Increased vascularisation enhances axonal regeneration within an acellular nerve conduit

Despite major advances in microsurgical techniques, the functional results of periphery nerve repair remain largely unsatisfactory. Furthermore, if a defect exists such that a nerve graft is required, the results are generally worse than those following a primary repair. The autologous nerve graft, the current 'gold standard', has inherent disadvantages and there has been a long quest to find a suitable alternative. The role of vascularisation in nerve regeneration is poorly defined and the aim of this work was to define and quantify the effects of increased vascularisation on nerve regeneration. Rat sciatic nerve defects (1 cm) were bridged with a silicone chamber containing vascular endothelial growth factor (VEGF; 500 or 700 ng/ml) in a laminin-based gel (Matrigel) known to support axonal regeneration. Chambers were harvested between 5 and 180 days to follow the progression of neural and vascular elements. Following immunohistochemical staining, computerised image analysis demonstrated that VEGF significantly increased vascular, Schwann cell and axonal regeneration within the chamber up to 30 days post-insertion, and stimulated regeneration of up to 78% more myelinated axons at 180 days, compared to plain Matrigel control. Furthermore, the non-linear vascular dose-response to VEGF was clearly reflected in the Schwann cell and axonal staining intensity, supporting the highly significant relationship between vascularisation and Schwann cell staining seen within the chamber (P <0.001). Target-organ re-innervation at 180 days was similarly enhanced by VEGF in an identical dose-dependant manner. VEGF at 500 ng/ml increased recovery of gastrocnemius muscle weight by 17% and footpad innervation by 51% (P <0.05) compared to control, indicating the long-term functional benefits of VEGF.