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Chi et al. Plast Aesthet Res 2023;10:56 https://dx.doi.org/10.20517/2347-9264.2023.48 Page 7 of 13

[62]
by the BDNF gene, and its receptor trkB . BDNF is a highly conserved developmental gene strongly
[12]
expressed in motor neurons that plays a central role in signal transduction via the cyclic AMP pathway .
By maintaining cAMP by BDNF-mediated phosphodiesterase inhibition, the Rho signaling pathway is
inhibited and tubulin cytoskeleton assembly is enhanced to promote nerve regeneration [63,64] .

Electrostimulation also appears to induce effects outside of the neuron by exerting influence on Schwann
cells. In vitro experiments on cultured Schwann cells found that an induced electrical field caused a greater
than 4-fold increase in nerve growth factor (NGF) and increased cellular proliferation that was mediated by
calcium signaling . Sciatic crush injuries in the rat model not only found increased axonal regeneration
[65]
mediated by BDNF but also earlier and increased myelination by Schwann cells . Industry efforts to
[66]
produce such specific upregulation of these neuroregenerative pathways have been challenging at best,
demonstrating the need for clinical translation of electrostimulation into the operating rooms and clinics .
[67]
Electrostimulation parameters
While most of the experimental studies studied immediate electrostimulation following immediate nerve
injury and repair, clinical practice does not fit that experimental picture since any surgical repair likely
occurs at some delayed time following the injury. Electrostimulation performed during delayed nerve repair
three months after injury found that axonal regeneration was still significantly increased . Furthermore,
[68]
when functional outcomes were assessed five months after electrostimulation, motor strength as measured
by twitch and contraction force was similar to the immediate repair and electrostimulation group.

The most commonly utilized duration of electrostimulation in animal studies has been one hour at 20 Hz
frequency; however, intraoperative stimulation of this duration would add significant financial and time
expenditures to nerve repair surgeries. To test whether a shorter duration of electrostimulation would still
be efficacious, ten-minute periods with a 2 mA current and 100-us pulse width were compared to one-hour
periods in a rat study. Using the tibial nerve transection model, the shorter time period was found to still
[69]
improve nerve regeneration and was not inferior to the one-hour duration [Figure 3A-C] . When the same
parameters were utilized on a propensity-matched cohort of patients undergoing cubital tunnel release, the
electrostimulation group demonstrated significant improvement in the Disabilities of the Arm, Shoulder,
and Hand (DASH) questionnaire by 11.7 points . At our institution, electrostimulation is usually applied
[70]
[71]
intra-operatively directly on the nerve surface with a blunt electrode probe .
Clinical trials
Based on these reproducible animal studies, the first randomized controlled clinical trial with 21 patients
enrolled to treat severe carpal tunnel syndrome by carpal tunnel release with and without intraoperative
[72]
electrostimulation was reported in 2010 . Using a 20 Hz 1-hour stimulation protocol, electrostimulation
patients demonstrated accelerated target reinnervation with complete reinnervation of thenar muscles after
12 months compared to the control group. In 2015, a double-blinded randomized controlled clinical trial of
31 patients with digital nerve transections was reported. These patients underwent surgical repair and
received 20 Hz 1-hour electrostimulation or sham n-stimulation in the post-op recovery room . Notably,
[73]
the electrostimulation group all reported normal values of two-point discrimination and Semmes-Weinstein
monofilament (indicating sensory nerve reinnervation of sensory organs) at 6 months follow-up, while
these values were still abnormal in the sham n-stimulation group. However, there was no significant
difference in functional recovery as reported by the DASH patient questionnaire.

In 2018, a double-blinded randomized controlled trial was reported on 54 head and neck cancer patients
scheduled to undergo a surgical Level IIb +/- Level V neck dissection where retraction of the spinal
accessory nerve is commonly performed and skeletonizing the nerve for lymphatic tissue is often necessary.