SMPs with drug molecules: i) the defined polymer morphology as required for the shape-memory function, ii) the strong effects that processing conditions such as drug-loading methodologies can have on the drug-release pattern from SMPs, and iii) the independent control of drug release and degradation by their timely separation.,Expert opinion: The combination of SMPs with a drug-release functionality leads to multifunctional carriers that are an interesting technology for pharmaceutical sciences and can be further expanded by new materials such as thermoplastic SMPs or temperature-memory polymers. Experimental studies should include relevant molecules as (model) drugs and provide a thermomechanical characterization also in an aqueous environment, report on the potential effect of drug type and loading levels on the shape-memory functionality, and explore the potential correlation of polymer degradation and drug release. %0 journal article %@ 0378-5173 %A Heilmann, S.,Kuechler, S.,Wischke, C.,Lendlein, A.,Stein, C.,Schaefer-Korting, M. %D 2013 %J International Journal of Pharmaceutics %N 1-2 %P 96-102 %R doi:10.1016/j.ijpharm.2013.01.027 %T A thermosensitive morphine-containing hydrogel for the treatment of large-scale skin wounds %U https://doi.org/10.1016/j.ijpharm.2013.01.027 1-2 %X Purpose,Topically applied opioids are an option to induce efficient analgesia in patients with severe skin wounds. For ongoing pain reduction, the vehicle should provide sustained drug release in order to increase the intervals during the regular wound dressing changes. In addition, the formulation should not impair wound healing. Hydrogels provide a moist wound environment, which is known to facilitate the healing process.,Methods and results,Investigating poloxamer hydrogels as a carrier system for morphine in terms of release behavior and (per-)cutaneous absorption, poloxamer 407 25 wt.% hydrogel sustained morphine release up to 24 h. The drug release rate decreased with increasing concentration of the gel forming triblock copolymer. Poloxamer 407 25 wt.% hydrogel retarded morphine uptake into reconstructed human skin and percutaneous drug absorption compared to a hydroxyethyl cellulose reference gel.,Conclusions,The results of our in vitro study indicate that the thermosensitive poloxamer 407 25 wt.% hydrogel is an appropriate carrier system for the topical application of morphine with regard to sustained drug release and ongoing analgesia. %0 journal article %@ 1022-1352 %A Sauter, T.,Kratz, K.,Lendlein, A. %D 2013 %J Macromolecular Chemistry and Physics %N 11 %P 1184-1188 %R doi:10.1002/macp.201300062 %T Pore-Size Distribution Controls Shape-Memory Properties on the Macro- and Microscale of Polymeric Foams %U https://doi.org/10.1002/macp.201300062 11 %X Open porous foams with identical foam density but different pore-size distributions (bimodal or monomodal) are prepared from a shape-memory polyetherurethane (PEU) by thermally induced phase separation. The shape-memory effect of the two PEU foams is explored by cyclic thermomechanical compression tests and microstructural analysis. The obtained results reveal that the PEU foam with a bimodal pore-size distribution exhibits an increased shape-recovery under stress-free conditions, both on the macro- (foam level) as well as the microscale (pore level). While bimodal pore-size distributions induce microscale bending during compression, buckling occurs in foams with monomodal pore-size distributions, leading to both a reduced and delayed shape recovery. %0 journal article %@ 0168-1656 %A Trescher, K.,Roch, T.,Cui, J.,Kratz, K.,Lendlein, A.,Jung, F. %D 2013 %J Journal of Biotechnology %N 1-2 %P 58-64 %R doi:10.1016/j.jbiotec.2013.04.012 %T Test system for evaluating the influence of polymer properties on primary human keratinocytes and fibroblasts in mono- and coculture %U https://doi.org/10.1016/j.jbiotec.2013.04.012 1-2 %X Interactions of cells with polymer-based biomaterials are influenced by properties of the substrate. Polymers, which are able to induce cell specific effects, gain increasing importance for biotechnology and regenerative therapies. A test system was developed, which allows studying primary human keratinocytes and fibroblasts in mono- and cocultures to analyze and operate the effect of polymer properties. This system offers to identify polymers for keratinocyte cultivation or wound dressings, since adherence, viability and functionality can be analyzed. Especially the coculture system enables the characterization of potential cell specific effects of polymer-based biomaterials. To establish a coculture test system, it is challenging to find a suitable culture medium, to identify initial seeding densities for comparable cell growth and to develop methods to distinguish and characterize both cell types.,Poly(n-butyl acrylate) networks (cPnBAs) as model biomaterials were used to demonstrate the applicability of our newly developed coculture screening system for differential cell growth. The apparent Young's modulus of the cPnBAs differentially regulated fibroblasts and keratinocytes. Particularly, cPnBA73 with an apparent Young's modulus of 930 ± 140 kPa measured in phosphate buffered saline (PBS) solution at ambient temperature seemed to have favoring properties for keratinocyte adhesion, while fibroblast adhesion was not affected. For keratinocytes the concentration of some pro-inflammatory cytokines was lower on cPnBA73 and a decreased deposition of collagen, elastin and fibronectin was observed in the coculture. %0 journal article %@ 1946-4274 %A Friess, F.,Lendlein, A.,Wischke, C. %D 2013 %J MRS Online Proceedings Library %N %P 173-178 %R doi:10.1557/opl.2013.815 %T Morphology of crosslinked poly(Epsilon-caprolactone) microparticles %U https://doi.org/10.1557/opl.2013.815 %X In order to explore the feasibility for preparing defined crosslinked particulate structures, oligo(ε-caprolactone) [oCL] derived microparticles (MPs) were crosslinked in non-molten, non-dissolved, i.e. solid state in aqueous suspension by applying a controlled regime with well-defined polymer network precursors either with or without photoinitiator. The MPs (diameter ∼ 40 μm) were prepared by an oil-in-water emulsion process from linear 2oCL or 4-arm star-shaped 4oCL with methacrylate end groups. Crosslinking was initiated by UV-laser irradiation (308 nm) at room temperature. Conversion of methacrylate was monitored by ATR-FTIR spectroscopy and crosslinking was confirmed by a lack of MP dissolution in dichloromethane. In a quantitative evaluation of swelling by dynamic light scattering, higher swelling ratios were detected for particles synthesized with photoinitiator. Wrinkled particle surfaces and distorted particle shapes were observed by light microscopy in the solvent-swollen state and by scanning electron microscopy after deswelling. This work indicated some limitations due to internal inhomogeneity of the MP, but particle crosslinking in solid state was generally possible and may be further improved by higher chain mobility during crosslinking. %0 journal article %@ 0032-3861 %A Ghobadi, E.,Heuchel, M.,Kratz, K.,Lendlein, A. %D 2013 %J Polymer %N 16 %P 4204-4211 %R doi:10.1016/j.polymer.2013.05.064 %T Influence of the addition of water to amorphous switching domains on the simulated shape-memory properties of poly(l-lactide) %U https://doi.org/10.1016/j.polymer.2013.05.064 16 %X It is well known that the environmental conditions e.g. humidity can alter the shape-memory properties of polymers. In this work we applied an atomistic molecular dynamics simulation approach to model the influence of the addition of 1 wt% and 2 wt% water on the simulated shape-memory behavior of the amorphous switching domains of poly(l-lactide) (PLLA) with a molecular weight of Mn = 52,000 g mol−1. For the dry as well as the water swollen PLLA-models, two subsequent uniaxial thermomechanical test cycles have been calculated, whereby the applied uniaxial deformation εm was varied between 50% and 150%.,All simulated PLLA models showed high shape fixity ratio of Rf ≥ 84%. The shape-memory properties obtained at εm = 100% for the dry PLLA and the models containing 1 wt% water were almost identical with a shape recovery ratio in the first and second test cycle around Rr = 61%–64%. In contrast PLLA with 2 wt% water exhibited higher values of Rr = 76% during the first test cycle, but a lower Rr = 52% in the subsequent second cycle. Furthermore, increasing the applied εm resulted in a decrease of Rr from 82% to 42% for the dry PLLA, whereas PLLA with 2 wt% water did not show a dependence of Rr on εm. We anticipate that these observations can be attributed to differences in the initial structure of the various simulated PLLA models e.g. the different distribution of the free volume elements. %0 journal article %@ 1934-8630 %A Braune, S.,Grunze, M.,Straub, A.,Jung, F. %D 2013 %J Biointerphases %N 1 %P 33 %R doi:10.1186/1559-4106-8-33 %T Are there sufficient standards for the in vitro hemocompatibility testing of biomaterials? %U https://doi.org/10.1186/1559-4106-8-33 1 %X No abstract %0 journal article %@ 0168-3659 %A Wischke, C.,Schneider, C.,Neffe, A.T.,Lendlein, A. %D 2013 %J Journal of Controlled Release %N 1 %P e 22 %R doi:10.1016/j.jconrel.2013.08.052 %T Sustained release hydrogels by in situ polymerized polyalkylcyanoacrylate coating %U https://doi.org/10.1016/j.jconrel.2013.08.052 1 %X No abstract %0 journal article %@ 0887-624X %A Khan, M.,Feng, Y.,Yang, D.,Zhou, W.,Tian, H.,Han, Y.,Zhang, L.,Yuan, W.,Zhang, J.,Guo, J.,Zhang, W. %D 2013 %J Journal of Polymer Science A %N 15 %P 3166-3176 %R doi:10.1002/pola.26703 %T Biomimetic design of amphiphilic polycations and surface grafting onto polycarbonate urethane film as effective antibacterial agents with controlled hemocompatibility %U https://doi.org/10.1002/pola.26703 15 %X The synthetic polycations are ideal candidates as antimicrobial agents, because they resemble natural antimicrobial peptides, but to render hemocompatibility to these materials is a great challenge. Herein, we used 2-(tert-butyl-aminoethyl) methacrylate (TBAEMA), to synthesize its homopolymer and pegylated random and diblock copolymers with polyethyleneglycol methacrylate (PEGMA, Mn = 360 Da) by single-electron transfer–living radical polymerization (SET-LRP). In the second step, the secondary amino groups in the precursor polymers were quaternized with iodomethane and bromohexane, to obtain three series of quaternized polymers. The antimicrobial properties of these quaternized polymers were evaluated against Escherichia coli (E. coli), by studying the minimum inhibitory concentrations (MICs) which ranged between 32 and 200 mg L−1 and showed higher values for the quaternized random than the diblock copolymers. In addition to, we have also demonstrated the grafting of these polycations onto polycarbonate urethane film surfaces, which showed good killing efficacy against E. coli. Furthermore, the hemolysis of these materials was investigated against human red blood cells, which indicated that except the quaternized homopolymers that showed highest hemolysis, all other amphiphilic polycations exhibited very low hemolytic activity. Therefore, our designed materials with controlled structures and functionality, synthesized from cheaply available resources could serve as useful agents in the field of biomedicines and implantable materials. %0 journal article %@ 0887-624X %A Zhang, L.,Feng, Y.,Tian, H.,Zhao, M.,Khan, M.,Guo, J. %D 2013 %J Journal of Polymer Science A %N 15 %P 3213-3226 %R doi:10.1002/pola.26713 %T Amphiphilic depsipeptide-based block copolymers as nanocarriers for controlled release of ibuprofen with doxorubicin %U https://doi.org/10.1002/pola.26713 15 %X Well-defined amphiphilic multiblock copolymers PDMAEMA-b-P(IBMD-co-PDO)-b-PEG-b-P(IBMD-co-PDO)-b-PDMAEMA [PDMAEMA-PIBMD-PPDO-PEG], based on poly(2-(dimethylamino)ethyl methacrylate) block (PDMAEMA), poly(3(S)-isobutyl-morpholine-2,5-dione-co-p-dioxanone) block (P(IBMD-co-PDO)), and poly(ethylene glycol) block (PEG) were successfully synthesized by combination of ring-opening polymerization (using 3(S)-isobutyl-morpholine-2,5-dione and p-dioxanone initiated by hydroxyl end of PEG) and atom transfer radical polymerization (ATRP). Furthermore, all these copolymers were characterized by 1H NMR, 13C NMR, Fourier transformed-infrared, gel permeation chromatography, differential scanning calorimetry, and thermogravimetric analysis measurements. The degradation experiments showed that the molecular weight of PDMAEMA-PIBMD-PPDO-PEG decreased along with degradation time. In addition, these copolymers could readily self-assemble into nanosized microspheres in phosphate buffered solution. Ibuprofen (IBU) and doxorubicin (DOX) as a kind of combined model drugs were loaded into these microspheres by the combination of ionic interaction and hydrophobic effect. These copolymer microspheres exhibited high loading capacity (LC, up to 26.88%), encapsulation efficiency (EE, up to 61.29%), and sustained release behavior of IBU–DOX in phosphate buffered solution. The results of transmission electron microscopy and dynamic light scattering showed that the microspheres were well-defined uniform spherical particles with average diameter less than 120 nm. Therefore, it can be envisaged that these copolymer systems are promising candidates for controlled release application. %0 journal article %@ 0168-3659 %A Wischke, C.,Neffe, A.T.,Hanh, B.D.,Kreiner, C.F.,Sternberg, K.,Stachs, O.,Guthoff, R.F.,Lendlein, A. %D 2013 %J Journal of Controlled Release %N 3 %P 1002-1010 %R doi:10.1016/j.jconrel.2013.10.021 %T A multifunctional bilayered microstent as glaucoma drainage device %U https://doi.org/10.1016/j.jconrel.2013.10.021 3 %X Commercial non-degradable glaucoma implants are often associated with undesired hypotony, fibrosis, long term failure, and damage of adjacent tissues, which may be overcome by a multifunctional polymeric microstent for suprachoroidal drainage. This study reports the design and fabrication of such devices with tailorable internal diameters (50–300 μm) by solvent-free, continuous hot melt extrusion from blends of poly[(ε-caprolactone)-co-glycolide] and poly(ε-caprolactone) [PCL]. A spatially directed release was supported by bilayered microstents with an internal drug-free PCL layer, and a quantitative description of release kinetics with diclofenac sodium as model drug was provided. Furthermore, the slow degradation pattern (> 1 year) was analyzed and potential effects of 1–5 wt.% drug loading on material properties were excluded. Translational aspects including sterilization by γ-irradiation on dry ice, in vitro biocompatibility, and in vivo implantation were addressed. The promising results support further functional analysis of long-term in vivo performance and suppression of disadvantageous capsule formation. %0 journal article %@ 1616-5187 %A Yang, J.,Lv, J.,Behl, M.,Lendlein, A.,Yang, D.,Zhang, L.,Shi, C.,Guo, J.,Feng, Y. %D 2013 %J Macromolecular Bioscience %N 12 %P 1681-1688 %R doi:10.1002/mabi.201300264 %T Functionalization of Polycarbonate Surfaces by Grafting PEG and Zwitterionic Polymers with a Multicomb Structure %U https://doi.org/10.1002/mabi.201300264 12 %X The hemocompatibility of polycarbonateurethane (PCU) surfaces is improved by decoration with poly(poly(ethylene glycol) methacrylate) (poly(PEGMA)) and zwitterionic poly(3-((2-(methacryloyloxy)ethyl)dimethylammonio)propane-1-sulfonate) (poly(DMAPS)) blocks providing a novel multicomb structure obtained by application of surface-initiated atom transfer radical polymerization (s-ATRP) conditions. The PCU-poly(PEGMA-g-DMAPS) surface shows high hydrophilicity with a low contact angle of 20.6 ± 1.8°, while PCU-poly(PEGMA-b-DMAPS) surface exhibitsed a contact angle of 30.5 ± 2.6°. Furthermore, PCU-poly(PEGMA-g-DMAPS) surface shows very low platelet adsorption indicating that multicomb structure modified PCUs are preferred candidate materials for blood-contacting materials. %0 journal article %@ 1386-0291 %A Rüder, C.,Sauter, T.,Kratz, K.,Haase, T.,Peter, J.,Jung, F.,Lendlein, A.,Zohlnhöfer, D. %D 2013 %J Clinical Hemorheology and Microcirculation %N 4 %P 513-522 %R doi:10.3233/CH-131787 %T Influence of fibre diameter and orientation of electrospun copolyetheresterurethanes on smooth muscle and endothelial cell behaviour %U https://doi.org/10.3233/CH-131787 4 %X Polymers exhibiting cell-selective effects represent an extensive research field with high relevance for biomedical applications e.g. in the cardiovascular field supporting re-endothelialization while suppressing smooth muscle cell overgrowth. Such an endothelial cell-selective effect could be recently demonstrated for a copolyetheresterurethane (PDC) containing biodegradable poly(p-dioxanone) and poly(ε-caprolactone) segments, which selectively enhanced the adhesion of human umbilical vein endothelial cells (HUVEC) while suppressing the attachment of smooth muscle cells (SMC). In this study we investigated the influence of the fibre orientation (random and aligned) and fibre diameter (2 μm and 500 nm) of electrospun PDC scaffolds on the adhesion, proliferation and apoptosis of HUVEC and SMC. Adhesion, viability and proliferation of HUVEC was diminished when the fibre diameter was reduced to a submicron scale, while the orientation of the microfibres did only slightly influence the cellular behaviour. In contrast, a submicron fibre diameter improved SMC viability. In conclusion, PDC scaffolds with micron-sized single fibres could be promising candidate materials for cell-selective stent coatings. %0 journal article %@ 1022-1352 %A Lendlein, A.,Sauter, T. %D 2013 %J Macromolecular Chemistry and Physics %N 11 %P 1175-1177 %R doi:10.1002/macp.201300098 %T Shape-Memory Effect in Polymers %U https://doi.org/10.1002/macp.201300098 11 %X No abstract %0 journal article %@ 1946-4274 %A Roch, T.,Behl, M.,Zierke, M.,Pierce, B.F.,Kratz, K.,Weigel, T.,Ma, N.,Lendlein, A. %D 2013 %J MRS Online Proceedings Library %N %P 21-26 %R doi:10.1557/opl.2013.830 %T The influence of the co-monomer ratio of poly[acrylonitrile-co-(N-vinylpyrrolidone)]s on primary human monocyte-derived dendritic cells %U https://doi.org/10.1557/opl.2013.830 %X A major goal in the field of regenerative medicine is to improve our understanding of how biomaterial properties affect cells of the immune system. Systematic variation of defined chemical properties could help to understand which factors determine and modulate cellular responses. A series of copolymers poly[acrylonitrile-co-(N-vinylpyrrolidone)]s (P(AN-co-NVP)) served as model system, in which increasing hydrophilicity was adjusted by increasing the content related to the NVP based repeating units (nNVP) (0, 4.6, 11.8, 22.3, and 29.4 mol%). The influence of increasing nNVP contents on cellular response of human primary monocyte derived dendritic cells (DC), which play a key role in the initiation of immune responses, was investigated. It was shown using the LAL-Test as well as a macrophage-based assay, that the materials were free of endotoxins and other microbial contaminations, which could otherwise bias the readout of the DC experiments. The increasing nNVP content led to a slightly increased cell death of DC, whereas the activation status of DC was not systematically altered by the different P(AN-co-NVP)s as demonstrated by the expression of co-stimulatory molecule and cytokine secretion. Similarly, under inflammatory conditions mimicked by the addition of lipopolysaccharides (LPS), neither the expression of co-stimulatory molecules nor the release of cytokines was influenced by the different copolymers. Conclusively, our data showed that this class of copolymers does not substantially influence the viability and the activation status of DC. %0 journal article %@ 1946-4274 %A Gebauer, T.,Neffe, A.T.,Lendlein, A. %D 2013 %J MRS Online Proceedings Library %N %P 15-20 %R doi:10.1557/opl.2013.839 %T Influence of diisocyanate reactivity and water solubility on the formation and the mechanical properties of gelatin-based networks in water %U https://doi.org/10.1557/opl.2013.839 %X Gelatin can be covalently crosslinked in aqueous solution by application of diisocyanates like L-lysine diisocyanate ethyl ester in order to form hydrogels. Reaction of isocyanate groups with water is however a limiting factor in hydrogel network formation and can strongly influence the outcome of the crosslinking process. Here, diisocyanates with different water solubility and reactivity were applied for the formation of gelatin-based hydrogel networks and the mechanical properties of the hydrogels were investigated to gain a better understanding of starting material/ hydrogel property relations. L-Lysin diisocyanate ethyl ester (LDI), 2, 4-toluene diisocyanate (TDI), 1, 4-butane diisocyanate (BDI), and isophorone diisocyanate (IPDI) were selected, having different solubility in water ranging from 10-4 to 10-2 mol·L-1. BDI and LDI were estimated to have average reactive isocyanates groups, whereas TDI is highly reactive and IPDI has low reactivity. Formed hydrogels showed different morphologies and were partially very inhomogeneous. Gelation time (1 to 50 minutes), water uptake (300 to 900 wt.-%), and mechanical properties determined by tensile tests (E-moduli 35 to 370 kPa) and rheology (Shear moduli 4.5 to 19.5 kPa) showed