TRR 67:  Functional Biomaterials for Controlling Healing Processes in Bone und Skin - From Material Science to Clinical Application

Final Report Abstract

The demographic trends in Germany and other industrialized nations result in a considerable increase in patients with bone defects and chronic wounds. This requires the development of novel functional biomaterials, which improve bone and skin regeneration in an aging, multimorbid population. Increasing knowledge about the role of the extracellular matrix (ECM) for the regeneration of tissues creates new opportunities for the design of innovative biomaterials. In particular, the structure and composition of ECM significantly influences cellular differentiation and function and the healing of tissues. Hence, the aim of the CRC 67 was to develop and investigate novel functional biomaterials based on naturally occurring and chemically modified, artificial ECM (aECM). Essential functional components of these materials are glycosaminoglycan (GAG) derivatives and proteoglycan (PG) analogs in combination with structural proteins or synthetic carrier components. It was our vision to exploit the newly gained knowledge on interactions of GAG-derivatives and PG-biomimetics with mediators, matrix components and cells to create novel biomaterials adapted specifically to the needs of patients with impaired regenerative capacities in skin and bone. From 2009 - 2021 we gained basic insights into the molecular interactions of GAG with different mediators. We could show that aECM-based biomaterials support wound healing of skin and bone; underlying mechanisms were characterized in detail at the atomic level. Finally, we increased the complexity of biomaterials to adapt them to the different phases of wound healing in skin and bone. In a translational setting, these multifunctional biomaterials were tested in relevant preclinical models with physiological and impaired regeneration in skin and bone. This led to the development of innovative treatment strategies for chronic wounds and a first phase I trial in humans to be started soon after completion of the TRR67 funding period. The CRC 67 was a joint effort of Leipzig University and Technische Universität Dresden with partners from the Technische Universität Berlin, the Helmholtz-Zentrum für Umweltforschung Leipzig-Halle GmbH, the Helmholtz-Zentrum Dresden-Rossendorf, the Leibniz-Institut für Polymerforschung Dresden e.V., INNOVENT e. V. and industry e.g. Firma Mathys Orthopädie GmbH. The CRC built on four research areas: 1) “Matrix engineering” comprised the material science/chemistry oriented projects, including analytics and modeling. 2) “Biological profiles” bundled projects with cell biological and preclinical orientation. 3) „Transfer” built – together with industrial partners – the base for later clinical testing of the new biomaterials. 4) “Central services” combined methodologically oriented projects that provided service to all subprojects, administration and the graduate school “Matrix Engineering“. A unique feature of the TRR67 was it‘s highly interdisciplinary character bringing together material science, bioinformatics, biophysics, bio- and glycochemistry, pharmaceutical technology, cell- and matrix biology, immunology and clinical medicine right from the start. This concept was highly succesful to establish very productive and close collaborations, many of which last beyond TRR67 funding.

Publications

• Apparatus and Methods for the Automated Synthesis of Oligosaccharides. US 7,160,517
  Seeberger PH, Plante OJ
  
• Linkers for Synthesis of Oligosaccharides on Solid Supports. US 6,579,725
  Seeberger PH, Andrade RB
  
• Growth promoting substrates for human dermal fibroblasts provided by artificial extracellular matrices composed of collagen I and sulfated glycosaminoglycans. Biomaterials. 2011, 32(34):8938-46
  van der Smissen A, Hintze V, Scharnweber D, Moeller S, Schnabelrauch M, Majok A, Simon JC. Anderegg U
  
• Stem cells and their use in skeletal tissue repair. Stem Cells and Regenerative Medicine: From molecular embryology to tissue engineering. 2011;103-124. ISBN:978-1-606761-859-1
  Baumgartner L, Savkovic V, Trettner S, Martin C, zur Nieden NI
  
• Sulfated glycosaminoglycan building blocks for the design of artificial extracellular matrices. Book chapter in: ACS Symposium Series. 2011; 1107, 315-28
  Becher J, Möller S, Riemer T, Schiller J, Hintze V, Bierbaum S, Scharnweber D, Worch H, Schnabelrauch M
  
• Sclerostin antibody treatment improves bone mass, bone strength, and bone defect regernation in rats with type 2 diabetes mellitus. J Bone Miner Res. 2012 Oct 29
  Hamann C, Rauner M, Höhna Y, Bernhardt R, Mettelsiefen J, Goettsch C, Günther KP, Stolina M, Han CY, Asuncion FJ, Ominsky MS, Hofbauer LC
  
• The effect of the degree of sulfation of glycosaminoglycans on osteoclast function and signaling pathways. Biomaterials. 2012, 33:8418-29
  Salbach J, Kliemt S, Rauner M, Rachner TD, Goettsch C, Kalkhof S, von Bergen M, Möller S, Schnabelrauch M, Hintze V, Scharnweber D, Hofbauer LC
  
• Verfahren zum Abbau von Polysacchariden. 2012. EP000003592807B1 (A10)
  Wyrwa R, Becher J, Schnabelrauch M
  
• Artificial extracellular matrices composed of collagen I and high-sulfated hyaluronan promote phenotypic and functional modulation of human pro-inflammatory M1 macrophages. Acta Biomater. 2013, 9(3):5621-9
  Franz S, Allenstein F, Kajahn J, Forstreuter I, Hintze V, Möller S, Simon JC
  
• Artificial extracellular matrix composed of collagen I and high-sulfated hyaluronan interferes with TGFβ1 signaling and prevents TGFβ1 induced myofibroblast differentiation. Acta Biomater. 2013, 9(8):7775-86
  van der Smissen A, Samsonov S, Hintze V, Scharnweber D, Moeller S, Schnabelrauch M, Pisabarro MT, Anderegg U
  
• Method and means for detecting the activity of osteoclasts. Deutsche Patentanmeldung; Offenlegung: DE10 209 013 957 A1; 2010.09.16. Europäische Patentanmeldung Nr. 0707908.9, 16. 01. 2013, Offenlegung: EP 2 406 626 B1
  Lutter AH, Hempel U, Dieter P
  
• Sulfated alginate hydrogels for cell culture and therapy. WO 2014/072035 A1, 2013
  Zenobi-Wong M, Palazzolo G, Mhanna R, Becher J, Möller S, Schnabelrauch M
  
• The promotion of osteoclastogenesis by sulfated hyaluronan through interference with osteoprotegerin and receptor activator of NF- κB ligand/osteoprotegerin complex formation. Biomaterials. 2013, 34:7653-7661
  Salbach-Hirsch J, Kraemer J, Rauner M, Samsonov SA, Pisabarro MT, Moeller S, Schnabelrauch M, Scharnweber D, Hofbauer LC and Hintze V
  
• The promotion of osteoclastogenesis by sulfated hyaluronan through interference with osteoprotegerin and receptor activator of NF-κB ligand/osteoprotegerin complex formation. Biomaterials. 2013, 34:7653-61
  Salbach-Hirsch J, Kraemer J, Rauner M, Samsonov SA, Pisabarro MT, Moeller S, Schnabelrauch M, Scharnweber D, Hofbauer LC, Hintze V
  
• Gelatin-based biomaterial engineering with anhydride-containing oligomeric cross-linkers. Biomacromolecules. 2014, 15,2104-18
  Loth T, Hötzel R, Kascholke C, Anderegg U, Schulz-Siegmund M, Hacker MC
  
• Increased bone remodelling around titanium implants coated with chondroitin sulfate in ovariectomized rats. Acta Biomater. 2014, 10: 2855-2865
  Dudeck J, Rehberg S, Bernhardt R, Schneiders W, Zierau O, Manjubala I, Goebbels J, Vollmer G, Fratzl P, Scharnweber D, Rammelt S
  
• Sulfated glycosaminoglycans exploit the conformational plasticity of bone morphogenetic protein-2 (BMP-2) and alter the interaction profile with its receptor. Biomacromolecules. 2014, 15(8):3083-3092
  Hintze V, Samsonov SA, Anselmi M, Möller S, Becher J, Schnabelrauch M, Scharnweber D, Pisabarro MT
  
• Bioinspired Collagen/Glycosaminoglycan-based Cellular Microenvironments for Tuning Osteoclastogenesis. ACS Appl Mater Interfaces. 2015, 7(42):23787-23797
  Rother S, Salbach-Hirsch J, Moeller S, Seemann T, Schnabelrauch M, Hofbauer LC, Hintze V, Scharnweber D
  
• Characterization and chemical Modification of Glycosaminoglycans of the extracellular Matrix. In: "Sulfated Polysaccharides", Nova Science Publishers. 2015;3:73-104
  Schiller J, Becher J, Möller S, Lemmnitzer K, Riemer T, Schnabelrauch M
  
• Highly adjustable biomaterial networks from three-armed biodegradable macromers. Acta Biomater. 2015, 26,82-96
  Loth R, Loth T, Schwabe K, Bernhardt R, Schulz-Siegmund M, Hacker MC
  
• Regeneration of organs and appendages in zebrafish: A Window into underlying control mechanisms. Encyclopedia of Life Sciences. Chichester: John Wiley & Sons, Ltd. 2015
  Antos CL, Knopf F, Brand M
  
• Structural and functional insights into sclerostin-glycosaminoglycan interactions in bone. Biomaterials. 2015, 67:335-45
  Salbach-Hirsch J, Samsonov SA, Hintze V, Hofbauer C, Picke AK, Rauner M, Gehrcke JP, Moeller S, Schnabelrauch M, Scharnweber D, Pisabarro MT, Hofbauer LC
  
• TGFβ functionalized starPEG-heparin hydrogels modulate human dermal fibroblast growth and differentiation. Acta Biomater. 2015, 25:56-75
  Watarai A, Schirmer L, Thönes S, Freudenberg U, Werner C, Simon JC, Anderegg U
  
• Chemoenzymatic synthesis of nonasulfated tetrahyaluronan with a paramagnetic Tag for studying its complex with interleukin-10. Chemistry. 2016, 22(16):5563-74
  Köhling S, Künze G, Lemmnitzer K, Bermudez M, Wolber G, Schiller J, Huster D, Rademann J
  
• Glycosaminoglycan-based biohybrid hydrogels: a sweet and smart choice for multifunctional biomaterials. Adv Mater. 2016; 28:8861-91
  Freudenberg U, Liang Y, Kiick KL, Werner C
  
• Multifunctional Coating Improves Cell Adhesion on Titanium by using Cooperatively Acting Peptides. Angew Chem Int Ed Engl. 2016, 55(15):4826-30
  Pagel M, Hassert R, John T, Braun K, Wießler M, Abel B, Beck-Sickinger AG
  
• Sulfated hyaluronan improves bone regeneration of diabetic rats by binding sclerostin and enhancing osteoblast function. Biomaterials. 2016, 96:11-23
  Picke AK, Salbach-Hirsch J, Hintze V, Rother S, Rauner M, Kascholke C, Möller S, Bernhardt R, Rammelt S, Pisabarro MT, Ruiz-Gómez G, Schnabelrauch M, Schulz-Siegmund M, Hacker MC, Scharnweber D, Hofbauer C, Hofbauer LC
  
• Sulfated hyaluronan improves bone regeneration of diabetic rats by binding sclerostin and enhancing osteoblast function. Biomaterials. 2016, 96:11-23
  Picke AK, Salbach-Hirsch J, Hintze V, Rother S, Rauner M, Kascholke C, Möller S, Bernhardt R, Rammelt S, Pisabarro MT, Ruiz-Gómez G, Schnabelrauch M, Schulz- Siegmund M, Hacker MC, Scharnweber D, Hofbauer C, Hofbauer LC
  
• Dermal fibroblasts promote alternative macrophage activation improving impaired wound healing. J Invest Dermatol. 2017, 137(4):941-950
  Ferrer RA, Saalbach A, Grünwedel M, Lohmann N, Forstreuter I, Saupe S, Wandel E, Simon JC, Franz S
  
• Glycosaminoglycan-based hydrogels capture chemokines and rescue wound healing deficiency. Sci Transl Med. 2017, 9(386)
  Lohmann N, Schirmer L, Atallah P, Wandel E, Ferrer RA, Werner C, Simon JC, Franz S, Freudenberg U
  
• Immune suppressive and bone inhibitory effects of prednisolone in growing and regenerating zebrafish tissues. J Bone Miner Res. 2017, 32, 2476-2488
  Geurtzen K, Vernet A, Freidin A, Rauner M, Hofbauer LC, Schneider JE, Brand M, Knopf F
  
• Instructing Human Macrophage Polarization by Stiffness and Glycosaminoglycan Functionalization in 3D Collagen Networks. Adv Healthc Mater. 2017, 6: 1600967
  Friedemann M, Kalbitzer L, Franz S, Moeller S, Schnabelrauch M, Simon JC, Pompe T, Franke K
  
• Sulfated Hyaluronan Alters Endothelial Cell Activation in Vitro by Controlling the Biological Activity of the Angiogenic Factors Vascular Endothelial Growth Factor-A and Tissue Inhibitor of Metalloproteinase-3. ACS Appl Mater Interfaces. 2017, 9(11):9539-9550
  Rother S, Samsonov SA, Moeller S, Schnabelrauch M, Rademann J, Blaszkiewicz J, Köhling S, Waltenberger J, Pisabarro MT, Scharnweber D, Hintze V
  
• Surface modification of copolymerized films from three-armed biodegradable macromers - an analytical platform for modified tissue engineering scaffolds. Acta Biomater. 2017, 51,148-160
  Müller BM, Loth R, Hoffmeister PG, Zühl F, Kalbitzer L, Hacker MC, Schulz-Siegmund M
  
• Fibril growth kinetics link buffer conditions and topology of 3D collagen I networks. Acta Biomater. 2018, 67: 206-214
  Kalbitzer L, Pompe T
  
• In situ-forming, cell-instructive hydrogels based on glycosaminoglycans with varied sulfation patterns. Biomaterials. 181, 2018, 227-239
  Atallah P, Schirmer L, Tsurkan MV, Limasale YDP, Zimmermann R, Werner C, Freudenberg U
  
• Syntheses of defined sulfated oligohyaluronans reveal structural effects, diversity and thermodynamics of GAG-protein binding. Chem Sci. 2018, 10(3):866-878
  Köhling S, Blaszkiewicz J, Ruiz-Gómez G, Fernández-Bachiller MI, Lemmnitzer K, Panitz N, Beck-Sickinger AG, Schiller J, Pisabarro MT, Rademann J
  
• Hyaluronan/collagen hydrogels containing sulfated hyaluronan improve wound healing by sustained release of heparin-binding EGF-like growth factor. Acta Biomater. 2019, 86:135-147
  Thönes S, Rother S, Wippold T, Blaszkiewicz J, Balamurugan K, Moeller S, Ruiz-Gómez G, Schnabelrauch M, Scharnweber D, Saalbach A, Rademann J, Pisabarro MT, Hintze V, Anderegg U
  
• Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signaling. Nat Metab. 2019, 1:111-24
  Rauner M, Baschant U, Roetto A, Pellegrino RM, Rother S, Salbach-Hirsch J, Weidner H, Hintze V, Campbell G, Petzold A, Lemaitre R, Henry I, Bellido T, Theurl I, Altamura S, Colucci S, Muckenthaler MU, Schett G, Komla-Ebri DSK, Bassett JHD, Williams GR, Platzbecker U, Hofbauer LC
  
• Glycosaminoglycan-based hydrogels with programmable host reactions, Biomaterials. 228, 2020, 119557
  Schirmer L, Chwalek K, Tsurkan MV, Freudenberg U, Werner C
  
• Multifunctional coatings combining bioactive peptides and affinity-based cytokine delivery for enhanced integration of degradable vascular grafts. Biomater Sci. 2020, 8(6):1734-1747
  Clauder F, Zitzmann FD, Friebe S, Mayr SG, Robitzki AA, Beck-Sickinger AG
  
• Scavenging of Dickkopf-1 by macromer-based biomaterials covalently decorated with sulfated hyaluronan displays proosteogenic effects. Acta Biomater. 2020, 114,76-89
  Gronbach M, Mitrach F, Lidzba V, Müller B, Möller S, Rother S, Salbach-Hirsch J, Hofbauer L C, Schnabelrauch M, Hintze V, Hacker M C, Schulz-Siegmund M
  
• The influence of different artificial extracellular matrix implant coatings on the regeneration of a critical size femur defect in rats. Mater Sci Eng C. 2020, 116:111157
  Förster Y, Schulze S, Penk A, Neuber C, Möller S, Hintze V, Scharnweber D, Schnabelrauch M, Pietzsch J, Huster D, Rammelt S
  
• Chemokine-capturing wound contact layer rescues dermal healing. Adv Sci. 2021, 2100293
  Schirmer L, Atallah P, Freudenberg U, Werner C
  
• Collagen/glycosaminoglycan-based matrices for controlling skin cell responses. Biol Chem. 2021
  Anderegg U, Halfter N, Schnabelrauch M, Hintze V
  
• Collagen/hyaluronan based hydrogels releasing sulfated hyaluronan improve dermal wound healing in diabetic mice via reducing inflammatory macrophage activity. Bioact Mat. 2021, 6:4342-4359
  Hauck S, Zager P, Halfter N, Wandel E, Torregrossa M, Kakpenova A, Rother S, Ordieres M, Räthel S, Berg A, Möller S, Schnabelrauch M, Simon JC, Hintze V, Franz S
  
• Immune responses to implants – a review of the mplications for the design of immunomodulatory biomaterials. Biomaterials. 2011, 32(28):6692-709
  Franz S, Rammelt S, Scharnweber D, Simon JC
  
• Injectable oligomer-cross-linked gelatine hydrogels via anhydride-amine-conjugation. J Mater Chem B. 2021, 9, 2295-2307
  Nawaz HA, Schröck K, Schmid M, Krieghoff J, Maqsood I, Kascholke C, Kohn-Polster C, Schulz-Siegmund M, Hacker MC
  
• Protease-triggered release of stabilized CXCL12 from coated 2 scaffolds in an ex vivo wound model. Pharmaceutics. 2021, 13, 1597
  Spiller S, Wippold T, Bellmann-Sickert K, Franz S, Saalbach A, Anderegg U, Beck-Sickinger AG
  
• Microtissues from mesenchymal stem cells and siRNA-loaded cross-linked gelatin microparticles for bone regeneration. Materials Today. Bio 13, 2022, S. 100190
  Hinkelmann, S., Springwald, A.H., Starke, A., Kalwa, H., Wölk, C., Hacker, M.C., Schulz-Siegmund, M.
  
• Overexpression of S100A9 in obesity impairs macrophage differentiation via TLR4-NFkB-signaling worsening inflammation and wound healing. Theranostics. 2022 12(4): 1659-1682
  Franz S, Ertel A, Engel KM, Simon JC, Saalbach A
  

Completed projects