Electrical Stimulation Accelerates Axonal and Functional Peripheral Nerve Regeneration across Long Gaps

Abstract

Short-term low-frequency electrical stimulation (ESTIM) of proximal peripheral nerve stumps prior to end-to-end coaptation or tubular bridging of small distances has been reported to increase preferential motor reinnervation and functional motor recovery in animal models and human patients undergoing carpal tunnel release surgery. We investigated the effects of ESTIM on regeneration across rat sciatic nerve gaps, which exceed distances that allow spontaneous regeneration. Three different reconstruction approaches were combined with ESTIM in the experimental groups. Nerve gaps (13 mm) were bridged using (I) nerve autotransplantation, (II) transplantation of differentially filled silicone tubes, or (III) transplantation of tubular grafts containing fibroblast growth factor-2 overexpressing Schwann cells (SCs) for gene therapy. The regeneration outcome was followed for up to 8 weeks, and functionally as well as histomorphometrically analyzed in comparison to non-stimulated control groups. Combining ESTIM with nerve autotransplantation significantly increased the nerve fiber density in the regenerated nerve, and the grade of functional recovery as detected by electrodiagnostic recordings from the gastrocnemius muscle. The combination of ESTIM with transplantation of naïve SCs increased the regeneration of gap-bridging nerve tissue. Although macroscopic tissue regeneration was not further improved after combining ESTIM with FGF-2(21/23-kD) gene therapy, the latter resulted in a high rate of regenerated nerves that functionally reconnected to the target muscle. Based on our results, brief ESTIM shows high potential to accelerate axonal as well as functional (motor and sensory) outcomes in the clinical setting of peripheral nerve gap reconstruction in human patients.

Chronic pudendal neuromodulation using an implantable microstimulator improves voiding function in diabetic rats

“…This finding indicated that the diabetic rats in our study underwent chronic subthreshold stimulation, because the fixed 10 μA intensity utilized in this study was lower than the threshold. Several studies have reported that monophasic stimulation pulses combined with a subthreshold stimulation intensity (1-10 μA) constituted an optimal ES parameter combination that successfully facilitated neuronal cell growth in transected sciatic nerves, as evidenced by a more mature nerve structure with a smaller cross-sectional area, more myelinated fibers, higher axon density, and a higher ratio of blood vessels to total nerve area compared with that in control groups [21,[30][31][32]. Although the pudendal nerve was not crushed or transected in our study, the same stimulation parameters (i.e.…”

Peripheral Nerve Regeneration Strategies: Electrically Stimulating Polymer Based Nerve Growth Conduits

“…96 Previous studies reported that the immediate application of ES following injury led to better nerve regeneration. 97 The intensity of applied ES, frequency, duration, and timing following nerve injury plays an important role in determining tissue healing. It was discovered that introducing a seven-day incubation (delayed ES) period following cell seeding led to an increased rate of regeneration and resulted in enhanced maturity of the neural components within the growth conduit.…”

The Parameters of Transcutaneous Electrical Nerve Stimulation Are Critical to Its Regenerative Effects When Applied Just after a Sciatic Crush Lesion in Mice

“…However, the parameters of electrical stimulation appear to be critical for obtaining the desired results. Numerous studies have shown that low-frequency electrical stimulation applied by means of electrodes in direct contact with the nerve after injury and surgical repair may improve nerve regeneration and accelerate reinnervation of the target organs [4], increase nerve fiber density and diameter [5], enhance myelination and angiogenesis [6], and increase nerve growth factor (NGF) [7] and brain-derived neurotrophic factor (BDNF) release and expression [8]. …”