Effect of Vascular Endothelial Growth Factor Administration on Nerve Regeneration after Autologous Nerve Grafting

Abstract

Background The aim of this study was to evaluate the effect of vascular endothelial growth factor (VEGF) administration around the autologous nerve graft on nerve recovery in a rat model.

Methods A total of 69 rats were randomly divided into three experimental groups. A 10-mm sciatic nerve defect was made and reconstructed with the reversed nerve segment. Group I received an osmotic pump with saline, group II received an osmotic pump with VEGF, and group III added a silicone tube around the nerve graft to decrease the surrounding blood supply. Nine animals in each group were sacrificed on day 3 to evaluate improvement in new vessel formation. In each group 14 animals were sacrificed at 16 weeks after the initial procedure to evaluate the functional motor nerve regeneration using compound muscle action potential, isometric tetanic force, wet muscle weight, and nerve histomorphometry.

Results The average vascular density on day 3 was 10.7% in group I, 21.4% in group II, and 0.9% in group III. These differences were significant. However, the average maximum isometric tetanic force at 16 weeks was 54.4% in group I, 57.5% in group II, and 47.6% in group III. No difference was found with or without VEGF administration. Histomorphometric analysis was also not significantly different between the groups.

Conclusions New vessel formation on autologous nerve graft was enhanced by VEGF administration. However, the neovascularization effect of VEGF administration did not translate into better motor nerve recovery.

Keywords

peripheral nerve regeneration - autologous nerve grafting - vascular endothelial growth factor

Note

Investigations were performed at the Microvascular Research Laboratory, Mayo Clinic, Rochester, MN.

• References

• 1 Beazley WC, Milek MA, Reiss BH. Results of nerve grafting in severe soft tissue injuries. Clin Orthop Relat Res 1984; (188) 208-212
• 2 Young VL, Wray RC, Weeks PM. The results of nerve grafting in the wrist and hand. Ann Plast Surg 1980; 5 (3) 212-215
• 3 Yu H, Peng J, Guo Q , et al. Improvement of peripheral nerve regeneration in acellular nerve grafts with local release of nerve growth factor. Microsurgery 2009; 29 (4) 330-336
• 4 Tiangco DA, Papakonstantinou KC, Mullinax KA, Terzis JK. IGF-I and end-to-side nerve repair: a dose-response study. J Reconstr Microsurg 2001; 17 (4) 247-256
• 5 Lee AC, Yu VM, Lowe III JB , et al. Controlled release of nerve growth factor enhances sciatic nerve regeneration. Exp Neurol 2003; 184 (1) 295-303
• 6 Hobson MI, Green CJ, Terenghi G. VEGF enhances intraneural angiogenesis and improves nerve regeneration after axotomy. J Anat 2000; 197 (Pt 4) 591-605
• 7 Hobson MI. Increased vascularisation enhances axonal regeneration within an acellular nerve conduit. Ann R Coll Surg Engl 2002; 84 (1) 47-53
• 8 Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 1995; 146 (5) 1029-1039
• 9 Fang T, Lineaweaver WC, Chen MB, Kisner C, Zhang F. Effects of vascular endothelial growth factor on survival of surgical flaps: a review of experimental studies. J Reconstr Microsurg 2014; 30 (1) 1-13
• 10 Ylä-Kotola TM, Kauhanen SC, Leivo IV, Haglund C, Tukiainen E. Vascular endothelial growth factor and its receptors are expressed in human nerve grafts. J Reconstr Microsurg 2011; 27 (3) 173-178
• 11 Koshima I, Harii K. Experimental study of vascularized nerve grafts: multifactorial analyses of axonal regeneration of nerves transplanted into an acute burn wound. J Hand Surg Am 1985; 10 (1) 64-72
• 12 Restrepo Y, Merle M, Michon J, Folliguet B, Barrat E. Free vascularized nerve grafts: an experimental study in the rabbit. Microsurgery 1985; 6 (2) 78-84
• 13 Kärcher H, Kleinert R. Regeneration in vascularized and free nerve grafts. A comparative morphological study in rats. J Maxillofac Surg 1986; 14 (6) 341-343
• 14 Kawai H, Baudrimont M, Travers V, Sedel L. A comparative experimental study of vascularized and nonvascularized nerve grafts. J Reconstr Microsurg 1990; 6 (3) 255-259
• 15 Ozcan G, Shenaq S, Mirabi B, Spira M. Nerve regeneration in a bony bed: vascularized versus nonvascularized nerve grafts. Plast Reconstr Surg 1993; 91 (7) 1322-1331
• 16 Sondell M, Lundborg G, Kanje M. Vascular endothelial growth factor stimulates Schwann cell invasion and neovascularization of acellular nerve grafts. Brain Res 1999; 846 (2) 219-228
• 17 Sondell M, Lundborg G, Kanje M. Vascular endothelial growth factor has neurotrophic activity and stimulates axonal outgrowth, enhancing cell survival and Schwann cell proliferation in the peripheral nervous system. J Neurosci 1999; 19 (14) 5731-5740
• 18 Wongtrakul S, Bishop AT, Friedrich PF. Vascular endothelial growth factor promotion of neoangiogenesis in conventional nerve grafts. J Hand Surg Am 2002; 27 (2) 277-285
• 19 Shin RH, Vathana T, Giessler GA, Friedrich PF, Bishop AT, Shin AY. Isometric tetanic force measurement method of the tibialis anterior in the rat. Microsurgery 2008; 28 (6) 452-457
• 20 Takagi T, Kimura Y, Shibata S , et al. Sustained bFGF-release tubes for peripheral nerve regeneration: comparison with autograft. Plast Reconstr Surg 2012; 130 (4) 866-876
• 21 Penna V, Wewetzer K, Munder B, Stark GB, Lang EM. The long-term functional recovery of repair of sciatic nerve transection with biogenic conduits. Microsurgery 2012; 32 (5) 377-382
• 22 Giusti G, Willems WF, Kremer T, Friedrich PF, Bishop AT, Shin AY. Return of motor function after segmental nerve loss in a rat model: comparison of autogenous nerve graft, collagen conduit, and processed allograft (AxoGen). J Bone Joint Surg Am 2012; 94 (5) 410-417
• 23 Pettersson J, Kalbermatten D, McGrath A, Novikova LN. Biodegradable fibrin conduit promotes long-term regeneration after peripheral nerve injury in adult rats. J Plast Reconstr Aesthet Surg 2010; 63 (11) 1893-1899
• 24 Panagis JS, Gelberman RH, Taleisnik J, Baumgaertner M. The arterial anatomy of the human carpus. Part II: The intraosseous vascularity. J Hand Surg Am 1983; 8 (4) 375-382
• 25 Shin RH, Friedrich PF, Crum BA, Bishop AT, Shin AY. Treatment of a segmental nerve defect in the rat with use of bioabsorbable synthetic nerve conduits: a comparison of commercially available conduits. J Bone Joint Surg Am 2009; 91 (9) 2194-2204
• 26 Penkert G, Bini W, Samii M. Revascularization of nerve grafts: an experimental study. J Reconstr Microsurg 1988; 4 (4) 319-325
• 27 McCullough CJ, Gagey O, Higginson DW, Sandin BM, Crow JC, Sebille A. Axon regeneration and vascularisation of nerve grafts. An experimental study. J Hand Surg [Br] 1984; 9 (3) 323-327
• 28 Shibata M, Tsai TM, Firrell J, Breidenbach WC. Experimental comparison of vascularized and nonvascularized nerve grafting. J Hand Surg Am 1988; 13 (3) 358-365
• 29 Daly PJ, Wood MB. Endoneural and epineural blood flow evaluation with free vascularized and conventional nerve grafts in the canine. J Reconstr Microsurg 1985; 2 (1) 45-49
• 30 Lind R, Wood MB. Comparison of the pattern of early revascularization of conventional versus vascularized nerve grafts in the canine. J Reconstr Microsurg 1986; 2 (4) 229-234
• 31 Prpa B, Huddleston PM, An KN, Wood MB. Revascularization of nerve grafts: a qualitative and quantitative study of the soft-tissue bed contributions to blood flow in canine nerve grafts. J Hand Surg Am 2002; 27 (6) 1041-1047
• 32 Best TJ, Mackinnon SE, Midha R, Hunter DA, Evans PJ. Revascularization of peripheral nerve autografts and allografts. Plast Reconstr Surg 1999; 104 (1) 152-160
• 33 Lee WP, Constantinescu MA, Butler PE. Effect of early mobilization on healing of nerve repair: histologic observations in a canine model. Plast Reconstr Surg 1999; 104 (6) 1718-1725
• 34 Rovak JM, Mungara AK, Aydin MA, Cederna PS. Effects of vascular endothelial growth factor on nerve regeneration in acellular nerve grafts. J Reconstr Microsurg 2004; 20 (1) 53-58