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Glycosaminoglycan derivatives: promising candidates for the design of functional biomaterials

  • Special Issue: ESB 2015
  • Tissue engineering constructs and cell substrates
  • Published:
Journal of Materials Science: Materials in Medicine Aims and scope Submit manuscript

Abstract

Numerous biological processes (tissue formation, remodelling and healing) are strongly influenced by the cellular microenvironment. Glycosaminoglycans (GAGs) are important components of the native extracellular matrix (ECM) able to interact with biological mediator proteins. They can be chemically functionalized and thereby modified in their interaction profiles. Thus, they are promising candidates for functional biomaterials to control healing processes in particular in health-compromised patients. Biophysical studies show that the interaction profiles between mediator proteins and GAGs are strongly influenced by (i) sulphation degree, (ii) sulphation pattern, and (iii) composition and structure of the carbohydrate backbone. Hyaluronan derivatives demonstrate a higher binding strength in their interaction with biological mediators than chondroitin sulphate for a comparable sulphation degree. Furthermore sulphated GAG derivatives alter the interaction profile of mediator proteins with their cell receptors or solute native interaction partners. These results are in line with biological effects on cells relevant for wound healing processes. This is valid for solute GAGs as well as those incorporated in collagen-based artificial ECM (aECMs). Prominent effects are (i) anti-inflammatory, immunomodulatory properties towards macrophages/dendritic cells, (ii) enhanced osteogenic differentiation of human mesenchymal stromal cells, (iii) altered differentiation of fibroblasts to myofibroblasts, (iv) reduced osteoclast activity and (v) improved osseointegration of dental implants in minipigs. The findings of our consortium Transregio 67 contribute to an improved understanding of structure–function relationships of GAG derivatives in their interaction with mediator proteins and cells. This will enable the design of bioinspired, functional biomaterials to selectively control and promote bone and skin regeneration.

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References

  1. Lienemann PS, Lutolf MP, Ehrbar M. Biomimetic hydrogels for controlled biomolecule delivery to augment bone regeneration. Adv Drug Deliv Rev. 2012;64(12):1078–89. doi:10.1016/j.addr.2012.03.010.

    Article  Google Scholar 

  2. Frantz C, Stewart KM, Weaver VM. The extracellular matrix at a glance. J Cell Sci. 2010;123(24):4195–200.

    Article  Google Scholar 

  3. Salbach J, Rachner TD, Rauner M, Hempel U, Anderegg U, Franz S, et al. Regenerative potential of glycosaminoglycans for skin and bone. J Mol Med. 2012;90(6):625–35.

    Article  Google Scholar 

  4. Gama CI, Hsieh-Wilson LC. Chemical approaches to deciphering the glycosaminoglycan code. Curr Opin Chem Biol. 2005;9(6):609–19.

    Article  Google Scholar 

  5. Merceron C, Portron S, Vignes-Colombeix C, Rederstorff E, Masson M, Lesoeur J, et al. Pharmacological modulation of human mesenchymal stem cell chondrogenesis by a chemically oversulfated polysaccharide of marine origin: potential application to cartilage regenerative medicine. Stem Cells. 2012;30(3):471–80.

    Article  Google Scholar 

  6. Pichert A, Schlorke D, Franz S, Arnhold J. Functional aspects of the interaction between interleukin-8 and sulfated glycosaminoglycans. Biomatter. 2012;2(3):142–8.

    Article  Google Scholar 

  7. Lutolf MP, Blau HM. Artificial stem cell niches. Adv Mater. 2009;21(32–33):3255–68. doi:10.1002/adma.200802582.

    Article  Google Scholar 

  8. Kliemt S, Lange C, Otto W, Hintze V, Möller S, von Bergen M, et al. Sulfated hyaluronan containing collagen matrices enhance cell-matrix-interaction, endocytosis, and osteogenic differentiation of human mesenchymal stromal cells. J Proteome Res. 2013;12(1):378–89. doi:10.1021/pr300640h.

    Article  Google Scholar 

  9. Hintze V, Samsonov SA, Anselmi M, Moeller S, Becher J, Schnabelrauch M, et al. 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. doi:10.1021/bm5006855.

    Article  Google Scholar 

  10. Schulz M, Korn P, Stadlinger B, Range U, Möller S, Becher J, et al. Coating with artificial matrices from collagen and sulfated hyaluronan influences the osseointegration of dental implants. J Mater Sci Mater Med. 2014;25(1):247–58. doi:10.1007/s10856-013-5066-3.

    Article  Google Scholar 

  11. Salbach-Hirsch J, Kraemer J, Rauner M, Samsonov S, Pisabarro MT, Moeller S, et al. 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.

    Article  Google Scholar 

  12. Schiller J, Becher J, Möller S, Nimptsch K, Riemer T, Schnabelrauch M. Synthesis and characterization of chemically modified hyaluronan and chondroitin sulfate. Mini-Rev Org Chem. 2010;7(4):290–9.

    Article  Google Scholar 

  13. Hintze V, Miron A, Moeller S, Schnabelrauch M, Wiesmann HP, Worch H, et al. Sulfated hyaluronan and chondroitin sulfate derivatives interact differently with human transforming growth factor-beta 1 (TGF-beta 1). Acta Biomater. 2012;8(6):2144–52.

    Article  Google Scholar 

  14. Hintze V, Moeller S, Schnabelrauch M, Bierbaum S, Viola M, Worch H, et al. Modifications of hyaluronan influence the interaction with human bone morphogenetic protein-4 (hBMP-4). Biomacromolecules. 2009;10(12):3290–7.

    Article  Google Scholar 

  15. Kunze R, Rösler M, Möller S, Schnabelrauch M, Riemer T, Hempel U, et al. Sulfated hyaluronan derivatives reduce the proliferation rate of primary rat calvarial osteoblasts. Glycoconj J. 2010;27(1):151–8.

    Article  Google Scholar 

  16. van der Smissen A, Hintze V, Scharnweber D, Moeller S, Schnabelrauch M, Majok A, et al. 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.

    Article  Google Scholar 

  17. Becher J, Möller S, Weiss D, Schiller J, Schnabelrauch M, editors. Synthesis of new regioselectively sulfated hyaluronans for biomedical application. Macromolecular symposia; 2010, Wiley Online Library.

  18. Hempel U, Preissler C, Vogel S, Möller S, Hintze V, Becher J, et al. Artificial extracellular matrices with oversulfated glycosaminoglycan derivatives promote the differentiation of osteoblast-precursor cells and premature osteoblasts. Biomed Res Int. 2014. doi:10.1155/2014/934848.

    Google Scholar 

  19. Hempel U, Hintze V, Moller S, Schnabelrauch M, Scharnweber D, Dieter P. Artificial extracellular matrices composed of collagen I and sulfated hyaluronan with adsorbed transforming growth factor beta 1 promote collagen synthesis of human mesenchymal stromal cells. Acta Biomater. 2012;8(2):659–66. doi:10.1016/j.actbio.2011.10.026.

    Article  Google Scholar 

  20. Hempel U, Moller S, Noack C, Hintze V, Scharnweber D, Schnabelrauch M, et al. Sulfated hyaluronan/collagen I matrices enhance the osteogenic differentiation of human mesenchymal stromal cells in vitro even in the absence of dexamethasone. Acta Biomater. 2012;8(11):4064–72.

    Article  Google Scholar 

  21. Miron A, Rother S, Huebner L, Hempel U, Käppler I, Moeller S, et al. Sulfated hyaluronan influences the formation of artificial extracellular matrices and the adhesion of osteogenic cells. Macromol Biosci. 2014;14(12):1783–94.

    Article  Google Scholar 

  22. Ruppert R, Hoffmann E, Sebald W. Human bone morphogenetic protein 2 contains a heparin-binding site which modifies its biological activity. Eur J Biochem. 1996;237(1):295–302.

    Article  Google Scholar 

  23. Lyon M, Rushton G, Gallagher JT. The interaction of the transforming growth factor-βs with heparin/heparan sulfate is isoform-specific. J Biol Chem. 1997;272(29):18000–6.

    Article  Google Scholar 

  24. Takada T, Katagiri T, Ifuku M, Morimura N, Kobayashi M, Hasegawa K, et al. Sulfated polysaccharides enhance the biological activities of bone morphogenetic proteins. J Biol Chem. 2003;278(44):43229–35.

    Article  Google Scholar 

  25. Zhao B, Katagiri T, Toyoda H, Takada T, Yanai T, Fukuda T, et al. Heparin potentiates the in vivo ectopic bone formation induced by bone morphogenetic protein-2. J Biol Chem. 2006;281(32):23246–53.

    Article  Google Scholar 

  26. Miyazaki T, Miyauchi S, Tawada A, Anada T, Matsuzaka S, Suzuki O. Oversulfated chondroitin sulfate-E binds to BMP-4 and enhances osteoblast differentiation. J Cell Physiol. 2008;217(3):769–77.

    Article  Google Scholar 

  27. Kanzaki S, Takahashi T, Kanno T, Ariyoshi W, Shinmyouzu K, Tujisawa T, et al. Heparin inhibits BMP-2 osteogenic bioactivity by binding to both BMP-2 and BMP receptor. J Cell Physiol. 2008;216(3):844–50.

    Article  Google Scholar 

  28. Salbach J, Kliemt S, Rauner M, Rachner TD, Goettsch C, Kalkhof S, et al. The effect of the degree of sulfation of glycosaminoglycans on osteoclast function and signaling pathways. Biomaterials. 2012;33(33):8418–29.

    Article  Google Scholar 

  29. Salbach-Hirsch J, Ziegler N, Thiele S, Moeller S, Schnabelrauch M, Hintze V, et al. Sulfated glycosaminoglycans support osteoblast functions and concurrently suppress osteoclasts. J Cell Biochem. 2014;115(6):1101–11.

    Article  Google Scholar 

  30. Franz S, Rammelt S, Scharnweber D, Simon J. Immune responses to implants—a review of the implications for the design of immunomodulatory biomaterials. Biomaterials. 2011;32(28):6692–709.

    Article  Google Scholar 

  31. Acharya AP, Dolgova NV, Clare-Salzler MJ, Keselowsky BG. Adhesive substrate-modulation of adaptive immune responses. Biomaterials. 2008;29(36):4736–50.

    Article  Google Scholar 

  32. Lutz MB, Schuler G. Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity? Trends Immunol. 2002;23(9):445–9.

    Article  Google Scholar 

  33. Rutella S, Danese S, Leone G. Tolerogenic dendritic cells: cytokine modulation comes of age. Blood. 2006;108(5):1435–40.

    Article  Google Scholar 

  34. Kajahn J, Franz S, Rueckert E, Forstreuter I, Hintze V, Moeller S, et al. Artificial extracellular matrices composed of collagen I and high sulfated hyaluronan modulate monocyte to macrophage differentiation under conditions of sterile inflammation. Biomatter. 2012;2(4):226–73.

    Article  Google Scholar 

  35. Franz S, Allenstein F, Kajahn J, Forstreuter I, Hintze V, Möller S, et al. 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.

    Article  Google Scholar 

  36. Hess R, Jaeschke A, Neubert H, Hintze V, Moeller S, Schnabelrauch M, et al. Synergistic effect of defined artificial extracellular matrices and pulsed electric fields on osteogenic differentiation of human MSCs. Biomaterials. 2012;33(35):8975–85.

    Article  Google Scholar 

  37. Wojak-Cwik IM, Hintze V, Schnabelrauch M, Moeller S, Dobrzynski P, Pamula E, et al. Poly(L-lactide-co-glycolide) scaffolds coated with collagen and glycosaminoglycans: impact on proliferation and osteogenic differentiation of human mesenchymal stem cells. J Biomed Mater Res, Part A. 2013;101(11):3109–22. doi:10.1002/jbm.a.34620.

    Google Scholar 

  38. van der Smissen A, Samsonov S, Hintze V, Scharnweber D, Moeller S, Schnabelrauch M, et al. Artificial extracellular matrix composed of collagen I and highly sulfated hyaluronan interferes with TGFβ 1 signaling and prevents TGFβ 1-induced myofibroblast differentiation. Acta Biomater. 2013;9(8):7775–86.

    Article  Google Scholar 

  39. Abe M, Harpel J, Metz C, Nunes I, Loskutoff D, Rifkin D. An assay for transforming growth factor-β using cells transfected with a plasminogen activator inhibitor-1 promoter-luciferase construct. Anal Biochem. 1994;216(2):276–84.

    Article  Google Scholar 

  40. Heldin C-H, Miyazono K, Ten Dijke P. TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997;390(6659):465–71.

    Article  Google Scholar 

  41. Korn P, Schulz M, Hintze V, Range U, Mai R, Eckelt U, et al. 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.

    Article  Google Scholar 

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Acknowledgments

The authors would like to thank the DFG Grant TRR67, (A2, A3, A7, B1, B2, B3, B4, Z3) for providing financial support to this Project.

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Authors and Affiliations

  1. Max Bergmann Center of Biomaterials, Institute of Materials Science, TU Dresden, Dresden, Germany

    Dieter Scharnweber, Linda Hübner, Sandra Rother & Vera Hintze

  2. Medical Department, Institute of Physiological Chemistry, TU Dresden, Dresden, Germany

    Ute Hempel

  3. Department of Dermatology, Venerology and Allergology, Leipzig University, Leipzig, Germany

    Ulf Anderegg, Sandra Franz & Jan Simon

  4. Structural Bioinformatics, BIOTEC, TU Dresden, Dresden, Germany

    Sergey A. Samsonov & M. Teresa Pisabarro

  5. Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III, TU Dresden Medical Center, Dresden, Germany

    Lorenz Hofbauer

  6. Biomaterials Department, INNOVENT e.V., Jena, Germany

    Matthias Schnabelrauch

Authors
  1. Dieter Scharnweber
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  2. Linda Hübner
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  4. Ute Hempel
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  7. M. Teresa Pisabarro
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  9. Matthias Schnabelrauch
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  10. Sandra Franz
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Corresponding author

Correspondence to Dieter Scharnweber.

Additional information

All Transregio 67 (www.trr67.de), Germany.

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Scharnweber, D., Hübner, L., Rother, S. et al. Glycosaminoglycan derivatives: promising candidates for the design of functional biomaterials. J Mater Sci: Mater Med 26, 232 (2015). https://doi.org/10.1007/s10856-015-5563-7

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  • DOI: https://doi.org/10.1007/s10856-015-5563-7

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