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Conditioning Electrical Stimulation to Enhance Regeneration and Reinnervation Following Peripheral Nerve Injury

  • Author / Creator
    Senger, Jenna-Lynn
  • Background: Peripheral nerve injury is common, identified in 3% of patients presenting to major emergency centers. 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), in which the nerve is crushed one week prior being cut and repaired, significantly accelerates axonal extension. Clinical translation of a CCL, however, is impossible due to the injurious nature of a crush lesion. Identification of a non-injurious technique to induce a conditioning effect is therefore of significant clinical importance.

    Hypothesis: Conditioning electrical stimulation (CES) is a clinically feasible method of delivering a conditioning-like effect to accelerate regeneration and improve functional nerve recovery.

    Aim 1: Determine if CES improves nerve regeneration and sensorimotor reinnervation.
    In a Sprague-Dawley rat model, the regenerative capacity of CES was compared to CCL and negative controls. CES was found to upregulate the genes necessary for regeneration, with axonal length and sensory (von Frey filaments, nerve counts) and motor (horizontal ladder, toespread width, nerve conduction studies, neuromuscular junction analysis) reinnervation outcomes superseding CCL. These results support our hypothesis that pre-injury electrical stimulation delivers a conditioning effect

    Aim 2: Compare the effects of CES with PES.
    Postoperative electrical stimulation (PES) delivered immediately after nerve repair improves patient sensorimotor outcomes, and is a clinical perioperative technique at many institutions. To compare CES vs. PES and determine if a synergistic effect can be obtained, animals were divided into a) CES, b) PES, c) CES+PES, and d) negative control. Animals treated with CES had significantly longer lengths of nerve regeneration and improved sensorimotor recovery compared to all other cohorts; no synergistic effect was identified when combining CES + PES.

    Aim 3: Investigate the effect of CES in three common clinical scenarios: nerve grafting, distal nerve transfer, and primary nerve repair, nerve grafting. To lay a strong foundation for clinical translation, we assessed the effects of CES on promoting reinnervation following three common nerve surgeries in which clinical outcomes are inadequate. In all three studies, length of regeneration and sensorimotor reinnervation outcomes were assessed as above.
    a) Nerve grafting: 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 PES or no-stimulation.
    b) Distal nerve transfer: a branch of tibial nerve was be sutured to the injured distal stump of the common peroneal nerve, in keeping with the common surgery to treat foot drop following common peroneal nerve injury. Animals treated with CES prior to nerve transfer had significantly greater motor recovery.
    c) Primary nerve repair: to mimic patients presenting with a nerve injury amenable to primary repair, the tibial nerve was transected; three days later, one cohort of animals received CES and the other did not. Nerve repair was performed 2 weeks after injury. Results demonstrate an improved length of regeneration and greater sensorimotor recovery in the CES animals, despite delaying surgery. As current guidelines mandate immediate nerve repair these results suggest the need for a change in clinical practice.

    Significance: Our results suggests CES significantly improves regeneration and reinnervation outcomes beyond the conditioning ‘gold-standard’ CCL. Unlike a crush lesion, however, CES can be translated to the bedside given its noninjurious nature. CES outcomes supersede the gold-standard adjuvant to surgical repair, PES, suggesting the need to change perioperative management of patients with peripheral nerve injury. CES consistently resulted in greater functional recovery in common surgical procedures including nerve autograft reconstruction, distal nerve transfer, and primary repair. As electrical stimulation is already established as safe in humans, randomized controlled trials to investigate CES in clinical practice are required. CES may dramatically improve clinical outcomes and quality of life for patients with peripheral nerve injury.

  • Subjects / Keywords
  • Graduation date
    Fall 2019
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/r3-5ead-3e17
  • License
    Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.