@misc{bhuvanesh_laminin__2023, author={Bhuvanesh, T., Nie, Y., Machatschek, R., Ma, N., Lendlein, A.}, title={Laminin - dynamic bonds enable multifunctionality in a biological 2D network}, year={2023}, howpublished = {journal article}, doi = {https://doi.org/10.1002/adfm.202304268}, abstract = {A layer of laminins, assembled on a thin sheet of collagen type IV (Col-IV) forms the backbone of the basal lamina, which controls biological processes such as embryogenesis, tissue homeostasis, and development. Here, the dynamic functions of laminin-111 (Lam-111) in ultrathin films at the air–water interface are investigated. It is shown that the 2D confinement induces polymerization and that expansion via adlayer formation occurs only with extended growth time. The highly robust self-assembly enables the functionalization of surfaces with cross-linked 2D Lam-111 networks of defined thickness using little more than a beaker. The 2D laminin material also displays two dynamic functions required for the maintenance of tissues – the capability for self-renewal and self-healing. By assembling Lam-111 2D networks at the surface of Col-IV sheets, freestanding bilayers closely mimicking the basal lamina can be produced in vitro. There is a marked difference in miPSC spreading and adhesion force between Lam-111 sheets assembled in the presence or absence of Col-IV. These fundamental studies highlight the importance of dynamic functions, encoded into the molecular structure of the building blocks, for the assembly, maintenance, and functioning of the complex material systems found in natural tissues and can provide cues for the molecular design of resilient technical systems.}, note = {Online available at: \url{https://doi.org/10.1002/adfm.202304268} (DOI). Bhuvanesh, T.; Nie, Y.; Machatschek, R.; Ma, N.; Lendlein, A.: Laminin - dynamic bonds enable multifunctionality in a biological 2D network. Advanced Functional Materials. 2023. vol. 33, no. 46, 2304268. DOI: 10.1002/adfm.202304268}} @misc{nie_a_model_2023, author={Nie, Y., Liu, Y., Xu, X., Wang, W., Scharnagl, N., Heuchel, M., Lendlein, A., Ma, N.}, title={A model of using the asymmetric polydopamine thin film for mimicking epithelial folding in vitro}, year={2023}, howpublished = {journal article}, doi = {https://doi.org/10.1002/admi.202202509}, abstract = {The basement membrane (BM) is a biointeractive ultrathin network with distinct composition and organization of its epithelial and stromal sides, which render BMs with asymmetric biofunctions and mechanical properties. There are difficulties in the recapitulation of the highly hierarchical structure and function of BM. Here, the interfacial assembly method for the generation of BM mimics is applied. Dopamine is the starting material for the polymerization and assembly of polydopamine (PDA) into asymmetric materials. Compared to the PDA coating formed at the solid/liquid interface (≈20 nm), the PDA film formed at the air/liquid interface displays a thickness of ≈100 nm. Moreover, it possesses an asymmetric surface topography and an apparent Young's modulus of ≈1.0 MPa, which is structurally and mechanically similar to natural BMs. Of interest, the airside and the waterside of the PDA film exhibit differences in their adhesion affinity to the human skin keratinocytes. With stronger active mechanical processes between living cells and the waterside of PDA film, epithelial folding could be mimicked. Together, the PDA film is able to recapitulate the structural and mechanical complexity of natural BMs, indicating the prospective future of using PDA films for in vitro modeling cell-BM interaction and tissue formation.}, note = {Online available at: \url{https://doi.org/10.1002/admi.202202509} (DOI). Nie, Y.; Liu, Y.; Xu, X.; Wang, W.; Scharnagl, N.; Heuchel, M.; Lendlein, A.; Ma, N.: A model of using the asymmetric polydopamine thin film for mimicking epithelial folding in vitro. Advanced Materials Interfaces. 2023. vol. 10, no. 18, 2202509. DOI: 10.1002/admi.202202509}} @misc{xu_histone_modification_2023, author={Xu, X., Wang, W., Zou, J., Kratz, K., Deng, Z., Lendlein, A., Ma, N.}, title={Histone modification of osteogenesis related genes triggered by substrate topography promotes human mesenchymal stem cell differentiation}, year={2023}, howpublished = {journal article}, doi = {https://doi.org/10.1021/acsami.3c01481}, abstract = {The clinical success of orthopedic implants is closely related to their integration in the bone tissue promoted by rough device surfaces. The biological response of precursor cells to their artificial microenvironments plays a critical role in this process. In this study, we elucidated the relation between cell instructivity and surface microstructure of polycarbonate (PC)-based model substrates. The rough surface structure (hPC) with an average peak spacing (Sm) similar to the trabecular spacing of trabecular bone improved osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs), as compared to the smooth surface (sPC) and the surface with a moderate Sm value (mPC). The hPC substrate promoted the cell adhesion and assembling of F-actin and enhanced cell contractile force by upregulating phosphorylated myosin light chain (pMLC) expression. The increased cell contractile force led to YAP nuclear translocation and the elongation of cell nuclei, presenting higher levels of active form of Lamin A/C. The nuclear deformation alternated the histone modification profile, particularly the decrease of H3K27me3 and increase of H3K9ac on the promoter region of osteogenesis related genes (ALPL, RUNX2, and OCN). Mechanism study using inhibitors and siRNAs elucidated the role of YAP, integrin, F-actin, myosin, and nuclear membrane proteins in such a regulatory process of surface topography on stem cell fate. These mechanistical insights on the epigenetic level give a new perspective in understanding of the interaction of substrate and stem cells as well as provide valuable criteria for designing bioinstructive orthopedic implants.}, note = {Online available at: \url{https://doi.org/10.1021/acsami.3c01481} (DOI). Xu, X.; Wang, W.; Zou, J.; Kratz, K.; Deng, Z.; Lendlein, A.; Ma, N.: Histone modification of osteogenesis related genes triggered by substrate topography promotes human mesenchymal stem cell differentiation. ACS Applied Materials and Interfaces. 2023. vol. 15, no. 25, 29752–29766. DOI: 10.1021/acsami.3c01481}} @misc{tung_in_vivo_2022, author={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.}, title={In Vivo Performance of a Cell and Factor Free Multifunctional Fiber Mesh Modulating Postinfarct Myocardial Remodeling}, year={2022}, howpublished = {journal article}, doi = {https://doi.org/10.1002/adfm.202110179}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1002/adfm.202110179} (DOI). Tung, W.; Maring, J.; Xu, X.; Liu, Y.; Becker, M.; Somesh, D.; Klose, K.; Wang, W.; Sun, X.; Ullah, I.; Kratz, K.; Neffe, A.; Stamm, C.; Ma, N.; Lendlein, A.: In Vivo Performance of a Cell and Factor Free Multifunctional Fiber Mesh Modulating Postinfarct Myocardial Remodeling. Advanced Functional Materials. 2022. vol. 32, no. 31, 2110179. DOI: 10.1002/adfm.202110179}} @misc{ullah_multiblock_copolymers_2022, author={Ullah, I., Wang, W., Ma, N., Lendlein, A.}, title={Multiblock copolymers type PDC- a family of multifunctional biomaterials for regenerative medicine}, year={2022}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-211264}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-211264} (DOI). Ullah, I.; Wang, W.; Ma, N.; Lendlein, A.: Multiblock copolymers type PDC- a family of multifunctional biomaterials for regenerative medicine. Clinical Hemorheology and Microcirculation. 2022. vol. 80, no. 3, 327-341. DOI: 10.3233/CH-211264}} @misc{zhou_prediction_of_2022, author={Zhou, S., Xu, X., Ma, N., Jung, F., Lendlein, A.}, title={Prediction of the epichlorohydrin derived cytotoxic substances from the eluent of poly(glycerol glycidyl ether) films}, year={2022}, howpublished = {journal article}, doi = {https://doi.org/10.1557/s43580-021-00132-y}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1557/s43580-021-00132-y} (DOI). Zhou, S.; Xu, X.; Ma, N.; Jung, F.; Lendlein, A.: Prediction of the epichlorohydrin derived cytotoxic substances from the eluent of poly(glycerol glycidyl ether) films. MRS Advances. 2022. vol. 7, 354-359. DOI: 10.1557/s43580-021-00132-y}} @misc{nie_the_response_2021, author={Nie, Y., Wang, W., Xu, X., Ma, N., Lendlein, A.}, title={The response of human induced pluripotent stem cells to cyclic temperature changes explored by BIO-AFM}, year={2021}, howpublished = {journal article}, doi = {https://doi.org/10.1557/s43580-021-00110-4}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1557/s43580-021-00110-4} (DOI). Nie, Y.; Wang, W.; Xu, X.; Ma, N.; Lendlein, A.: The response of human induced pluripotent stem cells to cyclic temperature changes explored by BIO-AFM. MRS Advances. 2021. vol. 6, 745-749. DOI: 10.1557/s43580-021-00110-4}} @misc{tung_structure_mechanical_2021, author={Tung, W., Sun, X., Wang, W., Xu, X., Ma, N., Lendlein, A.}, title={Structure, mechanical properties and degradation behavior of electrospun PEEU fiber meshes and films}, year={2021}, howpublished = {journal article}, doi = {https://doi.org/10.1557/s43580-020-00001-0}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1557/s43580-020-00001-0} (DOI). Tung, W.; Sun, X.; Wang, W.; Xu, X.; Ma, N.; Lendlein, A.: Structure, mechanical properties and degradation behavior of electrospun PEEU fiber meshes and films. MRS Advances. 2021. vol. 6, no. 10, 276-282. DOI: 10.1557/s43580-020-00001-0}} @misc{deng_biofunction_of_2021, author={Deng, Z., Wang, W., Xu, X., Nie, Y., Liu, Y., Gould, O., Ma, N., Lendlein, A.}, title={Biofunction of Polydopamine Coating in Stem Cell Culture}, year={2021}, howpublished = {journal article}, doi = {https://doi.org/10.1021/acsami.0c22565}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1021/acsami.0c22565} (DOI). Deng, Z.; Wang, W.; Xu, X.; Nie, Y.; Liu, Y.; Gould, O.; Ma, N.; Lendlein, A.: Biofunction of Polydopamine Coating in Stem Cell Culture. ACS Applied Materials and Interfaces. 2021. vol. 13, no. 9, 10748-10759. DOI: 10.1021/acsami.0c22565}} @misc{xu_periodic_thermomechanical_2021, author={Xu, X., Nie, Y., Wang, W., Ma, N., Lendlein, A.}, title={Periodic thermomechanical modulation of toll-like receptor expression and distribution in mesenchymal stromal cells}, year={2021}, howpublished = {journal article}, doi = {https://doi.org/10.1557/s43579-021-00049-5}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1557/s43579-021-00049-5} (DOI). Xu, X.; Nie, Y.; Wang, W.; Ma, N.; Lendlein, A.: Periodic thermomechanical modulation of toll-like receptor expression and distribution in mesenchymal stromal cells. MRS Communications. 2021. vol. 11, no. 4, 425-431. DOI: 10.1557/s43579-021-00049-5}} @misc{deng_polydopaminebased_biofunctional_2021, author={Deng, Z., Wang, W., Xu, X., Ma, N., Lendlein, A.}, title={Polydopamine-based biofunctional substrate coating promotes mesenchymal stem cell migration}, year={2021}, howpublished = {journal article}, doi = {https://doi.org/10.1557/s43580-021-00091-4}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1557/s43580-021-00091-4} (DOI). Deng, Z.; Wang, W.; Xu, X.; Ma, N.; Lendlein, A.: Polydopamine-based biofunctional substrate coating promotes mesenchymal stem cell migration. MRS Advances. 2021. vol. 6, 739-744. DOI: 10.1557/s43580-021-00091-4}} @misc{zhou_influence_of_2021, author={Zhou, S., Xu, X., Ma, N., Jung, F., Lendlein, A.}, title={Influence of sterilization conditions on sulfate-functionalized polyGGE}, year={2021}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-211241}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-211241} (DOI). Zhou, S.; Xu, X.; Ma, N.; Jung, F.; Lendlein, A.: Influence of sterilization conditions on sulfate-functionalized polyGGE. Clinical Hemorheology and Microcirculation. 2021. vol. 79, no. 4, 597-608. DOI: 10.3233/CH-211241}} @misc{zhou_defeating_antibioticresistant_2021, author={Zhou, S., Di Luca, M., Xu, X., Ma, N., Jung, F., Lendlein, A.}, title={Defeating antibiotic-resistant bacteria with protein-resistant polyGGE film}, year={2021}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-211250}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-211250} (DOI). Zhou, S.; Di Luca, M.; Xu, X.; Ma, N.; Jung, F.; Lendlein, A.: Defeating antibiotic-resistant bacteria with protein-resistant polyGGE film. Clinical Hemorheology and Microcirculation. 2021. vol. 79, no. 4, 609-623. DOI: 10.3233/CH-211250}} @misc{xu_generation_of_2021, author={Xu, X., Nie, Y., Wang, W., Ullah, I., Tung, W., Ma, N., Lendlein, A.}, title={Generation of 2.5D lung bud organoids from human induced pluripotent stem cells}, year={2021}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-219111}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-219111} (DOI). Xu, X.; Nie, Y.; Wang, W.; Ullah, I.; Tung, W.; Ma, N.; Lendlein, A.: Generation of 2.5D lung bud organoids from human induced pluripotent stem cells. Clinical Hemorheology and Microcirculation. 2021. vol. 79, no. 1, 217-230. DOI: 10.3233/CH-219111}} @misc{maring_cellular_response_2021, author={Maring, J., Becker, M., Tung, W., Stamm, C., Ma, N., Lendlein, A.}, title={Cellular response of blood-borne immune cells to PEEU fiber meshes}, year={2021}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-219114}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-219114} (DOI). Maring, J.; Becker, M.; Tung, W.; Stamm, C.; Ma, N.; Lendlein, A.: Cellular response of blood-borne immune cells to PEEU fiber meshes. Clinical Hemorheology and Microcirculation. 2021. vol. 79, no. 1, 205-216. DOI: 10.3233/CH-219114}} @misc{xu_finetuning_of_2020, author={Xu, X., Wang, W., Nie, Y., Kratz, K., Ma, N., Lendlein, A.}, title={Fine-tuning of Rat Mesenchymal Stem Cell Senescence via Microtopography of Polymeric Substrates}, year={2020}, howpublished = {journal article}, doi = {https://doi.org/10.1557/adv.2019.446}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1557/adv.2019.446} (DOI). Xu, X.; Wang, W.; Nie, Y.; Kratz, K.; Ma, N.; Lendlein, A.: Fine-tuning of Rat Mesenchymal Stem Cell Senescence via Microtopography of Polymeric Substrates. MRS Advances. 2020. vol. 5, no. 12 - 13, 643-653. DOI: 10.1557/adv.2019.446}} @misc{nie_polydopaminemediated_surface_2020, author={Nie, Y., Deng, Z., Wang, W., Bhuvanesh, T., Ma, N., Lendlein, A.}, title={Polydopamine-mediated Surface Modification Promotes the Adhesion and Proliferation of Human Induced Pluripotent Stem Cells}, year={2020}, howpublished = {journal article}, doi = {https://doi.org/10.1557/adv.2019.405}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1557/adv.2019.405} (DOI). Nie, Y.; Deng, Z.; Wang, W.; Bhuvanesh, T.; Ma, N.; Lendlein, A.: Polydopamine-mediated Surface Modification Promotes the Adhesion and Proliferation of Human Induced Pluripotent Stem Cells. MRS Advances. 2020. vol. 5, no. 12 - 13, 591-599. DOI: 10.1557/adv.2019.405}} @misc{zou_afm_assessment_2020, author={Zou, J., Wang, W., Sun, X., Tung, W., Ma, N., Lendlein, A.}, title={AFM Assessment of the Mechanical Properties of Stem Cells During Differentiation}, year={2020}, howpublished = {journal article}, doi = {https://doi.org/10.1557/adv.2019.402}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1557/adv.2019.402} (DOI). Zou, J.; Wang, W.; Sun, X.; Tung, W.; Ma, N.; Lendlein, A.: AFM Assessment of the Mechanical Properties of Stem Cells During Differentiation. MRS Advances. 2020. vol. 5, no. 12 - 13, 601-607. DOI: 10.1557/adv.2019.402}} @misc{sun_elasticity_of_2020, author={Sun, X., Tung, W., Zou, J., Wang, W., Kratz, K., Ma, N., Lendlein, A.}, title={Elasticity of fiber meshes from multiblock copolymers influences endothelial cell behavior}, year={2020}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-190696}, abstract = {These results suggested that tuning the fiber meshes’ elasticity might be a potential strategy for modulating the formation or regeneration of blood vessels.}, note = {Online available at: \url{https://doi.org/10.3233/CH-190696} (DOI). Sun, X.; Tung, W.; Zou, J.; Wang, W.; Kratz, K.; Ma, N.; Lendlein, A.: Elasticity of fiber meshes from multiblock copolymers influences endothelial cell behavior. Clinical Hemorheology and Microcirculation. 2020. vol. 74, no. 4, 405-415. DOI: 10.3233/CH-190696}} @misc{deng_polymeric_sheet_2020, author={Deng, Z., Wang, W., Xu, X., Gould, O.E.C, Kratz, K., Ma, N., Lendlein, A.}, title={Polymeric sheet actuators with programmable bioinstructivity}, year={2020}, howpublished = {journal article}, doi = {https://doi.org/10.1073/pnas.1910668117}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1073/pnas.1910668117} (DOI). Deng, Z.; Wang, W.; Xu, X.; Gould, O.; Kratz, K.; Ma, N.; Lendlein, A.: Polymeric sheet actuators with programmable bioinstructivity. Proceedings of the National Academy of Sciences of the United States of America: PNAS. 2020. vol. 117, no. 4, 1895-1901. DOI: 10.1073/pnas.1910668117}} @misc{bhuvanesh_selfstabilized_fibronectin_2020, author={Bhuvanesh, T., Machatschek, R., Liu, Y., Ma, N., Lendlein, A.}, title={Self-stabilized fibronectin films at the air/water interface}, year={2020}, howpublished = {journal article}, doi = {https://doi.org/10.1557/adv.2019.401}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1557/adv.2019.401} (DOI). Bhuvanesh, T.; Machatschek, R.; Liu, Y.; Ma, N.; Lendlein, A.: Self-stabilized fibronectin films at the air/water interface. MRS Advances. 2020. vol. 5, no. 12 - 13, 609-620. DOI: 10.1557/adv.2019.401}} @misc{tung_coaxial_electrospinning_2020, author={Tung, W., Zou, J., Sun, X., Wang, W., Gould, O., Kratz, K., Ma, N., Lendlein, A.}, title={Coaxial electrospinning of PEEU/gelatin to fiber meshes with enhanced mesenchymal stem cell attachment and proliferation}, year={2020}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-199235}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-199235} (DOI). Tung, W.; Zou, J.; Sun, X.; Wang, W.; Gould, O.; Kratz, K.; Ma, N.; Lendlein, A.: Coaxial electrospinning of PEEU/gelatin to fiber meshes with enhanced mesenchymal stem cell attachment and proliferation. Clinical Hemorheology and Microcirculation. 2020. vol. 74, no. 1, 53-66. DOI: 10.3233/CH-199235}} @misc{nie_spheroid_formation_2020, author={Nie, Y., Xu, X., Wang, W., Ma, N., Lendlein, A.}, title={Spheroid formation of human keratinocyte: Balancing between cell-substrate and cell-cell interaction}, year={2020}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-209217}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-209217} (DOI). Nie, Y.; Xu, X.; Wang, W.; Ma, N.; Lendlein, A.: Spheroid formation of human keratinocyte: Balancing between cell-substrate and cell-cell interaction. Clinical Hemorheology and Microcirculation. 2020. vol. 76, no. 2, 329-340. DOI: 10.3233/CH-209217}} @misc{nie_the_effects_2020, author={Nie, Y., Xu, X., Wang, W., Ma, N., Lendlein, A.}, title={The effects of oscillatory temperature on HaCaT keratinocyte behaviors}, year={2020}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-209208}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-209208} (DOI). Nie, Y.; Xu, X.; Wang, W.; Ma, N.; Lendlein, A.: The effects of oscillatory temperature on HaCaT keratinocyte behaviors. Clinical Hemorheology and Microcirculation. 2020. vol. 76, no. 2, 317-327. DOI: 10.3233/CH-209208}} @misc{deng_modulation_of_2020, author={Deng, Z., Wang, W., Xu, X., Ma, N., Lendlein, A.}, title={Modulation of Mesenchymal Stem Cell Migration using Programmable Polymer Sheet Actuators}, year={2020}, howpublished = {journal article}, doi = {https://doi.org/10.1557/adv.2020.235}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1557/adv.2020.235} (DOI). Deng, Z.; Wang, W.; Xu, X.; Ma, N.; Lendlein, A.: Modulation of Mesenchymal Stem Cell Migration using Programmable Polymer Sheet Actuators. MRS Advances. 2020. vol. 5, no. 46 - 47, 2381-2390. DOI: 10.1557/adv.2020.235}} @misc{deng_dedifferentiation_of_2019, author={Deng, Z., Zou, J., Wang, W., Nie, Y., Tung, W.-T., Ma, N., Lendlein, A.}, title={Dedifferentiation of mature adipocytes with periodic exposure to cold}, year={2019}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-199005}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-199005} (DOI). Deng, Z.; Zou, J.; Wang, W.; Nie, Y.; Tung, W.; Ma, N.; Lendlein, A.: Dedifferentiation of mature adipocytes with periodic exposure to cold. Clinical Hemorheology and Microcirculation. 2019. vol. 71, no. 4, 415-424. DOI: 10.3233/CH-199005}} @misc{nie_enhancement_of_2019, author={Nie, Y., Wang, W., Xu, X., Zou, J., Bhuvanesh, T., Schulz, B., Ma, N., Lendlein, A.}, title={Enhancement of human induced pluripotent stem cells adhesion through multilayer laminin coating}, year={2019}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-189318}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-189318} (DOI). Nie, Y.; Wang, W.; Xu, X.; Zou, J.; Bhuvanesh, T.; Schulz, B.; Ma, N.; Lendlein, A.: Enhancement of human induced pluripotent stem cells adhesion through multilayer laminin coating. Clinical Hemorheology and Microcirculation. 2019. vol. 70, no. 4, 531-542. DOI: 10.3233/CH-189318}} @misc{zou_evaluation_of_2019, author={Zou, J., Wang, W., Kratz, K., Xu, X., Nie, Y., Ma, N., Lendlein, A.}, title={Evaluation of human mesenchymal stem cell senescence, differentiation and secretion behavior cultured on polycarbonate cell culture inserts}, year={2019}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-189322}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-189322} (DOI). Zou, J.; Wang, W.; Kratz, K.; Xu, X.; Nie, Y.; Ma, N.; Lendlein, A.: Evaluation of human mesenchymal stem cell senescence, differentiation and secretion behavior cultured on polycarbonate cell culture inserts. Clinical Hemorheology and Microcirculation. 2019. vol. 70, no. 4, 573-583. DOI: 10.3233/CH-189322}} @misc{bhuvanesh_collagen_typeiv_2019, author={Bhuvanesh, T., Machatschek, R., Lysyakova, L., Kratz, K., Schulz, B., Ma, N., Lendlein, A.}, title={Collagen type-IV Langmuir and Langmuir-Schaefer layers as model biointerfaces to direct stem cell adhesion}, year={2019}, howpublished = {journal article}, doi = {https://doi.org/10.1088/1748-605X/aaf464}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1088/1748-605X/aaf464} (DOI). Bhuvanesh, T.; Machatschek, R.; Lysyakova, L.; Kratz, K.; Schulz, B.; Ma, N.; Lendlein, A.: Collagen type-IV Langmuir and Langmuir-Schaefer layers as model biointerfaces to direct stem cell adhesion. Biomedical Materials. 2019. vol. 14, no. 2, 024101. DOI: 10.1088/1748-605X/aaf464}} @misc{wang_modulating_human_2019, author={Wang, W., Xu, X., Li, Z., Kratz, K., Ma, N., Lendlein, A.}, title={Modulating human mesenchymal stem cells using poly(Eta-butyl acrylate) networks in vitro with elasticity matching human arteries}, year={2019}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-189418}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-189418} (DOI). Wang, W.; Xu, X.; Li, Z.; Kratz, K.; Ma, N.; Lendlein, A.: Modulating human mesenchymal stem cells using poly(Eta-butyl acrylate) networks in vitro with elasticity matching human arteries. Clinical Hemorheology and Microcirculation. 2019. vol. 71, no. 2, 277-289. DOI: 10.3233/CH-189418}} @misc{hausmann_fibroblast_origin_2019, author={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.}, title={Fibroblast origin shapes tissue homeostasis, epidermal differentiation, and drug uptake}, year={2019}, howpublished = {journal article}, doi = {https://doi.org/10.1038/s41598-019-39770-6}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1038/s41598-019-39770-6} (DOI). Hausmann, C.; Zoschke, C.; Wolff, C.; Darvin, M.; Sochorova, M.; Kovacik, A.; Wanjiku, B.; Schumacher, F.; Tigges, J.; Kleuser, B.; Lademann, J.; Fritsche, E.; Vavrova, K.; Ma, N.; Schaefer-Korting, M.: Fibroblast origin shapes tissue homeostasis, epidermal differentiation, and drug uptake. Scientific Reports. 2019. vol. 9, 2913. DOI: 10.1038/s41598-019-39770-6}} @misc{liu_therapeutic_potential_2019, author={Liu, Y., Niu, R., Li, W., Lin, J., Stamm, C., Steinhoff, G., Ma, N.}, title={Therapeutic potential of menstrual blood-derived endometrial stem cells in cardiac diseases}, year={2019}, howpublished = {journal article}, doi = {https://doi.org/10.1007/s00018-019-03019-2}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1007/s00018-019-03019-2} (DOI). Liu, Y.; Niu, R.; Li, W.; Lin, J.; Stamm, C.; Steinhoff, G.; Ma, N.: Therapeutic potential of menstrual blood-derived endometrial stem cells in cardiac diseases. Cellular and Molecular Life Sciences. 2019. vol. 76, no. 9, 1681-1695. DOI: 10.1007/s00018-019-03019-2}} @misc{elango_collagen_peptide_2019, author={Elango, J., Robinson, J., Zhang, J., Bao, B., Ma, N., Maté Sánchez de Val, J., Wu, W.}, title={Collagen Peptide Upregulates Osteoblastogenesis from Bone Marrow Mesenchymal Stem Cells through MAPK-Runx2}, year={2019}, howpublished = {journal article}, doi = {https://doi.org/10.3390/cells8050446}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3390/cells8050446} (DOI). Elango, J.; Robinson, J.; Zhang, J.; Bao, B.; Ma, N.; Maté Sánchez de Val, J.; Wu, W.: Collagen Peptide Upregulates Osteoblastogenesis from Bone Marrow Mesenchymal Stem Cells through MAPK-Runx2. Cells. 2019. vol. 8, no. 5, 446. DOI: 10.3390/cells8050446}} @misc{tung_mechanical_characterization_2019, author={Tung, W., Wang, W., Liu, Y., Gould, O., Kratz, K., Ma, N., Lendlein, A.}, title={Mechanical characterization of electrospun polyesteretherurethane (PEEU) meshes by atomic force microscopy}, year={2019}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-199201}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-199201} (DOI). Tung, W.; Wang, W.; Liu, Y.; Gould, O.; Kratz, K.; Ma, N.; Lendlein, A.: Mechanical characterization of electrospun polyesteretherurethane (PEEU) meshes by atomic force microscopy. Clinical Hemorheology and Microcirculation. 2019. vol. 73, no. 1, 229-236. DOI: 10.3233/CH-199201}} @misc{sun_the_effect_2019, author={Sun, X., Tung, W., Wang, W., Xu, X., Zou, J., Gould, O., Kratz, K., Ma, N., Lendlein, A.}, title={The effect of stiffness variation of electrospun fiber meshes of multiblock copolymers on the osteogenic differentiation of human mesenchymal stem cells}, year={2019}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-199206}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-199206} (DOI). Sun, X.; Tung, W.; Wang, W.; Xu, X.; Zou, J.; Gould, O.; Kratz, K.; Ma, N.; Lendlein, A.: The effect of stiffness variation of electrospun fiber meshes of multiblock copolymers on the osteogenic differentiation of human mesenchymal stem cells. Clinical Hemorheology and Microcirculation. 2019. vol. 73, no. 1, 219-228. DOI: 10.3233/CH-199206}} @misc{zou_microscale_roughness_2019, author={Zou, J., Wang, W., Nie, Y., Xu, X., Ma, N., Lendlein, A.}, title={Microscale roughness regulates laminin-5 secretion of bone marrow mesenchymal stem cells}, year={2019}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-199205}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-199205} (DOI). Zou, J.; Wang, W.; Nie, Y.; Xu, X.; Ma, N.; Lendlein, A.: Microscale roughness regulates laminin-5 secretion of bone marrow mesenchymal stem cells. Clinical Hemorheology and Microcirculation. 2019. vol. 73, no. 1, 237-247. DOI: 10.3233/CH-199205}} @misc{cheng_a_waterprocessable_2018, author={Cheng, C., Zhang, J., Li, S., Xia, Y., Nie, C., Shi, Z., Cuellar-Camacho, J.L., Ma, N., Haag, R.}, title={A Water-Processable and Bioactive Multivalent Graphene Nanoink for Highly Flexible Bioelectronic Films and Nanofibers}, year={2018}, howpublished = {journal article}, doi = {https://doi.org/10.1002/adma.201705452}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1002/adma.201705452} (DOI). Cheng, C.; Zhang, J.; Li, S.; Xia, Y.; Nie, C.; Shi, Z.; Cuellar-Camacho, J.; Ma, N.; Haag, R.: A Water-Processable and Bioactive Multivalent Graphene Nanoink for Highly Flexible Bioelectronic Films and Nanofibers. Advanced Materials. 2018. vol. 30, no. 5, 1705452. DOI: 10.1002/adma.201705452}} @misc{balke_visualizing_oxidative_2018, author={Balke, J., Volz, P., Neumann, F., Brodwolf, R., Wolf, A., Pischon, H., Radbruch, M., Mundhenk, L., Gruber, A.D., Ma, N., Alexiev, U.}, title={Visualizing Oxidative Cellular Stress Induced by Nanoparticles in the Subcytotoxic Range Using Fluorescence Lifetime Imaging}, year={2018}, howpublished = {journal article}, doi = {https://doi.org/10.1002/smll.201800310}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1002/smll.201800310} (DOI). Balke, J.; Volz, P.; Neumann, F.; Brodwolf, R.; Wolf, A.; Pischon, H.; Radbruch, M.; Mundhenk, L.; Gruber, A.; Ma, N.; Alexiev, U.: Visualizing Oxidative Cellular Stress Induced by Nanoparticles in the Subcytotoxic Range Using Fluorescence Lifetime Imaging. Small. 2018. vol. 14, no. 23, 1800310. DOI: 10.1002/smll.201800310}} @misc{chen_computeraided_design_2018, author={Chen, J., Sun, J., Han, W., Wang, W., Cheng, G., Lin, J., Ma, N., Chen, H., Ou, L., Li, W.}, title={Computer-aided design of short peptide ligands targeting tumor necrosis factor-alpha for adsorbent applications}, year={2018}, howpublished = {journal article}, doi = {https://doi.org/10.1039/c8tb00563j}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1039/c8tb00563j} (DOI). Chen, J.; Sun, J.; Han, W.; Wang, W.; Cheng, G.; Lin, J.; Ma, N.; Chen, H.; Ou, L.; Li, W.: Computer-aided design of short peptide ligands targeting tumor necrosis factor-alpha for adsorbent applications. Journal of Materials Chemistry B. 2018. vol. 6, no. 26, 4368-4379. DOI: 10.1039/c8tb00563j}} @misc{zou_adipogenic_differentiation_2017, author={Zou, J., Wang, W., Neffe, A.T., Xu, X., Li, Z., Deng, Z., Sun, X. Ma, N., Lendlein, A.}, title={Adipogenic differentiation of human adipose derived mesenchymal stem cells in 3D architectured gelatin based hydrogels (ArcGel)}, year={2017}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-179210}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-179210} (DOI). Zou, J.; Wang, W.; Neffe, A.; Xu, X.; Li, Z.; Deng, Z.; Sun, X.; Lendlein, A.: Adipogenic differentiation of human adipose derived mesenchymal stem cells in 3D architectured gelatin based hydrogels (ArcGel). Clinical Hemorheology and Microcirculation. 2017. vol. 67, no. 3-4, 297-307. DOI: 10.3233/CH-179210}} @misc{dimde_synthesis_of_2017, author={Dimde, M., Steinhilber, D., Neumann, F., Li, Y., Paulus, F., Ma, N., Haag, R.}, title={Synthesis of pH-Cleavable dPG-Amines for Gene Delivery Application}, year={2017}, howpublished = {journal article}, doi = {https://doi.org/10.1002/mabi.201600190}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1002/mabi.201600190} (DOI). Dimde, M.; Steinhilber, D.; Neumann, F.; Li, Y.; Paulus, F.; Ma, N.; Haag, R.: Synthesis of pH-Cleavable dPG-Amines for Gene Delivery Application. Macromolecular Bioscience. 2017. vol. 17, no. S 1, 1600190. DOI: 10.1002/mabi.201600190}} @misc{edlich_specific_uptake_2017, author={Edlich, A., Gerecke, C., Giulbudagian, M., Neumann, F., Hedtrich, S., Schaefer-Korting, M., Ma, N., Calderon, M., Kleuser, B.}, title={Specific uptake mechanisms of well-tolerated thermoresponsive polyglycerol-based nanogels in antigen-presenting cells of the skin}, year={2017}, howpublished = {journal article}, doi = {https://doi.org/10.1016/j.ejpb.2016.12.016}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1016/j.ejpb.2016.12.016} (DOI). Edlich, A.; Gerecke, C.; Giulbudagian, M.; Neumann, F.; Hedtrich, S.; Schaefer-Korting, M.; Ma, N.; Calderon, M.; Kleuser, B.: Specific uptake mechanisms of well-tolerated thermoresponsive polyglycerol-based nanogels in antigen-presenting cells of the skin. European Journal of Pharmaceutics and Biopharmaceutics. 2017. vol. 116, 155-163. DOI: 10.1016/j.ejpb.2016.12.016}} @misc{bhuvanesh_langmuirschaefer_films_2017, author={Bhuvanesh, T., Saretia, S., Roch, T., Schoene, A.-C., Rottke, F.O., Kratz, K., Wang, W., Ma, N., Schulz, B., Lendlein, A.}, title={Langmuir–Schaefer films of fibronectin as designed biointerfaces for culturing stem cells}, year={2017}, howpublished = {journal article}, doi = {https://doi.org/10.1002/pat.3910}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1002/pat.3910} (DOI). Bhuvanesh, T.; Saretia, S.; Roch, T.; Schoene, A.; Rottke, F.; Kratz, K.; Wang, W.; Ma, N.; Schulz, B.; Lendlein, A.: Langmuir–Schaefer films of fibronectin as designed biointerfaces for culturing stem cells. Polymers for Advanced Technologies. 2017. vol. 28, no. 10, 1305-1311. DOI: 10.1002/pat.3910}} @misc{radbruch_dendritic_coremultishell_2017, author={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.}, title={Dendritic Core-Multishell Nanocarriers in Murine Models of Healthy and Atopic Skin}, year={2017}, howpublished = {journal article}, doi = {https://doi.org/10.1186/s11671-017-1835-0}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1186/s11671-017-1835-0} (DOI). 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.: Dendritic Core-Multishell Nanocarriers in Murine Models of Healthy and Atopic Skin. Nanoscale Research Letters. 2017. vol. 12, 64. DOI: 10.1186/s11671-017-1835-0}} @misc{li_modulation_of_2017, author={Li, Z., Xu, X., Wang, W., Kratz, K., Sun, X., Zou, J., Deng, Z., Jung, F., Gossen, M., Ma, N., Lendlein, A.}, title={Modulation of the mesenchymal stem cell migration capacity via preconditioning with topographic microstructure}, year={2017}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-179208}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-179208} (DOI). Li, Z.; Xu, X.; Wang, W.; Kratz, K.; Sun, X.; Zou, J.; Deng, Z.; Jung, F.; Gossen, M.; Ma, N.; Lendlein, A.: Modulation of the mesenchymal stem cell migration capacity via preconditioning with topographic microstructure. Clinical Hemorheology and Microcirculation. 2017. vol. 67, no. 3-4, 267-278. DOI: 10.3233/CH-179208}} @misc{gerecke_biocompatibility_and_2017, author={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.}, title={Biocompatibility and characterization of polyglycerol-based thermoresponsive nanogels designed as novel drug-delivery systems and their intracellular localization in keratinocytes}, year={2017}, howpublished = {journal article}, doi = {https://doi.org/10.1080/17435390.2017.1292371}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1080/17435390.2017.1292371} (DOI). Gerecke, C.; Edlich, A.; Giulbudagian, M.; Schumacher, F.; Zhang, N.; Said, A.; Yealland, G.; Lohan, S.; Neumann, F.; Meinke, M.; Ma, N.; Calderon, M.; Hedtrich, S.; Schaefer-Korting, M.; Kleuser, B.: Biocompatibility and characterization of polyglycerol-based thermoresponsive nanogels designed as novel drug-delivery systems and their intracellular localization in keratinocytes. Nanotoxicology. 2017. vol. 11, no. 2, 267-277. DOI: 10.1080/17435390.2017.1292371}} @misc{tschiche_correction_crosslinked_2017, author={Tschiche, A., Thota, B.N.S., Neumann, F., Schaefer, A., Ma, N., Haag, R.}, title={Correction: Crosslinked Redox-Responsive Micelles Based on Lipoic Acid-Derived Amphiphiles for Enhanced siRNA Delivery}, year={2017}, howpublished = {journal article}, doi = {https://doi.org/10.1002/mabi.201600533}, abstract = {No abstract}, note = {Online available at: \url{https://doi.org/10.1002/mabi.201600533} (DOI). Tschiche, A.; Thota, B.; Neumann, F.; Schaefer, A.; Ma, N.; Haag, R.: Correction: Crosslinked Redox-Responsive Micelles Based on Lipoic Acid-Derived Amphiphiles for Enhanced siRNA Delivery. Macromolecular Bioscience. 2017. vol. 17, no. 2, 1600533. DOI: 10.1002/mabi.201600533}} @misc{wang_folate_receptor_2017, author={Wang, W., Li, W., Wang, J., Hu, Q., Balk, M., Bieback, K., Stamm, C., Jung, F., Tang, G., Lendlein, A., Ma, N.}, title={Folate receptor mediated genetic modification of human mesenchymal stem cells via folic acid-polyethylenimine-grafted poly(N-3-hydroxypropyl)aspartamide}, year={2017}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-179209}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-179209} (DOI). Wang, W.; Li, W.; Wang, J.; Hu, Q.; Balk, M.; Bieback, K.; Stamm, C.; Jung, F.; Tang, G.; Lendlein, A.; Ma, N.: Folate receptor mediated genetic modification of human mesenchymal stem cells via folic acid-polyethylenimine-grafted poly(N-3-hydroxypropyl)aspartamide. Clinical Hemorheology and Microcirculation. 2017. vol. 67, no. 3-4, 279-295. DOI: 10.3233/CH-179209}} @misc{wang_functional_nanoparticles_2017, author={Wang, W., Deng, Z., Xu, X., Li, Z., Jung, F., Ma, N., Lendlein, A.}, title={Functional Nanoparticles and their Interactions with Mesenchymal Stem Cells}, year={2017}, howpublished = {journal article}, doi = {https://doi.org/10.2174/1381612823666170622110654}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.2174/1381612823666170622110654} (DOI). Wang, W.; Deng, Z.; Xu, X.; Li, Z.; Jung, F.; Ma, N.; Lendlein, A.: Functional Nanoparticles and their Interactions with Mesenchymal Stem Cells. Current Pharmaceutical Design. 2017. vol. 23, no. 26, 3814-3832. DOI: 10.2174/1381612823666170622110654}} @misc{grohmann_biotransformation_of_2017, author={Grohmann, L., Becker, D., Rademann, J., Ma, N., Schaefer-Korting, M., Weindl, G.}, title={Biotransformation of 2,4-toluenediamine in human skin and reconstructed tissues}, year={2017}, howpublished = {journal article}, doi = {https://doi.org/10.1007/s00204-017-1954-5}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1007/s00204-017-1954-5} (DOI). Grohmann, L.; Becker, D.; Rademann, J.; Ma, N.; Schaefer-Korting, M.; Weindl, G.: Biotransformation of 2,4-toluenediamine in human skin and reconstructed tissues. Archives of Toxicology. 2017. vol. 91, no. 10, 3307-3316. DOI: 10.1007/s00204-017-1954-5}} @misc{xu_microwell_geometry_2017, author={Xu, X., Wang, W., Li, Z., Kratz, K., Ma, N., Lendlein, A.}, title={Microwell Geometry Modulates Interleukin-6 Secretion in Human Mesenchymal Stem Cells}, year={2017}, howpublished = {journal article}, doi = {https://doi.org/10.1557/adv.2017.487}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1557/adv.2017.487} (DOI). Xu, X.; Wang, W.; Li, Z.; Kratz, K.; Ma, N.; Lendlein, A.: Microwell Geometry Modulates Interleukin-6 Secretion in Human Mesenchymal Stem Cells. MRS Advances. 2017. vol. 2, no. 47, 2561-2570. DOI: 10.1557/adv.2017.487}} @misc{roch_transparent_substrates_2017, author={Roch, T., Hahne, S., Kratz, K., Ma, N., Lendlein, A.}, title={Transparent Substrates Prepared From Different Amorphous Polymers Can Directly Modulate Primary Human B cell functions}, year={2017}, howpublished = {journal article}, doi = {https://doi.org/10.1002/biot.201700334}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1002/biot.201700334} (DOI). Roch, T.; Hahne, S.; Kratz, K.; Ma, N.; Lendlein, A.: Transparent Substrates Prepared From Different Amorphous Polymers Can Directly Modulate Primary Human B cell functions. Biotechnology Journal. 2017. vol. 12, no. 12, 1700334. DOI: 10.1002/biot.201700334}} @misc{wang_polydepsipeptide_blockstabilized_2017, author={Wang, W., Naolou, T., Ma, N., Deng, Z., Xu, X., Mansfeld, U., Wischke, C., Gossen, M., Neffe, A.T., Lendlein, A.}, title={Polydepsipeptide Block-Stabilized Polyplexes for Efficient Transfection of Primary Human Cells}, year={2017}, howpublished = {journal article}, doi = {https://doi.org/10.1021/acs.biomac.7b01034}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1021/acs.biomac.7b01034} (DOI). Wang, W.; Naolou, T.; Ma, N.; Deng, Z.; Xu, X.; Mansfeld, U.; Wischke, C.; Gossen, M.; Neffe, A.; Lendlein, A.: Polydepsipeptide Block-Stabilized Polyplexes for Efficient Transfection of Primary Human Cells. Biomacromolecules. 2017. vol. 18, no. 11, 3819-3833. DOI: 10.1021/acs.biomac.7b01034}} @misc{li_construction_of_2017, author={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.}, title={Construction of Functional Coatings with Durable and Broad-Spectrum Antibacterial Potential Based on Mussel-Inspired Dendritic Polyglycerol and in Situ-Formed Copper Nanoparticles}, year={2017}, howpublished = {journal article}, doi = {https://doi.org/10.1021/acsami.7b10541}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1021/acsami.7b10541} (DOI). Li, M.; Gao, L.; Schlaich, C.; Zhang, J.; Donskyi, I.; Yu, G.; Li, W.; Tu, Z.; Rolff, J.; Schwerdtle, T.; Haag, R.; Ma, N.: Construction of Functional Coatings with Durable and Broad-Spectrum Antibacterial Potential Based on Mussel-Inspired Dendritic Polyglycerol and in Situ-Formed Copper Nanoparticles. ACS Applied Materials and Interfaces. 2017. vol. 9, no. 40, 35411-35418. DOI: 10.1021/acsami.7b10541}} @misc{dimde_defined_phsensitive_2017, author={Dimde, M., Neumann, F., Reisbeck, F., Ehrmann, S., Cuellar-Camacho, J.L., Steinhilber, D., Ma, N., Haag, R.}, title={Defined pH-sensitive nanogels as gene delivery platform for siRNA mediated in vitro gene silencing}, year={2017}, howpublished = {journal article}, doi = {https://doi.org/10.1039/C7BM00729A}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1039/C7BM00729A} (DOI). Dimde, M.; Neumann, F.; Reisbeck, F.; Ehrmann, S.; Cuellar-Camacho, J.; Steinhilber, D.; Ma, N.; Haag, R.: Defined pH-sensitive nanogels as gene delivery platform for siRNA mediated in vitro gene silencing. Biomaterials Science. 2017. vol. 5, no. 11, 2328-2336. DOI: 10.1039/C7BM00729A}} @misc{li_integrin_1_2017, author={Li, Z., Wang, W., Xu, X., Kratz, K., Zou, J., Lysyakova, L., Heuchel, M., Kurtz, A., Gossen, M., Ma, N., Lendlein, A.}, title={Integrin β1 activation by micro-scale curvature promotes pro-angiogenic secretion of human mesenchymal stem cells}, year={2017}, howpublished = {journal article}, doi = {https://doi.org/10.1039/C7TB01232B}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1039/C7TB01232B} (DOI). Li, Z.; Wang, W.; Xu, X.; Kratz, K.; Zou, J.; Lysyakova, L.; Heuchel, M.; Kurtz, A.; Gossen, M.; Ma, N.; Lendlein, A.: Integrin β1 activation by micro-scale curvature promotes pro-angiogenic secretion of human mesenchymal stem cells. Journal of Materials Chemistry B. 2017. vol. 5, no. 35, 7415-7425. DOI: 10.1039/C7TB01232B}} @misc{wang_engineering_biodegradable_2016, author={Wang, W., Balk, M., Deng, Z., Wischke, C., Gossen, M., Behl, M., Ma, N., Lendlein, A.}, title={Engineering biodegradable micelles of polyethylenimine-based amphiphilic block copolymers for efficient DNA and siRNA delivery}, year={2016}, howpublished = {journal article}, doi = {https://doi.org/10.1016/j.jconrel.2016.08.004}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1016/j.jconrel.2016.08.004} (DOI). Wang, W.; Balk, M.; Deng, Z.; Wischke, C.; Gossen, M.; Behl, M.; Ma, N.; Lendlein, A.: Engineering biodegradable micelles of polyethylenimine-based amphiphilic block copolymers for efficient DNA and siRNA delivery. Journal of Controlled Release. 2016. vol. 242, 71-79. DOI: 10.1016/j.jconrel.2016.08.004}} @misc{du_development_of_2016, author={Du, F., Hoenzke, S., Neumann, F., Keilitz, J., Chen, W., Ma, N., Hedtrich, S., Haag, R.}, title={Development of biodegradable hyperbranched core-multishell nanocarriers for efficient topical drug delivery}, year={2016}, howpublished = {journal article}, doi = {https://doi.org/10.1016/j.jconrel.2016.06.048}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1016/j.jconrel.2016.06.048} (DOI). Du, F.; Hoenzke, S.; Neumann, F.; Keilitz, J.; Chen, W.; Ma, N.; Hedtrich, S.; Haag, R.: Development of biodegradable hyperbranched core-multishell nanocarriers for efficient topical drug delivery. Journal of Controlled Release. 2016. vol. 242, 42-49. DOI: 10.1016/j.jconrel.2016.06.048}} @misc{tschiche_crosslinked_redoxresponsive_2016, author={Tschiche, A., Thota, B.N.S., Neumann, F., Schaefer, A., Ma, N., Haag, R.}, title={Crosslinked Redox-Responsive Micelles Based on Lipoic Acid-Derived Amphiphiles for Enhanced siRNA Delivery}, year={2016}, howpublished = {journal article}, doi = {https://doi.org/10.1002/mabi.201500363}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1002/mabi.201500363} (DOI). Tschiche, A.; Thota, B.; Neumann, F.; Schaefer, A.; Ma, N.; Haag, R.: Crosslinked Redox-Responsive Micelles Based on Lipoic Acid-Derived Amphiphiles for Enhanced siRNA Delivery. Macromolecular Bioscience. 2016. vol. 16, no. 6, 811-823. DOI: 10.1002/mabi.201500363}} @misc{dong_a_highly_2016, author={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.}, title={A Highly Photostable Hyperbranched Polyglycerol-Based NIR Fluorescence Nanoplatform for Mitochondria-Specific Cell Imaging}, year={2016}, howpublished = {journal article}, doi = {https://doi.org/10.1002/adhm.201600212}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1002/adhm.201600212} (DOI). 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.: A Highly Photostable Hyperbranched Polyglycerol-Based NIR Fluorescence Nanoplatform for Mitochondria-Specific Cell Imaging. Advanced Healthcare Materials. 2016. vol. 5, no. 17, 2214-2226. DOI: 10.1002/adhm.201600212}} @misc{vogt_nanocarriers_for_2016, author={Vogt, A., Wischke, C., Neffe, A.T., Ma, N., Alexiev, U., Lendlein, A.}, title={Nanocarriers for drug delivery into and through the skin - Do existing technologies match clinical challenges?}, year={2016}, howpublished = {journal article}, doi = {https://doi.org/10.1016/j.jconrel.2016.07.027}, abstract = {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?}, note = {Online available at: \url{https://doi.org/10.1016/j.jconrel.2016.07.027} (DOI). Vogt, A.; Wischke, C.; Neffe, A.; Ma, N.; Alexiev, U.; Lendlein, A.: Nanocarriers for drug delivery into and through the skin - Do existing technologies match clinical challenges?. Journal of Controlled Release. 2016. vol. 242, 3-15. DOI: 10.1016/j.jconrel.2016.07.027}} @misc{roch_inflammatory_responses_2016, author={Roch, T., Kratz, K., Ma, N., Lendlein, A.}, title={Inflammatory responses of primary human dendritic cells towards polydimethylsiloxane and polytetrafluoroethylene}, year={2016}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-168033}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-168033} (DOI). Roch, T.; Kratz, K.; Ma, N.; Lendlein, A.: Inflammatory responses of primary human dendritic cells towards polydimethylsiloxane and polytetrafluoroethylene. Clinical Hemorheology and Microcirculation. 2016. vol. 64, no. 4, 899-910. DOI: 10.3233/CH-168033}} @misc{xu_surface_geometry_2016, author={Xu, X., Wang, W., Li, Z., Kratz, K., Ma, N., Lendlein, A.}, title={Surface geometry of poly(ether imide) boosts mouse pluripotent stem cell spontaneous cardiomyogenesis via modulating the embryoid body formation process}, year={2016}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-168107}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-168107} (DOI). Xu, X.; Wang, W.; Li, Z.; Kratz, K.; Ma, N.; Lendlein, A.: Surface geometry of poly(ether imide) boosts mouse pluripotent stem cell spontaneous cardiomyogenesis via modulating the embryoid body formation process. Clinical Hemorheology and Microcirculation. 2016. vol. 64, no. 3, 367-382. DOI: 10.3233/CH-168107}} @misc{li_influence_of_2016, author={Li, Z., Wang, W., Kratz, K., Kuechler, J., Xu, X., Zou, J., Deng, Z., Sun, X., Gossen, M., Ma, N., Lendlein, A.}, title={Influence of surface roughness on neural differentiation of human induced pluripotent stem cells}, year={2016}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-168121}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-168121} (DOI). Li, Z.; Wang, W.; Kratz, K.; Kuechler, J.; Xu, X.; Zou, J.; Deng, Z.; Sun, X.; Gossen, M.; Ma, N.; Lendlein, A.: Influence of surface roughness on neural differentiation of human induced pluripotent stem cells. Clinical Hemorheology and Microcirculation. 2016. vol. 64, no. 3, 355-366. DOI: 10.3233/CH-168121}} @misc{ren_surface_modification_2015, author={Ren, X., Feng, Y., Guo, J., Wang, H., Li, Q., Yang, J., Hao, X., Lv, J., Ma, N., Li, W.}, title={Surface modification and endothelialization of biomaterials as potential scaffolds for vascular tissue engineering applications}, year={2015}, howpublished = {journal article}, doi = {https://doi.org/10.1039/c4cs00483c}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1039/c4cs00483c} (DOI). Ren, X.; Feng, Y.; Guo, J.; Wang, H.; Li, Q.; Yang, J.; Hao, X.; Lv, J.; Ma, N.; Li, W.: Surface modification and endothelialization of biomaterials as potential scaffolds for vascular tissue engineering applications. Chemical Society Reviews. 2015. vol. 44, no. 15, 5680-5742. DOI: 10.1039/c4cs00483c}} @misc{neffe_one_step_2015, author={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.}, title={One Step Creation of Multifunctional 3D Architectured Hydrogels Inducing Bone Regeneration}, year={2015}, howpublished = {journal article}, doi = {https://doi.org/10.1002/adma.201404787}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1002/adma.201404787} (DOI). Neffe, A.; Pierce, B.; Tronci, G.; Ma, N.; Pittermann, E.; Gebauer, T.; Frank, O.; Schossig, M.; Xu, X.; Willie, B.; Forner, M.; Ellinghaus, A.; Lienau, J.; Duda, G.; Lendlein, A.: One Step Creation of Multifunctional 3D Architectured Hydrogels Inducing Bone Regeneration. Advanced Materials. 2015. vol. 27, no. 10, 1738-1744. DOI: 10.1002/adma.201404787}} @misc{roch_cellbased_detection_2015, author={Roch, T., Ma, N., Kratz, K., Lendlein, A.}, title={Cell-based detection of microbial biomaterial contaminations}, year={2015}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-151939}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-151939} (DOI). Roch, T.; Ma, N.; Kratz, K.; Lendlein, A.: Cell-based detection of microbial biomaterial contaminations. Clinical Hemorheology and Microcirculation. 2015. vol. 60, no. 1, 51-63. DOI: 10.3233/CH-151939}} @misc{vijayabhaskar_single_and_2015, author={Vijaya Bhaskar, T.B., Roch, T., Romero, O., Ma, N., Kratz, K., Lendlein, A.}, title={Single and competitive protein adsorption on polymeric surfaces}, year={2015}, howpublished = {journal article}, doi = {https://doi.org/10.1002/pat.3639}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1002/pat.3639} (DOI). Vijaya Bhaskar, T.; Roch, T.; Romero, O.; Ma, N.; Kratz, K.; Lendlein, A.: Single and competitive protein adsorption on polymeric surfaces. Polymers for Advanced Technologies. 2015. vol. 26, no. 12, 1387-1393. DOI: 10.1002/pat.3639}} @misc{julichgruner_synthesis_and_2015, author={Julich-Gruner, K.K., Roch, T., Ma, N., Neffe, A.T., Lendlein, A.}, title={Synthesis and characterization of star-shaped oligo(ethylene glycol) with tyrosine derived moieties under variation of their molecular weight}, year={2015}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-151938}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-151938} (DOI). Julich-Gruner, K.; Roch, T.; Ma, N.; Neffe, A.; Lendlein, A.: Synthesis and characterization of star-shaped oligo(ethylene glycol) with tyrosine derived moieties under variation of their molecular weight. Clinical Hemorheology and Microcirculation. 2015. vol. 60, no. 1, 13-23. DOI: 10.3233/CH-151938}} @misc{wang_the_interaction_2015, author={Wang, W., Kratz, K., Behl, M., Yan, W., Liu, Y., Xu, X., Baudis, S., Li, Z., Kurtz, A., Lendlein, A., Ma, N.}, title={The interaction of adipose-derived human mesenchymal stem cells and polyether ether ketone}, year={2015}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-152001}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-152001} (DOI). Wang, W.; Kratz, K.; Behl, M.; Yan, W.; Liu, Y.; Xu, X.; Baudis, S.; Li, Z.; Kurtz, A.; Lendlein, A.; Ma, N.: The interaction of adipose-derived human mesenchymal stem cells and polyether ether ketone. Clinical Hemorheology and Microcirculation. 2015. vol. 61, no. 2, 301-321. DOI: 10.3233/CH-152001}} @misc{goers_immunocompatibility_of_2015, author={Goers, J., Roch, T., Tartivel, L., Behl, M., Ma, N., Lendlein, A.}, title={Immuno-compatibility of amphiphilic ABA triblock copolymer-based hydrogel films for biomedical applications}, year={2015}, howpublished = {journal article}, doi = {https://doi.org/10.1002/pat.3676}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1002/pat.3676} (DOI). Goers, J.; Roch, T.; Tartivel, L.; Behl, M.; Ma, N.; Lendlein, A.: Immuno-compatibility of amphiphilic ABA triblock copolymer-based hydrogel films for biomedical applications. Polymers for Advanced Technologies. 2015. vol. 26, no. 12, 1378-1386. DOI: 10.1002/pat.3676}} @misc{vijayabhaskar_the_interaction_2015, author={Vijaya Bhaskar, T.B., Ma, N., Lendlein, A., Roch, T.}, title={The interaction of human macrophage subsets with silicone as a biomaterial}, year={2015}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-151991}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-151991} (DOI). Vijaya Bhaskar, T.; Ma, N.; Lendlein, A.; Roch, T.: The interaction of human macrophage subsets with silicone as a biomaterial. Clinical Hemorheology and Microcirculation. 2015. vol. 61, no. 2, 119-133. DOI: 10.3233/CH-151991}} @misc{roch_polymeric_inserts_2015, author={Roch, T., Kratz, K., Ma, N., Lendlein, A.}, title={Polymeric inserts differing in their chemical composition as substrates for dendritic cell cultivation}, year={2015}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-152004}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-152004} (DOI). Roch, T.; Kratz, K.; Ma, N.; Lendlein, A.: Polymeric inserts differing in their chemical composition as substrates for dendritic cell cultivation. Clinical Hemorheology and Microcirculation. 2015. vol. 61, no. 2, 347-357. DOI: 10.3233/CH-152004}} @misc{roch_immunocompatibility_of_2015, author={Roch, T., Julich-Gruner, K.K., Neffe, A.T., Ma, N., Leindlein, A.}, title={Immuno-compatibility of desaminotyrosine and desaminotyrosyl tyrosine functionalized star-shaped oligo(ethylene glycol)s with different molecular weights}, year={2015}, howpublished = {journal article}, doi = {https://doi.org/10.1557/opl.2015.327}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1557/opl.2015.327} (DOI). Roch, T.; Julich-Gruner, K.; Neffe, A.; Ma, N.; Leindlein, A.: Immuno-compatibility of desaminotyrosine and desaminotyrosyl tyrosine functionalized star-shaped oligo(ethylene glycol)s with different molecular weights. MRS Online Proceedings Library. 2015. vol. 1718, DOI: 10.1557/opl.2015.327}} @misc{klopsch_spray_and_2015, author={Klopsch, C., Gaebel, R., Kaminski, A., Mark, P., Wang, W., Toelk, A., Delyagina, E., Kleiner, G., Koch, L., Chichkov, B., Mela, P., Jockenhoevel, S., Ma, N., Steinhoff, G.}, title={Spray- and laser-assisted biomaterial processing for fast and efficient autologous cell-plus-matrix tissue engineering}, year={2015}, howpublished = {journal article}, doi = {https://doi.org/10.1002/term.1657}, abstract = {might have potential for intraoperative table-side TE considering the procedural duration and ease of implementation. LaBP might accelerate engraftment with precise patterns.}, note = {Online available at: \url{https://doi.org/10.1002/term.1657} (DOI). Klopsch, C.; Gaebel, R.; Kaminski, A.; Mark, P.; Wang, W.; Toelk, A.; Delyagina, E.; Kleiner, G.; Koch, L.; Chichkov, B.; Mela, P.; Jockenhoevel, S.; Ma, N.; Steinhoff, G.: Spray- and laser-assisted biomaterial processing for fast and efficient autologous cell-plus-matrix tissue engineering. Journal of Tissue Engineering and Regenerative Medicine. 2015. vol. 9, no. 12, E177-E190. DOI: 10.1002/term.1657}} @misc{roch_expression_pattern_2014, author={Roch, T., Akymenko, O., Krueger, A., Jung, F., Ma, N., Lendlein, A.}, title={Expression pattern analysis and activity determination of matrix metalloproteinase derived from human macrophage subsets}, year={2014}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-141885}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-141885} (DOI). Roch, T.; Akymenko, O.; Krueger, A.; Jung, F.; Ma, N.; Lendlein, A.: Expression pattern analysis and activity determination of matrix metalloproteinase derived from human macrophage subsets. Clinical Hemorheology and Microcirculation. 2014. vol. 58, no. 1, 147-158. DOI: 10.3233/CH-141885}} @misc{xu_cover_picture_2014, author={Xu, X., Wang, W., Kratz, K., Fang, L., Li, Z., Kurtz, A., Ma, N., Lendlein, A.}, title={Cover Picture - Stem Cells: Controlling Major Cellular Processes of Human Mesenchymal Stem Cells using Microwell Structures}, year={2014}, howpublished = {journal article}, doi = {https://doi.org/10.1002/adhm.201470060}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1002/adhm.201470060} (DOI). Xu, X.; Wang, W.; Kratz, K.; Fang, L.; Li, Z.; Kurtz, A.; Ma, N.; Lendlein, A.: Cover Picture - Stem Cells: Controlling Major Cellular Processes of Human Mesenchymal Stem Cells using Microwell Structures. Advanced Healthcare Materials. 2014. vol. 3, no. 12, 1933. DOI: 10.1002/adhm.201470060}} @misc{xu_controlling_major_2014, author={Xu, X., Wang, W., Kratz, K., Fang, L., Li, Z., Kurtz, A., Ma, N., Lendlein, A.}, title={Controlling Major Cellular Processes of Human Mesenchymal Stem Cells using Microwell Structures}, year={2014}, howpublished = {journal article}, doi = {https://doi.org/10.1002/adhm.201400415}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1002/adhm.201400415} (DOI). Xu, X.; Wang, W.; Kratz, K.; Fang, L.; Li, Z.; Kurtz, A.; Ma, N.; Lendlein, A.: Controlling Major Cellular Processes of Human Mesenchymal Stem Cells using Microwell Structures. Advanced Healthcare Materials. 2014. vol. 3, no. 12, 1991-2003. DOI: 10.1002/adhm.201400415}} @misc{wang_genetic_engineering_2014, author={Wang, W., Xu, X., Li, Z., Lendlein, A., Ma, N.}, title={Genetic engineering of mesenchymal stem cells by non-viral gene delivery}, year={2014}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-141883}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-141883} (DOI). Wang, W.; Xu, X.; Li, Z.; Lendlein, A.; Ma, N.: Genetic engineering of mesenchymal stem cells by non-viral gene delivery. Clinical Hemorheology and Microcirculation. 2014. vol. 58, no. 1, 19-48. DOI: 10.3233/CH-141883}} @misc{roch_interaction_of_2014, author={Roch, T., Schulz, C., Jung, F., Ma, N., Lendlein, A.}, title={Interaction of poly(ether imide) films with early immune mechanisms}, year={2014}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-141831}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.3233/CH-141831} (DOI). Roch, T.; Schulz, C.; Jung, F.; Ma, N.; Lendlein, A.: Interaction of poly(ether imide) films with early immune mechanisms. Clinical Hemorheology and Microcirculation. 2014. vol. 57, no. 2, 203-212. DOI: 10.3233/CH-141831}} @misc{roch_the_influence_2013, author={Roch, T., Behl, M., Zierke, M., Pierce, B.F., Kratz, K., Weigel, T., Ma, N., Lendlein, A.}, title={The influence of the co-monomer ratio of poly[acrylonitrile-co-(N-vinylpyrrolidone)]s on primary human monocyte-derived dendritic cells}, year={2013}, howpublished = {journal article}, doi = {https://doi.org/10.1557/opl.2013.830}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1557/opl.2013.830} (DOI). Roch, T.; Behl, M.; Zierke, M.; Pierce, B.; Kratz, K.; Weigel, T.; Ma, N.; Lendlein, A.: The influence of the co-monomer ratio of poly[acrylonitrile-co-(N-vinylpyrrolidone)]s on primary human monocyte-derived dendritic cells. MRS Online Proceedings Library. 2013. vol. 1569, 21-26. DOI: 10.1557/opl.2013.830}} @misc{schmidt_correlating_the_2013, author={Schmidt, S., Roch, T., Mathew, S., Ma, N., Wischke, C., Lendlein, A.}, title={Correlating the Uptake and Dendritic Cell Activation by MDP-loaded Microparticles}, year={2013}, howpublished = {journal article}, doi = {https://doi.org/10.1557/opl.2013.816}, abstract = {Polymer-based, degradable microparticles (MP) are attractive delivery vehicles for vaccines as the polymer properties can be specifically tailored and the carrier can be loaded with adjuvant. For all newly developed carrier systems it is important to analyze cellular uptake efficiency and the specific effects mediated by the encapsulated agent when phagocytosed by the cells, which is barely reported so far. By the encapsulation of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) labeled with fluoresceinisothiocyanat (FITC) in poly[(rac-lactide)-co-glycolide] (PLGA) MP, the MP was fluorescent and used to visualize the phagocytic uptake. Since encapsulated MDP can activate dendritic cells (DC) via the cytosolic nucleotide-binding oligomerization domain receptors (NOD), it can be investigated whether only cells that have phagocytosed the MP are activated or whether bystander effects occur, resulting in activation of cells, which did not take up MDP-FITC loaded MP. Here, it is demonstrated that increasing MP concentrations in the culture medium had no impact on the viability of DC and that the MP uptake efficiency was dose dependent. Interestingly, it could be shown by the CD86 expression, that only DC, which had engulfed MP, were significantly stronger activated than DC, which had not phagocytosed MDP-FITC loaded MP. On the one hand these results indicate that sufficient amounts of MDP were released from the PLGA carriers into the cytosol of the DC. On the other hand, based on the correlation of uptake and activation on the single cell level, minimal MP induced bystander effects may be expected forin vivo applications.}, note = {Online available at: \url{https://doi.org/10.1557/opl.2013.816} (DOI). Schmidt, S.; Roch, T.; Mathew, S.; Ma, N.; Wischke, C.; Lendlein, A.: Correlating the Uptake and Dendritic Cell Activation by MDP-loaded Microparticles. MRS Online Proceedings Library. 2013. vol. 1569, 179-184. DOI: 10.1557/opl.2013.816}} @misc{roch_the_influence_2013, author={Roch, T., Kratz, K., Ma, N., Jung, F., Lendlein, A.}, title={The influence of polystyrene and poly(ether imide) inserts with different roughness, on the activation of dendritic cells}, year={2013}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-131699}, abstract = {Dendritic cells (DC) have a pivotal role during inflammation. DC efficiently present antigens to T cells and shape the subsequent immune response by the secretion of pro- or anti-inflammatory cytokines and by the expression of co-stimulatory molecules. They respond to “danger signals” such as microbial products or fragments from necrotic cells or tissues, but were also described to be reactive towards biomaterials. However, how mechanical and physical properties of the subjacent substrate influences the DC activation is currently poorly understood. In this study micro patterned inserts prepared from polystyrene (PS) as well as from poly (ether imide) (PEI) with three different roughness levels of i) Rq = 0.29 μm (PS) and 0.23 μm (PEI); ii) Rq = 3.47 μm (PS) and 3.92 μm (PEI); and iii) Rq = 22.16 μm (PS) and 22.65 μm (PEI) were analyzed for their capacity to influence the activation of human monocytes derived DC. Since the DC were directly cultured in the inserts, the effects of the testing material alone could be investigated and influences from additional culture dish material could be excluded. The viability, the expression of the DC activation markers, and their cytokine/chemokine secretion were determined after the incubation with the different inserts in vitro. Both the PS and the PEI inserts did not influence the survival of the DC and their expression of co-stimulatory molecules. The expression of inflammatory cytokines was not altered by the PEI and PS inserts. However, the secretion of chemokines such as CCL2, CCL3, and CCL4 was influenced by the different roughness levels, indicating that material roughness has the capacity to modulate the DC phenotype. The data presented here will help to understand the interaction of DC with structured polymer surfaces. Biomaterial-induced immuno-modulatory effects mediated by DC may promote tissue regeneration or could potentially reduce inflammation caused by the implant material.}, note = {Online available at: \url{https://doi.org/10.3233/CH-131699} (DOI). Roch, T.; Kratz, K.; Ma, N.; Jung, F.; Lendlein, A.: The influence of polystyrene and poly(ether imide) inserts with different roughness, on the activation of dendritic cells. Clinical Hemorheology and Microcirculation. 2013. vol. 55, no. 1, 157-168. DOI: 10.3233/CH-131699}} @misc{xu_cultivation_and_2013, author={Xu, X., Kratz, K., Wang, W., Li, Z., Roch, T., Jung, F., Lendlein, A., Ma, N.}, title={Cultivation and spontaneous differentiation of rat bone marrow-derived mesenchymal stem cells on polymeric surfaces}, year={2013}, howpublished = {journal article}, doi = {https://doi.org/10.3233/CH-131698}, abstract = {Accumulating evidence demonstrated many physical and chemical cues from the local microenvironment could influence mesenchymal stem cells (MSCs) maintenance and differentiation. In this study, we systematically investigated the interaction of rat bone marrow-derived mesenchymal stem cells (rBMSCs) and polymeric substrates. Adhesion, proliferative capacity, cytoskeleton alteration, cytotoxicity, apoptosis, senescence, and adipogenesis potential of rBMSCs were determined on these polymeric inserts prepared from polyetherurethane (PEU) and poly(ether imide) (PEI). Inserts for culture plates were applied to ensure that the rBMSCs were solely in contact to the tested material. The explored inserts exhibited advancing contact angles of 84° (PEU) and 93° (PEI). Finally, the micromechanical properties determined by atomic force microscopy (AFM) indentation varied in the range from 6 GPa (PEU) to 13 GPa (PEI). We found that both PEU and PEI showed a good cell compatibility to rBMSCs. rBMSCs could adherent on both polymeric surfaces with the similar adhesion ratio and subsequent division rate. However, cells cultured on PEU exhibited higher apoptosis level and senescence ratio, which resulted in lower cell density (22061 ± 3000/cm2) compared to that on PEI (68395 ± 8000/cm2) after 20 days cultivation. Morphological differences of rBMSCs were detected after 5 days cultivation. Cells on PEU exhibited flat and enlarged shape with rearranged filamentous actin (F-actin) cytoskeleton, while cells on PEI and tissue culture plate (TCP) had similar spindle-shape morphology and oriented F-actin. After 20 days, lipid droplets were spontaneously formed in rBMSCs on PEU and PEI but not on TCP. Both PEU and PEI might trigger rBMSCs towards spontaneous adipogenic commitment, whereas PEI provided better cell compatibility on rBMSCs apoptosis, senescence and proliferation.}, note = {Online available at: \url{https://doi.org/10.3233/CH-131698} (DOI). Xu, X.; Kratz, K.; Wang, W.; Li, Z.; Roch, T.; Jung, F.; Lendlein, A.; Ma, N.: Cultivation and spontaneous differentiation of rat bone marrow-derived mesenchymal stem cells on polymeric surfaces. Clinical Hemorheology and Microcirculation. 2013. vol. 55, no. 1, 143-156. DOI: 10.3233/CH-131698}} @misc{julichgruner_immunological_investigations_2013, author={Julich-Gruner, K.K., Roch, T., Ma, N., Neffe, A.T., Lendlein, A.}, title={Immunological investigations of oligoethylene glycols functionalized with desaminotyrosine and desaminotyrosyltyrosine}, year={2013}, howpublished = {journal article}, doi = {https://doi.org/10.1557/opl.2013.831}, abstract = {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.}, note = {Online available at: \url{https://doi.org/10.1557/opl.2013.831} (DOI). Julich-Gruner, K.; Roch, T.; Ma, N.; Neffe, A.; Lendlein, A.: Immunological investigations of oligoethylene glycols functionalized with desaminotyrosine and desaminotyrosyltyrosine. MRS Online Proceedings Library. 2013. vol. 1569, 9-14. DOI: 10.1557/opl.2013.8