The experimental study of peripheral nerve regeneration has depended heavily on the use of a nerve chamber in which the stumps of the transected nerve are inserted. A large variety of chamber fillings and chamber types have been used in an effort to induce a higher quality of regeneration across the gap initially separating the two stumps. In this study we studied the morphology of nerves regenerated across a 15 mm gap following implantation of a series of five chambers. The chambers were fabricated from type I collagen and possessed identical pore volume fractions as well as average pore diameters, but differed in cross-link density continuously along the series. The residual mass of the implanted chambers at 9 weeks was observed to increase continuously with increasing cross-link density along the series, indicating a continuous decrease in degradation rate. The quality of regenerated nerves, determined by the number of large diameter fibers (A-fibers) per nerve, the average diameter of all axons and the ratio of area occupied by axons (N-Ratio), was superior at an intermediate level of chamber degradation rate. The maximal quality of peripheral nerve regeneration corresponded to an optimal degradation rate with an estimated chamber half-life of approximately 2–3 weeks following implantation. A speculative mechanistic explanation of the observed optimum focuses on the hypothetical role of cell and cytokine traffic that may take place through holes in the chamber generated by the degradation process. The data show the presence of a hitherto unreported optimal chamber degradation rate that leads to regenerated nerves of maximum quality.

Keywords:
Peripheral nerve, Regeneration, Collagen tube, Degradation rate
1.
Aebischer, P., V. Guenard, S.R. Winn, R.F. Valentini, P.M. Galletti (1988) Blind-ended semipermeable guidance channels support peripheral nerve regeneration in the absence of a distal stump nerve. Brain Res 454: 179–187.
2.
Aebischer, P., A.N. Salessiotis, S.R. Winn (1989) Basic fibroblast growth factor released from synthetic guidance channels facilitates regeneration across long nerve gaps. J Neurosci Res 23: 282–289.
3.
Ansselin, A.D., T. Fink, D.F. Davey (1997) Peripheral nerve regeneration through nerve guides seeded with adult Schwann cells. Neuropathol Appl Neurobiol 23: 387–398.
4.
Arbuthnott, R., A. Boyd, K.U. Kalu (1980) Ultrastructural dimensions of myelinated peripheral nerve fibers in the cat and their relation to conduction velocity. J Physiol 308: 125–157.
5.
Archibald, S.J., C. Krarup, J. Shefner, S.-T. Li, R.D. Madison (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.
6.
Archibald, S.J., J. Shefner, C. Krarup, R.D. Madison (1995) Monkey median nerve repaired by nerve graft or collagen nerve guide tube. J Neurosci 15: 4109–4123.
7.
Bailey, S.B., M.E. Eichler, A. Villadiego, K.M. Rich (1993) The influence of fibronectin and laminin during Schwann cell migration and peripheral nerve regeneration through silicon chambers. J Neurocytol 22: 176–184.
8.
Borkenhagen, M., R.C. Stoll, P. Neuenschwander, U.W. Suter, P. Aebischer (1998) In vivo performance of a new biodegradable polyester urethane system used as a nerve guidance channel. Biomaterials 19: 2155–2165.
9.
Carr, M.M., T.J. Best, S.E. Mackinnon, P.J. Evans (1992) Strain differences in autotomy in rats undergoing sciatic nerve transection or repair. Ann Plast Surg 28: 538–544.
10.
Chamberlain, L.J. (1998) Influence of Implant Parameters on the Mechanisms of Peripheral Nerve Regeneration; PhD thesis Massachusetts Institute of Technology, Cambridge.
11.
Chamberlain, L.J., I.V. Yannas (1998) Preparation of collagen-glycosaminoglycan copolymers for tissue regeneration; in Morton, J.R., M.L. Yarmush (eds): Methods in Molecular Medicine: Tissue Engineering Methods and Protocols. Totowa, Humana Press, vol 20, pp 3–17.
12.
Chamberlain, L.J., I.V. Yannas, H.-P. Hsu, M. Spector (2000) Connective tissue response to tubular implants for peripheral nerve regeneration: The role of myofibroblasts. J Comp Neurol 417: 415–430.
13.
Chamberlain, L.J., I.V. Yannas, H.P. Hsu, G. Strichartz, M. Spector (1998) Collagen-GAG substrate enhances the quality of nerve regeneration through collagen tubes up to level of autograft. Exp Neurol 154: 315–329.
14.
Chang, A.S.-P. (1998) Electrophysiological recovery of peripheral nerves regenerated by biodegradable polymer matrix; MS thesis Massachusetts Institute of Technology, Cambridge.
15.
Chang, A.S., I.V. Yannas (1992) Peripheral nerve regeneration; in Smith, B., G. Adelman (eds): Neuroscience Year. Boston, Birkhäuser.
16.
Chang, A.S., I.V. Yannas, S. Perutz, H. Loree, R.R. Sethi, C. Krarup, T.V. Norregaard, N.T. Zervas, J. Silver (1990) Electrophysiological study of recovery of peripheral nerves regenerated by a collagen-glycosaminoglycan copolymer matrix; in Gebelin, C.G., R.L. Dunn (eds): Progress in Biomedical Polymers. New York, Plenum Press, pp 107–119.
17.
Cragg, B.G., P.K. Thomas (1964) The conduction velocity of regenerated peripheral nerve fibres. J Physiol 171: 164–175.
18.
den Dunnen, W.F.A., J.M. Schakenraad, G.J. Zondervan, A.J. Pennings, B. van der Lei, P.H. Robinson (1993) A new PLLA/PCL copolymer for nerve regeneration. J Mater Sci Mater Med 4: 521–525.
19.
den Dunnen, W.F.A., I. Stokroos, E.H. Blaauw, A. Holwerda, A.J. Pennings, P.H. Robinson, J.M. Schakenraad (1996) Light microscopic and electron-microscopic evaluation of short term nerve regeneration using a biodegradable poly(DL-lactide-caprolacton) nerve guide. J Biomed Mater Res 31: 105–115.
20.
Fields, R.D., J.M. LeBeau, F.M. Longo, M.H. Ellisman (1989) Nerve regeneration through artificial tubular implants. Prog Neurobiol 33: 87–134.
21.
Grillo, H.C., J. Gross (1962) Thermal reconstitution of collagen from solution, and the response to its heterologous implantation. J Surg Res 2: 69–82.
22.
Hollowell, J.P., A. Villadiego, K.M. Rich (1990) Sciatic nerve regeneration across gaps within silicone chambers: Long-term effects of NGF and consideration of axonal branching. Exp Neurol 110: 45–51.
23.
Huang, C., I.V. Yannas (1977) Mechanochemical studies of enzymatic degradation of insoluble collagen fibers. J Biomed Mater Res 11: 137–154.
24.
Hursh, J.B. (1939) Conduction velocity and diameter of nerve fibers. Am J Physiol 127: 131–139.
25.
Itoh, S., K. Takakuda, S. Ichinose, M. Kikuchi, K. Schinomiya (2001) A study of induction of nerve regeneration using bioabsorbable tubes. J Reconstr Microsurg 17/2: 115–123.
26.
Jenq, C.-B., R.E. Coggeshall (1985) Nerve regeneration through holey silicone tubes. Brain Res 361: 233–241.
27.
Jenq, C.-B., R.E. Coggeshall (1987) Permeable tubes increase the length of the gap that regenerating axons can span. Brain Res 408: 239–242.
28.
Jenq, C.-B., L.L. Jenq, R.E. Coggeshall (1987) Nerve regeneration changes with filters of different pore size. Exp Neurol 97: 662–671.
29.
Kim, D.H., S.E. Connolly, S. Zhao, R.W. Beuerman, R.M. Vorhies, D.G. Kline (1993) Comparison of macropore, semipermeable, and nonpermeable collagen conduits in nerve repair. J Reconstr Microsurg 9: 415–420.
30.
Kline, D.G., G.J. Hayes (1964) The use of resorbable wrapper for peripheral nerve repair. J Neurosurg 21: 737–750.
31.
Krarup, C., S.J. Archibald, R.D. Madison (2002) factors that influence peripheral nerve regeneration: An electrophysiological study of the monkey median nerve. Ann Neurol 51: 69–81
32.
Labrador, R.O., M. Buti, X. Navarro (1998) Influence of collagen and laminin gels concentration on nerve regeneration after resection and tube repair. Exp Neurol 149: 243–252.
33.
Le Beau, J.M., M.H. Ellisman, H.C. Powell (1988) Ultrastructural and morphometric analysis of long-term peripheral nerve regeneration through silicone tubes. J Neurocytol 17: 161–172.
34.
Lee, C.R., A.J. Grodzinsky, M. Spector (2001) The effects of crosslinking of collagen-glycosaminoglycan scaffolds on compressive stiffness, chondrocyte-mediated contraction, proliferation, and biosynthesis. Biomaterials 22: 3145–3154.
35.
Li, S.-T., S.J. Archibald, C. Krarup, S.D. Madison (1990) Semipermeable collagen nerve conduits for peripheral nerve regeneration. Polym Mater Sci Eng 62: 575–582.
36.
Li, S.-T., S.J. Archibald, C. Krarup, R.D. Madison (1992) Peripheral nerve repair with collagen conduits. Clin Materials 9: 195–200.
37.
Loree, H.M., I.V. Yannas, B. Mikic, A.S.-P. Chang, S.M. Perutz, T.V. Norregaard, C. Krarup (1989) A freeze-drying process for fabrication of polymeric bridges for peripheral nerve regeneration. Proc Annu Northeast Bioeng Conf, pp 53–54.
38.
Lundborg, G., L.B. Dahlin, N. Danielsen, R.H. Gelberman, F.M. Longo, H.C. Powell, C. Varon (1982) Nerve regeneration in silicone chambers: Influence of gap length and of distal stump components. Exp Neurol 76: 361–375.
39.
Lundborg, G., L. Dahlin, D. Dohi, M. Kanje, N. Terada (1997) A new type of ‘bioartificial’ nerve graft for bridging extended defects in nerves. J Hand Surg 22B: 299–303.
40.
Madison, R.D., S.J. Archibald, C. Krarup (1992) Peripheral nerve injury; in Cohen, I.K., R.F. Diegelmann, W.J. Lindblad (eds): Wound Healing: Biochemical and Clinical Aspects. Philadelphia, Saunders, pp 450–487.
41.
Madison, R.D., C.F. da Silva, P. Dikkes (1988) Entubulation repair with protein additives increases the maximum nerve gap distance successfully bridged with tubular prostheses. Brain Res 447: 325–334.
42.
Merle, M., A.L. Dellon, J.N. Campbell, P.S. Chang (1989) Complications from silicone-polymer intubulation of nerves. Microsurgery 10: 130–133.
43.
Mohammad, J., J. Shenaq, E. Rabinovsky, S. Shenaq (2000) Modulation of peripheral nerve regeneration: A tissue-engineering approach. The role of amnion tube nerve conduit across a 1-cm nerve gap. Plast Reconstr Surg 105: 660–666.
44.
Molander, H., O. Engkvist, J. Hagglund, Y. Olsson, E. Torebjork (1983) Nerve repair using a polyglactin tube and nerve graft: An experimental study in the rabbit. Biomaterials 4: 276–280.
45.
Navarro, X., F.J. Rodriguez, R.O. Labrador, M. Buti, D. Ceballos, N. Gomez, J. Cuadra, G. Perego (1996) Peripheral nerve regeneration through bioresorbable and durable nerve guides. J Peripher Nerv Syst 1: 53–64.
46.
Properzi, F., R.A. Asher, J.W. Fawcett (2003) Chondroitin sulphate proteoglycans in the central nervous system: Changes and synthesis after injury. Biochem Soc Trans 31: 335–336.
47.
Robinson, P.H., B. van der Lei, H.J. Hoppen, J.W. Leenslag, A.J. Pennings, P. Nieuwenhuis (1991) Nerve regeneration through a two-ply biodegradable nerve guide in the rat and the influence of ACTH4–9 nerve growth factor. Microsurgery 12: 412–419.
48.
Rodriguez, F.J., N. Gomez, G. Perego, X. Navarro (1999) Highly permeable polylactide-caprolactone nerve guides enhance peripheral nerve regeneration through long gaps. Biomaterials 20: 1489–1500.
49.
Rodriguez, F.J., E. Verdu, D. Ceballos, X. Navarro (2000) Nerve guides seeded with autologous Schwann cells improve nerve regeneration. Exp Neurol 161: 571–584.
50.
Seckel, B.R., T.H. Chiu, E. Nyilas, R.L. Sidman (1984) Nerve regeneration through synthetic biodegradable nerve guides: Regulation by the target organ. Plast Reconstr Surg 74: 173–181.
51.
Spilker, M.H. (2000) Peripheral Nerve Regeneration through Tubular Devices: A Comparison of Assays of Device Effectiveness; PhD thesis Massachusetts Institute of Technology, Cambridge.
52.
Valero-Cabre, A., K. Tsironis, E. Skouras, G. Perego, X. Navarro, W.F. Neiss (2001) Superior muscle reinnervation after autologous nerve graft or poly-L-lactide-epsilon-caprolactone (PLC) tube implantation in comparison to silicone tube repair. J Neurosci Res 63/2: 214–223.
53.
Valentini, R.F., P. Aebischer, S.R. Winn, P.M. Galletti (1987) Collagen- and laminin-containing gels impede peripheral nerve regeneration through semipermeable nerve guidance channels. Exp Neurol 98: 350–356.
54.
Walter, M.A., R. Kurouglu, J.B. Caulfield, L.O. Vasconez, J.A. Thompson (1993) Enhanced peripheral nerve regeneration by acidic fibroblast growth factor. Lymphokine Cytokine Res 12: 135–141.
55.
Wang, S., A.C. Wan, X. Xu, S. Gao, H.Q. Mao, K.W. Leong, H. Yu (2001) A new nerve guide conduit material composed of a biodegradable poly(phosphoester). Biomaterials 22/10: 1157–1169.
56.
Williams, L.R., N. Danielson, H. Muller, S. Varon (1987) Exogenous matrix precursors promote functional nerve regeneration across a 15 mm gap within a silicone chamber in the rat. J Comp Neurol 264: 284–290.
57.
Williams, L.R., F.M. Longo, H.C. Powell, G. Lundborg, S. Varon (1983) Spatial-temporal progress of peripheral nerve regeneration within a silicone chamber: Parameters for a bioassay. J Comp Neurol 218: 460–470.
58.
Yannas, I.V. (1972) Collagen and gelatin in the solid state. J Macromol Sci Rev Macromol Chem C7: 49–104.
59.
Yannas, I.V. (1997) Models of organ regeneration processes induced by templates. Ann NY Acad Sci 831: 280–293.
60.
Yannas, I.V. (2001) Tissue and Organ Regeneration in Adults. New York, Springer.
61.
Yannas, I.V., J.F. Burke (1980) Design of an artificial skin. I. Basic design principles. J Biomed Mater Res 14: 65–81.
62.
Yannas, I.V., J.F. Burke, P.L. Gordon, C. Huang, R.H. Rubinstein (1980) Design of an artificial skin II: Control of chemical composition. J Biomed Mater Res 14: 107–131.
63.
Yannas, I.V., J.F. Burke, C. Huang, P.L. Gordon (1975) Correlation of in vivo collagen degradation rate with in vitro measurements. J Biomed Mater Res 6: 623–625.
64.
Yannas, I.V., A.S. Chang, C. Krarup, R. Sethi, T.V. Norregaard, N.T. Zervas (1988) Conduction properties of peripheral nerves regenerated by use of copolymer matrices with different biodegradation rates. Soc Neurosci Abstr 14: 165.
65.
Yannas, I.V., E. Lee, D.P. Orgill, E.M. Skrabut, G.F. Murphy (1989) Synthesis and characterization of a model extracellular matrix that induces partial regeneration of adult mammalian skin. Proc Natl Acad Sci USA 86: 933–937.
66.
Yannas, I.V., D.P. Orgill, J. Silver, T.V. Norregaard, N.T. Zervas, W.C. Schoene (1985) Polymeric template facilitates regeneration of sciatic nerve across 15 mm gap. Trans Soc Biomater 8: 146.
67.
Yannas, I.V., A.V. Tobolsky (1967) Cross-linking of gelatine by dehydration. Nature 215: 509–510.
68.
Yu, X., R.V. Bellamkonda (2001) Dorsal root ganglia neurite extension is inhibited by mechanical and chondroitin sulfate-rich interfaces. J Neurosci Res 66: 303–310.
69.
Zar, J.H. (1984) Biostatistical Analysis, ed 2. Englewood Cliffs, Prentice Hall.
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