An early rapamycin-releasing nerve wrap with dual function for nerve regeneration and adhesion prevention

Limited ability of nerve regeneration and the formation of nerve adhesions result to poor outcomes of peripheral nerve injury (PNI) following surgical nerve repair. Currently, there is no efficient therapy for the improvement of functional recovery after surgical repair. Rapamycin (Rapa) has been found useful for promoting nerve regeneration through removing cellular debris at the early stages after PNI. However, its lower oral bioavailability and significant adverse effects limit its clinical application. In this study, we developed a biocompatible nerve wrap based on biocompatible monomethoxy poly (ethylene glycol)-poly (lactic-co-glycolic acid) (mPEG-PLGA) for the local delivery of Rapa. The Rapa-mPEG-PLGA nerve wrap exhibited a rough surface and good hydrophilicity with strong mechanical strength. In vitro release studies revealed an initial rapid phase within the first 8 days, followed by a stable release about 10 days. The released Rapa remained its bioactivity to induce autophagy and promote cell migration. In a rat model of sciatic nerve transection and immediate repair, the implantation of Rapa-mPEG-PLGA nerve wrap significantly enhanced axonal regeneration and myelination. Furthermore, the nerve wraps effectively prevented the occurrence of nerve adhesions. Improved functional recovery was observed with Rapa-mPEG-PLGA membrane wrap post-surgery 4 weeks and 8 weeks. In summary, the Rapa-loaded mPEG-PLGA nerve wrap promoted nerve regeneration by releasing Rapa at the early stage after injury, and acted as a physical barrier to reduce nerve adhesions. This local dual-action strategy is a promising candidate for clinical translation in the treatment of PNI following surgical repair.