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Page 2 of 13 Chi et al. Plast Aesthet Res 2023;10:56 https://dx.doi.org/10.20517/2347-9264.2023.48

INTRODUCTION
The treatment of peripheral nerve injuries has grown significantly over the last several decades as scientific
discovery and mechanistic understanding of peripheral nerve regeneration have led to surgical advances.
Causes of peripheral nerve injuries are wide-ranging, with multiple potential causes ranging from sharp
traumatic injuries to gradual systemic degeneration. Of the over 400,000 traumatic injuries to the
extremities each year in the United States, 2.3% of these patients are diagnosed with a peripheral nerve
[1,2]
injury . Furthermore, a significant fraction (10%-15%) of diagnosed peripheral nerve injuries are
[3]
iatrogenic in nature .
Compared to their counterparts in the central nervous system, peripheral nerves have the capacity to
[4]
regenerate and restore function to their distal end targets . These cumulative injuries lead to an estimated
50,000 nerve repairs performed each year in the United States alone . However, complete functional
[5,6]
recovery following peripheral nerve injury is uncommon even after nerve surgery techniques such as nerve
grafting and nerve transfers are performed . After severe peripheral nerve injuries, Wallerian degeneration
[7-9]
ensues where nerve fibers distal to the injury undergo degradation, and phagocytosis of these now-
disconnected axons from the cell body by infiltrating macrophages and Schwann cells occurs [10,11] . To fill in
this nerve gap, peripheral nerves regenerate at an average rate of 1mm per day and may have to traverse
relatively long distances to reinnervate their target muscle fibers or sensory organs. Importantly, this rate
applies to the earliest “pioneer” axons. Depending on the location of the nerve injury, recovery, even after a
surgically optimized repair, can be delayed through the downregulation of the neuroregenerative factors
secreted by Schwann cells [12,13] . Furthermore, denervated target organs may undergo irreversible fibrosis and
atrophy over time and become unresponsive by the time the regenerating axonal front reaches the
target [14,15] . In particular, both motor end plates and sensory receptors only remain viable for 12-18 months
[16]
after denervation . The pathway across nerve grafts itself is also affected by the length and time of
denervation, as Schwann cells become senescent and no longer support reinnervation [14,17-19] . To emphasize
the importance of timely nerve reconstruction and the need for neurotherapeutic strategies, delayed
regeneration can result in diminished muscle mass and function [17,19] .

New therapeutics and surgical techniques are needed to improve repair and recovery in these patients.
Translational studies using animal models have been a major aid to innovations that have now made their
way to the operating room and clinical arena. In particular, this review will survey the known landscape of
FK506 (Tacrolimus) and electrostimulation as two strategies that hold great promise in aiding nerve
regeneration [Figure 1A-C].

FK506 (TACROLIMUS) FOR PERIPHERAL NERVE INJURY
Early studies
FK506 (Tacrolimus) is an immunosuppressive macrocyclic lactone isolated in 1984 and is now approved by
the FDA for use in preventing immune rejection after organ transplantation [20,21] . Compared to the
cyclosporine that was previously used for immunosuppression in solid organ transplantation, FK506 has
been preferentially used given its greater efficacy and comparatively improved side effect profile, and
reduced nephrotoxicity . Its immunosuppressive functions are mediated by downregulating T cell-
[22]
associated transcription factors like NFAT, resulting in transcriptional inhibition of T cell activation .
[23]
Interestingly, just several years after FK506 was discovered, several research groups elucidated its pro-
neuroregenerative effects in vitro and in vivo. Using cultured neurons and sensory ganglia, treatment with
FK506 stimulated neurite outgrowth . Moving on to the rodent model, FK506 treatment after a rat sciatic
[24]
nerve crush injury stimulated nerve regeneration with faster recovery of motor and sensory function
compared to saline-treated rats . Gold credits his discovery of the effect of FK506 to enhance nerve
[25]