Project Summary/Abstract The proposed effort addresses the need for novel therapeutic tools that improve chronic wound healing outcome. Recent studies show that patients with diabetic foot ulcers have a 40% recurrence rate within 1 year after treatment and healing, nearly 60% within 3 years, and 65% within 5 years, while the 5-year mortality rate is exceeded only by lung cancer. Lower limb wounds in the diabetic population are generally caused by endothelial dysfunction, the leading cause of blood circulation issues such as peripheral artery disease (PAD) and microvascular disorder. Endothelial dysfunction is often missed until the symptoms become advanced enough to cause critical limb threatening ischemia (CLTI), ischemic and neuro-ischemic foot ulcers, wounds, and amputations. In addition, therapeutic strategies for diabetic wound healing are stymied by their lack of effectiveness in addressing the challenges associated with disruption of pathways involved in the healing response. The changes in the wound environment include hyperglycemia-related perfusion deficiency, dysfunction of leukocyte function and accumulation of advanced glycation-end products and disrupted ECM. Hydrogen sulfide (H2S), a recently discovered 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 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 healing rate in ischemic wounds. However, systemic and widespread therapeutic 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 transdermally detects endogenous levels of H2S while delivering an exogenous amount needed to locally maintain the H2S levels within a therapeutic window. In this collaborative effort between Exhalix and the University of New Mexico School of Medicine, we will show the feasibility and merits of this therapeutic approach for ischemic wound healing improvements over baseline conditions 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.