Altering the injury microenvironment with a macrophage and Schwann Cell recruiting extracellular matrix-based hydrogel to improve laryngeal nerve injury recovery

PROJECT SUMMARY ABSTRACT Vocal fold paralysisVFPoccurs when the recurrent laryngeal nerveRLNis injuredmost commonly during surgery of the neckBilateral injury to the RLN can result in potentially life threatening airway obstruction and the need for tracheostomyThe RLN can regenerate some of its axonsbut in many patients with paralysis some form of intervention is required to correct the airway obstruction and voice changesThis is most frequently achieved through reinnervation of the laryngeal muscles to restore functionCurrent practice is to waitmonths before any intervention is performed as spontaneous recovery can occurThis delay before repair allows chronic changes in the nerve distal to the site of injury to occur and results in poor recoveryThe overall goal of this proposal is to accelerate recovery after RLN injury and reduce the consequences of prolonged denervation before nerve graftPrevious work has focused mainly on events that occur late in the repair and remodeling processLittle is known about how manipulating events in the early stages of repair can be used to improve recoveryWe have recently shown that modifying the type of macrophages accumulating at the graft site early after injury increases Schwann cell migration in the regenerative bridge and improves recoveryOur preliminary data demonstrate that a novel injectable medical devicePeripheral Nerve MatrixPNMcan promote axon extension and Schwann cell migration across the site of nerve injury and promote functional recovery after injuryThese preliminary data have been developed with optimal surgical conditions using a research grade materialIn this proposal we determine the effects of a range of conditions that might be encountered in the operating roomparticularly temperatureon polymerization of the gel and its ability to improve nerve repairWe then test the ability of PNM to improve outcomes after immediate and delayed nerve graft and assess local effects on protein expressionaxon extension and Schwann cell migrationWe then assess downstream effects on neuromuscular junction formation and peak tetanic force of the target muscleFor these experiments we use an animal model which is highly relevant to nerve graft repair of the RLNThe ability to accelerate recovery following RLN injuryby intervening intra operativelywould reduce the consequences of delayed repair and improve recovery for patients with VFP Project Narrative This project determines the ability of a novel injectable medical device for use as an adjunct to standard of care nerve graft procedures following recurrent laryngeal nerve injuryPeripheral Nerve MatrixPNMis a flowable gel obtained from porcine nerve tissue by mechanicalchemicaland enzymatic processingWe will determine how a range of non ideal physiological conditions that might be encountered in the Operating Room affect gelation and polymerizationWe then determine how assess the effects of commercial processing of PNM for clinical use on restitution time of the gelgelation kineticsrheologybioactivity and cytotoxicityWe then determine the efficacy of PNM to promote recovery following immediate and delayed nerve graft as these techniques are used after RLN injury