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Development and characterization of artificial extracellular matrices based on collagen and glycosaminoglycan (GAG)-derivatives

PD Dr. rer. nat. Vera Hintze, Linda Köhler (geb. Hübner), Dr. Sandra Rother

The demographical development with an increasing number of elderly, multimorbid patients has led to an accretive need for novel, functional biomaterials actively supporting tissue regeneration. The overall aim of this project A3 is to develop and characterize tissue-specific two- and three-dimensional artificial extracellular matrices (aECM). These aECM represent defined adjustable microenvironments to control cellular functions in bone and skin cells, e.g. by influencing mediator proteins (growth factors, interleukins) present during wound healing in vivo. Another focus of this project is to elucidate the structure-function relationship of glycosaminoglycan (GAG) derivatives in their interaction with mediator proteins relevant to healing processes. Biochemical and biophysical interaction analyses (e.g. surface plasmon resonance (SPR)) significantly contribute to an improved understanding of the molecular mechanisms by which GAG derivatives influence healing processes. Ultimately aECM with defined activity profiles should be available in particular for elderly, health-compromised patients.

Fig. 1: SPR interaction analysis of GAG with TIMP-3 (tissue inhibitor of metalloprotease-3) and biological consequences of this interplay on the TIMP-3 activity (upper panel). Influence of GAG on the morphology of collagen fibrils and effects of aECM on cells relevant for wound healing (here: keratinocytes) (lower panel).


Project-related Publications

  1. Rother S, Galiazzo V, Kilian D, Fiebig KM, Becher J, Moeller S, Schnabelrauch M, Waltenberger J, Hintze V and Scharnweber D. Hyaluronan/collagen hydrogels with sulfated hyaluronan for improved repair of vascularized tissue tune the binding of proteins and promote endothelial cell growth. Macromolecular Bioscience, 2017; accepeted.
  2. Bhowmick S, Rother S, Zimmermann H, Lee PS, Moeller S, Schnabelrauch M, Koul V, Jordan R, Hintze V, Scharnweber D. Biomimetic electrospun scaffolds from main extracellular matrix components for skin tissue engineering application - The role of chondroitin sulfate and sulfated hyaluronan. Mater Sci Eng C Mater Biol Appl. 2017; 79:15-22.
  3. Koehler L, Samsonov S, Rother S, Vogel S, Köhling S, Moeller S, Schnabelrauch M, Rademann J, Hempel U, Pisabarro MT, Scharnweber D, Hintze V. Sulfated Hyaluronan Derivatives Modulate TGF-ß1:Receptor Complex Formation: Possible Consequences for TGF-ß1 Signaling. Sci Rep. 2017; 7(1):1210.
  4. Rother S, Samsonov SA, Moeller S, Schnabelrauch M, Rademann J, Blaszkiewicz J, Köhling S, Waltenberger J, Pisabarro MT, Scharnweber D, Hintze V. 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.
  5. Metzger W, Rother S, Pohlemann T, Möller S, Schnabelrauch M, Hintze V, Scharnweber D. Evaluation of cell-surface interaction using a 3D spheroid cell culture model on artificial extracellular matrices. Mater Sci Eng C Mater Biol Appl. 2017; 73:310-318.
  6. Förster Y, Bernhardt R, Hintze V, Möller S, Schnabelrauch M, Scharnweber D, Rammelt S. Collagen/glycosaminoglycan coatings enhance new bone formation in a critical size bone defect - A pilot study in rats. Mater Sci Eng C Mater Biol Appl. 2017; 71:84-92.
  7. Rother S, Samsonov SA, Hofmann T, Blaszkiewicz J, Köhling S, Moeller S, Schnabelrauch M, Rademann J, Kalkhof S, von Bergen M, Pisabarro MT, Scharnweber D, Hintze V. Structural and functional insights into the interaction of sulfated glycosaminoglycans with tissue inhibitor of metalloproteinase-3 – a possible regulatory role on extracellular matrix homeostasis. Acta Biomater. 2016;45:143-154.
  8. Rother S, Samsonov SA, Hempel U, Vogel S, Moeller S, Blaszkiewicz J, Köhling S, Schnabelrauch M, Rademann J, Pisabarro MT, Hintze V, Scharnweber D. Sulfated hyaluronan alters the interaction profile of TIMP-3 with the endocytic receptor LRP-1 cluster II and IV and increas-es the extracellular TIMP-3 level of human bone marrow stromal cells. Biomacromolecules. 2016;17:3252-61.
  9. 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 regenera-tion of diabetic rats by binding sclerostin and enhancing osteoblast function. Biomaterials. 2016;96:11-23.
  10. 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. Structural and func-tional insights into sclerostin-glycosaminoglycan interactions in bone. Biomaterials. 2015;67:335-45.
  11. Rother S, Salbach-Hirsch J, Moeller S, Seemann T, Schnabelrauch M, Hofbauer LC, Hintze V, Scharnweber D. Bioinspired collagen/glycosaminoglycan-based cellular microenvironments for tuning osteoclastogenesis. ACS Appl Mater Interfaces. 2015;7:23787-97.
  12. Miron A, Rother S, Huebner L, Hempel U, Käppler I, Moeller I, Schnabelrauch M, Scharnweber D ,Hintze V. Sulfated Hyaluronan Influences the Formation of Artificial Extracellular Matrices and the Adhesion of Osteogenic Cells. Macromolecular Bioscience, 2014;14:1783-94.
  13. Hintze V, Samsonov SA, Anselmi M, Moeller S, Becher J, Schnabelrauch M, Scharnweber D, Pisabarro MT. 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): 3083-92.
  14. Hempel U, Preissler C, Vogel S, Möller S, Hintze V, Becher J, Schnabelrauch M, Rauner M, Hofbauer LC, Dieter P. Artificial Extracellular Matrices with Oversulfated Glycosaminoglycan Derivatives Promote the Differentiation of Osteoblast-Precursor Cells and Premature Osteoblasts. BioMed Research International 2014, DOI 10.1155/2014/93;8368.
  15. Hempel U, Matthäus C, Preissler C, Möller S, Hintze V, Dieter P., Artificial matrices with high-sulfated glycosaminoglycans and collagen are anti-inflammatory and pro-osteogenic for human mesenchymal stromal cells. J Cell Biochem. 2014; 115 (9): 1561-71.
  16. Salbach-Hirsch J, Ziegler N, Thiele S, Moeller S, Schnabelrauch M, Hintze V, Scharnweber D, Rauner M, Hofbauer LC. Sulfated Glycosaminoglycans Support Osteoblast Functions and Concurrently Suppress Osteoclasts. J Cell Biochem. 2014; 115 (6): 1101-11.
  17. Förster Y, Hintze V, Rentsch C, Rentsch B, Bierbaum S, Wiesmann HP, Scharnweber D, Worch H,Rammelt S. Surface functionalization of biomaterials with tissue-inductive artificial extracellular matrices. BioNanoMat 2013; 14 (3-4): 143–152.
  18. De Barros RRM, Novaes AB, Korn P, Queiroz A, de Almeida ALG, Hintze V, Scharnweber D, Bierbaum S, Stadlinger. Bone formation in a local defect around dental implants coated with extracellular matrix components. Clin Implant Dent Relat Res 2013, DOI: 10.1111/cid.12179.
  19. Schulz MC, Korn P,  Stadlinger B, Range U, Moeller S, Becher J, Schnabelrauch M, Mai, R, Scharnweber D, Eckelt U, Hintze V. Coating with artificial matrices from collagen and sulfated hyaluronan influences the osseointegration of dental implants. J Mater Sci Mater Med. 2014; 25 (1): 247-258.
  20. Korn P, Schulz MC, Hintze V, Range U, Mai R, Eckelt U, Schnabelrauch M, Möller S, Becher J, Scharnweber D, Stadlinger B. Chondroitin sulfate and sulfated hyaluronan containing collagen coatings of titanium implants influence peri-implant bone formation in a minipig model. J Biomed Mater Res A. 2014; 102 (7): 2334-44.
  21. Salbach-Hirsch J, Kraemer J, Rauner M, Samsonov SA, Pisabarro MT, Moeller S, Schnabelrauch M, Scharnweber D, Hofbauer LCHintze V
  22. The promotion of osteoclastogenesis by sulfated hyaluronan through interference with osteoprotegerin and receptor activator of NF-?B ligand/osteoprotegerin complex formation. Biomaterials 2013, 34:7653-7661.
  23. van der Smissen A, Samsonov S, Hintze V, Scharnweber D, Moeller S, Schnabelrauch M, Pisabarro MT, Anderegg U. Artificial extracellular matrix composed of collagen I and highly sulfated hyaluronan interferes with TGF?(1) signaling and prevents TGF?(1)-induced myofibroblast differentiation. Acta Biomater. 2013, 9: 7775–7786.
  24. Wojak-Cwik IM, Hintze V, Schnabelrauch M, Moeller S, Dobrzynski P, Pamula E, Scharnweber D. Poly(L-lactide-co-glycolide) scaffolds coated with collagen and glycosaminoglycans: mpact on proliferation and osteogenic differentiation of human mesenchymal stem cells. J Biomedical Mater Res A. 2013, 101(11):3109-22.
  25. Hess R, Jeschnke A, Neubert H, Hintze V, Moeller S, Schnabelrauch M, Wiesmann HP, Hart DA, Scharnweber D. Synergistic effect of defined artificial extracellular matrices and pulsed electric fields on osteogenic differentiation of human MSCs. Biomaterials. 2012;33:8975-85.
  26. Bierbaum S, Hintze V, Scharnweber D. Functionalization of biomaterials surfaces using artificial extracellular matrices. Biomatter. 2012;2:132-41.
  27. Hempel U, Möller S, Noack C, Hintze V, Scharnweber S, Schnabelrauch M, Dieter P. Sulfated hyaluronan/collagen I-matrices enhance osteogenic differentiation of human mesenchymal stromal cells in vitro even in the absence of dexamethasone. Acta Biomater. 2012;8:4064-72.
  28. Hintze V, Miron A, Möller S, Schnabelrauch M, Heinemann S, Worch H, Scharnweber D. Artificial extracellular matrices of collagen and sulfated hyaluronan enhance the differentiation of human mesenchymal stem cells in the presence of dexamethasone. J Tissue Eng Regen Med. 2012;doi 10.1k02/term.1528.
  29. Hempel U, Hintze V, Möller S, Schnabelrauch M, Scharnweber D, Dieter P. Artifical extracellular matrices composed of collagenI and sulfated hyaluronan with adsorbed transforming growth factor ?-1 promote collagen synthesis of human mesenchymal stromal cells. Acta Biomater. 2012;8:659-66.
  30. Becher J, Möller S, Riemer T, Schiller J, Hintze V, Bierbaum S, Scharnweber D, Worch H, Schnabelrauch M. Sulfated glycosaminoglycan building blocks for the design of artificial extracellular matrices. Book chapter in: ACS Symposium Series. 2012;1107:315-28.
  31. Bierbaum S, Hintze V, Scharnweber D. Functionalization of biomaterials surfaces using artificial extracellular matrices. Biomatter. 2012;2:132-41.
  32. Stadlinger B, Hintze V, Bierbaum S, Möller S, Schulz MC, Maia R, Heinemann S, Scharnweber D, Schnabelrauch M, Eckelt U. Biological functionalization of dental implants with collagen and glycosaminoglycans – a comparative study. J Biomed Mater Res B Appl Biomater. 2012;100:331-41.
  33. Franz S, Forstreuter I, Hintze V, Möller S, Scharnweber D, Schnabelrauch M, Simon JC. Immunomodulatory effects on dendritic cells of biomaterial coatings based on artificial extracellular matrices (aECM). Experimental Dermatology. 2011;20:182.
  34. van der Smissen A, Hintze V, Scharnweber D, Moeller S, Schnabelrauch M, Majok A, Simon JC, Anderegg U. Growth promoting substrates for human dermal fibroblasts provided by artifical extracellular matrices composed of collagen I and sulfated glycosaminoglycans. Biomaterials. 2011;32:8938-46.
  35. Campbell GM, Bernhardt R, Scharnweber D, Boyd SK. The bone architecture is enhanced with combined PTH and alendronate treatment compared to monotherapy while maintaining the state of surface mineralization in the OVX rat. Bone. 2011;49:225-32.   
  36. Franz S, Rammelt S, Scharnweber D, Simon JC. Immune responses to implants - A review of the implications for the design of immunomodulatory biomaterials. Biomaterials. 2011;32:6692-709.
  37. Hintze V, Moeller S, Schnabelrauch M, Bierbaum S, Viola M, Worch H, Scharnweber D. Modifications of Hyaluronan Influence the Interaction with Human Bone Morphogenetic Protein-4 (hBMP-4). Biomacromolecules. 2009;10:3290-3297.
  38. Wojak I, Pamula E, Dobrzynski P, Zimmermann H, Worch H, Scharnweber D, Hintze V. Coating of poly(L-actide-co-glycolide) scaffolds with collagen /glycosaminoglycan matrices and their effect on osteoblast behaviour. Engineering of Biomaterials. 2009;86:9-13.
  39. Stadlinger B, Pilling E, Huhle M, Mai R, Bierbaum S, Scharnweber D, Kuhlisch E, Loukota R, Eckelt U. Evaluation of osseointegration of dental implants coated with collagen, chondroitin sulphate and BMP-4: an animal study. Int J Oral Maxillofac Surg. 2008;37:54-9.
  40. Douglas T, Hempel U, Mietrach C, Viola M, Vigetti D, Heinemann S, Bierbaum S, Scharnweber D, Worch H. Influence of collagen-fibril-based coatings containing decorin and biglycan on osteoblast behavior. J Biomed Mater Res A 2008;84:805-16.
  41. Stadlinger B, Pilling E, Mai R, Bierbaum S, Berhardt R, Scharnweber D, Eckelt U. Effect of biological implant surface coatings on bone formation, applying collagen, proteoglycans, glycosaminoglycans and growth factors. J Mater Sci Mater Med. 2008;19:1043-9.
  42. Douglas T, Heinemann S, Mietrach C, Hempel U, Bierbaum S, Scharnweber D, Worch H. Interactions of Collagen Types I and II with Chondroitin Sulfates A-C and Their Effect on Osteoblast Adhesion. Biomacromolecules 2007;8:1085-92.
  43. Bierbaum S, Douglas T, Hanke T, Scharnweber D, Tippelt S, Monsees TK, Funk RH, Worch H. Collageneous matrix coatings on titanium implants modified with decorin and chondroitin sulfate: characterization and influence on osteoblastic cells. J Biomed Mater Res A. 2006;77:551-62.
  44. Bierbaum S, Beutner R, Hanke T, Scharnweber D, Hempel U, Worch H. Modification of Ti6Al4V surfaces using collagen I, III and fibronectin. I. Biochemical and morphological characteristics of the adsorbed matrix. J Biomed Mater Res A. 2003;67:421-30.