Rapid-stretch injury to peripheral nerves: implications from an animal model

Abstract

OBJECTIVERapid-stretch nerve injuries are among the most devastating lesions to peripheral nerves, yielding unsatisfactory functional outcomes. No animal model has yet been developed that uses only stretch injury for investigation of the pathophysiology of clinical traction injuries. The authors’ objective was to define the behavioral and histopathological recovery after graded rapid-stretch nerve injury.METHODSFour groups of male B6.Cg-Tg(Thy1-YFP)HJrs/J mice were tested: sham injury (n = 11); stretch within elastic limits (elastic group, n = 14); stretch beyond elastic limits but before nerve rupture (inelastic group, n = 14); and stretch-ruptured nerves placed in continuity (rupture group, n = 16). Mice were injured at 8 weeks of age, comparable with human late adolescence. Behavioral outcomes were assessed using the sciatic functional index (SFI), tapered-beam dexterity, Von Frey monofilament testing, and the Hargreaves method. Nerve regeneration outcomes were assessed by wet muscle weight and detailed nerve histology after 48 days.RESULTSPost hoc biomechanical assessment of strain and deformation confirmed that the differences between the elastic and inelastic cohorts were statistically significant. After elastic injury, there was a temporary increase in foot faults on the tapered beam (p < 0.01) and mild reduction in monofilament sensitivity, but no meaningful change in SFI, muscle weight, or nerve histology. For inelastic injuries, there was a profound and maintained decrease in SFI (p < 0.001), but recovery of impairment was observed in tapered-beam and monofilament testing by days 15 and 9, respectively. Histologically, axon counts were reduced (p = 0.04), muscle atrophy was present (p < 0.01), and there was moderate neuroma formation on trichrome and immunofluorescent imaging. Stretch-ruptured nerves healed in continuity but without evidence of regeneration. Substantial and continuous impairment was observed in SFI (p < 0.001), tapered beam (p < 0.01), and monofilament (p < 0.01 until day 48). Axon counts (p < 0.001) and muscle weight (p < 0.0001) were significantly reduced, with little evidence of axonal or myelin regeneration concurrent with neuroma formation on immunofluorescent imaging.CONCLUSIONSThe 3 biomechanical grades of rapid-stretch nerve injuries displayed consistent and distinct behavioral and histopathological outcomes. Stretch within elastic limits resembled neurapraxic injuries, whereas injuries beyond elastic limits demonstrated axonotmesis coupled with impoverished regeneration and recovery. Rupture injuries uniquely failed to regenerate, despite physical continuity of the nerve. This is the first experimental evidence to correlate stretch severity with functional and histological outcomes. Future studies should focus on the pathophysiological mechanisms that reduce regenerative capacity after stretch injury.