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Chi et al. Plast Aesthet Res 2023;10:56 https://dx.doi.org/10.20517/2347-9264.2023.48 Page 5 of 13

To assess whether tacrolimus had any effect on promoting nerve regeneration after peripheral nerve injury
and subsequent repair, a small Phase II trial was undertaken to evaluate the safety and efficacy of tacrolimus
[42]
administered for two months after nerve repair . Results in this study of five patients were inconclusive
because although they all tolerated tacrolimus without any adverse effects and Tinel’s sign progression was
faster than expected, motor recovery was incomplete, and sensory two-point discrimination was greater
than >10 mm in all patients. Therefore, no beneficial effect of FK506 on peripheral nerve regeneration
following repair was reported by the authors. However, the patient cohort had a heterogeneous range of
nerve injuries with different types of nerves involved and various nerve repair techniques, from primary
repair to unreported lengths of nerve grafting. Furthermore, inclusion criteria ranged widely from primary
nerve repair within 1 week of injury and nerve grafting up to 4 months of injury. It thus remains possible
that FK506 may be helpful when administered more effectively or for the optimal dose or duration.

Timing of administration
Since immediate dosing of tacrolimus at the time of injury is not clinically practical, many studies have
attempted to determine effective windows of administering FK506 after injury and any surgical repair.
When FK506 treatment was delayed by 3 days or 5 days following rat tibial nerve injury and repair, all
timing groups demonstrated improved neuroregeneration compared to the untreated control . However,
[43]
the effect size of the tacrolimus therapeutic benefit did diminish with time. To further demonstrate the
temporal relationship between injury, repair, and FK506 treatment, another rat study grouped rats into four
cohorts of immediate repair +/- tacrolimus and 7-day delayed repair +/- tacrolimus found that delays in
both repair and tacrolimus treatment were associated with suboptimal recovery . Interestingly, priming of
[44]
the involved rat by administering FK506 prior to nerve injury and repair appears to initiate regenerative
[32]
mechanisms that result in improved functional recovery . Clinically, this would be useful since many nerve
transfer surgeries are performed on an elective basis, and priming the donor nerve for regeneration through
the impending nerve coaptation may facilitate improved surgical outcomes.

Method of administration
Given the systemic side effects from FK506 treatment, much attention has been brought to developing
targeted delivery of tacrolimus to only the site of nerve injury . First, topical application of tacrolimus to
[45]
the area of facial nerve repair in rabbits found that local deposition of FK506 resulted in improved nerve
regeneration of the buccal branch with spontaneous movement and the highest functional score and
[46]
greatest recovery upon histomorphometric analysis .
Other methods with controlled sustained local release of FK506 have made use of fibrin hydrogels with
embedded FK506-containing microspheres. Utilizing the rat sciatic nerve cut-and-repair model, this
hydrogel delivery system released FK506 for 28 days and resulted in a significant increase in regeneration of
sensory and motor axons compared to the control groups . For side-effect mitigation, FK506 was only
[47]
detected at the sciatic nerve repair site and spinal cord, demonstrating successful sequestration away from
other organs and potentially obviating systemic immunosuppression and toxicity.

Having been popularized as a method of bridging small nerve gaps without requiring nerve autografting,
nerve conduits represent a potential mode of drug delivery to enhance nerve regeneration. Various nerve
conduits made of natural polymers like chitosan and synthetic polymers like polytetrafluoroethylene
(PTFE) have demonstrated efficacy in controlled diffusion of FK506 when implanted across nerve gaps
in vivo with significantly improved axonal regeneration and compound muscle action potentials compared
to controls [48,49] . However, while conduits may be useful in drug delivery, significant concerns remain over
the possibility of compression neuropathy during post-operative swelling, and more work on their clinical
utility is required. [Figure 2] summarizes more recent areas of interest in FK506 for nerve injuries.