Principal Investigator: Anthony J. Windebank, MD
Organization: Mayo Clinic
Americans incur over 300,000 nerve injuries annually. Nerve injury leads to lost of limb function and oftentimes is accompanied by neuropathic pain. It causes significant personal hardship and socioeconomic burdens. In wounded warriors, 37% have nerve involvement in limb injury. Disability following nerve injury accounted for over half of the cumulative disability, the most common cause of inability to return to service. The current gold standard for nerve defect repair is autologous nerve graft. However, its usefulness is limited by the need for a second surgical procedure for nerve harvesting, donor site morbidities, size mismatch and limited graft availability, especially in multi-trauma scenario that is common in wounded warriors. There is unmet clinical need to find an alternative to nerve autograft.
An off-the-shelf synthetic nerve conduit can overcome these disadvantages and change the clinical paradigm when it is effective in bridging long nerve gaps. Currently FDA-approved nerve conduits are limited to only repair nerve defects up to 3 cm. The limitation that precluded the use of nerve conduits from repairing larger nerve defects stems from the lack of luminal additives in these single lumen conduits. The ultimate goal of nerve reconstruction is to restore function. Suboptimal functional recovery is common in large nerve defect cases. In addition to the challenge of regeneration across a long gap, muscle deterioration while awaiting reinnervation is another obstacle to a successful functional recovery.
Our project aims to address these challenges using a multi-faceted approach. We will combine a biocompatible and biodegradable polymer nerve conduit with extracellular vesicles (EVs) to create an “enhanced” nerve conduit to accelerate nerve regeneration and earlier muscle reinnervation. We will also apply EVs intramuscularly to the target muscles to preserve motor end plates and delay denervation atrophy. Extracellular vesicles are nanovesicles containing lipids, nucleic acids and proteins secreted by cells. EVs promote axonal regrowth, Schwann cell activation, vascular regeneration, and inflammatory regulation. There is also evidence that EVs decrease atrophy and improve muscle regeneration and biomechanical properties. Targeting both nerve regeneration and muscle reinnervation provides a solution for repairing critical size nerve defect and restoring better function.
This project will first be carried out in small animal models for proof of concept and dose escalation studies. When optimal dosage of EVs used as a nerve conduit filler and optimal EV dosage for intramuscular application are determined, the multi-faceted approach will be carried out in large animal models to acquire safety and efficacy data.
The clinical translation of this approach will circumvent the disadvantages of autograft, benefit warriors and general population patients with nerve injuries, and ease personal hardship and socioeconomic burdens.