Electrical Stimulation Promotes Regeneration of Defective Peripheral Nerves after Delayed Repair Intervals Lasting under One Month

Abstract

BackgroundElectrical stimulation (ES) has been proven to be an effective means of enhancing the speed and accuracy of nerve regeneration. However, these results were recorded when the procedure was performed almost immediately after nerve injury. In clinical settings, most patients cannot be treated immediately. Some patients with serious trauma or contaminated wounds need to wait for nerve repair surgery. Delays in nerve repair have been shown to be associated with poorer results than immediate surgery. It is not clear whether electrical stimulation still has any effect on nerve regeneration after enough time has elapsed.MethodsA delayed nerve repair model in which the rats received delayed nerve repair after 1 day, 1 week, 1 month, and 2 months was designed. At each point in time, the nerve stumps of half the rats were bridged with an absorbable conduit and the rats were given 1 h of weak electrical stimulation. The other half was not treated. In order to analyze the morphological and molecular differences among these groups, 6 ES rats and 6 sham ES rats per point in time were killed 5 days after surgery. The other rats in each group were allowed to recover for 6 weeks before the final functional test and tissue observation.ResultsThe amounts of myelinated fibers in the distal nerve stumps decreased as the delay in repair increased for both ES rats and sham ES rats. In the 1-day-delay and 1-week-delay groups, there were more fibers in ES rats than in sham ES rats. And the compound muscle action potential (CMAP) and motor nerve conduction velocity (MNCV) results were better for ES rats in these two groups. In order to analyze the mechanisms underlying these differences, Masson staining was performed on the distal nerves and quantitative PCR on the spinal cords. Results showed that, after delays in repair of 1 month and 2 months, there was more collagen tissue hyperplasia in the distal nerve in all rats. The brain-derived neurotrophic factor (BDNF) and trkB expression levels in the spinal cords of ES rats were higher than in sham ES rats. However, these differences decreased as the delay in repair increased.ConclusionsElectrical stimulation does not continue to promote nerve regeneration after long delays in nerve repair. The effective interval for nerve regeneration after delayed repair was found to be less than 1 month. The mechanism seemed to be related to the expression of nerve growth factors and regeneration environment in the distal nerves.

Rehabilitative Surgery

“…The number of regenerating motoneurons and myelinated axons in the distal nerve stump declined dramatically in the 3-and 6-month groups with greater muscle atrophy and neuromuscular junction changes. Key changes of muscles include fragmentation of the neuromuscular junction [350]. Electrical stimulation accelerates peripheral nerve regeneration up to 1 month after injury but not in nerves that were repaired more than a month after injury, possibly due to fibrosis in the distal stump [92,124,340,351].…”

Chronic Electrical Nerve Stimulation as a Therapeutic Intervention for Peripheral Nerve Repair

“…A metallic wire (cathode) is typically wrapped around the proximal nerve, and a second wire electrode (anode) is inserted within a distal muscle or wrapped along the nerve distally. Such an electrode configuration is commonly implemented for acute stimulation following a nerve crush injury, nerve transection with end-to-end suturing of the proximal and distal nerve stumps (16)(17)(18)(19)(25)(26)(27) or nerve repair facilitated by a biocompatible conduit sutured between both nerve stumps (21,28). Their impedance is typically in the 10-s MΩ range because of their small effective surface area.…”

“…To facilitate retrograde protein transport along the axons, neurofilament genes (NF-L/M/H mRNA) are concomitantly downregulated (7). Acute electrical stimulation (1 h, 20 Hz) applied immediately after injury proximal to the injured nerve appears to lead to a more robust and earlier phenotypic switch (16,17) with, for example, enhanced mRNA and protein expression of BDNF and GAP-43 in adult sensory neurons (21,26,29,30). In a recent study, androgen receptor signaling was elucidated as a possible cascade activated by electrical stimulation (31).…”

“…Electrical stimulation has been also envisioned as a potential complementary therapy to microsurgical repair after peripheral nerve injury to improve functional outcomes by promoting a greater and faster axonal regeneration. A number of preclinical studies across a number of nerve injury models have shown that direct stimulation of injured peripheral nerves can enhance peripheral sensory (14,15) and motor (16)(17)(18) axon regeneration, increase target reinnervation (17,19) and improve electrophysiological outcomes (20,21) and functional recovery (14,15). To date, however, electrical stimulation is rarely used in a clinical context of nerve repair.…”

Improving Outcomes in Immediate and Delayed Nerve Grafting of Peripheral Nerve Gaps Using Light-Activated Sealing of Neurorrhaphy Sites with Human Amnion Wraps

“…[6][7][8][9][10] At the cellular level, others have reported success following the supplementation of stem cells and neurotrophic factors. [11][12][13][14] We propose a novel method that may enhance outcomes following delayed nerve gap repair by sealing the neurorrhaphy site, capturing endogenous regenerative factors within, and excluding unwanted mediators of scarring and inflammation.…”