Project Summary/Abstract The proposed effort addresses the need for a novel therapeutic tool that improves the recovery of at-risk surgical incisions. There are 48.3 million surgical procedures performed in the United States each year, 1/3 of which are performed on individuals older than 65. Among this population, a significant number suffer from endothelial dysfunction and impaired blood flow leading to peripheral artery disease and chronic limb threatening ischemia (CLTI), thus requiring lower limb revascularization. Despite a recent surge in the number of percutaneous and endovascular interventions, open surgery is still a preferred method of revascularization for a large number of CLTI cases due to long term durability, lower rate of restenosis and better hemodynamic efficiency in certain anatomies. Given the high cost of readmission related to post- operative healing complications, there is a critical need for development of advanced techniques to address the at-risk and disadvantaged incision healing failure. Hydrogen sulfide (H2S), an endogenous VOC and recently recognized as a gasotransmitter, has been shown to promote angiogenesis-related behavior in endothelial cells through activation of pathways that include nitric oxide signaling and the canonical HIF-1 and VEGF-A-mediated angiogenesis cascade. There is also significant evidence linking deficiency in endogenous H2S to endothelial dysfunction and consequently microvascular disorder and poor perfusion. Systemic administration of (exogenous) H2S donors have been shown to markedly improve the rate of regeneration in ischemic tissue. However, systemic and widespread delivery of H2S can lead to unintended consequences including hypotension, hepatotoxicity, and malignant angiogenesis. This leaves a significant opportunity for individualizing patient care through targeted, precision delivery of H2S. In the proposed SBIR Phase I study, we intend to demonstrate a unique therapeutic system that locally delivers a precisely controlled exogenous amount needed to sustain the concentration of H2S at the target location within a therapeutic window by transdermally detecting the local endogenous and exogenous H2S levels. In this collaborative effort between Exhalix and the University of New Mexico School of Medicine, we will show the feasibility and merits of this sustained ReLIS™ therapeutic approach for treatment of surgical incisions on small animal models. We anticipate that the proposed feasibility study will last 12 months and success in reaching our objectives will lead to a Phase II effort for development of prototypes and demonstration on larger animals.