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- ItemGlycosaminoglycan-based hydrogels to modulate heterocellular communication in in vitro angiogenesis models(London : Nature Publishing Group, 2014) Chwalek, K.; Tsurkan, M.V.; Freudenberg, U.; Werner, C.Angiogenesis, the outgrowth of blood vessels, is crucial in development, disease and regeneration. Studying angiogenesis in vitro remains challenging because the capillary morphogenesis of endothelial cells (ECs) is controlled by multiple exogenous signals. Therefore, a set of in situ-forming starPEG-heparin hydrogels was used to identify matrix parameters and cellular interactions that best support EC morphogenesis. We showed that a particular type of soft, matrix metalloproteinase-degradable hydrogel containing covalently bound integrin ligands and reversibly conjugated pro-angiogenic growth factors could boost the development of highly branched, interconnected, and lumenized endothelial capillary networks. Using these effective matrix conditions, 3D heterocellular interactions of ECs with different mural cells were demonstrated that enabled EC network modulation and maintenance of stable vascular capillaries over periods of about one month in vitro. The approach was also shown to permit in vitro tumor vascularization experiments with unprecedented levels of control over both ECs and tumor cells. In total, the introduced 3D hydrogel co-culture system could offer unique options for dissecting and adjusting biochemical, biophysical, and cell-cell triggers in tissue-related vascularization models.
- ItemCryogel-supported stem cell factory for customized sustained release of bispecific antibodies for cancer immunotherapy(London : Nature Publishing Group, 2017) Aliperta, Roberta; Welzel, Petra B.; Bergmann, Ralf; Freudenberg, Uwe; Berndt, Nicole; Feldmann, Anja; Arndt, Claudia; Koristka, Stefanie; Stanzione, Marcello; Cartellieri, Marc; Ehninger, Armin; Ehninger, Gerhard; Werner, Carsten; Pietzsch, Jens; Steinbach, Jörg; Bornhäuser, Martin; Bachmann, Michael P.Combining stem cells with biomaterial scaffolds provides a promising strategy for the development of drug delivery systems. Here we propose an innovative immunotherapeutic organoid by housing human mesenchymal stromal cells (MSCs), gene-modified for the secretion of an anti-CD33-anti-CD3 bispecific antibody (bsAb), in a small biocompatible star-shaped poly(ethylene glycol)-heparin cryogel scaffold as a transplantable and low invasive therapeutic machinery for the treatment of acute myeloid leukemia (AML). The macroporous biohybrid cryogel platform displays effectiveness in supporting proliferation and survival of bsAb-releasing-MSCs overtime in vitro and in vivo, avoiding cell loss and ensuring a constant release of sustained and detectable levels of bsAb capable of triggering T-cell-mediated anti-tumor responses and a rapid regression of CD33 + AML blasts. This therapeutic device results as a promising and safe alternative to the continuous administration of short-lived immunoagents and paves the way for effective bsAb-based therapeutic strategies for future tumor treatments.
- ItemZebrafish In-Vivo Screening for Compounds Amplifying Hematopoietic Stem and Progenitor Cells: - Preclinical Validation in Human CD34+ Stem and Progenitor Cells(London : Nature Publishing Group, 2017) Arulmozhivarman, Guruchandar; Kräter, Martin; Wobus, Manja; Friedrichs, Jens; Bejestani, Elham Pishali; Müller, Katrin; Lambert, Katrin; Alexopoulou, Dimitra; Dahl, Andreas; Stöter, Martin; Bickle, Marc; Shayegi, Nona; Hampe, Jochen; Stölzel, Friedrich; Brand, Michael; von Bonin, Malte; Bornhäuser, MartinThe identification of small molecules that either increase the number and/or enhance the activity of human hematopoietic stem and progenitor cells (hHSPCs) during ex vivo expansion remains challenging. We used an unbiased in vivo chemical screen in a transgenic (c-myb:EGFP) zebrafish embryo model and identified histone deacetylase inhibitors (HDACIs), particularly valproic acid (VPA), as significant enhancers of the number of phenotypic HSPCs, both in vivo and during ex vivo expansion. The long-term functionality of these expanded hHSPCs was verified in a xenotransplantation model with NSG mice. Interestingly, VPA increased CD34+ cell adhesion to primary mesenchymal stromal cells and reduced their in vitro chemokine-mediated migration capacity. In line with this, VPA-treated human CD34+ cells showed reduced homing and early engraftment in a xenograft transplant model, but retained their long-term engraftment potential in vivo, and maintained their differentiation ability both in vitro and in vivo. In summary, our data demonstrate that certain HDACIs lead to a net expansion of hHSPCs with retained long-term engraftment potential and could be further explored as candidate compounds to amplify ex-vivo engineered peripheral blood stem cells.
- ItemSolid-state 31P and 1H chemical MR micro-imaging of hard tissues and biomaterials with magic angle spinning at very high magnetic field(London : Nature Publishing Group, 2017) Yon, Maxime; Sarou-Kanian, Vincent; Scheler, Ulrich; Bouler, Jean-Michel; Bujoli, Bruno; Massiot, Dominique; Fayon, FranckIn this work, we show that it is possible to overcome the limitations of solid-state MRI for rigid tissues due to large line broadening and short dephasing times by combining Magic Angle Spinning (MAS) with rotating pulsed field gradients. This allows recording ex vivo 31P 3D and 2D slice-selected images of rigid tissues and related biomaterials at very high magnetic field, with greatly improved signal to noise ratio and spatial resolution when compared to static conditions. Cross-polarization is employed to enhance contrast and to further depict spatially localized chemical variations in reduced experimental time. In these materials, very high magnetic field and moderate MAS spinning rate directly provide high spectral resolution and enable the use of frequency selective excitation schemes for chemically selective imaging. These new possibilities are exemplified with experiments probing selectively the 3D spatial distribution of apatitic hydroxyl protons inside a mouse tooth with attached jaw bone with a nominal isotropic resolution nearing 100 μm.
- ItemDiscovery of 505-million-year old chitin in the basal demosponge Vauxia gracilenta(London : Nature Publishing Group, 2013) Ehrlich, H.; Rigby, J.K.; Botting, J.P.; Tsurkan, M.V.; Werner, C.; Schwille, P.; Petrášek, Z.; Pisera, A.; Simon, P.; Sivkov, V.N.; Vyalikh, D.V.; Molodtsov, S.L.; Kurek, D.; Kammer, M.; Hunoldt, S.; Born, R.; Stawski, D.; Steinhof, A.; Bazhenov, V.V.; Geisler, T.Sponges are probably the earliest branching animals, and their fossil record dates back to the Precambrian. Identifying their skeletal structure and composition is thus a crucial step in improving our understanding of the early evolution of metazoans. Here, we present the discovery of 505-million-year-old chitin, found in exceptionally well preserved Vauxia gracilenta sponges from the Middle Cambrian Burgess Shale. Our new findings indicate that, given the right fossilization conditions, chitin is stable for much longer than previously suspected. The preservation of chitin in these fossils opens new avenues for research into other ancient fossil groups.
- ItemBio-responsive polymer hydrogels homeostatically regulate blood coagulation(London : Nature Publishing Group, 2013) Maitz, Manfred F.; Freudenberg, U.; Tsurkan, M.V.; Fischer, M.; Beyrich, T.; Werner, C.Bio-responsive polymer architectures can empower medical therapies by engaging molecular feedback-response mechanisms resembling the homeostatic adaptation of living tissues to varying environmental constraints. Here we show that a blood coagulation-responsive hydrogel system can deliver heparin in amounts triggered by the environmental levels of thrombin, the key enzyme of the coagulation cascade, which - in turn - becomes inactivated due to released heparin. The bio-responsive hydrogel quantitatively quenches blood coagulation over several hours in the presence of pro-coagulant stimuli and during repeated incubation with fresh, non-anticoagulated blood. These features enable the introduced material to provide sustainable, autoregulated anticoagulation, addressing a key challenge of many medical therapies. Beyond that, the explored concept may facilitate the development of materials that allow the effective and controlled application of drugs and biomolecules.
- ItemDefined Geldrop Cultures Maintain Neural Precursor Cells(London : Nature Publishing Group, 2018) Vogler, Steffen; Prokoph, Silvana; Freudenberg, Uwe; Binner, Marcus; Tsurkan, Mikhail; Werner, Carsten; Kempermann, GerdDistinct micro-environmental properties have been reported to be essential for maintenance of neural precursor cells (NPCs) within the adult brain. Due to high complexity and technical limitations, the natural niche can barely be studied systematically in vivo. By reconstituting selected environmental properties (adhesiveness, proteolytic degradability, and elasticity) in geldrop cultures, we show that NPCs can be maintained stably at high density over an extended period of time (up to 8 days). In both conventional systems, neurospheres and monolayer cultures, they would expand and (in the case of neurospheres) differentiate rapidly. Further, we report a critical dualism between matrix adhesiveness and degradability. Only if both features are functional NPCs stay proliferative. Lastly, Rho-associated protein kinase was identified as part of a pivotal intracellular signaling cascade controlling cell morphology in response to environmental cues inside geldrop cultures. Our findings demonstrate that simple manipulations of the microenvironment in vitro result in an important preservation of stemness features in the cultured precursor cells.
- ItemBone marrow niche-mimetics modulate HSPC function via integrin signaling(London : Nature Publishing Group, 2017) Kräter, Martin; Jacobi, Angela; Otto, Oliver; Tietze, Stefanie; Müller, Katrin; Poitz, David M.; Palm, Sandra; Zinna, Valentina M.; Biehain, Ulrike; Wobus, Manja; Chavakis, Triantafyllos; Werner, Carsten; Guck, Jochen; Bornhauser, MartinThe bone marrow (BM) microenvironment provides critical physical cues for hematopoietic stem and progenitor cell (HSPC) maintenance and fate decision mediated by cell-matrix interactions. However, the mechanisms underlying matrix communication and signal transduction are less well understood. Contrary, stem cell culture is mainly facilitated in suspension cultures. Here, we used bone marrow-mimetic decellularized extracellular matrix (ECM) scaffolds derived from mesenchymal stromal cells (MSCs) to study HSPC-ECM interaction. Seeding freshly isolated HSPCs adherent (AT) and non-adherent (SN) cells were found. We detected enhanced expansion and active migration of AT-cells mediated by ECM incorporated stromal derived factor one. Probing cell mechanics, AT-cells displayed naïve cell deformation compared to SN-cells indicating physical recognition of ECM material properties by focal adhesion. Integrin αIIb (CD41), αV (CD51) and β3 (CD61) were found to be induced. Signaling focal contacts via ITGβ3 were identified to facilitate cell adhesion, migration and mediate ECM-physical cues to modulate HSPC function.
- ItemMechanochemical route to the synthesis of nanostructured Aluminium nitride(London : Nature Publishing Group, 2016) Rounaghi, S.A.; Eshghi, H.; Scudino, S.; Vyalikh, A.; Vanpoucke, D.E.P.; Gruner, W.; Oswald, S.; Rashid, A.R. Kiani; Khoshkhoo, M. Samadi; Scheler, U.; Eckert, J.Hexagonal Aluminium nitride (h-AlN) is an important wide-bandgap semiconductor material which is conventionally fabricated by high temperature carbothermal reduction of alumina under toxic ammonia atmosphere. Here we report a simple, low cost and potentially scalable mechanochemical procedure for the green synthesis of nanostructured h-AlN from a powder mixture of Aluminium and melamine precursors. A combination of experimental and theoretical techniques has been employed to provide comprehensive mechanistic insights on the reactivity of melamine, solid state metal-organic interactions and the structural transformation of Al to h-AlN under non-equilibrium ball milling conditions. The results reveal that melamine is adsorbed through the amine groups on the Aluminium surface due to the long-range van der Waals forces. The high energy provided by milling leads to the deammoniation of melamine at the initial stages followed by the polymerization and formation of a carbon nitride network, by the decomposition of the amine groups and, finally, by the subsequent diffusion of nitrogen into the Aluminium structure to form h-AlN.
- ItemPlasmonic nanomeshes: Their ambivalent role as transparent electrodes in organic solar cells(London : Nature Publishing Group, 2017) Stelling, Christian; Singh, Chetan R.; Karg, Matthias; König, Tobias A.F.; Thelakkat, Mukundan; Retsch, MarkusIn this contribution, the optical losses and gains attributed to periodic nanohole array electrodes in polymer solar cells are systematically studied. For this, thin gold nanomeshes with hexagonally ordered holes and periodicities (P) ranging from 202 nm to 2560 nm are prepared by colloidal lithography. In combination with two different active layer materials (P3HT:PC 61 BM and PTB7:PC 71 BM), the optical properties are correlated with the power conversion efficiency (PCE) of the solar cells. A cavity mode is identified at the absorption edge of the active layer material. The resonance wavelength of this cavity mode is hardly defined by the nanomesh periodicity but rather by the absorption of the photoactive layer. This constitutes a fundamental dilemma when using nanomeshes as ITO replacement. The highest plasmonic enhancement requires small periodicities. This is accompanied by an overall low transmittance and high parasitic absorption losses. Consequently, larger periodicities with a less efficient cavity mode, yet lower absorptive losses were found to yield the highest PCE. Nevertheless, ITO-free solar cells reaching ∼77% PCE compared to ITO reference devices are fabricated. Concomitantly, the benefits and drawbacks of this transparent nanomesh electrode are identified, which is of high relevance for future ITO replacement strategies.