Skip to main content

Peptide Amphiphiles and Porous Biodegradable Scaffolds for Tissue Regeneration in the Brain and Spinal Cord

  • Protocol
  • First Online:
Biomedical Nanotechnology

Part of the book series: Methods in Molecular Biology ((MIMB,volume 726))

Abstract

Many promising strategies have been developed for controlling the release of drugs from scaffolds, yet there are still challenges that need to be addressed in order for these scaffolds to serve as successful treatments. The RADA4 self-assembling peptide spontaneously forms nanofibers, creating a scaffold-like tissue-bridging structure that provides a three-dimensional environment for the migration of living cells. We have found that RADA4: (1) facilitates the regeneration of axons in the brain of young and adult hamsters, leading to functional return of behavior and (2) demonstrates robust migration of host cells and growth of blood vessels and axons, leading to the repair of injured spinal cords in rats.

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

Access this chapter

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ellis-Behnke, R. G., Teather, L. A., Schneider, G. E., and So, K. F. (2007) Using nanotechnology to design potential therapies for CNS regeneration. Curr. Pharm. Des. 13, 2519–2528.

    Article  CAS  Google Scholar 

  2. Zhang, S., Holmes, T., Lockshin, C., and Rich, A. (1993) Spontaneous assembly of a self-complementary oligopeptide to form a stable macroscopic membrane. Proc. Natl Acad. Sci. USA 90, 3334–3338.

    Article  CAS  Google Scholar 

  3. Takenaga, M., Ohta, Y., Tokura, Y., Hamaguchi, A., Suzuki, N., Nakamura, M., et al. (2007) Plasma as a scaffold for regeneration of neural precursor cells after transplantation into rats with spinal cord injury. Cell Transplant. 16, 57–65.

    Google Scholar 

  4. Willerth, S. M. and Sakiyama-Elbert, S. E. (2008) Cell therapy for spinal cord regeneration. Adv. Drug Deliv. Rev. 60, 263–276.

    Article  CAS  Google Scholar 

  5. Langer, R. (1998) Drug delivery and targeting. Nature 392, 5–10.

    CAS  Google Scholar 

  6. Holmes, T. C., de Lacalle, S., Su, X., Liu, G., Rich, A., and Zhang, S. (2000) Extensive neurite outgrowth and active synapse formation on self-assembling peptide scaffolds. Proc. Natl Acad. Sci. USA 97, 6728–6733.

    Article  CAS  Google Scholar 

  7. Schmidt, C. E. and Leach, J. B. (2003) Neural tissue engineering: strategies for repair and regeneration. Annu. Rev. Biomed. Eng. 5, 293–347.

    Article  CAS  Google Scholar 

  8. Zhang, S., Holmes, T. C., DiPersio, C. M., Hynes, R. O., Su, X., and Rich, A. (1995) Self-complementary oligopeptide matrices support mammalian cell attachment. Biomaterials 16, 1385–1393.

    Article  Google Scholar 

  9. Kataoka, K., Suzuki, Y., Kitada, M., Hashimoto, T., Chou, H., Bai, H., et al. (2004) Alginate enhances elongation of early regenerating axons in spinal cord of young rats. Tissue Eng. 10, 493–504.

    Article  CAS  Google Scholar 

  10. Kataoka, K., Suzuki, Y., Kitada, M., Ohnishi, K., Suzuki, K., Tanihara, M., et al. (2001) Alginate, a bioresorbable material derived from brown seaweed, enhances elongation of amputated axons of spinal cord in infant rats. J. Biomed. Mater. Res. 54, 373–384.

    Article  CAS  Google Scholar 

  11. Prang, P., Muller, R., Eljaouhari, A., Heckmann, K., Kunz, W., Weber, T., et al. (2006) The promotion of oriented axonal regrowth in the injured spinal cord by alginate-based anisotropic capillary hydrogels. Biomaterials 27, 3560–3569.

    CAS  Google Scholar 

  12. Crompton, K. E., Goud, J. D., Bellamkonda, R. V., Gengenbach, T. R., Finkelstein, D. I., Horne, M. K., et al. (2007) Polylysine-functionalised thermoresponsive chitosan hydrogel for neural tissue engineering. Biomaterials 28, 441–449.

    Article  CAS  Google Scholar 

  13. Freier, T., Koh, H. S., Kazazian, K., and Shoichet, M. S. (2005) Controlling cell adhesion and degradation of chitosan films by N-acetylation. Biomaterials 26, 5872–5878.

    Article  CAS  Google Scholar 

  14. Freier, T., Montenegro, R., Shan Koh, H., and Shoichet, M. S. (2005) Chitin-based tubes for tissue engineering in the nervous system. Biomaterials 26, 4624–4632.

    Article  CAS  Google Scholar 

  15. Archibald, S. J., Krarup, C., Shefner, J., Li, S. T., and Madison, R. D. (1991) A collagen-based nerve guide conduit for peripheral nerve repair: an electrophysiological study of nerve regeneration in rodents and nonhuman primates. J. Comp. Neurol. 306, 685–696.

    Article  CAS  Google Scholar 

  16. Mahoney, M. J., Krewson, C., Miller, J., and Saltzman, W. M. (2006) Impact of cell type and density on nerve growth factor distribution and bioactivity in 3-dimensional collagen gel cultures. Tissue Eng. 12, 1915–1927.

    Article  CAS  Google Scholar 

  17. Herbert, C. B., Bittner, G. D., and Hubbell, J. A. (1996) Effects of fibinolysis on neurite growth from dorsal root ganglia cultured in two- and three-dimensional fibrin gels. J. Comp. Neurol. 365, 380–391.

    Article  CAS  Google Scholar 

  18. Sakiyama, S. E., Schense, J. C., and Hubbell, J. A. (1999) Incorporation of heparin-binding peptides into fibrin gels enhances neurite extension: an example of designer matrices in tissue engineering. FASEB J. 13, 2214–2224.

    CAS  Google Scholar 

  19. Sakiyama-Elbert, S. E. and Hubbell, J. A. (2000) Controlled release of nerve growth factor from a heparin-containing fibrin-based cell ingrowth matrix. J. Control. Release 69, 149–158.

    Article  CAS  Google Scholar 

  20. Sakiyama-Elbert, S. E. and Hubbell, J. A. (2000) Development of fibrin derivatives for controlled release of heparin-binding growth factors. J. Control. Release 65, 389–402.

    Article  CAS  Google Scholar 

  21. Taylor, S. J., McDonald III, J. W., and Sakiyama-Elbert, S. E. (2004) Controlled release of neurotrophin-3 from fibrin gels for spinal cord injury. J. Control. Release 98, 281–294.

    Article  CAS  Google Scholar 

  22. Taylor, S. J., Rosenzweig, E. S., McDonald III, J. W., and Sakiyama-Elbert, S. E. (2006) Delivery of neurotrophin-3 from fibrin enhances neuronal fiber sprouting after spinal cord injury. J. Control. Release 113, 226–235.

    Article  CAS  Google Scholar 

  23. Taylor, S. J. and Sakiyama-Elbert, S. E. (2006) Effect of controlled delivery of neurotrophin-3 from fibrin on spinal cord injury in a long term model. J. Control. Release 116, 204–210.

    Article  CAS  Google Scholar 

  24. Gupta, D., Tator, C. H., and Shoichet, M. S. (2006) Fast-gelling injectable blend of hyaluronan and methylcellulose for intrathecal, localized delivery to the injured spinal cord. Biomaterials 27, 2370–2379.

    Article  CAS  Google Scholar 

  25. Hahn, S. K., Jelacic, S., Maier, R. V., Stayton, P. S., and Hoffman, A. S. (2004) Anti-inflammatory drug delivery from hyaluronic acid hydrogels. J. Biomater. Sci. Polym. Ed. 15, 1111–1119.

    Article  CAS  Google Scholar 

  26. Tian, W. M., Hou, S. P., Ma, J., Zhang, C. L., Xu, Q. Y., Lee, I. S., et al. (2005) Hyaluronic acid-poly-d-lysine-based three-dimensional hydrogel for traumatic brain injury. Tissue Eng. 11, 513–525.

    Article  CAS  Google Scholar 

  27. Segura, T., Anderson, B. C., Chung, P. H., Webber, R. E., Shull, K. R., and Shea, L. D. (2005) Crosslinked hyaluronic acid hydrogels: a strategy to functionalize and pattern. Biomaterials 26, 359–371.

    Article  CAS  Google Scholar 

  28. Willerth, S. M. and Sakiyama-Elbert, S. E. (2007) Approaches to neural tissue engineering using scaffolds for drug delivery. Adv. Drug Deliv. Rev. 59, 325–338.

    Article  CAS  Google Scholar 

  29. Retrieved from HemCon Medical Technologies, Inc. on 1/20/2011: HemCon ­bandage FAQ/Shellfish allergy study at www.hemcon.com/Products/HemConBandageOverview.aspx.

  30. Ellis-Behnke, R. G., Liang, Y. X., Tay, D. K., Kau, P. W., Schneider, G. E., Zhang, S., et al. (2006) Nano hemostat solution: immediate hemostasis at the nanoscale. Nanomedicine 2, 207–215.

    Article  CAS  Google Scholar 

  31. Leach, J. B., Brown, X. Q., Jacot, J. G., Dimilla, P. A., and Wong, J. Y. (2007) Neurite outgrowth and branching of PC12 cells on very soft ­substrates sharply decreases below a threshold of substrate rigidity. J. Neural Eng. 4, 26–34.

    Article  Google Scholar 

  32. Guan, J., Stankus, J. J., and Wagner, W. R. (2006) Development of composite porous scaffolds based on collagen and biodegradable poly(ester urethane)urea. Cell Transpl. 15 Suppl. 1, S17–S27.

    Article  Google Scholar 

  33. Burdick, J. A., Ward, M., Liang, E., Young, M. J., and Langer, R. (2006) Stimulation of neurite outgrowth by neurotrophins delivered from degradable hydrogels. Biomaterials 27, 452–459.

    Article  CAS  Google Scholar 

  34. Krause, T. L. and Bittner, G. D. (1990) Rapid morphological fusion of severed myelinated axons by polyethylene glycol. Proc. Natl Acad. Sci. USA 87, 1471–1475.

    Article  CAS  Google Scholar 

  35. Mahoney, M. J. and Anseth, K. S. (2006) Three-dimensional growth and function of neural tissue in degradable polyethylene glycol hydrogels. Biomaterials 27, 2265–2274.

    Article  CAS  Google Scholar 

  36. Piantino, J., Burdick, J. A., Goldberg, D., Langer, R., and Benowitz, L. I. (2006) An injectable, biodegradable hydrogel for trophic factor delivery enhances axonal rewiring and improves performance after spinal cord injury. Exp. Neurol. 201, 359–367.

    Article  CAS  Google Scholar 

  37. Aubert-Pouessel, A., Venier-Julienne, M. C., Clavreul, A., Sergent, M., Jollivet, C., Montero-Menei, C. N., et al. (2004) In vitro study of GDNF release from biodegradable PLGA microspheres. J. Control. Release 95, 463–475.

    Article  CAS  Google Scholar 

  38. Kim, D. H. and Martin, D. C. (2006) Sustained release of dexamethasone from hydrophilic matrices using PLGA nanoparticles for neural drug delivery. Biomaterials 27, 3031–3037.

    Article  CAS  Google Scholar 

  39. Lam, X. M., Duenas, E. T., and Cleland, J. L. (2001) Encapsulation and stabilization of nerve growth factor into poly(lactic-co-glycolic) acid microspheres. J. Pharm. Sci. 90, 1356–1365.

    Article  CAS  Google Scholar 

  40. Patist, C. M., Mulder, M. B., Gautier, S. E., Maquet, V., Jerome, R., and Oudega, M. (2004) Freeze-dried poly(d,l-lactic acid) macroporous guidance scaffolds impregnated with brain-derived neurotrophic factor in the transected adult rat thoracic spinal cord. Biomaterials 25, 1569–1582.

    Article  CAS  Google Scholar 

  41. Teng, Y. D., Lavik, E. B., Qu, X., Park, K. I., Ourednik, J., Zurakowski, D., et al. (2002) Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc. Natl Acad. Sci. USA 99, 3024–3029.

    Article  CAS  Google Scholar 

  42. Belkas, J. S., Munro, C. A., Shoichet, M. S., Johnston, M., and Midha, R. (2005) Long-term in vivo biomechanical properties and biocompatibility of poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) nerve conduits. Biomaterials 26, 1741–1749.

    Article  CAS  Google Scholar 

  43. Carone, T. W. and Hasenwinkel, J. M. (2006) Mechanical and morphological characterization of homogeneous and bilayered poly(2-hydroxyethyl methacrylate) scaffolds for use in CNS nerve regeneration. J. Biomed. Mater. Res. B, Appl. Biomater. 78, 274–282.

    Google Scholar 

  44. Nomura, H., Katayama, Y., Shoichet, M. S., and Tator, C. H. (2006) Complete spinal cord transection treated by implantation of a reinforced synthetic hydrogel channel results in syringomyelia and caudal migration of the rostral stump. Neurosurgery 59, 183–192; discussion 183–192.

    Google Scholar 

  45. Tsai, E. C., Dalton, P. D., Shoichet, M. S., and Tator, C. H. (2004) Synthetic hydrogel guidance channels facilitate regeneration of adult rat brainstem motor axons after complete spinal cord transection. J. Neurotrauma 21, 789–804.

    Article  Google Scholar 

  46. Tsai, E. C., Dalton, P. D., Shoichet, M. S., and Tator, C. H. (2006) Matrix inclusion within synthetic hydrogel guidance channels improves specific supraspinal and local axonal regeneration after complete spinal cord transection. Biomaterials 27, 519–533.

    Article  CAS  Google Scholar 

  47. Newman, K. D. and McBurney, M. W. (2004) Poly(d,l lactic-co-glycolic acid) microspheres as biodegradable microcarriers for pluripotent stem cells. Biomaterials 25, 5763–5771.

    Article  CAS  Google Scholar 

  48. Lloyd, D. A., Ansari, T. I., Gundabolu, P., Shurey, S., Maquet, V., Sibbons, P. D., et al. (2006) A pilot study investigating a novel subcutaneously implanted pre-cellularised scaffold for tissue engineering of intestinal mucosa. Eur. Cell Mater. 11, 27–33; discussion 34.

    CAS  Google Scholar 

  49. Zhang, S. (2003) Fabrication of novel biomaterials through molecular self-assembly. Nat. Biotechnol. 21, 1171–1178.

    Article  CAS  Google Scholar 

  50. Zhang, S., Marini, D. M., Hwang, W., and Santoso, S. (2002) Design of nanostructured biological materials through self-assembly of peptides and proteins. Curr. Opin. Chem. Biol. 6, 865–871.

    Article  Google Scholar 

  51. Garreta, E., Genove, E., Borros, S., and Semino, C. E. (2006) Osteogenic differentiation of mouse embryonic stem cells and mouse embryonic fibroblasts in a three-dimensional self-assembling peptide scaffold. Tissue Eng. 12, 2215–2227.

    Article  CAS  Google Scholar 

  52. Zhang, S., Gelain, F., and Zhao, X. (2005) Designer self-assembling peptide nanofiber scaffolds for 3D tissue cell cultures. Semin. Cancer Biol. 15, 413–420.

    Article  Google Scholar 

  53. Holmes, T. C. (2002) Novel peptide-based biomaterial scaffolds for tissue engineering. Trends Biotechnol. 20, 16–21.

    Article  CAS  Google Scholar 

  54. Lupi, O., Madkan, V., and Tyring, S. K. (2006) Tropical dermatology: bacterial tropical diseases. J. Am. Acad. Dermatol. 54, 559–578.

    Article  Google Scholar 

  55. Ellis-Behnke, R. G., Liang, Y. X., You, S. W., Tay, D. K., Zhang, S., So, K. F., et al. (2006) Nano neuro knitting: peptide nanofiber scaffold for brain repair and axon regeneration with functional return of vision. Proc. Natl Acad. Sci. USA 103, 5054–5059.

    Article  CAS  Google Scholar 

  56. Davis, M. E., Hsieh, P. C., Takahashi, T., Song, Q., Zhang, S., Kamm, R. D., et al. (2006) Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction. Proc. Natl Acad. Sci. USA 103, 8155–8160.

    Article  CAS  Google Scholar 

  57. Guo, J., Su, H., Zeng, Y., Liang, Y. X., Wong, W. M., Ellis-Behnke, R. G., et al. (2007) Reknitting the injured spinal cord by self-assembling peptide nanofiber scaffold. Nanomedicine 3, 311–321.

    Article  CAS  Google Scholar 

  58. Schneider, G. E., Ellis-Behnke, R. G., Liang, Y. X., Kau, P. W., Tay, D. K., and So, K. F. (2006) Behavioral testing and preliminary analysis of the hamster visual system. Nat. Protoc. 1, 1898–1905.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge Dr. David K. C. Tay in the Department of Anatomy at the University of Hong Kong Faculty of Medicine for reviewing the chapter and for taking pictures.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rutledge G. Ellis-Behnke .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Ellis-Behnke, R.G., Schneider, G.E. (2011). Peptide Amphiphiles and Porous Biodegradable Scaffolds for Tissue Regeneration in the Brain and Spinal Cord. In: Hurst, S. (eds) Biomedical Nanotechnology. Methods in Molecular Biology, vol 726. Humana Press. https://doi.org/10.1007/978-1-61779-052-2_17

Download citation

  • DOI: https://doi.org/10.1007/978-1-61779-052-2_17

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-61779-051-5

  • Online ISBN: 978-1-61779-052-2

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics