Conditioning Electrical Stimulation Enhances Regenerative Potential in Chronic Nerve Injuries
Jenna-Lynn B Senger, MD, PhD1, Karyne Rabey, PhD1, Ming Chan, MD, FRCP2 and Christine A Webber, PhD1, (1)University of Alberta, Edmonton, AB, Canada, (2)Division of Plastic and Reconstructive Surgery, University of Alberta, Edmonton, AB, Canada
Background: Chronically injured nerves pose a significant clinical challenge that usually results in poor functional recovery despite surgical management. There are currently few clinically feasible perioperative techniques to upregulate a pro-regenerative environment in the setting of a chronic nerve injury. Our lab has shown that conditioning electrical stimulation (CES) significantly improves sensorimotor recovery in acute nerve injury to the tibial and common fibular nerves.
Methods: The tibial nerve of fifty Sprague-Dawley rats was cut and the proximal ends were inserted into the closely apposed hamstring muscles to prevent spontaneous reinnervation into the distal nerve stump. Two months post-injury, animals were randomized and half were treated with one hour of CES to the sciatic nerve. Twenty animals were culled three days following conditioning to evaluate the effects of CES on the expression of regeneration associated genes (RAGs) at the cell body and Schwann cells activation in the nerve. In the remaining thirty animals, the tibial nerve defect was reconstructed using a 1 cm autograft. Length of nerve regeneration was assessed three weeks post-grafting (n=5/cohort), and functional recovery was evaluated weekly between seven and seventeen weeks of regeneration (n=10/cohort).
Results: CES to the chronically injured nerves induced pro-regenerative changes in the microenvironment typically identified in the setting of an acute nerve injury, such as upregulation of RAGs including brain derived neurotrophic factor, growth associated factor 43 and glial fibrillary associated protein. Chronically injured nerves treated with CES prior to grafting had a significantly longer length of nerve regeneration (p<0.01). Von Frey analysis identified improved sensory recovery amongst animals treated with CES (p<0.01). Motor reinnervation was improved, as assessed by kinetics and kinematics evaluation and skilled motor tasks; these findings were supported by immunohistochemical quantification of motor endplate reinnervation (p<0.05).
Conclusions: Regeneration following chronic axotomy and denervation is impaired due to downregulation of the pro-regenerative environment generated acutely following nerve injury. CES delivered to a chronically injured nerve influences the cell body and the nerve to re-upregulate an environment that supports axonal extension, resulting in significant improvements in sensory and motor functional recovery. Percutaneous CES may be a preoperative strategy to significantly improve outcomes for patients undergoing delayed nerve reconstruction.
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