Skip to main content
SpringerLink
Log in

Novel crosslinked alginate/hyaluronic acid hydrogels for nerve tissue engineering

  • Research Article
  • Published:
Frontiers of Materials Science Aims and scope Submit manuscript

Abstract

Artificial tissue engineering scaffolds can potentially provide support and guidance for the regrowth of severed axons following nerve injury. In this study, a hybrid biomaterial composed of alginate and hyaluronic acid (HA) was synthesized and characterized in terms of its suitability for covalent modification, biocompatibility for living Schwann cells and feasibility to construct three dimensional (3D) scaffolds. Carbodiimide mediated amide formation for the purpose of covalent crosslinking of the HA was carried out in the presence of calciumions that ionically crosslink alginate. Amide formation was found to be dependent on the concentrations of carbodiimide and calcium chloride. The double-crosslinked composite hydrogels display biocompatibility that is comparable to simple HA hydrogels, allowing for Schwann cell survival and growth. No significant difference was found between composite hydrogels made from different ratios of alginate and HA. A 3D BioPlotter™ rapid prototyping system was used to fabricate 3D scaffolds. The result indicated that combining HA with alginate facilitated the fabrication process and that 3D scaffolds with porous inner structure can be fabricated from the composite hydrogels, but not from HA alone. This information provides a basis for continuing in vitro and in vivo tests of the suitability of alginate/HA hydrogel as a biomaterial to create living cell scaffolds to support nerve regeneration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Causa F, Netti P A, Ambrosio L. A multi-functional scaffold for tissue regeneration: the need to engineer a tissue analogue. Biomaterials, 2007, 28(34): 5093–5099

    Article  CAS  Google Scholar 

  2. Hollister S J. Porous scaffold design for tissue engineering. Nature Materials, 2005, 4(7): 518–524

    Article  CAS  Google Scholar 

  3. Mondrinos M J, Dembzynski R, Lu L, et al. Porogen-based solid freeform fabrication of polycaprolactone-calcium phosphate scaffolds for tissue engineering. Biomaterials, 2006, 27(25): 4399–4408

    Article  CAS  Google Scholar 

  4. Malda J, Woodfield T B, van der Vloodt F, et al. The effect of PEGT/PBT scaffold architecture on the composition of tissue engineered cartilage. Biomaterials, 2005, 26(1): 63–72

    Article  CAS  Google Scholar 

  5. Burd D A R, Ritz M, Regauer S, et al. Hyaluronan and wound healing: a new perspective. British Journal of Plastic Surgery, 1991, 44(8): 579–584

    Article  CAS  Google Scholar 

  6. Ozgenel G Y. Effects of hyaluronic acid on peripheral nerve scarring and regeneration in rats. Microsurgery, 2003, 23(6): 575–581

    Article  Google Scholar 

  7. Lee H S, Kim J C. Effect of amniotic fluid in corneal sensitivity and nerve regeneration after excimer laser ablation. Cornea, 1996, 15(5): 517–524

    Article  CAS  Google Scholar 

  8. Ikeda K, Yamauchi D, Osamura N, et al. Hyaluronic acid prevents peripheral nerve adhesion. British Journal of Plastic Surgery, 2003, 56(4): 342–347

    Article  CAS  Google Scholar 

  9. Peattie R A, Nayate A P, Firpo M A, et al. Stimulation of in vivo angiogenesis by cytokine-loaded hyaluronic acid hydrogel implants. Biomaterials, 2004, 25(14): 2789–2798

    Article  CAS  Google Scholar 

  10. Khaing Z Z, Milman B D, Vanscoy J E, et al. High molecular weight hyaluronic acid limits astrocyte activation and scar formation after spinal cord injury. Journal of Neural Engineering, 2011, 8(4): 046033

    Article  Google Scholar 

  11. Struve J, Maher P C, Li Y Q, et al. Disruption of the hyaluronanbased extracellular matrix in spinal cord promotes astrocyte proliferation. Glia, 2005, 52(1): 16–24

    Article  Google Scholar 

  12. Bourguignon L Y W, Peyrollier K, Gilad E, et al. Hyaluronan-CD44 interaction with neural Wiskott-Aldrich syndrome protein (N-WASP) promotes actin polymerization and ErbB2 activation leading to β-catenin nuclear translocation, transcriptional upregulation, and cell migration in ovarian tumor cells. The Journal of Biological Chemistry, 2007, 282(2): 1265–1280

    Article  CAS  Google Scholar 

  13. Aruffo A, Stamenkovic I, Melnick M, et al. CD44 is the principal cell surface receptor for hyaluronate. Cell, 1990, 61(7): 1303–1313

    Article  CAS  Google Scholar 

  14. Entwistle J, Hall C L, Turley E A. HA receptors: regulators of signalling to the cytoskeleton. Journal of Cellular Biochemistry, 1996, 61(4): 569–577

    Article  CAS  Google Scholar 

  15. Hou S, Xu Q, Tian W, et al. The repair of brain lesion by implantation of hyaluronic acid hydrogels modified with laminin. Journal of Neuroscience Methods, 2005, 148(1): 60–70

    Article  CAS  Google Scholar 

  16. Tian W M, Hou S P, Ma J, et al. Hyaluronic acid-poly-D-lysine-based three-dimensional hydrogel for traumatic brain injury. Tissue Engineering, 2005, 11(3–4): 513–525

    Article  CAS  Google Scholar 

  17. Tian WM, Zhang C L, Hou S P, et al. Hyaluronic acid hydrogel as Nogo-66 receptor antibody delivery system for the repairing of injured rat brain: in vitro. Journal of Controlled Release, 2005, 102(1): 13–22

    Article  CAS  Google Scholar 

  18. Wei Y-T, He Y, Xu C-L, et al. Hyaluronic acid hydrogel modified with nogo-66 receptor antibody and poly-L-lysine to promote axon regrowth after spinal cord injury. Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2010, 95B(1): 110–117

    Article  CAS  Google Scholar 

  19. Perets A, Baruch Y, Weisbuch F, et al. Enhancing the vascularization of three-dimensional porous alginate scaffolds by incorporating controlled release basic fibroblast growth factor microspheres. Journal of Biomedical Materials Research Part A, 2003, 65A(4): 489–497

    Article  CAS  Google Scholar 

  20. Tobias C A, Dhoot N O, Wheatley M A, et al. Grafting of encapsulated BDNF-producing fibroblasts into the injured spinal cord without immune suppression in adult rats. Journal of Neurotrauma, 2001, 18(3): 287–301

    Article  CAS  Google Scholar 

  21. Suzuki K, Suzuki Y, Ohnishi K, et al. Regeneration of transected spinal cord in young adult rats using freeze-dried alginate gel. Neuroreport, 1999, 10(14): 2891–2894

    Article  CAS  Google Scholar 

  22. Suzuki Y, Kitaura M, Wu S, et al. Electrophysiological and horseradish peroxidase-tracing studies of nerve regeneration through alginate-filled gap in adult rat spinal cord. Neuroscience Letters, 2002, 318(3): 121–124

    Article  CAS  Google Scholar 

  23. Prang P, Muller R, Eljaouhari A, et al. The promotion of oriented axonal regrowth in the injured spinal cord by alginate-based anisotropic capillary hydrogels. Biomaterials, 2006, 27(19): 3560–3569

    CAS  Google Scholar 

  24. Khalil S, Nam J, Sun W. Multi-nozzle deposition for construction of 3D biopolymer tissue scaffolds. Rapid Prototyping Journal, 2005, 11(1): 9–17

    Article  Google Scholar 

  25. Haug A, Larsen B, Samuelsson B, et al. The solubility of alginate at low pH. Acta Chemica Scandinavica, 1963, 17(6): 1653–1662

    Article  CAS  Google Scholar 

  26. Nakajima N, Ikada Y. Mechanism of amide formation by carbodiimide for bioconjugation in aqueous media. Bioconjugate Chemistry, 1995, 6(1): 123–130

    Article  CAS  Google Scholar 

  27. Danishefsky I, Siskovic E. Conversion of carboxyl groups of mucopolysaccharides into amides of amino acid esters. Carbohydrate Research, 1971, 16(1): 199–205

    Article  CAS  Google Scholar 

  28. LeRoux M A, Guilak F, Setton L A. Compressive and shear properties of alginate gel: effects of sodium ions and alginate concentration. Journal of Biomedical Materials Research, 1999, 47(1): 46–53

    Article  CAS  Google Scholar 

  29. Rowley J A, Madlambayan G, Mooney D J. Alginate hydrogels as synthetic extracellular matrix materials. Biomaterials, 1999, 20(1): 45–53

    Article  CAS  Google Scholar 

  30. Pouyani T, Prestwich G D. Functionalized derivatives of hyaluronic acid oligosaccharides: drug carriers and novel biomaterials. Bioconjugate Chemistry, 1994, 5(4): 339–347

    Article  CAS  Google Scholar 

  31. Suri S, Schmidt C E. Cell-laden hydrogel constructs of hyaluronic acid, collagen, and laminin for neural tissue engineering. Tissue Engineering Part A, 2010, 16(5): 1703–1716

    Article  CAS  Google Scholar 

  32. Campbell W W. Evaluation and management of peripheral nerve injury. Clinical Neurophysiology, 2008, 119(9): 1951–1965

    Article  Google Scholar 

  33. Papastefanaki F, Chen J, Lavdas A A, et al. Grafts of Schwann cells engineered to express PSA-NCAM promote functional recovery after spinal cord injury. Brain, 2007, 130(8): 2159–2174

    Article  Google Scholar 

  34. Hill C E, Moon L D, Wood P M, et al. Labeled Schwann cell transplantation: cell loss, host Schwann cell replacement, and strategies to enhance survival. Glia, 2006, 53(3): 338–343

    Article  Google Scholar 

  35. Oudega M, Xu X M. Schwann cell transplantation for repair of the adult spinal cord. Journal of Neurotrauma, 2006, 23(3–4): 453–467

    Article  Google Scholar 

  36. Goto E, Mukozawa M, Mori H, et al. A rolled sheet of collagen gel with cultured Schwann cells: model of nerve conduit to enhance neurite growth. Journal of Bioscience and Bioengineering, 2010, 109(5): 512–518

    Article  CAS  Google Scholar 

  37. Deng L X, Hu J, Liu N, et al. GDNF modifies reactive astrogliosis allowing robust axonal regeneration through Schwann cell-seeded guidance channels after spinal cord injury. Experimental Neurology, 2011, 229(2): 238–250

    Article  CAS  Google Scholar 

  38. Sherman L, Skroch-Angel P, Moll J, et al. Schwann cell tumors express characteristic patterns of CD44 splice variants. Journal of Neuro-Oncology, 1995, 26(3): 171–184

    Article  CAS  Google Scholar 

  39. Maharjan A S, Pilling D, Gomer R H. High and low molecular weight hyaluronic acid differentially regulate human fibrocyte differentiation. PLoS ONE, 2011, 6(10): e26078–e26087

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Biomedical Engineering, University of Saskatchewan, 57 Campus Dr., Saskatoon, SK, S7N5A9, Canada

    Min-Dan Wang, Peng Zhai, David J. Schreyer & Xiong-Biao Chen

  2. Department of Anatomy and Cell Biology, University of Saskatchewan, 107 Wiggins Rd., Saskatoon, SK, S7N5E5, Canada

    David J. Schreyer

  3. School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, China

    Ruo-Shi Zheng, Xiao-Dan Sun & Fu-Zhai Cui

  4. Department of Mechanical Engineering, University of Saskatchewan, 57 Campus Dr., Saskatoon, SK, S7N5A9, Canada

    Xiong-Biao Chen

Authors
  1. Min-Dan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peng Zhai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David J. Schreyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ruo-Shi Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiao-Dan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fu-Zhai Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiong-Biao Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Min-Dan Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, MD., Zhai, P., Schreyer, D.J. et al. Novel crosslinked alginate/hyaluronic acid hydrogels for nerve tissue engineering. Front. Mater. Sci. 7, 269–284 (2013). https://doi.org/10.1007/s11706-013-0211-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11706-013-0211-y

Keywords

Search

Navigation