Role of timing in assessment of nerve regeneration

Abstract

Small animal models are indispensable for research on nerve injury and reconstruction, but their superlative regenerative potential may confound experimental interpretation. This study investigated time-dependent neuroregenerative phenomena in rodents. Forty-six Lewis rats were randomized to three nerve allograft groups treated with 2 mg/(kg day) tacrolimus; 5 mg/(kg day) Cyclosporine A; or placebo injection. Nerves were subjected to histomorphometric and walking track analysis at serial time points. Tacrolimus increased fiber density, percent neural tissue, and nerve fiber count and accelerated functional recovery at 40 days, but these differences were undetectable by 70 days. Serial walking track analysis showed a similar pattern of recovery. A 'blow-through' effect is observed in rodents whereby an advancing nerve front overcomes an experimental defect given sufficient time, rendering experimental groups indistinguishable at late time points. Selection of validated time points and corroboration in higher animal models are essential prerequisites for the clinical application of basic research on nerve regeneration.Much of our understanding of nerve regeneration is derived from experiments in small animal models. This research is premised upon the notion that observations in mice or rats have direct implications for related biological phenomena in human patients. While rodent models offer advantages of small size and suitability for performing experimental neurorrhaphy, data from these models must be evaluated critically. In the rodent, exceptional regenerative capacity, short limb length, and biological variability among animals all conspire to obscure key differences between experimental groups. As a result, type II errors -in which a difference exists between groups but fails to be detected-may be more common than generally recognized.It was hypothesized that, due to superior regenerative potential observed in rodents, there exists only a finite window of opportunity for making accurate assessments of nerve regeneration in this model. The present study employed an established nerve allograft model

The new heterologous fibrin sealant in combination with low-level laser therapy (LLLT) in the repair of the buccal branch of the facial nerve

“…Processing for optical microscopy and transmission electron microscopy After 5 and 10 weeks of the surgical procedure [30,31], in each period, five animals in the control group and eight animals from each experimental group were euthanized with an Boverdose^of anesthesia to collect the intact buccal branch of the facial nerve from the control group and the distal stump from the buccal branch of the facial nerve in animals from the experimental groups.…”

Comparison of the Performance of Chronically Versus Freshly Denervated Autograft in Nerve Repair

“…A recently described "blowthrough" effect in this animal model suggests that regardless of experimental variables, if too much time is allowed for nerve regeneration, enough axons will eventually regenerate to skew study outcomes. 24 The sweet spot between functional recovery and this blowthrough effect is still being worked out. We chose the 8-week recovery time used in this study to fall within this time range, although serial testing would be necessary to confirm this.…”

The Effect of Chondroitinase on Nerve Regeneration Following Composite Tissue Allotransplantation

“…At longer end points, it has been shown that the superlative regenerative capacities of rodents will mask real differences between treatment groups, with axonal counts eventually equalizing over time. 29 Having demonstrated early histological evidence of improved nerve regeneration, for the reasons mentioned earlier, follow-up studies using longer time points are now necessary to assess functional return. However, the results from this study serve to highlight the promise of chondroitinase as an agent to enhance nerve regeneration and functional outcomes after hand transplantation.…”