Conditioning electrical stimulation after nerve injury: a clinically feasible strategy to enhance peripheral nerve regeneration.

Abstract

Early repair of transected peripheral nerves is advocated to maximize recovery; however, clinical delays are common. Conditioning, a well-known method accelerating nerve regeneration, has never been used in a postinjury setting. The authors tested whether postinjury, prerepair conditioning electrical stimulation (CES) can biologically bridge the interval to surgery so that a delayed repair (DR) yields outcomes comparable to, or greater than, an immediate repair (IR). Adult male Sprague Dawley rats were randomized to 4 cohorts: 1) CES-cut-IR (CES 1 week before nerve cut + IR), 2) cut-IR (cut and IR, no CES), 3) cut-DR (cut, DR 10 days later, no CES), and 4) cut-CES-DR (nerve cut, CES on postinjury day 3, DR 7 days later). Outcomes evaluated included axon extension 14 days postrepair, sensory recovery (von Frey thresholds, intraepidermal nerve fiber density), and motor recovery (toe-spread and ladder-rung performance, compound muscle action potential [CMAP] amplitudes, gastrocnemius mass, and innervated neuromuscular junctions [NMJs]). For all outcomes evaluated, postinjury CES significantly improved regeneration and reinnervation when compared with no-CES controls. Furthermore, this cohort also had outcomes comparable to the IR cohort that had been treated with CES. Axon extension was comparable between the cut-CES-DR (12.5 ± 0.9 mm) and the CES-cut-IR positive-control cohort (12.1 ± 0.7 mm), and significantly longer than cut-IR (6.9 ± 0.6 mm, p < 0.001) and cut-DR (7.2 ± 0.5 mm, p < 0.001) controls. Between 7 and 8 weeks postrepair, sensory recovery assessed with von Frey filaments identified sensory recovery in the cut-CES-DR cohort comparable to the CES-cut-IR positive control, and significantly greater than the cut-IR and cut-DR controls (both p < 0.001); these results were confirmed on intraepidermal nerve fiber density counts. At 8 weeks, motor function was improved in the cut-CES-DR cohort (toe spread 73.2% contralateral; ladder score 5.0 ± 0.1) versus cut-IR and cut-DR cohorts (approximately 43%; scores 3.6 and 3.3, respectively; p < 0.001), approximating CES-cut-IR cohort. This was confirmed by CMAP amplitudes, gastrocnemius muscle mass, and quantification of innervation NMJs, which demonstrated similar trends. A single, brief CES session delivered after injury and before repair enables delayed neurorrhaphy to recapitulate IR biology, significantly improving regeneration and reinnervation over delayed or IR without CES. This is the first demonstration of a conditioning-like effect in the clinically relevant situation of an already transected nerve. These results position postinjury CES as a practical bridge to surgery for timing-constrained nerve repairs.