Embedded Files
Our research aims to accelerate nerve regeneration to improve sensory and motor outcomes.
Our research aims to accelerate nerve regeneration to improve sensory and motor outcomes.
In our animal work, we have shown that electrical stimulation a week before a nerve repair surgery 'primes' the nerve for regeneration. If we compare the speed of nerve regeneration of a tibial nerve repair surgery with or without this conditioning electrical stimulation (one week prior), the conditioned electrically stimulated nerves grow 4-5 times as fast. We have gone on to show that at 2-3 months post nerve repair surgery, these animals have improved sensation to their feet, and improved motor control over their feet, compared to the animals that did not received electrical stimulation prior to the nerve repair surgery.
As electrical stimulation has been used clinically (same amount and length of stimulation) with no adverse effects we will be able to transition to clinical trials in the future.
Diagrammatic representation of distal nerve transfer to mimic foot drop repair surgery. (A) Diagram shows the normal anatomy of the sciatica nerve and its 3 main nerve branches at its trifurcation site. The tibial nerve innervates the gastrocnemius muscle, whereas the common fibular nerve innervates the tibialis anterior muscle, which is responsible for ankle dorsiflexion of the toes during the step cycle. (B) For the nerve length and the behavioral analyses, all animals first received common fibular nerve transection on day 0, and 1 week later half of those animals received conditioning electrical stimulation (CES; depicted as a lightning bolt). (C) All animals underwent distal nerve transfer surgery on day 14 in which the tibial branch to the lateral of the gastrocnemius muscle (depicted as the blue nerve) was relocated to the distal stump of the common fibular nerve.
Our work has shown that conditioning electrical stimulation promotes nerve regeneration,
following nerve repair surgery, up to 5 fold more than unconditioned control nerves (Senger et al., 2018;
Senger et al., 2019).
We have two streams of research in which to follow this basic science study.
- Design experiments to provide a clinically feasible paradigm to test the effects of conditioning electrical stimulation
a. Chronic nerve injury: Patients with chronic nerve injury undergo surgical nerve repair to try to improve the nerve’s functional outcome. We have designed a chronic nerve injury condition in the rat in which to determine if conditioning electrical stimulation will accelerate nerve regeneration to improve the often poor outcome of these surgeries.
b. Graft nerve transfer: Patients will acute nerve injury may need a nerve transfer (use a piece of nerve from another part of the body) to bridge the gap between the proximal and distal injury sites. We have designed a nerve graft experiment in which a conditioning electrical stimulation prior to the nerve graft surgery will promotes nerve regeneration.
c. Distal nerve transfer: Patients with nerve injury can have a nearby nerve re-routed to reinnervate the area recently denervated by the injury. We have designed an animal paradigm in which the nerve is conditioned with electrical stimulation prior to the distal nerve transfer surgery.
Experimental design of surgical and treatment paradigms.(A) Artistic illustration of the investigations to determine which combination of CES ± PES promotes the greatest extent of nerve regeneration. Animals were divided into four cohorts: CES, PES, CES + PES, and no ES. CES was delivered to the tibial nerve 7 days prior to nerve transection and repair. PES was delivered to the tibial nerve proximal to the site of nerve injury and coaptation, immediately following repair. CES + PES received electrical stimulation at both time points and negative control animals received neither stimulation paradigm.
Experimental design of conditioning paradigm and cut and microsurgical repair.Step 1 (Day 0): conditioning of the common peroneal (CP) nerve with CCL, CES, or sham CES 20 mm distal to the sciatic trifurcation. The naïve group does not undergo surgery at this time. Step 2 (Day 7): the CP nerve is cut 10 mm proximal to the site of conditioning (10 mm distal to the sciatic trifurcation) and an epineurial repair is performed.
2. Design experiments to determine the mechanism in which conditioning electrical stimulation promotes nerve regeneration.
2. Design experiments to determine the mechanism in which conditioning electrical stimulation promotes nerve regeneration.
This is an elaborate basic science series of experiments to determine the signaling pathways, ion channels, time-line of events, role of inflammation, gene and protein regulation etc. evoked by conditioning electrical stimulation to promote nerve regeneration.
CES promotes nerve regeneration greater than PES or CES + PES.
A) Representative photomicrographs of NF-200 labelled longitudinal sections (12 μm thick) of the tibial nerve at 7 days of regeneration. Yellow line depicts the site of cut and coaptation, and green lines indicate the distal-most point of regeneration to which a minimum of 10 axons extended. Positive immunostaining beyond the green line depicts neurofilament undergoing Wallerian degeneration which is easily identified under the microscope. (B) Line graph depicts the average length of axonal regeneration on the x-axis and number of regenerating axons on the y-axis. Nerves treated with CES (blue) had a significantly longer length of axon extension and a greater number of axons present at every 250 μm intervals, when compared to nerves treated with PES (red), CES + PES (purple), and negative controls (green). (C) The average length of regeneration demonstrated that at one week, the CES cohort was superior to PES, CES + PES, and no ES animals (p < .001). ANOVA statistical analysis was performed followed by Bonferroni post-hoc analysis (*p < .05, **p < .01, ***p < .001). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Page updated
Report abuse