From left to right: Christine A. Webber, PhD; Jenna-Lynn Senger, MD, PhD; K. Ming Chan, MD
Conditioning Electrical Stimulation Accelerates Nerve Regeneration to Promote Functional Recovery
Jenna-Lynn Senger, MD PhD1; K. Ming Chan, MD2; Christine A. Webber, PhD3.
1Division of Plastic Surgery, Department of Surgery; 2Division of Physical Rehabilitation; 3Division of Anatomy, Department of Surgery, University of Alberta, Edmonton, CANADA
Corresponding Author: Christine A. Webber
Peripheral nerve injuries are heterogeneous in the patient population affected, extent of functional deficits, and projected recovery. Poor outcomes are attributable to the slow intrinsic rate of nerve regeneration. A strategy to accelerate this process is of paramount clinical importance. A conditioning crush lesion (CCL) – crushing a nerve one week prior to nerve cut and repair – significantly accelerates axonal extension. However, clinical translation of a CCL is impossible due to its injurious nature. Our laboratory has shown that conditioning electrical stimulation (CES) is a clinically feasible method of delivering a conditioning-like effect to accelerate regeneration and improve functional nerve recovery (Senger et al., 2018; 2019).
In a Sprague-Dawley rat model, the regenerative capacity of CES was compared to CCL and negative controls (Figure 1). Our results demonstrated that CES upregulates genes necessary for regeneration, with axonal length and sensory (von Frey filaments, nerve counts) and motor (horizontal ladder, toe spread width, nerve conduction studies, neuromuscular junction analysis) reinnervation outcomes superseding CCL (Senger et al., 2018; 2019). These results support our hypothesis that pre-injury electrical stimulation delivers a conditioning effect.
To lay a foundation for clinical translation, we assessed the effects of CES on promoting reinnervation in nerve grafting (Figure 1). To mimic autologous nerve graft repair surgeries, a gap was created in the rat tibial nerve and repaired with a 0.5 cm nerve autograft. Regeneration and reinnervation outcomes of animals treated with CES were significantly greater animals treated with post-operative electrical stimulation (PES) or no-stimulation (presented at ASPN, 2019).
Our results suggest CES significantly improves regeneration and reinnervation outcomes beyond the conditioning ‘gold-standard’ CCL; however, unlike a CCL, electrical stimulation has been translated to the bedside (Gordon et al., 2010; Wong et al., 2015; Power et al., 2019). There are key questions that need to be answered to optimize CES for patients, the most obvious being the influence of the nerve length discrepancy between rats and humans. Is a week gap between CES and nerve surgery adequate or is more time needed to account for the increased nerve length in humans? Does the CES need to be at the site immediately proximal to the injury repair site (as we have done in our rodent model?) or can CES be performed much more proximally? Importantly, what is the mechanism in which CES promotes nerve regeneration and repair? It would be ideal to uncover the answer to these questions to provide a foundation for clinical translation.
The potential clinical applications for CES are numerous. Significantly, as more nerve injuries are being treated electively rather than urgently, the ability to provide CES prior to surgical management is increasing.