STTR Phase I: Near Infrared Nerve-Specific Fluorophores for Fluorescence-Guided Surgery

The broader impact of this Small Business Innovation Research (SBIR) Phase I project is the development of a technology that will reduce intraoperative nerve damage using fluorescence imaging to enable surgeons to see the unseen. Intraoperative nerve injury is a major complication of surgery, affecting all specialties and often causing irreparable damage. Nerve damage occurs in ~17% of all surgeries and intraoperative nerve injuries affect 50 million patients annually worldwide, incurring undue pain, loss of function, and high costs to the healthcare system. Currently, no clinically approved technology exists to enhance intraoperative nerve recognition - surgeons rely solely on anatomical knowledge and visualization. The proposed project will finalize development of first-in-kind nerve targeted substance allowing surgeons to “cut by color” – identifying and sparing nerves more effectively to reduce these complications and the associated costs, estimated at $12.5 billion annually. The proposed project is focused on the development of near-infrared nerve-specific fluorophores for fluorescence-guided surgery (FGS) that are clinically viable for translation to human studies. Recent work has allowed modification of the base structures of the fluorophores to significantly improve brightness, solubility, and toxicity while maintaining high nerve specificity. The immediate milestones of the work proposed herein include (1) characterization of a library of benzo[c]phenoxazine small molecule derivatives with chemically tuned water solubility and quantified nerve specificity, (2) elucidation of the biological target and mechanistic understanding of nerve-specificity for the fluorophores, (3) preliminary single-dose toxicology analysis in rodents, (4) quantified pharmacokinetics, pharmacodynamics, and biodistribution to determine the optimal imaging dose and time window, and (5) identification of a lead compound for clinical translation. Successful completion of the proposed work will enable selection of a lead candidate with a proven safety profile and bright, long-lasting (~1 hour) nerve-specific fluorescence for identification of buried nerve structures at up to 1 cm depths. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.