Project Grant R44GM144027

HEALS?: AN ACTIVE HYDROGEN SULFIDE DELIVERY TECHNIQUE FOR ACCELERATED, EFFECTIVE WOUND HEALING - 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. HEALS IS A UNIQUE THERAPEUTIC SYSTEM FOR SAFE AND CONTROLLED DELIVERY OF H2S WITHIN A THERAPEUTIC WINDOW AND ONLY TO THE WOUND SITE WHERE IT MATTERS MOST. IN THE SBIR PHASE I FEASIBILITY STUDY, EXHALIX AND THE UNIVERSITY OF NEW MEXICO TEAM DEVELOPED AND USED A LABORATORY VERSION OF HEALS TO PERFORM PRELIMINARY ANIMAL STUDIES ON HEALING OF ISCHEMIC FLAP WOUNDS IN SPRAGUE- DAWLEY RATS. IT WAS SHOWN THAT SUSTAINED, LOCAL INFUSION OF H2S DRAMATICALLY IMPROVED ANGIOGENESIS, VASCULARIZATION, PERFUSION, AND HEALING EFFECTIVENESS OVER NORMAL HEALING. IN CONTRAST, H2S DEFICIENT WOUNDS CREATED BY INFUSION OF AN H2S INHIBITOR, PAG, RESULTED IN THE DEVELOPMENT OF MARKEDLY HIGHER TISSUE NECROSIS OVER BASELINE HEALING CONDITIONS. DURING THE PROPOSED SBIR PHASE II RENEWAL STUDIES, WE INTEND TO CONTINUE THE DEVELOPMENT OF ADVANCED PROTOTYPES OF HEALS. THESE PROTOTYPES WILL BE TESTED FOR SAFETY AND EFFICACY WITH HEALTHY AND DIABETIC RATS OF BOTH SEXES AT THE UNIVERSITY OF NEW MEXICO, AS WELL AS MINIATURE SWINE AT TEXAS A & M UNIVERSITY. WE ANTICIPATE THAT SUCCESSFUL DEVELOPMENT AND VALIDATION OF HEALS DURING PHASE II WILL LEAD TO PHASE IIB CLINICAL STUDIES AND COMMERCIALIZATION OF THE TECHNOLOGY.