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Chi et al. Plast Aesthet Res 2023;10:56 https://dx.doi.org/10.20517/2347-9264.2023.48 Page 9 of 13

[75]
Hz 1-hour electrostimulation or sham stimulation immediately after cubital tunnel release . The
electrostimulation cohort reported significantly greater functional improvement at one year and
significantly more motor unit potentials as detected by nerve conduction studies at three years.
Representing the two most common compression neuropathies, carpal tunnel syndrome and cubital tunnel
syndrome, clinical trials demonstrate that electrostimulation has efficacy in improving outcomes in chronic
neuropathy [72,75] .

Future directions
Currently, there are several ongoing clinical trials assessing the efficacy of electrostimulation following
nerve transfers, various electrostimulation devices, and optimizing electrostimulation parameters such as
the shorter duration periods as previously discussed [55,76] . Interestingly, electrostimulation has recently been
compared to tacrolimus treatment, and as expected, both the electrostimulation and tacrolimus groups
demonstrated robust improvement in function and increased number of regenerated myelinated axons
[77]
compared to controls . These findings are intriguing given the similar nerve regeneration phenotypes but
with different mechanisms of action. When electrostimulation and tacrolimus were given as combination
therapy in a recent study, the combination therapy was significant for achieving early functional recovery
based on the grid-walk assessment and increased muscle mass compared to any of the single treatments .
[78]
Additionally, while the effect size of the combination treatment was roughly similar to the single treatments,
the variance of the combination results in behavioral analyses was smaller than any of the treatment groups.
Implications of this study suggest that these combined therapeutics may provide more reliable and
consistent outcomes, and clearly, further investigations are required to optimize therapies for nerve
regeneration. [Figure 2] indicates further areas of interest.

CONCLUSION
Functional recovery after nerve injury is often unsatisfactory, even after timely and appropriate surgical
intervention. FK506 and electrostimulation remain two promising therapeutics to augment outcomes and
improve recovery. Despite different proposed mechanisms of action, each therapeutic has been shown to
improve neuroregeneration in data driven largely by small animal models and in vitro experiments
[Table 1]. These models have laid the groundwork for translation to the clinical realm, mainly in assisting in
the standardization of protocols for each therapeutic. For electrostimulation, it has been shown first that 1 h
of stimulation produces results equal to 24 h, and subsequently that 20 min produces non-inferior results to
1 h For FK506, it has been proposed that its mechanism of neuroregeneration is distinct from that of
immunosuppression, and thus a sub-immunosuppressive dose may suffice to augment regeneration without
unnecessary side effects. Each of these findings brings the field one step closer to optimal translation to the
clinical setting. However, there is still much to be discovered about these potential clinical therapeutic
options. Further elucidation of clinical benefits in humans must be shown with more thorough clinical
trials. While electrostimulation has already proven to have benefits in some clinical trials, the use of FK506
has not yet been backed up by clinical data. Appropriate patient selection will be key in studying FK506 in
humans going forward to assess for clinical benefit. Ongoing and future clinical trials will build on this body
of work to improve surgeons’ use of these adjunct treatments and reveal how nerve regeneration can best be
augmented.