Project Grant R43NS127689

INTRAOPERATIVE NERVE DAMAGE ASSESSMENT USING NERVE-SPECIFIC FLUORESCENCE GUIDED SURGERY - PROJECT SUMMARY ACUTE PERIPHERAL NERVE CRUSH INJURIES FREQUENTLY RESULT FROM CLOSED OR OPEN FRACTURES, JOINT DISLOCATIONS, AND HIGH- ENERGY COLLISIONS. NERVE CRUSH, STRETCH, OR TRANSECTION CAN LEAD TO FUNCTIONAL DEFICITS RANGING FROM NUMBNESS TO COMPLETE MOTOR AND SENSORY FUNCTION LOSS, AFFECTING ~1.6M TRAUMA PATIENTS ANNUALLY. ASSESSMENT OF THE DEGREE OF INJURY AND THE POSSIBILITY FOR FUNCTIONAL RECOVERY AFTER INJURY REMAINS CHALLENGING AND INTRAOPERATIVE NERVE STIMULATION, THE ONLY METHODOLOGY TO AID IN DECISION-MAKING DURING NERVE REPAIR SURGERY, OFTEN YIELDS MINIMALLY USEFUL INFORMATION. THUS, SURGEONS ARE LEFT TO MAKE NERVE DAMAGE ASSESSMENTS VIA GROSS VISUAL EXAMINATION, WHICH FAILS TO CAPTURE THE DEGREE OF AXONAL DISRUPTION, LEAVING ~50% OF PATIENTS WITH POOR FUNCTIONAL RECOVERY OUTCOMES. SURGEONS AND PATIENTS WOULD BENEFIT FROM A RAPID INTRAOPERATIVE ASSESSMENT OF NERVE DAMAGE TO MAKE INFORMED TREATMENT DECISIONS. WE HYPOTHESIZE THAT FLUORESCENCE IMAGING USING A NOVEL NERVE- SPECIFIC FLUOROPHORE COULD PROVIDE AN OBJECTIVE METHODOLOGY TO DETERMINE THE DEGREE AND RECOVERABILITY OF NERVE INJURY, GUIDING SURGICAL INTERVENTION IN REAL-TIME TO IMPROVE PATIENT OUTCOMES FOLLOWING ORTHOPAEDIC TRAUMA SURGERY. WE HAVE DEVELOPED A LIBRARY OF FIRST-IN-KIND, TARGETED, NEAR-INFRARED (NIR) FLUOROPHORES THAT LABEL NERVE TISSUE WITH HIGH AFFINITY AND ARE CURRENTLY UNDERGOING PRECLINICAL PHARMACOLOGY AND TOXICOLOGY TESTING TO FACILITATE FIRST-IN-HUMAN (FIH) TRIALS FOR IMPROVED INTRAOPERATIVE NERVE VISUALIZATION. THESE FLUOROPHORES PROVIDE NERVE VISUALIZATION WITH HIGH CONTRAST AT MILLIMETER TO CENTIMETER TISSUE DEPTHS IN MICE, RATS, AND SWINE AND PRELIMINARY STUDIES SHOW CLEAR IDENTIFICATION BETWEEN HEALTHY AND INJURED NERVE TISSUES FOLLOWING TOPICAL OR SYSTEMIC ADMINISTRATION. HEREIN, WE PROPOSE TO FULLY CHARACTERIZE THE FLUORESCENT UPTAKE PROFILES AND INTENSITY DIFFERENCES BETWEEN HEALTHY AND DAMAGED NERVE TISSUE USING OUR NIR NERVE-SPECIFIC FLUOROPHORES TO PROVIDE AN OBJECTIVE METHODOLOGY FOR INTRAOPERATIVE NERVE DAMAGE ASSESSMENT. THIS STUDY'S IMMEDIATE MILESTONES WILL INCLUDE (1) SELECTION OF AN ADMINISTRATION TIME POINT FOR THE DEVELOPED METHODOLOGY, (2) QUANTIFICATION OF FLUORESCENCE INTENSITY (FI) AND UPTAKE PARAMETERS IN HEALTHY, PERMANENTLY DAMAGED, AND RECOVERING NERVE TISSUE IN MOUSE SCIATIC NERVE INJURY MODELS AND (3) VALIDATION OF THE DEVELOPED NERVE DAMAGE ASSESSMENT METHODOLOGY IN A BLINDED RAT SCIATIC NERVE INJURY STUDY FOR FUTURE CLINICAL TRANSLATION. COMPLETION OF THE PROPOSED AIMS WILL RESULT IN THE FIRST OBJECTIVE NERVE DAMAGE ASSESSMENT METHODOLOGY FOR TRAUMA SURGERY UTILIZING NOVEL NIR NERVE-SPECIFIC FLUOROPHORES DEVELOPED BY INHERENT TARGETING. THE PROPOSED STUDIES WILL PROVIDE PROOF-OF-CONCEPT FOR THE EXPANDED UTILITY OF OUR NOVEL PROBE FOR FUTURE CLINICAL TRANSLATION, ENABLING A ROBUST DIAGNOSTIC ASSESSMENT FOR PATIENTS. THIS WORK WILL BUILD UPON WORK UNDERWAY TO OBTAIN CLINICAL APPROVAL FOR THESE NOVEL NERVE-SPECIFIC PROBES AND PROVIDE A STRONG FOUNDATION AS A PLATFORM TECHNOLOGY FOR INTRAOPERATIVE GUIDANCE. IN PHASE II OF THIS PROJECT, FIH TRIALS WILL BE COMPLETED FOR THE DEVELOPED NERVE DAMAGE ASSESSMENT METHODOLOGY TO VALIDATE TRANSLATION TO TRAUMA PATIENTS UNDERGOING REPARATIVE SURGERY.