Dokument-ID Dokumenttyp Verfasser/Autoren Herausgeber Haupttitel Abstract Auflage Verlagsort Verlag Erscheinungsjahr Seitenzahl Schriftenreihe Titel Schriftenreihe Bandzahl ISBN Quelle der Hochschulschrift Konferenzname Quelle:Titel Quelle:Jahrgang Quelle:Heftnummer Quelle:Erste Seite Quelle:Letzte Seite URN DOI Abteilungen OPUS4-30401 Wissenschaftlicher Artikel Xu, Jietao; Fahmy-Garcia, Shorouk; Wesdorp, Marinus A.; Kops, Nicole; Forte, Lucia; De Luca, Claudio; Misciagna, Massimiliano Maraglino; Dolcini, Laura; Filardo, Giuseppe; Labberté, Margot; Vancíková, Karin; Kok, Joeri; van Rietbergen, Bert; Nickel, Joachim; Farrell, Eric; Brama, Pieter A. J.; van Osch, Gerjo J. V. M. Effectiveness of BMP-2 and PDGF-BB adsorption onto a collagen/collagen-magnesium-hydroxyapatite scaffold in weight-bearing and non-weight-bearing osteochondral defect bone repair: in vitro, ex vivo and in vivo evaluation Despite promising clinical results in osteochondral defect repair, a recently developed bi-layered collagen/collagen-magnesium-hydroxyapatite scaffold has demonstrated less optimal subchondral bone repair. This study aimed to improve the bone repair potential of this scaffold by adsorbing bone morphogenetic protein 2 (BMP-2) and/or platelet-derived growth factor-BB (PDGF-BB) onto said scaffold. The in vitro release kinetics of BMP-2/PDGF-BB demonstrated that PDGF-BB was burst released from the collagen-only layer, whereas BMP-2 was largely retained in both layers. Cell ingrowth was enhanced by BMP-2/PDFG-BB in a bovine osteochondral defect ex vivo model. In an in vivo semi-orthotopic athymic mouse model, adding BMP-2 or PDGF-BB increased tissue repair after four weeks. After eight weeks, most defects were filled with bone tissue. To further investigate the promising effect of BMP-2, a caprine bilateral stifle osteochondral defect model was used where defects were created in weight-bearing femoral condyle and non-weight-bearing trochlear groove locations. After six months, the adsorption of BMP-2 resulted in significantly less bone repair compared with scaffold-only in the femoral condyle defects and a trend to more bone repair in the trochlear groove. Overall, the adsorption of BMP-2 onto a Col/Col-Mg-HAp scaffold reduced bone formation in weight-bearing osteochondral defects, but not in non-weight-bearing osteochondral defects. 2023 Journal of Functional Biomaterials 14 2 urn:nbn:de:bvb:20-opus-304019 10.3390/jfb14020111 Lehrstuhl für Tissue Engineering und Regenerative Medizin OPUS4-25758 Wissenschaftlicher Artikel Borova, Solomiia; Schlutt, Christine; Nickel, Joachim; Luxenhofer, Robert A Transient Initiator for Polypeptoids Postpolymerization α-Functionalization via Activation of a Thioester Group Here, a postpolymerization modification method for an α-terminal functionalized poly-(N-methyl-glycine), also known as polysarcosine, is introduced. 4-(Methylthio)phenyl piperidine-4-carboxylate as an initiator for the ring-opening polymerization of N-methyl-glycine-N-carboxyanhydride followed by oxidation of the thioester group to yield an α-terminal reactive 4-(methylsulfonyl)phenyl piperidine-4-carboxylate polymer is utilized. This represents an activated carboxylic acid terminus, allowing straightforward modification with nucleophiles under mild reaction conditions and provides the possibility to introduce a wide variety of nucleophiles as exemplified using small molecules, fluorescent dyes, and model proteins. The new initiator yielded polymers with well-defined molar mass, low dispersity, and high end-group fidelity, as observed by gel permeation chromatography, nuclear magnetic resonance spectroscopy, and matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy. The introduced method can be of great interest for bioconjugation, but requires optimization, especially for protein conjugation. 2022 Macromolecular Chemistry and Physics 223 3 urn:nbn:de:bvb:20-opus-257587 10.1002/macp.202100331 Institut für Funktionsmaterialien und Biofabrikation OPUS4-28457 Wissenschaftlicher Artikel Siverino, Claudia; Fahmy-Garcia, Shorouk; Mumcuoglu, Didem; Oberwinkler, Heike; Muehlemann, Markus; Mueller, Thomas; Farrell, Eric; van Osch, Gerjo J. V. M.; Nickel, Joachim Site-directed immobilization of an engineered bone morphogenetic protein 2 (BMP2) variant to collagen-based microspheres induces bone formation in vivo For the treatment of large bone defects, the commonly used technique of autologous bone grafting presents several drawbacks and limitations. With the discovery of the bone-inducing capabilities of bone morphogenetic protein 2 (BMP2), several delivery techniques were developed and translated to clinical applications. Implantation of scaffolds containing adsorbed BMP2 showed promising results. However, off-label use of this protein-scaffold combination caused severe complications due to an uncontrolled release of the growth factor, which has to be applied in supraphysiological doses in order to induce bone formation. Here, we propose an alternative strategy that focuses on the covalent immobilization of an engineered BMP2 variant to biocompatible scaffolds. The new BMP2 variant harbors an artificial amino acid with a specific functional group, allowing a site-directed covalent scaffold functionalization. The introduced artificial amino acid does not alter BMP2′s bioactivity in vitro. When applied in vivo, the covalently coupled BMP2 variant induces the formation of bone tissue characterized by a structurally different morphology compared to that induced by the same scaffold containing ab-/adsorbed wild-type BMP2. Our results clearly show that this innovative technique comprises translational potential for the development of novel osteoinductive materials, improving safety for patients and reducing costs. 2022 International Journal of Molecular Sciences 23 7 urn:nbn:de:bvb:20-opus-284572 10.3390/ijms23073928 Julius-von-Sachs-Institut für Biowissenschaften OPUS4-19386 Wissenschaftlicher Artikel Nickel, Joachim; Mueller, Thomas D. Specification of BMP signaling Bone Morphogenetic Proteins (BMPs) together with the Growth and Differentiation Factors (GDFs) form the largest subgroup of the Transforming Growth Factor (TGF)β family and represent secreted growth factors, which play an essential role in many aspects of cell communication in higher organisms. As morphogens they exert crucial functions during embryonal development, but are also involved in tissue homeostasis and regeneration in the adult organism. Their involvement in maintenance and repair processes of various tissues and organs made these growth factors highly interesting targets for novel pharmaceutical applications in regenerative medicine. A hallmark of the TGFβ protein family is that all of the more than 30 growth factors identified to date signal by binding and hetero-oligomerization of a very limited set of transmembrane serine-threonine kinase receptors, which can be classified into two subgroups termed type I and type II. Only seven type I and five type II receptors exist for all 30plus TGFβ members suggesting a pronounced ligand-receptor promiscuity. Indeed, many TGFβ ligands can bind the same type I or type II receptor and a particular receptor of either subtype can usually interact with and bind various TGFβ ligands. The possible consequence of this ligand-receptor promiscuity is further aggravated by the finding that canonical TGFβ signaling of all family members seemingly results in the activation of just two distinct signaling pathways, that is either SMAD2/3 or SMAD1/5/8 activation. While this would implicate that different ligands can assemble seemingly identical receptor complexes that activate just either one of two distinct pathways, in vitro and in vivo analyses show that the different TGFβ members exert quite distinct biological functions with high specificity. This discrepancy indicates that our current view of TGFβ signaling initiation just by hetero-oligomerization of two receptor subtypes and transduction via two main pathways in an on-off switch manner is too simplified. Hence, the signals generated by the various TGFβ members are either quantitatively interpreted using the subtle differences in their receptor-binding properties leading to ligand-specific modulation of the downstream signaling cascade or additional components participating in the signaling activation complex allow diversification of the encoded signal in a ligand-dependent manner at all cellular levels. In this review we focus on signal specification of TGFβ members, particularly of BMPs and GDFs addressing the role of binding affinities, specificities, and kinetics of individual ligand-receptor interactions for the assembly of specific receptor complexes with potentially distinct signaling properties. 2019 1579 Cells 8 12 urn:nbn:de:bvb:20-opus-193869 10.3390/cells8121579 Julius-von-Sachs-Institut für Biowissenschaften OPUS4-19596 Wissenschaftlicher Artikel Stuckensen, Kai; Lamo-Espinosa, José M.; Muiños-López, Emma; Ripalda-Cemboráin, Purificación; López-Martínez, Tania; Iglesias, Elena; Abizanda, Gloria; Andreu, Ion; Flandes-Iparraguirre, María; Pons-Villanueva, Juan; Elizalde, Reyes; Nickel, Joachim; Ewald, Andrea; Gbureck, Uwe; Prósper, Felipe; Groll, Jürgen; Granero-Moltó, Froilán Anisotropic cryostructured collagen scaffolds for efficient delivery of RhBMP−2 and enhanced bone regeneration In the treatment of bone non-unions, an alternative to bone autografts is the use of bone morphogenetic proteins (BMPs), e.g., BMP-2, BMP-7, with powerful osteoinductive and osteogenic properties. In clinical settings, these osteogenic factors are applied using absorbable collagen sponges for local controlled delivery. Major side effects of this strategy are derived from the supraphysiological doses of BMPs needed, which may induce ectopic bone formation, chronic inflammation, and excessive bone resorption. In order to increase the efficiency of the delivered BMPs, we designed cryostructured collagen scaffolds functionalized with hydroxyapatite, mimicking the structure of cortical bone (aligned porosity, anisotropic) or trabecular bone (random distributed porosity, isotropic). We hypothesize that an anisotropic structure would enhance the osteoconductive properties of the scaffolds by increasing the regenerative performance of the provided rhBMP-2. In vitro, both scaffolds presented similar mechanical properties, rhBMP-2 retention and delivery capacity, as well as scaffold degradation time. In vivo, anisotropic scaffolds demonstrated better bone regeneration capabilities in a rat femoral critical-size defect model by increasing the defect bridging. In conclusion, anisotropic cryostructured collagen scaffolds improve bone regeneration by increasing the efficiency of rhBMP-2 mediated bone healing. 2019 Materials 12 19 urn:nbn:de:bvb:20-opus-195966 10.3390/ma12193105 Lehrstuhl für Tissue Engineering und Regenerative Medizin OPUS4-19726 Wissenschaftlicher Artikel Belka, Janina; Nickel, Joachim; Kurth, Dirk G. Growth on metallo-supramolecular coordination polyelectrolyte (MEPE) stimulates osteogenic differentiation of human osteosarcoma cells (MG63) and human bone marrow derived mesenchymal stem cells Background: Culturing of cells is typically performed on standard tissue culture plates generating growth conditions, which in general do not reflect the native three-dimensional cellular environment. Recent investigations provide insights in parameters, which strongly affect the general cellular behavior triggering essential processes such as cell differentiation. The physical properties of the used material, such as stiffness, roughness, or topology, as well as the chemical composition of the cell-surface interface are shown to play a key role in the initiation of particular cellular responses. Methods: We extended our previous research, which identified thin films of metallo-supramolecular coordination polyelectrolytes (MEPEs) as substrate to trigger the differentiation of muscular precursor cells. Results: Here, we show that the same MEPEs similarly stimulate the osteogenic differentiation of pre-osteoblasts. Remarkably, MEPE modified surfaces also trigger the differentiation of primary bone derived mesenchymal stem cells (BMSCs) towards the osteogenic lineage. Conclusion: This result leads to the conclusion that these surfaces individually support the specification of cell differentiation toward lineages that correspond to the natural commitment of the particular cell types. We, therefore, propose that Fe-MEPEs may be used as scaffold for the treatment of defects at least in muscular or bone tissue. 2019 1090 Polymers 11 7 urn:nbn:de:bvb:20-opus-197264 10.3390/polym11071090 Institut für Funktionsmaterialien und Biofabrikation OPUS4-17634 Wissenschaftlicher Artikel Kress, Sebastian; Baur, Johannes; Otto, Christoph; Burkard, Natalie; Braspenning, Joris; Walles, Heike; Nickel, Joachim; Metzger, Marco Evaluation of a miniaturized biologically vascularized scaffold in vitro and in vivo In tissue engineering, the generation and functional maintenance of dense voluminous tissues is mainly restricted due to insufficient nutrient supply. Larger three-dimensional constructs, which exceed the nutrient diffusion limit become necrotic and/or apoptotic in long-term culture if not provided with an appropriate vascularization. Here, we established protocols for the generation of a pre-vascularized biological scaffold with intact arterio-venous capillary loops from rat intestine, which is decellularized under preservation of the feeding and draining vascular tree. Vessel integrity was proven by marker expression, media/blood reflow and endothelial LDL uptake. In vitro maintenance persisted up to 7 weeks in a bioreactor system allowing a stepwise reconstruction of fully vascularized human tissues and successful in vivo implantation for up to 4 weeks, although with time-dependent decrease of cell viability. The vascularization of the construct lead to a 1.5× increase in cellular drug release compared to a conventional static culture in vitro. For the first time, we performed proof-of-concept studies demonstrating that 3D tissues can be maintained within a miniaturized vascularized scaffold in vitro and successfully implanted after re-anastomosis to the intrinsic blood circulation in vivo. We hypothesize that this technology could serve as a powerful platform technology in tissue engineering and regenerative medicine. 2018 Scientific Reports 8 4719 urn:nbn:de:bvb:20-opus-176343 10.1038/s41598-018-22688-w Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I) OPUS4-17735 Wissenschaftlicher Artikel Schliermann, Anna; Nickel, Joachim Unraveling the connection between fibroblast growth factor and bone morphogenetic protein signaling Ontogeny of higher organisms as well the regulation of tissue homeostasis in adult individuals requires a fine-balanced interplay of regulating factors that individually trigger the fate of particular cells to either stay undifferentiated or to differentiate towards distinct tissue specific lineages. In some cases, these factors act synergistically to promote certain cellular responses, whereas in other tissues the same factors antagonize each other. However, the molecular basis of this obvious dual signaling activity is still only poorly understood. Bone morphogenetic proteins (BMPs) and fibroblast growth factors (FGFs) are two major signal protein families that have a lot in common: They are both highly preserved between different species, involved in essential cellular functions, and their ligands vastly outnumber their receptors, making extensive signal regulation necessary. In this review we discuss where and how BMP and FGF signaling cross paths. The compiled data reflect that both factors synchronously act in many tissues, and that antagonism and synergism both exist in a context-dependent manner. Therefore, by challenging a generalization of the connection between these two pathways a new chapter in BMP FGF signaling research will be introduced. 2018 International Journal of Molecular Sciences 19 10 urn:nbn:de:bvb:20-opus-177358 10.3390/ijms19103220 Lehrstuhl für Tissue Engineering und Regenerative Medizin OPUS4-15899 Wissenschaftlicher Artikel Lagler, Charlotte; El-Mesery, Mohamed; Kübler, Alexander Christian; Müller-Richter, Urs Dietmar Achim; Stühmer, Thorsten; Nickel, Joachim; Müller, Thomas Dieter; Wajant, Harald; Seher, Axel The anti-myeloma activity of bone morphogenetic protein 2 predominantly relies on the induction of growth arrest and is apoptosis-independent Multiple myeloma (MM), a malignancy of the bone marrow, is characterized by a pathological increase in antibody-producing plasma cells and an increase in immunoglobulins (plasmacytosis). In recent years, bone morphogenetic proteins (BMPs) have been reported to be activators of apoptotic cell death in neoplastic B cells in MM. Here, we use bone morphogenetic protein 2 (BMP2) to show that the "apoptotic" effect of BMPs on human neoplastic B cells is dominated by anti-proliferative activities and cell cycle arrest and is apoptosis-independent. The anti-proliferative effect of BMP2 was analysed in the human cell lines KMS12-BM and L363 using WST-1 and a Coulter counter and was confirmed using CytoTox assays with established inhibitors of programmed cell death (zVAD-fmk and necrostatin-1). Furthermore, apoptotic activity was compared in both cell lines employing western blot analysis for caspase 3 and 8 in cells treated with BMP2 and FasL. Additionally, expression profiles of marker genes of different cell death pathways were analysed in both cell lines after stimulation with BMP2 for 48h using an RT-PCR-based array. In our experiments we observed that there was rather no reduction in absolute cell number, but cells stopped proliferating following treatment with BMP2 instead. The time frame (48-72 h) after BMP2 treatment at which a reduction in cell number is detectable is too long to indicate a directly BMP2-triggered apoptosis. Moreover, in comparison to robust apoptosis induced by the approved apoptotic factor FasL, BMP2 only marginally induced cell death. Consistently, neither the known inhibitor of apoptotic cell death zVAD-fmk nor the necroptosis inhibitor necrostatin-1 was able to rescue myeloma cell growth in the presence of BMP2. 2017 e0185720 PLoS ONE 12 10 urn:nbn:de:bvb:20-opus-158993 Klinik und Poliklinik für Mund-, Kiefer- und Plastische Gesichtschirurgie OPUS4-15814 Wissenschaftlicher Artikel Seher, Axel; Lagler, Charlotte; Stühmer, Thorsten; Müller-Richter, Urs Dietmar Achim; Kübler, Alexander Christian; Sebald, Walter; Müller, Thomas Dieter; Nickel, Joachim Utilizing BMP-2 muteins for treatment of multiple myeloma Multiple myeloma (MM) represents a haematological cancer characterized by the pathological hyper proliferation of antibody-producing B-lymphocytes. Patients typically suffer from kidney malfunction and skeletal disorders. In the context of MM, the transforming growth factor β (TGFβ) member Activin A was recently identified as a promoter of both accompanying symptoms. Because studies have shown that bone morphogenetic protein (BMP)-2-mediated activities are counteracted by Activin A, we analysed whether BMP2, which also binds to the Activin A receptors ActRII and ActRIIB but activates the alternative SMAD-1/5/8 pathway, can be used to antagonize Activin A activities, such as in the context of MM. Therefore three BMP2 derivatives were generated with modified binding activities for the type II (ActRIIB) and/or type I receptor (BMPRIA) showing either increased or decreased BMP2 activity. In the context of MM these BMP2 muteins show two functionalities since they act as a) an anti-proliferative/apoptotic agent against neoplastic B-cells, b) as a bone-formation promoting growth factor. The molecular basis of both activities was shown in two different cellular models to clearly rely on the properties of the investigated BMP2 muteins to compete for the binding of Activin A to the Activin type II receptors. The experimental outcome suggests new therapeutic strategies using BMP2 variants in the treatment of MM-related pathologies. 2017 e0174884 PLoS ONE 12 5 urn:nbn:de:bvb:20-opus-158144 10.1371/journal.pone.0174884 Theodor-Boveri-Institut für Biowissenschaften