Enhancement of peripheral nerve regeneration with controlled local release of Tacrolimus (FK506)

Despite substantial improvements in microsurgical techniques, patients with peripheral nerve injuries rarely recover fully. FK506, an FDA approved immunosuppressant, improves functional recovery and reinnervation following peripheral nerve injury in animal models. However, systemically delivered FK506 causes undesirable global immunosuppression. We have therefore engineered a biodegradable local delivery system for FK506 using fibrin gel as a drug reservoir that can be placed at a site of nerve injury. We used our FK506 delivery system to enhance nerve regeneration in clinically applicable models of nerve injuries. We further investigated the mechanism of action by which local FK506 promoted peripheral nerve regeneration. In the first aim of this study, the drug delivery system was engineered to provide sustained and controlled release of bioactive FK506. Moreover, the optimal local FK506 dose delivered to the peripheral nerve tissue was investigated in a three-dimensional organotypic system. In the second aim, we demonstrated the efficacy of local FK506 release from the delivery system on enhancing axon regeneration and functional recovery in clinically applicable models of nerve injury in rats. We documented the biodistribution of FK506 within the nervous system in vivo following the drug release from the delivery system implanted at the site of nerve repair. In the third aim, the neuroregenerative mechanism of action for the local FK506 administration was investigated both in vitro and in vivo. The analysis of FK506 binding proteins (FKBP)s’ localization within the peripheral nerve in vivo suggested Schwann cells containing FKBP52 at the site of nerve injury and repair can be a cellular target for the locally applied FK506. FKBP52 was further confirmed to be a molecular target for the FK506 mediated neuroregeneration effect in vitro. In the studies presented in this thesis, we demonstrated the local application of FK506 using our engineered drug delivery system resulted in superior axon regeneration while preventing the toxicity of systemic FK506 that has prevented clinicians from using FK506 routinely for treating peripheral nerve injuries. The findings in this study provide compelling evidence that the tested FK506 delivery system can provide a new and effective clinical solution for treatment of peripheral nerve injury.Ph.D.2019-05-19 00:00:0