Project Summary Millions of anastomoses, or surgical connections between arteries or veins, are performed in vascular, transplant, and reconstruction procedures in the US each year. Neointimal hyperplasia, or proliferation and migration of vascular smooth muscles cells into the vessel lumen space, develops immediately at the site of anastomosis due to the local damage caused by the surgical procedure. The resulting stenosis, or narrowing of the vessel after the anastomosis, is the main contributor to arterial, venous, arteriovenous, and prosthetic graft failure. Preventing anastomotic stenosis is the key to long-term efficacy of all types of vascular surgery, and will improve patient prognosis. The gold standard for anastomotic surgery is to use non-absorbable sutures, like nylon or polypropylene. We hypothesize that sutures can be produced that locally release anti-proliferative drugs at the site of anastomosis for several weeks or longer, thereby preventing neointimal overgrowth and stenosis without disrupting normal surgical workflow. Used during anastomosis procedure, the suture will provide sustained release of drugs for several weeks or longer to prevent neointimal overgrowth. We describe a novel electrospinning platform capable of producing both non-absorbable and absorbable drug- eluting sutures for vascular surgery: (i) nylon sutures that are wrapped in drug-eluting and degradable, polymer nanofibers, and (ii) fully absorbable, high-strength, drug-eluting, twisted polymer nanofiber sutures. We have loaded these sutures with rapamycin, which is a promising anti-proliferative drug that has been used in combination with stents for preventing in-stent restenosis. Our preliminary results demonstrate that nanofiber- coated nylon sutures provide sustained rapamycin release that decreases neointimal hyperplasia in a rat anastomosis model in a drug dose dependent fashion for several weeks. Here, we aim to further optimize our suture formulations for drug loading and drug release to prevent neointimal hyperplasia while maintaining anastomosis repair and minimizing systemic side effects. The sutures will be evaluated in our rat anastomosis model, and the most promising candidates will be tested in a large animal model that is considered to best recapitulate the human vasculature. If successful, our sutures could serve as a platform technology for preventing stenosis in any type of organ anastomosis.