Short-Duration, Pulsatile, Electrical Stimulation Therapy Accelerates Axon Regeneration and Recovery following Tibial Nerve Injury and Repair in Rats

Abstract

Background: Repair of nerve injuries can fail to achieve adequate functional recovery. Electrical stimulation applied at the time of nerve repair can accelerate axon regeneration, which may improve the likelihood of recovery. However, widespread use of electrical stimulation may be limited by treatment protocols that increase operative time and complexity. This study evaluated whether a short-duration electrical stimulation protocol (10 minutes) was efficacious to enhance regeneration following nerve repair using rat models. Methods: Lewis and Thy1–green fluorescent protein rats were randomized to three groups: 0 minutes of electrical stimulation (no electrical stimulation; control), 10 minutes of electrical stimulation, and 60 minutes of electrical stimulation. All groups underwent tibial nerve transection and repair. In the intervention groups, electrical stimulation was delivered after nerve repair. Outcomes were assessed using immunohistochemistry, histology, and serial walking track analysis. Results: Two weeks after nerve repair, Thy1–green fluorescent protein rats demonstrated increased green fluorescent protein–positive axon outgrowth from the repair site with electrical stimulation compared to no electrical stimulation. Serial measurement of walking tracks after nerve repair revealed recovery was achieved more rapidly in both electrical stimulation groups as compared to no electrical stimulation. Histologic analysis of nerve distal to the repair at 8 weeks revealed robust axon regeneration in all groups. Conclusions: As little as 10 minutes of intraoperative electrical stimulation therapy increased early axon regeneration and facilitated functional recovery following nerve transection with repair. Also, as early axon outgrowth increased following electrical stimulation with nerve repair, these findings suggest electrical stimulation facilitated recovery because of earlier axon growth across the suture-repaired site into the distal nerve to reach end-organ targets. Clinical Relevance Statement: Brief (10-minute) electrical stimulation therapy can provide similar benefits to the 60-minute protocol in an acute sciatic nerve transection/repair rat model and merit further studies, as they represent a translational advantage.

The Effect of Electrical Stimulation on Nerve Regeneration Following Peripheral Nerve Injury

“…Both ES groups, however, demonstrated accelerated axonal regeneration compared to control based on labeled regenerating motoneuron axons, myelinated axon counts, and walking track analysis [ 88 ]. Roh et al further corroborated these findings, showing that 10 min of ES is sufficient to elicit similar therapeutic effects to one-hour of ES in transection and repair murine models [ 64 ]. The mechanism of ES remains incompletely understood.…”

“…Al-Majed additionally demonstrated that short-term ES (one-hour) was equally beneficial to long-term (2 weeks) [ 17 ]. Further evidence from Roh et al found that 10 min of ES (16 Hz, 100 μsec) was equally beneficial to one-hour of continuous ES highlighting the clinical translatability of ES therapy [ 64 ].…”

“…The most heavily researched protocol for delivering ES therapy has been one-hour delivered immediately following nerve repair. However, this protocol increases operative time and creates additional complexity for both the surgeon and hospital [ 64 ]. Short-duration ES protocols (i.e., 10 min) would improve clinical translation and limit peri-operative complexity.…”

“…The mechanism of ES remains incompletely understood. This evidence suggests that axonal regeneration is not entirely dependent on the duration of ES, but other metrics, perhaps the number of elicited action potentials [ 64 ]. Further studies are warranted to understand the mechanism of 10 min protocols on axonal regeneration.…”

“…Building on promising pre-clinical evidence [ 64 , 88 ], a multi-center, double-blind RCT from Moore et al is evaluating patient outcomes following a 10 min ES protocol [ 114 ]. In this study, patients undergoing cubital tunnel decompression surgery are randomized to receive 10 min of 20 Hz ES intraoperatively or no stimulation.…”