Download PDF
J Reconstr Microsurg 2003; 19(2): 125-134
DOI: 10.1055/s-2003-37820
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1 (212) 584-4662

Enhanced Peripheral Nerve Regeneration Elicited by Cell-Mediated Events Delivered via a Bioresorbable PLGA Guide

David J. Bryan1,2 , Jin Bo Tang1 , Antonia H. Holway1 , Kimberly M. Rieger-Christ3 , Debra J. Trantolo4 , Donald L. Wise4 , Ian C. Summerhayes1,3
  • 1Tissue Engineering Laboratory, Research and Education Institute, Lahey Clinic, Burlington, Massachusetts
  • 2Department of Plastic and Reconstructive Surgery, Research and Education Institute, Lahey Clinic, Burlington, Massachusetts
  • 3Cell and Molecular Biology Laboratory, Research and Education Institute, Lahey Clinic, Burlington, Massachusetts
  • 4Cambridge Scientific Inc., Cambridge, Massachusetts
Further Information

Publication History

Publication Date:
10 March 2003 (online)

Also available at
    Permissions and Reprints

ABSTRACT

Using an established rat peripheral-nerve regeneration model, the authors have demonstrated enhancement of regeneration following subcutaneous priming of bioresorbable poly(lactic-co-glycolic)acid (PLGA) guides in vivo. Four weeks after nerve reconstruction, regeneration of the peripheral nerve through the cell-infiltrated guides displayed a significant increase in the total axon number and myelination status recorded in primed over unprimed guides, demonstrating the importance of cell-mediated events in the regeneration process. To define the different components enhancing nerve regeneration in this model, they have focused on identifying factors capable of eliciting Schwann-cell migration, since this has been identified as an early and necessary event in nerve regeneration. Using an in vitro migration assay, screening of a limited number of cellular and extracellular factors has demonstrated differential promotion of Schwann-cell migration. Of interest, combining fibronectin and bFGF resulted in a two-fold enhancement in Schwann-cell migration over that recorded with either alone. These results describe a rapid screening process for identifying various molecules and combinations thereof, with potential involvement in Schwann-cell migration. Coupling these findings to the use of the PLGA guide as an in vivo delivery system provides a rationale for the selection of exogenous factors to test for the enhancement of peripheral-nerve regeneration.

KEYWORDS

Peripheral nerve regeneration - bioresorbable nerve guides - Schwann-cell migration

REFERENCES

  • 1 Bryan D J, Holway A H, Wang K K. et al . Influence of glial growth factor and Schwann cells in a bioresorbable guidance channel on peripheral nerve regeneration.  Tissue Eng . 2000;  6 129-138.
    CrossrefPubMedSearch in Google Scholar
  • 2 Thanos P K, Okajima S, Terzis J K. Ultrastructure and cellular biology of nerve regeneration.  J Reconstr Microsurg . 1998;  14 423-435
    Thieme ConnectPubMedSearch in Google Scholar
  • 3 Berry M, Rees L, Hall S, Sievers J. Optic axons regenerate into sciatic nerve isografts only in the presence of Schwann cells.  Brain Res Bull . 1988;  20 223-231
    CrossrefPubMedSearch in Google Scholar
  • 4 Nadim W, Anderson P N, Turmaine M. The role of Schwann cells and basal lamina tubes in the regeneration of axons through long length of freeze-killed nerve grafts.  Neuropathol Appl Neurobiol . 1990;  16 411-421
    PubMedSearch in Google Scholar
  • 5 Bunge R P. Expanding roles for the Schwann-cell: ensheathment, myelination, trophism and regeneration.  Curr Opin Neurobiol . 1993;  3 805-809
    CrossrefPubMedSearch in Google Scholar
  • 6 Feneley M R, Fawcett J W, Keynes R J. The role of Schwann cells in the regeneration of peripheral nerve axons through muscle basal lamina grafts.  Exp Neurol . 1991;  114 275-285
    CrossrefPubMedSearch in Google Scholar
  • 7 Bryan D J, Wang K K, Chakalis-Haley D. Effect of Schwann cells in the enhancement of peripheral nerve regeneration.  J Reconstr Microsurg . 1996;  12 439-446
    PubMedSearch in Google Scholar
  • 8 Bryan D J, Wang K K, Summerhayes I C. Migration of Schwann cells in peripheral nerve regeneration.  J Reconstr Microsurg . 1999;  15 591-596
    PubMedSearch in Google Scholar
  • 9 Guenard V, Dinarello C A, Weston P J, Aebisher P. Peripheral nerve regeneration is impeded by interleukin-1 receptor antagonist released from polymeric guidance channel.  J Neurosci Res . 1991;  29 396-400
    CrossrefPubMedSearch in Google Scholar
  • 10 Stoll G, Griffin J W, Li C Y, Trapp B D. Wallerian degeneration in the peripheral nervous system: participation of both Schwann cells and macrophages in myelin degeneration.  J Neurocytol . 1989;  18 671-683
    CrossrefPubMedSearch in Google Scholar
  • 11 Bunge M B, Bunge R P, Kleitman N, Dean A C. Role of peripheral nerve extracellular matrix in Schwann-cell function and in neurite regeneration.  Dev Neurosci . 1989;  11 348-360
    CrossrefPubMedSearch in Google Scholar
  • 12 Hagg T, Gulati A K, Behzadian A. et al . Nerve growth factor promotes CNS cholinergic axonal regeneration into acellular peripheral nerve graft.  Exp Neurol . 1991;  112 79-88
    CrossrefPubMedSearch in Google Scholar
  • 13 Ide C, Tohyama K, Yokota R, Nitatori T, Onodera S. Schwann-cell basal lamina and nerve regeneration.  Brain Res . 1983;  288 61-75
    CrossrefPubMedSearch in Google Scholar
  • 14 Letourneau P C. Cell-to-substratum adhesion and guidance of axonal elongation.  Dev Biol . 1975;  44 92-101
    CrossrefPubMedSearch in Google Scholar
  • 15 Livesey F J, O'Brien J A, Meng L. et al . A Schwann-cell mitogen accompanying regeneration of motor neurons.  Nature . 1997;  390 614-618
    CrossrefPubMedSearch in Google Scholar
  • 16 Madison R D, Zomorodi A, Robinson G A. Netrin-1 and peripheral nerve regeneration in the adult rat.  Exp Neurol . 2000;  161 563-570
    CrossrefPubMedSearch in Google Scholar
  • 17 Muir D, Gennrich C, Varon S, Manthorpe M. Rat sciatic nerve Schwann-cell microcultures: responses to mitogens and production of trophic and neurite-promoting factors.  Neurochem Res . 1989;  14 1003-1012
    CrossrefPubMedSearch in Google Scholar
  • 18 Nakao Y. An experimental study of the effect of laminin in vivo on promoting regeneration on axons.  J Jpn Orthop Assoc . 1992;  66 334-349
    PubMedSearch in Google Scholar
  • 19 Osawa T, Tohyama K, Ide C. Allogenic nerve grafts in the rat, with special reference to the role of Schwann-cell basal lamina in nerve regeneration.  J Neurocytol . 1992;  19 833-849
    PubMedSearch in Google Scholar
  • 20 Rivas R J, Burmeister D W, Goldberg D J. Rapid effects of laminin on the growth cone.  Neuron . 1992;  8 107-115
    CrossrefPubMedSearch in Google Scholar
  • 21 Wang G Y, Hirai K, Shimada H. The role of laminin, a component of Schwann-cell basal lamina, in a rat sciatic nerve regeneration model within antiserum-treated nerve grafts.  Brain Res . 1992;  570 116-125
    CrossrefPubMedSearch in Google Scholar
  • 22 Carroll S L, Miller M L, Frohnert P W, Kim S S, Corbett J A. Expression of neuregulins and their putative receptors, erbB2 and erbB3 induced during Wallerian degeneration.  J Neurosci . 1997;  17 1642-1659
    PubMedSearch in Google Scholar
  • 23 Goodearl A D, Davis J B, Mistry K. et al . Purification of multiple forms of glial growth factor.  J Biol Chem . 1993;  268 18095-18102
    PubMedSearch in Google Scholar
  • 24 Marchionni M A, Goodearl A D, Chen M S. et al . Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system.  Nature . 1993;  362 312-318
    CrossrefPubMedSearch in Google Scholar
  • 25 Minghetti L, Goodearl A D, Mistry K, Stroobant P. Glial growth factors I-III are specific mitogens for glial cells.  J Neurosci Res . 1996;  43 684-693
    CrossrefPubMedSearch in Google Scholar
  • 26 Svenningsen A F, Kanje M. Insulin and insulin like growth factors I and II are mitogenic to cultured rat sciatic nerve segments and stimulate (3H)-Thymidine incorporation through their respective receptors.  Glia . 1996;  18 68-72
    CrossrefPubMedSearch in Google Scholar
  • 27 Assouline J G, Bosch P, Lim R. et al . Rat astrocytes and Schwann cells in culture synthesize nerve growth factor-like neurite-promoting factors.  Devlop Brain Res . 1987;  31 103-118
    PubMedSearch in Google Scholar
  • 28 Brockes J P, Fields K L, Raff M C. Studies on cultured rat Schwann cells. I. Establishment of purified populations from cultures of peripheral nerve.  Brain Res . 1979;  165 105-118
    CrossrefPubMedSearch in Google Scholar
  • 29 Pories S E, Weber T K, Simpson H. et al . Immortalization and neoplastic transformation of normal rat colon epithelium: an in vitro model of colonic neoplastic progression.  Gastroenterology . 1993;  104 1346-1355
    PubMedSearch in Google Scholar
  • 30 Brown M, McCormack M, Zinn K G, Farrell M P, Bikel I. A recombinant murine retrovirus for simian virus 40 large T cDNA transforms mouse fibroblasts to anchorage independent growth.  J Virol . 1986;  60 290-293
    PubMedSearch in Google Scholar
  • 31 Guenard V, Kleitman N, Morrissey T K, Bunge R P, Aebischer P. Syngeneic Schwann cells derived from adult nerves seeded in semipermeable guidance channels enhance peripheral nerve regeneration.  J Neurosci . 1992;  12 3310-3320
    PubMedSearch in Google Scholar
  • 32 Guest J D, Rao A, Olson L, Bunge M B, Bunge R P. The ability of human Schwann-cell grafts to promote regeneration in the transected nude rat spinal cord.  Exp Neurol . 1997;  148 502-522
    CrossrefPubMedSearch in Google Scholar
  • 33 Hadlock T A, Sundback C A, Hunter D A, Vacanti J P, Cheney M L. A new artificial nerve graft containing rolled Schwann-cell monolayers.  Microsurgery . 2001;  21 96-101
    CrossrefPubMedSearch in Google Scholar
  • 34 Strauch B, Rodriguez D M, Diaz J, Kaplan G, Weinstein D E. Autologous Schwann cells drive regeneration through a 6-cm autogenous venous nerve conduit.  J Reconstr Microsurg . 2001;  17 589-595
    Thieme ConnectPubMedSearch in Google Scholar
  • 35 Evans G R, Brandt K, Katz S. et al . Bioactive poly(L-lactic acid) conduits seeded with Schwann cells for peripheral nerve regeneration.  Biomaterials . 2002;  23 841-848
    CrossrefPubMedSearch in Google Scholar
  • 36 Rodriguez F J, Verdu E, Ceballos D, Navarro X. Nerve guides seeded with autologous Schwann cells improve nerve regeneration.  Exp Neurol . 2000;  161 571-584
    CrossrefPubMedSearch in Google Scholar
  • 37 Mathon N F, Malcolm D S, Harrisingh M C, Cheng L, Lloyd A C. Lack of replicative senescence in normal rodent glia.  Science . 2001;  291 872-875
    CrossrefPubMedSearch in Google Scholar
  • 38 Thi A D, Evrard C, Rouget P. Proliferation and differentiation properties of permanent Schwann-cell lines immortalized with a temperature-sensitive oncogene.  J Exp Biol . 1998;  201 851-860
    PubMedSearch in Google Scholar
  • 39 Miller C, Jeftinija S, Mallapragada S. Micropatterned Schwann-cell-seeded biodegradable polymer substrates significantly enhance neurite alignment and outgrowth.  Tissue Eng . 2001;  7 705-715
    CrossrefPubMedSearch in Google Scholar
  • 40 Meek M F, Coert J H. Clinical use of nerve conduits in peripheral-nerve repair: review of the literature.  J Reconstr Microsurg . 2002;  18 97-109
    Thieme ConnectPubMedSearch in Google Scholar
  • 41 Baron-Van Evercooren A, Kleinman H K, Sappa H E, Rentier B, Dubois-Dalcq M. Fibronectin promotes rat Schwann-cell growth and motility.  J Cell Biol . 1982;  93 211-216
    CrossrefPubMedSearch in Google Scholar
  • 42 Chernousove M A, Carey D J. Schwann-cell extracellular matrix molecules and their receptors.  Histol Histopathol . 2000;  15 593-601
    PubMedSearch in Google Scholar
  • 43 Bryan D J, Miller R, Costas P, Wang K K, Seckel B. Immunocytochemistry of skeletal muscle basal lamina grafts in nerve regeneration.  Plast Reconstr Surg . 1993;  92 927-940
    CrossrefPubMedSearch in Google Scholar
  • 44 Smahel J, Jentsch B. Stimulation of peripheral nerve regeneration by an isolated nerve segment.  Ann Plast Surg . 1986;  16 494-501
    PubMedSearch in Google Scholar
  • 45 Tang J B. Vein conduits with interposition of nerve tissue for peripheral nerve defects.  J Reconstr Microsurg . 1995;  11 21-26
    Thieme ConnectPubMedSearch in Google Scholar
  • 46 Tang J B, Gu Y Q, Song Y S. Repair of digital nerve defect with autogenous vein graft during flexor tendon surgery in zone 2.  J Hand Surg . 1993;  18B 449-453
    PubMedSearch in Google Scholar
  • 47 Tang J B. Group fascicular grafts with interposition of nerve slices for long ulnar nerve defects: report of three cases.  Microsurgery . 1993;  14 404-408
    CrossrefPubMedSearch in Google Scholar
  • 48 Stanec S, Stanec Z. Reconstruction of upper-extremity peripheral-nerve injuries with ePTFE conduits.  J Reconstr Microsurg . 1998;  14 227-232
    Thieme ConnectPubMedSearch in Google Scholar
  • 49 Scarlato M, Xu T, Bannerman P. et al . Axon-Schwann-cell interactions regulate the expression of fibroblast growth factor-5 (FGF-5).  J Neurosci Res . 2001;  66 16-22
    CrossrefPubMedSearch in Google Scholar
  • 50 Grothe C, Meisinger C, Claus P. In vivo expression and localization of the fibroblast growth factor system in the intact and lesioned rat peripheral nerve and spinal ganglia.  J Comp Neurol . 2001;  434 342-349
    PubMedSearch in Google Scholar
  • 51 Grothe C, Nikkhah G. The role of basic fibroblast growth factor in peripheral nerve regeneration.  Anat Embryol . 2001;  204 171-177
    CrossrefPubMedSearch in Google Scholar
  • 52 Chalazonitis A, Kessler J A, Twardzik D R, Morrison R S. Transforming growth factor-α but not epidermal growth factor, promotes survival of sensory neurons in vitro.  J Neurosci . 1992;  12 583-594
    PubMedSearch in Google Scholar
  • 53 Gonzalez A M, Buscaglia M, Ong M, Baird A. Distribution of basic fibroblast growth factor in the 18-day rat fetus.  J Cell Biol . 1990;  110 753-765
    CrossrefPubMedSearch in Google Scholar