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

Abstract

Peripheral nerve injuries (PNI) are common and often result in lifelong disability. The peripheral nervous system has an inherent ability to regenerate following injury, yet complete functional recovery is rare. Despite advances in the diagnosis and repair of PNIs, many patients suffer from chronic pain, and sensory and motor dysfunction. One promising surgical adjunct is the application of intraoperative electrical stimulation (ES) to peripheral nerves. ES acts through second messenger cyclic AMP to augment the intrinsic molecular pathways of regeneration. Decades of animal studies have demonstrated that 20 Hz ES delivered post-surgically accelerates axonal outgrowth and end organ reinnervation. This work has been translated clinically in a series of randomized clinical trials, which suggest that ES can be used as an efficacious therapy to improve patient outcomes following PNIs. The aim of this review is to discuss the cellular physiology and the limitations of regeneration after peripheral nerve injuries. The proposed mechanisms of ES protocols and how they facilitate nerve regeneration depending on timing of administration are outlined. Finally, future directions of research that may provide new perspectives on the optimal delivery of ES following PNI are discussed.

Keywords: electrical stimulation; nerve regeneration; nerve repair; peripheral nerve.

Figure 1

Activated Schwann cells (SCs) and recruited macrophages phagocytose axonal and myelin debris following a nerve injury. Neurotrophic factors stimulate SCs to replicate and extend over arrays of extracellular matrix proteins to form the bands of Büngner, which guide the extending growth cone across the site of injury. Prolonged denervation can result in poor nerve regrowth and target scar formation. (Used with permission of Mayo Foundation for Medical Education and Research, all rights reserved.).

Figure 2

Electrical stimulation proximal to the injury site stimulates the upregulation of RAG through a calcium-dependent mechanism. Increased expression of BDNF and trkB drives increased expression of cAMP which activates CREB to maximize the pro-regenerative axon phenotype, stimulating axonal sprouting and neuron survival. BDNF = brain derived neurotrophic factor; cAMP = cyclic adenosine monophosphate; CREB = cAMP response element binding protein; trkB = tyrosine receptor kinase B; pKA = phosphokinase A; GAP-43 = growth-associated protein; MAPK = mitogen-activated protein kinase. Adapted from Zuo, K. J., Gordon, T., Chan, K. M., & Borschel, G. H. (2020). Electrical stimulation to enhance peripheral nerve regeneration: Update in molecular investigations and clinical translation. Experimental Neurology, 332, 113397.

Figure 3

Keane et al. investigated the interaction between perioperative lidocaine (3 mL of 2%) and 10 min of postoperative ES (20 Hz). Rats were randomized to receive (a) ES alone, (b) ES + pre-operative (PreOp) lidocaine, or (c) ES + post-operative (PostOp) lidocaine. Quantitative evaluation of histomorphometric parameters 21 days after tibial nerve transection and repair. Data was expressed as mean $\pm$ SD (n = 12/group). ** p < 0.01, * p < 0.05. Lido = lidocaine; SD = standard deviation; ES = electrical stimulation. Used with permission from SAGE publishing from Keane, G.C.; Marsh, E.B.; Hunter, D.A.; Schellhardt, L.; Walker, E.R.; Wood, M.D. Lidocaine Nerve Block Diminishes the Effects of Therapeutic Electrical Stimulation to Enhance Nerve Regeneration in Rats. Hand (NY) 2022.