Functional analysis of peripheral nerve regeneration in the rat and the partitioning of regeneration into 'regrowth' and 'functional recovery'

The rat sciatic nerve crush is the most widely used model of peripheral nerve injury. Nerve regeneration is most often assessed using histology, electrophysiology, or footprint analysis. Though useful indicators of regeneration, these measures do not necessarily correlate with functional recovery. The present study utilized an integrative approach to analyze functional recovery after peripheral nerve injury in rats requisite to evaluating the effects of insulin-like growth factor I (IGF-I), a know neurotrophic factor, on the regenerating rodent sciatic nerve. Techniques employed include high-speed videography during treadmill locomotion, force platform analysis, and in situ physiological measurements of the medial gastrocnemius (MG). Recovery was monitored every seven days for a 28-day recovery period following a defined sciatic nerve crush (500 g for 10 minutes). Significant findings are as follows: First, there is a 'period of functional reinnervation' occurring between post-operative day (POD)-14 and 21 coincident with reinnervation of the hindlimb and recovery of function. Second, hindlimb posture---documented by measuring the maximum angle formed by the foot and the horizontal and by assessing the location of the foot's center of pressure (COP) while stepping on a force platform---changes significantly from digitigrade (pre-crush) to plantigrade (post-crush) and back to digitigrade (recovery). Third, these postural changes correlate with reinnervation of the triceps surae evidenced by approximately 85% recovery of MG tetanic force output at POD-28. Fourth, at POD-14 there is no statistical indication of functional recovery by any of the assays employed though there is clearly nerve regrowth as evidenced by force produced by the MG. This suggests that there is a fundamental difference between nerve 'regrowth' and 'functional recovery' and the evaluation of regeneration should be similarly partitioned---at least one assay should evaluate regrowth and one should evaluate functional recovery. Finally, when employed to evaluate the effects of IGF-I delivered to the crush injury from ethylene vinyl acetate rods, there was no discernable augmentation of regeneration detected by any component of the model. Either IGF-I is not neurotrophic in the context of rigorous functional evaluation of motor recovery or too little IGF-I was used in an attempt to avoid side-effects.