Advertisement

Tissue Engineered Nerve Conduits: The Use of Biodegradable Poly-DL-lactic-co-glycolic Acid (PLGA) Scaffolds in Peripheral Nerve Regeneration

  • G. R. D. Evans
  • K. Brandt
  • M. Widmer
  • A. Gürlek
  • T. Savel
  • P. Gupta
  • R. Lohman
  • J. Williams
  • J. Hodges
  • A. Nabawi
  • C. Patrick
  • A. Mikos

Abstract

Introducion. Tissue engineering holds great promise for nerve replacement and restoration. The present study evaluated the efficacy of utilizing poly-DL-lactic-co-glycolic acid (PLGA) formed tubes through an extrusion process for peripheral nerve regeneration.

Material and Methods. Conduits were manufactured by dissolving 75:25 PLGA in methylene chloride, and salt crystals (150 and 300 µm) were added to the polymer solution. The formed suspension was allowed to evaporate, and the resulting PLGA/salt composite disks were cut, placed into a piston extrusion tool, and heated to 250 °C. After heating, the PLGA/salt composite was extruded to form a tube with an inner diameter of 1.6 mm and an outer diameter of 3.2 mm. Twenty Sprague Dawley (250 g) rats were anesthetized and had the 12-mm PLGA conduits interposed into the right sciatic nerve using 10-0 nylon sutures under microsurgical technique. Functional evaluation was performed monthly by walking track analysis. At 16 and 12 weeks, electrical conduction was performed and sections of the proximal, grafted, and distal nerve were harvested for histomorphometric analysis.

Results. All conduits remained flexible, allowing mobility of the rat extremity without breakage. No severe inflammatory reaction could be identified, and no neuromas were apparent clinically. Evaluation of the Sciatic Functional Index demonstrated improved functional recovery, noting muscle reinnervation; however, no electrical conduction could be elicited. Histomorphology demonstrated axonal migration and nerve tissue advancement through the entire conduit and into the distal nerve stump at 12 weeks. The number of axons/mm2 and nerve fiber density in the distal nerve was 5793 and 0.2231, respectively.

Conclusion. Each year, the prolonged recovery from traditionally treated nerve injuries results in millions of dollars in lost revenue and increased compensation benefits. The proposed methodology for peripheral nerve restoration described herein has the potential to lead to more cost-effective and less morbid strategies for nerve replacement.

Keywords

Nerve Growth Factor Sciatic Nerve Schwann Cell Nerve Regeneration Nerve Graft 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Mikos AG, Throsen AJ, Czerwonka LA, Bao Y, Langer R, Winslow DN, Vacanti JP (1994) Preparation and characterization of poly(L-lactic acid) foams. Polymer 35:1068–1077.CrossRefGoogle Scholar
  2. 2.
    Evans GRD, Brandt K, Mikos A, Peden E, Crane GM, Riley S (1996) Biodegradable tissue engineered polymer nerve conduits: their use as scaffold in peripheral nerve regeneration. Poster presentation, Tissue Engineering Society, Orlando, FL, Dec 13–15. Google Scholar
  3. 3.
    Evans GRD, Brandt K, Conley MW, Gupta P, Savel T, Widmer MS, Patrick CW, Mikos AG (1997) Tissue engineered nerve conduits: the use of biodegradable polymer scaffolds in peripheral nerve regeneration: a preliminary report. Fifteenth Annual Houston Conference on Biomedical Engineering Research, Houston, TX, Feb 13–14. Google Scholar
  4. 4.
    Aebischer P, Guénard V, Brace S (1989) Peripheral nerve regeneration through blind-ended semipermeable guidance channels: effect of the molecular weight cutoff. J Neuroscience 9:3590–3595.Google Scholar
  5. 5.
    Aebischer P, Guénard V, Valentini RF (1990) The morphology of regeneration peripheral nerves is modulated by the surface micro geometry of polymeric guidance channels. Brain Research 531:211–218.PubMedCrossRefGoogle Scholar
  6. 6.
    Guénard V (1991) Influence of surface texture of polymeric sheets on peripheral nerve regeneration in a two-compartmental guidance system. Biomaterials 21:259–263.CrossRefGoogle Scholar
  7. 7.
    Hare GMT, Evans PJ, MacKinnon SE, Best TJ, Bain JR, Szalai JP, Hunter DA (1992) Walking track analysis: a long-term assessment of peripheral nerve recovery. Plast Re-constr Surg 89:251–2588.CrossRefGoogle Scholar
  8. 8.
    Jennrich RI, Schluchter MD (1986) Unbalanced repeated measurements models with structured covariance matrices. Biometrics 42:805–820.PubMedCrossRefGoogle Scholar
  9. 9.
    Laird NM, Ware JH (1982) Random-effects models for longitudinal data. Biomaterials 38:963–974.Google Scholar
  10. 10.
    Aldini NN, Perego G, Cella GD, Maltarello MC, Fini M, Rocca M, Giardino R (1996) Effectiveness of a bioabsorbable conduit in the repair of peripheral nerves. Biomaterials 17:959–962.CrossRefGoogle Scholar
  11. 11.
    Archibald SJ, Krarup C, Shefher J, Li ST, Madison RD (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.PubMedCrossRefGoogle Scholar
  12. 12.
    Dellon AL, Mackinnon SE (1988) An alternative to the classical nerve graft for the management of the short nerve gap. Plast Reconstr Surg 82:849–856.PubMedCrossRefGoogle Scholar
  13. 13.
    den Dunner WFA, Strokroos I, Blaauw EH, Holwerda A, Pennings AJ, Robinson PH, Schakenraad JM (1996) Light-microscopic and electron-microscopic evaluation of short-term nerve regeneration using a biodegradable poly(DL)-lactice-s-caprolacton) nerve guide. J Biomed Materials Research 31:105–115.CrossRefGoogle Scholar
  14. 14.
    Fields RD, Ellisman MH (1986) Axons regenerated through silicone tube splices. Experimental Neurology 92:48–60.PubMedCrossRefGoogle Scholar
  15. 15.
    Glück T (1880) Über Neuroplastik auf dem Wege der Transplantation. Arch Klin Chir 25:606–616.Google Scholar
  16. 16.
    Holland SJ (1986) Polymers for biodegradable medical devices: the potential of polyesters as controlled macromolecular release systems. J Controlled Release 4:155–180.CrossRefGoogle Scholar
  17. Kiyotani T, Nakamura T, Shimizu Y, Endo K (1995) Experimental study of nerve regeneration in a biodegradable tube made from collagen and polyglycolic acid. ASAIO Journal 41: M 657–661. Google Scholar
  18. 18.
    Lundborg G, Hansson HA (1980) Nerve regeneration through preformed pseudosynovial tubes. J Hand Surg 5:35–38.Google Scholar
  19. 19.
    Madison RD, da Silva CF, Dikkes P (1988) Entubulation repair with protein additives increases the maximum nerve gap distance successfully bridged with tubular prostheses. Brain Research 447:325–334.PubMedCrossRefGoogle Scholar
  20. 20.
    Rosen JM, Padilla JA, Nguyen KD, Siedman J, Pham HN (1992) Artificial nerve graft using glycol ide trimethylene carbonate as a nerve conduit filled with collagen compared to sutured auto graft in a rat model. Journal of Rehabilitation Research and Development 29:1–12.PubMedCrossRefGoogle Scholar
  21. 21.
    Seckel BR (1984) Nerve regeneration through synthetic biodegradable nerve guides: regulation by the target organ. Plast Reconstr Surg 74:173–181.PubMedCrossRefGoogle Scholar
  22. 22.
    Wang KK, Costas PD, Jones DS, Miller RA, Seckel BR (1992) Sleeve insertion and collagen coating improve nerve regeneration through vein conduits. J Reconstruc Micro-surg 9:39–48.CrossRefGoogle Scholar
  23. 23.
    Guénard V, Kleitman N, Morrissey TK, Bunge RP, Aebischer P (1992) Syngeneic Schwann cells derived from adult nerves seeded in semipermeable guidance channels enhance peripheral nerve regeneration. J Neurosci 12:3310–3320.PubMedGoogle Scholar
  24. 24.
    Seckel BR, Jones D, Hekimian KJ, Wang KK, Chakalis DP, Costas PD (1995) Hyaluronic acid through a new injectable nerve guide delivery system enhances peripheral nerve regeneration in the rat. J Neurosci Research 40:318–324.CrossRefGoogle Scholar
  25. 25.
    Valentini RF, Aebischer P, Winn SR, Galletti PM (1987) Collagen- and laminin-contain-ing gels impede peripheral nerve regeneration through semipermeable nerve guidance channels. Experimental Neurology 98:350–356.PubMedCrossRefGoogle Scholar
  26. 26.
    Thomson RC (1995) Biodegradable polymer scaffolds to regenerate organs. Advances in Polymer Science 122:245–274.Google Scholar
  27. 27.
    De Vries GH (1993) Schwann cell proliferation. In: Dyck PJ, Thomas PK (eds) Peripheral neuropathy. Philadelphia, W.B. Saunders, 290–298.Google Scholar
  28. 28.
    Levi ADO, Guenard V, Aebischer P, Bunge RP (1994) The functional characteristics of Schwann cells cultured from human peripheral nerve after transplantation into a gap within the rat sciatic nerve. J Neurosci 14:1309–1319.PubMedGoogle Scholar
  29. 29.
    Madison RD (1994) Point sources of Schwann cells result in growth into nerve entubulation repair site in the absence of axons: effects of freeze-thawing. Exp Neurol 128:266–275.PubMedCrossRefGoogle Scholar
  30. 30.
    Morissey TK, Kleitman N, Bunge RP (1991) Isolation and functional characterization of Schwann cells derived from adult peripheral nerve. J Neurosci 11:2433–2442.Google Scholar
  31. 31.
    Rath EM, Kelly D, Bouldin TW, Popko B (1995) Impaired peripheral nerve regeneration in a mutant strain of mice (Enr) with a Schwann cell defect. J Neuroscience 15:7228–723732. Levi-Montalcini R, Hamburger V (1953) A diffusible agent of mouse sarcoma producing hyperplasia of sympathetic ganglia and hyperneurontization of viscera in the chick embryo. J Exp Zool 123:233.CrossRefGoogle Scholar
  32. 33.
    Anton ES, Weskamp G, Reichardt LF, Metthew WD (1994) Nerve growth factor and its low-affinity receptor promote Schwann cell migration. Proc Natl Acad Sci USA 91:2795–2799.PubMedCrossRefGoogle Scholar
  33. 34.
    Raivich G, Kreutzberg GW (1993) Peripheral nerve regeneration: role of growth factors and their receptors. Int J Devel Neuroscience 11:322–324.Google Scholar
  34. 35.
    Whitworth IH, Brown RA, Dore CJ, Anand P, Green CJ, Terenchi G (1996) Nerve growth factor enhances nerve regeneration through fibronectin grafts. J Hand Surg 21B:514–522.Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • G. R. D. Evans
  • K. Brandt
  • M. Widmer
  • A. Gürlek
  • T. Savel
  • P. Gupta
  • R. Lohman
  • J. Williams
  • J. Hodges
  • A. Nabawi
  • C. Patrick
  • A. Mikos

There are no affiliations available

Personalised recommendations