PROJECT SUMMARY Iatrogenic nerve injury represents one of the most feared surgical complications. Nerves are critically important to the function of most tissues and nerve injury can lead to permanent disability. Surgery is performed commonly in the U.S. with approximately 40 million operations annually, incurring up to 600,000 iatrogenic nerve injuries. Essential nerves may be injured across surgical specialties including general, thoracic, cardiac, urologic, plastic, colorectal, spinal, neuro-, otolaryngologic and orthopaedic surgery. Surprisingly, no clinically approved technol- ogy can directly enhance intraoperative nerve visualization, which is typically performed through neuroanatomi- cal knowledge, conventional white light imaging and electrophysiologic monitoring. This work will directly address this unmet clinical need. Fluorescence guided surgery (FGS) is a form of surgical guidance that seeks to improve the safety and efficacy of surgery through machine-assisted visual identification of critical tissues that require removal (e.g., tumors) or structures that must be preserved to maintain post-operative function (e.g., nerves). Clinical open and laparoscopic FGS vision systems operate nearly exclusively in the near infrared (NIR, 650- 900 nm). To employ FGS, clinicians typically administer a fluorescent contrast agent intravenously (IV) prior to surgery that accumulates or marks tissues of interest (e.g., blood vessels, tumors, etc.) and deploy intraoperative FGS vision systems capable of imaging the contrast agent distribution in the surgical field in real time. While novel contrast agents for surgery are under development with the first molecularly targeted agent (i.e., pafola- cianine) reaching recent FDA approval, clinical adoption and routine use for surgery remain an open question. Part of this challenge stems from the integration of administration of the contrast agent into the existing clinical workflow. Most of the developed targeted contrast agents require IV administration, presenting specific chal- lenges to integration into the existing surgical workflow. IV administration of probes requires either a special trip and appointment to the hospital or surgical center or a substantially earlier start time to accommodate the phar- macokinetic (PK) profile of the probe. For patients that live in a rural setting, requiring long distance travel to their surgical center or critically ill patients, this creates hardships and further challenges to availability of care. For surgical centers and hospitals that are already straining to keep up with the workload, the IV contrast administra- tion requires additional time and costs to integrate FGS into the clinical workflow. To alleviate these challenges, we will explore additional routes for nerve contrast agent administration, including orally and subcutaneously using agents with long pharmacokinetic profiles. Our overall vision for this technological advance is that nerve- specific contr...