Project Grant R41DK135288

SYMHEAL: A NOVEL THERAPY FOR TREATING NON-HEALING DIABETIC ULCERS - PROJECT SUMMARY NON-HEALING WOUNDS ARE A SIGNIFICANT CLINICAL PROBLEM BOTH IN THE UNITED STATES AND GLOBALLY. THESE WOUNDS, DEFINED AS WOUNDS THAT REMAIN UNHEALED FOR UPWARDS OF 12 WEEKS, RESULT IN DIMINISHED QUALITY OF LIFE FOR PATIENTS AND GREATLY INCREASE THEIR SUSCEPTIBILITY TO SERIOUS INFECTIONS SUCH AS GANGRENE THAT MAY LEAD TO AMPUTATIONS. NON-HEALING WOUNDS OFTEN ARISE AS A SIDE EFFECT OF OTHER CHRONIC HEALTH CONDITIONS, WITH DIABETIC FOOT ULCERS BEING ONE OF THE MOST PREVALENT FORMS OF NON-HEALING WOUNDS IN THE DOMESTIC AND GLOBAL POPULATION. THE PREVALENCE OF THESE WOUNDS IS PROJECTED TO INCREASE OVER THE NEXT 25 YEARS AS INCIDENCE RATES OF DIABETES MELLITUS RISE WORLDWIDE. EFFECTIVE HEALING OF THESE WOUNDS IS COMPLICATED BY THE UNIQUE MICROENVIRONMENT PRESENT WITHIN NON-HEALING WOUNDS, AND WITHIN DIABETIC ULCERS IN PARTICULAR; UPREGULATION OF MATRIX METALLOPROTEINASES IN THE WOUND BED PREVENT THE ROBUST FORMATION OF NEW EXTRACELLULAR MATRIX, LIMITING THE ABILITY OF FIBROBLASTS AND KERATINOCYTES TO MIGRATE INTO THE WOUND BED AND RESULTING IN A SENESCENT "BARRIER" OF CELLS AROUND THE WOUND EDGE THAT FURTHER INHIBITS HEALING. CURRENT TREATMENTS FOR DIABETIC WOUNDS INCLUDE LIVING SKIN EQUIVALENTS, SCAFFOLDS, PLATELET-RICH PLASMA, AND HIGH DOSE GROWTH FACTORS; HOWEVER, THESE THERAPIES ARE LIMITED BY HIGH COST, IMMUNOLOGIC CONCERNS, LACK OF FULL BIOCHEMICAL AND/OR MECHANICAL SUPPORT FOR COMPLETE WOUND REPAIR, SUPPLY SHORTAGES, VARIABILITY IN PREPARATION METHODS AND EFFICACY, AND RISK OF OFF-TARGET COMPLICATIONS SUCH AS TUMORIGENESIS. WE HAVE RECENTLY DEVELOPED SYMHEAL, A SYNTHETIC, PLATELET-MIMETIC TECHNOLOGY CAPABLE OF INTERFACING WITH NASCENT FIBRIN WITHIN THE WOUND BED TO FORM MICRO-SCALE FIBRIN-COLLOID SCAFFOLDS THAT CAN INDUCE CLOT CONTRACTION AND MECHANICALLY ACTIVATE FIBROBLAST MIGRATION INTO AND WITHIN THE WOUND BED VIA DUROTAXIS. OUR INITIAL STUDIES DEMONSTRATE THAT SYMHEAL IS CAPABLE OF RECAPITULATING PLATELET-MIMETIC CLOT CONTRACTION AND IMPROVING WOUND HEALING OUTCOMES IN BOTH IN VITRO AND IN VIVO MURINE MODELS OF DERMAL WOUND HEALING; HOWEVER, SYMHEAL HAS NOT YET BEEN EVALUATED IN A MODEL OF CHRONIC WOUND HEALING, LIMITING THE CURRENT TRANSLATIONAL POTENTIAL OF THIS TECHNOLOGY. THE LONG-TERM GOAL OF THIS PROJECT IS TO DEVELOP SYMHEAL FOR USE IN TOPICAL TREATMENT OF NON-HEALING CHRONIC WOUNDS, PARTICULARLY DIABETIC ULCERS, IN ORDER TO BETTER ADDRESS A SIGNIFICANT CLINICAL NEED WITHIN THE WOUND HEALING FIELD AND FACILITATE FURTHER CLINICAL TRANSLATION OF THIS TECHNOLOGY FOR USE IN DIABETIC PATIENTS. THE OBJECTIVE IN THIS APPLICATION IS TO EVALUATE SYMHEAL EFFICACY ALONE AND IN COMBINATION WITH LOADED PLATELET-DERIVED GROWTH FACTOR (PDGF) FOR THE IMPROVEMENT OF FIBROBLAST MIGRATION AND WOUND HEALING IN DIABETIC MODELS IN VITRO AND IN VIVO. OUR CENTRAL HYPOTHESIS IS THAT SYMHEAL WILL GREATLY IMPROVE HEALING AND FIBROBLAST MIGRATION RELATIVE TO UNTREATED AND CLINICAL CONTROLS IN BOTH MODELS, AND THAT SYMHEAL LOADED WITH PDGF WILL BRING ABOUT THE GREATEST IMPROVEMENT IN WOUND HEALING IN BOTH THE IN VITRO AND IN VIVO MODEL AT LOWER DOSING THAN IS CURRENTLY REQUIRED CLINICALLY, THEREBY SUPPORTING MOVING THIS TECHNOLOGY FORWARD INTO FURTHER PRECLINICAL DEVELOPMENT IN LARGE ANIMAL MODELS. THE SPECIFIC AIMS OF THIS PROJECT ARE 1) EVALUATE SYMHEAL EFFICACY IN AN IN VITRO MODEL OF DIABETIC WOUND HEALING AND 2) DETERMINE SYMHEAL EFFICACY IN AN IN VIVO MODEL OF DIABETIC WOUND HEALING.