Local Delivery of FK506 to a Mouse Sciatic Nerve Injury Increases Nerve Regeneration Outcomes
Brett Davis, MS, David Hilgart, Sierra Erickson, BS, Pratima Labroo, PhD, Joshua Burton, MS, Himanshu Sant, PhD, Jill Shea, Bruce Gale, PhD, Jay Agarwal, MD.
University of Utah, Salt Lake City, UT, USA.
In the clinic, there are limited treatment strategies for the repair of peripheral nerve injuries, and the majority of off-the-shelf nerve repair devices lack added functionality. Direct repair is among the most commonly performed nerve repair procedures and presently there is no clinical therapeutic available that improves outcomes after direct repair. The objective of this study is to assess the efficacy of local, controlled delivery of FK506 to improve nerve regeneration outcomes in the setting of nerve transection injury and repair.
Solvent casting techniques were used to embed FK506 into poly(lactide-co-caprolactone) (PLC) films for the creation of a nerve wrap – drug delivery system that is capable of an extended, localized release of FK506 to injured nerves. In vitro drug rate of release testing and drug bioactivity assays were performed to determine the FK506 release profile and to verify release FK506 bioactivity. A mouse sciatic transection and direct-suture repair model was used to evaluate the effect local, controlled FK506 delivery could have on nerve regeneration outcomes greater than direct-suture repair alone. Animals were sacrificed at 6 weeks for electrophysiological assessment, determination of gastrocnemius muscle mass recovery, and sciatic nerve histological evaluation.
A linear release (R2=0.991) of FK506 for 30+ days was observed for two FK506 loading concentrations (0.01 % and 0.05% w/w of FK506/PLC). The released FK506 matched control FK506 levels of neurite extension in the dorsal root ganglion assay. Relative gastrocnemius muscle weight, relative foot EMG, and total number of axons distal of the repair site were significantly greater in mice treated with the 0.01% FK506 nerve wrap than the non-drug groups. For the 0.05% nerve wraps, the total axon count distal to the repair site was found to be significantly greater, but no significant differences were observed for the other metrics.
Results of this study indicate that extended, localized delivery of FK506 to a mouse sciatic transection and direct repair can improve nerve regeneration outcomes in a sciatic nerve transection and repair model. A dose-dependent response in the nerve regeneration metrics was observed, indicating there is an optimal dose range for local delivery of FK506.
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