A Biodegradable, Tacrolimus-releasing Nerve Wrap Promotes Peripheral Nerve Regeneration

Abstract

Axonal regeneration following nerve repair is slow and often incomplete, resulting in poor functional recovery and sometimes lifelong disability. Yet, there are no FDA-approved therapies available to promote nerve regeneration. Tacrolimus accelerates axonal regeneration, but systemic side-effects presently outweigh its potential benefits for peripheral nerve surgery. We have developed a biodegradable drug delivery system for the sustained local release of tacrolimus at the nerve repair site, with suitable properties for large-scale manufacturing and clinical application, aiming to promote axonal regeneration and functional recovery with minimal systemic drug exposure. Tacrolimus is encapsulated in polycarbonate-urethane nanofibers and electrospun to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days. Size and drug loading are adjustable for applications in small and large caliber nerves, and the wrap degrades within 120 days into biocompatible byproducts. Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while systemic drug exposure is reduced by 80% compared to systemic delivery. Given its surgical suitability and preclinical efficacy and safety, this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.

Sustained Release of Tacrolimus From a Topical Drug Delivery System Promotes Corneal Reinnervation

“…2 A). 52 Tacrolimus was encapsulated in the core of each fiber to create a sustained-release profile. Detailed physical characterization, drug release kinetics, and bioactivity studies for this biodegradable nanofiber DDS have been reported previously.…”

“…Detailed physical characterization, drug release kinetics, and bioactivity studies for this biodegradable nanofiber DDS have been reported previously. 52 Briefly, the electrospun matrices were sectioned in 0.5 × 2.5-mm sheets, yielding 223 ± 65 µg tacrolimus each. The DDSs were subsequently irradiation sterilized (25 Gy) and stored at 4°C until use.…”

“…Based on recent work in our laboratory, we used an electrospun, core–shell nanofiber matrix composed of a biodegradable polycarbonate–urethane polymer. 52 Tacrolimus was embedded in the core of each nanofiber to achieve a sustained-release characteristic of at least 31 days ( Fig. 2 B).…”

“…We have previously applied this matrix as a tacrolimus-releasing implant and demonstrated its biocompatibility, reliable drug delivery , and full degradation into nontoxic byproducts within a clinically reasonable time. 52 For translation to ophthalmic use, we created a 50% smaller DDS loaded with 100 µg tacrolimus and first tested its biocompatibility and biodegradability following topical application and subsequent tarsorrhaphy in a rat model. To achieve a homogeneous drug distribution, we placed two DDSs into each eye, one into the upper and one in the lower conjunctival fornix.…”

“…Liquid chromatography–tandem mass spectrometry (LC-MS/MS) was used to determine tacrolimus loading as previously reported. 52 Drug release was determined from six DDSs derived from three different matrices. Samples were incubated in sterile phosphate buffered saline (PBS) in a water bath shaker (37°C, 50 rpm), and the solution was collected for tacrolimus content analysis via LC-MS/MS.…”