Dog Tibial Nerve Regeneration across a 30-mm Defect Bridged by a PRGD/PDLLA/β-TCP/NGF Sustained-Release Conduit

Abstract

Nerve conduits have emerged as alternatives to autologous nerve grafts, but their use in large-diameter, critical nerve repairs is limited. In the previous study, we prepared a PRGD/PDLLA/β-TCP/NGF sustained-release nerve conduit, which was made of RGD peptide modified poly{(lactic acid)-co-[(glycolic acid)-alt-(L-lysine)]} (PRGD), poly(d,l-lactic acid) (PDLLA), β-tricalcium phosphate (β-TCP) and nerve growth factor (NGF). Here we attempted to use the PRGD/PDLLA/β-TCP/NGF sustained-release nerve conduit to bridge a 30-mm dog tibial nerve defect in six beagles. The other beagles were divided into group autograft (n = 6) as positive control and group PDLLA (n = 6) as negative control. After 9 months of implantation, nerve conduction velocities, the density of myelinated fibers, the mean diameter of axon, and the average thickness of myelin sheath in tibial nerves bridged with PRGD/PDLLA/β-TCP/NGF sustained-release nerve conduits were similar to those treated with autologous nerve (p > 0.05). Neither electrophysiological nor histological restoration was obtained in group PDLLA. Evidence is thus provided in support of the use of PRGD/PDLLA/β-TCP/NGF sustained-release nerve conduits as alternatives to autologous nerve grafts for treatment of large-diameter, critical defects in peripheral nerves.

Keywords

dog - tibial nerve - nerve growth factor - sustained-release - nerve conduit

• References

• 1 Jiang X, Lim SH, Mao HQ, Chew SY. Current applications and future perspectives of artificial nerve conduits. Exp Neurol 2010; 223: 86-101
• 2 Huelsenbeck SC, Rohrbeck A, Handreck A , et al. C3 peptide promotes axonal regeneration and functional motor recovery after peripheral nerve injury. Neurotherapeutics 2012; 9: 185-198
• 3 Lundborg G. A 25-year perspective of peripheral nerve surgery: evolving neuroscientific concepts and clinical significance. J Hand Surg Am 2000; 25: 391-414
• 4 Mackinnon SE, Hudson AR. Clinical application of peripheral nerve transplantation. Plast Reconstr Surg 1992; 90: 695-699
• 5 Midha R, Mackinnon SE, Evans PJ , et al. Comparison of regeneration across nerve allografts with temporary or continuous cyclosporin A immunosuppression. J Neurosurg 1993; 78: 90-100
• 6 Lundborg G, Rosén B, Abrahamson SO, Dahlin L, Danielsen N. Tubular repair of the median nerve in the human forearm. Preliminary findings. J Hand Surg [Br] 1994; 19: 273-276
• 7 Ignatiadis IA, Yiannakopoulos CK, Barbitsioti AD , et al. Diverse types of epineural conduits for bridging short nerve defects. An experimental study in the rabbit. Microsurgery 2007; 27: 98-104
• 8 Wang XD, Hu W, Cao Y, Yao J, Wu J, Gu XS. Dog sciatic nerve regeneration across a 30-mm defect bridged by a chitosan/PGA artificial nerve graft. Brain 2005; 128 (Pt 8) 1897-1910
• 9 Nakayama K, Takakuda K, Koyama Y , et al. Enhancement of peripheral nerve regeneration using bioabsorbable polymer tubes packed with fibrin gel. Artif Organs 2007; 31: 500-508
• 10 Schnell E, Klinkhammer K, Balzer S , et al. Guidance of glial cell migration and axonal growth on electrospun nanofibers of poly-epsilon-caprolactone and a collagen/poly-epsilon-caprolactone blend. Biomaterials 2007; 28: 3012-3025
• 11 Alluin O, Wittmann C, Marqueste T , et al. Functional recovery after peripheral nerve injury and implantation of a collagen guide. Biomaterials 2009; 30: 363-373
• 12 Ao Q, Fung CK, Tsui AYP , et al. The regeneration of transected sciatic nerves of adult rats using chitosan nerve conduits seeded with bone marrow stromal cell-derived Schwann cells. Biomaterials 2011; 32: 787-796
• 13 Ray WZ, Mackinnon SE. Management of nerve gaps: autografts, allografts, nerve transfers, and end-to-side neurorrhaphy. Exp Neurol 2010; 223: 77-85
• 14 Moore AM, Kasukurthi R, Magill CK, Farhadi HF, Borschel GH, Mackinnon SE. Limitations of conduits in peripheral nerve repairs. Hand (NY) 2009; 4: 180-186
• 15 Derby A, Engleman VW, Frierdich GE, Neises G, Rapp SR, Roufa DG. Nerve growth factor facilitates regeneration across nerve gaps: morphological and behavioral studies in rat sciatic nerve. Exp Neurol 1993; 119: 176-191
• 16 Lee AC, Yu VM, Lowe III JB , et al. Controlled release of nerve growth factor enhances sciatic nerve regeneration. Exp Neurol 2003; 184: 295-303
• 17 Uebersax L, Mattotti M, Papaloïzos M, Merkle HP, Gander B, Meinel L. Silk fibroin matrices for the controlled release of nerve growth factor (NGF). Biomaterials 2007; 28: 4449-4460
• 18 Xu X, Yee WC, Hwang PY , et al. Peripheral nerve regeneration with sustained release of poly(phosphoester) microencapsulated nerve growth factor within nerve guide conduits. Biomaterials 2003; 24: 2405-2412
• 19 Server AC, Shooter EM. Nerve growth factor. Adv Protein Chem 1977; 31: 339-409
• 20 Haller MF, Saltzman WM. Nerve growth factor delivery systems. J Control Release 1998; 53: 1-6
• 21 Wang Y, Yin Y, Dai H, Li S. Evaluation of a novel bioabsorbable PRGD/PDLLA/β-TCP/NGF composites in repair of peripheral nerves. Journal of Wuhan University of Technology–Materials Science Edition 2009; 24: 409-414
• 22 Griffin JW, Pan BH, Polley MA, Hoffman PN, Farah MH. Measuring nerve regeneration in the mouse. Exp Neurol 2010; 223: 60-71
• 23 Baetge EE, Hammang JP. Neurite outgrowth in PC12 cells deficient in GAP-43. Neuron 1991; 6: 21-30
• 24 Dijkmans TF, van Hooijdonk LWA, Schouten TG , et al. Temporal and functional dynamics of the transcriptome during nerve growth factor-induced differentiation. J Neurochem 2008; 105: 2388-2403
• 25 Meilander NJ, Yu XJ, Ziats NP, Bellamkonda RV. Lipid-based microtubular drug delivery vehicles. J Control Release 2001; 71: 141-152
• 26 Xu X, Yee WC, Hwang PYK , et al. Peripheral nerve regeneration with sustained release of poly(phosphoester) microencapsulated nerve growth factor within nerve guide conduits. Biomaterials 2003; 24: 2405-2412
• 27 Wan Z, Yin Y, Yuan L, Yan Q, Yan Y, Li S. A novel nerve guidance conduit with sustained release of NGF enhances sciatic nerve regeneration. Journal of Wuhan University of Technology–Materials Science Edition 2010; 25: 944-947
• 28 Greene LA, Tischler AS. Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A 1976; 73: 2424-2428
• 29 Cowley S, Paterson H, Kemp P, Marshall CJ. Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 1994; 77: 841-852
• 30 Loeb DM, Maragos J, Martin-Zanca D, Chao MV, Parada LF, Greene LA. The trk proto-oncogene rescues NGF responsiveness in mutant NGF-nonresponsive PC12 cell lines. Cell 1991; 66: 961-966
• 31 Gage FH, Batchelor P, Chen KS , et al. NGF receptor reexpression and NGF-mediated cholinergic neuronal hypertrophy in the damaged adult neostriatum. Neuron 1989; 2: 1177-1184
• 32 Holtzman DM, Li YW, Parada LF , et al. p140trk mRNA marks NGF-responsive forebrain neurons: evidence that trk gene expression is induced by NGF. Neuron 1992; 9: 465-478
• 33 Snyder SE, Pintar JE, Salton SR. Developmental expression of VGF mRNA in the prenatal and postnatal rat. J Comp Neurol 1998; 394: 64-90
• 34 Salton SRJ, Fischberg DJ, Dong KW. Structure of the gene encoding VGF, a nervous system-specific mRNA that is rapidly and selectively induced by nerve growth factor in PC12 cells. Mol Cell Biol 1991; 11: 2335-2349
• 35 Koike T, Martin DP, Johnson Jr EM. Role of Ca2+ channels in the ability of membrane depolarization to prevent neuronal death induced by trophic-factor deprivation: evidence that levels of internal Ca2+ determine nerve growth factor dependence of sympathetic ganglion cells. Proc Natl Acad Sci U S A 1989; 86: 6421-6425
• 36 Lyons WE, George EB, Dawson TM, Steiner JP, Snyder SH. Immunosuppressant FK506 promotes neurite outgrowth in cultures of PC12 cells and sensory ganglia. Proc Natl Acad Sci U S A 1994; 91: 3191-3195
• 37 Chen MH, Chen PR, Chen MH, Hsieh ST, Huang JS, Lin FH. An in vivo study of tricalcium phosphate and glutaraldehyde crosslinking gelatin conduits in peripheral nerve repair. J Biomed Mater Res B Appl Biomater 2006; 77: 89-97