The effect of scarring on regeneration following peripheral nerve repair

Objectives: Recovery following peripheral nerve repair is variable and never complete. This study was designed to establish whether scar formation at the repair site influences the outcome by forming a mechanical barrier to the regenerating axons. Methods: Regeneration of the sciatic nerve was assessed in C57-black-6 mice and compared with the outcome in two transgenic strains; IL-4/IL-10 null and mannose-6-phosphate receptor/IGF2 null, which have an increased and decreased propensity for scarring respectively (10 animals/group). Under general anaesthesia (Fentanyl/Fluanisone 0.8ml/kg & Midazolam 4mg/kg, i.p. Janissen/Roche) the nerve was sectioned and repaired using 4 epineurial sutures. After 6 weeks the outcome was assessed blind by determining; (1) the percentage area of picrosirius red staining (PAS) for collagen at the repair site (2) the ratio of the compound action potential (CAP) modulus evoked by electrical stimulation 2mm distal or proximal to the repair, and the conduction velocity of the fastest fibres (3) the number, area and density of myelinated axons at the same sites. Comparisons were made with data from sham-operated controls. Results: As predicted the PAS for collagen was significantly higher in the IL-4/IL-10 null group (median 6.35%) than the M6PR/IGF2 group (3.78%, p<0.01, Kruskal-Wallis test). CAP ratios were smaller in the IL-4/IL-10 group (median 0.34) than in the M6PR/IGF2 group (0.55, p<0.05). Conduction velocities were significantly slower in the IL-4/IL-10 group (mean 21.0 m s-1) than in sham-operated controls (40.5 m s-1, p<0.01, Tukey-Kramer test), but the M6PR/IGF2 group were not significantly different from controls. Cross-sectional areas of the nerve trunks were lower distally in the IL-4/IL-10 group, and the population density of myelinated fibres was higher. Conclusion: These data show that scarring at a site of peripheral nerve repair significantly impedes regeneration and suggest that the therapeutic application of scar-preventing agents could be beneficial. Supported by the Wellcome Trust (074500).