Non-healing wounds are a significant clinical problem both in the United States and globally. Thesewounds, defined as wounds that remain unhealed for upwards of 12 weeks, result in diminished qualityof life for patients and greatly increase their susceptibility to serious infections such as gangrene that maylead 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 domesticand global population. The prevalence of these wounds is projected to increase over the next 25 yearsas incidence rates of diabetes mellitus rise worldwide. Effective healing of these wounds is complicatedby the unique microenvironment present within non-healing wounds, and within diabetic ulcers inparticular; upregulation of matrix metalloproteinases in the wound bed prevent the robust formation ofnew extracellular matrix, limiting the ability of fibroblasts and keratinocytes to migrate into the wound bedand resulting in a senescent "barrier" of cells around the wound edge that further inhibits healing. Currenttreatments for diabetic wounds include living skin equivalents, scaffolds, platelet-rich plasma, and highdose growth factors; however, these therapies are limited by high cost, immunologic concerns, lack offull biochemical and/or mechanical support for complete wound repair, supply shortages, variability inpreparation methods and efficacy, and risk of off-target complications such as tumorigenesis. We haverecently developed SymHeal, a synthetic, platelet-mimetic technology capable of interfacing with nascentfibrin within the wound bed to form micro-scale fibrin-colloid scaffolds that can induce clot contraction andmechanically activate fibroblast migration into and within the wound bed via durotaxis. Our initial studiesdemonstrate that SymHeal is capable of recapitulating platelet-mimetic clot contraction and improvingwound 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 currenttranslational potential of this technology. The long-term goal of this project is to develop SymHeal for usein topical treatment of non-healing chronic wounds, particularly diabetic ulcers, in order to better addressa significant clinical need within the wound healing field and facilitate further clinical translation of thistechnology for use in diabetic patients. The objective in this application is to evaluate SymHeal efficacyalone and in combination with loaded platelet-derived growth factor (PDGF) for the improvement offibroblast migration and wound healing in diabetic models in vitro and in vivo. Our central hypothesis isthat SymHeal will greatly improve healing and fibroblast migration relative to untreated and clinicalcontrols in both models, and that SymHeal loaded with PDGF will bring about the greatest improvementin 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 animalmodels. The specific aims of this project are 1) Evaluate SymHeal efficacy in an in vitro model of diabeticwound healing and 2) Determine SymHeal efficacy in an in vivo model of diabetic wound healing.
Public Health Relevance Statement: RELEVANCE TO PUBLIC HEALTH
This project is relevant to NIH's mission as it focuses on developing a novel platelet-like particle therapeutic
(SymHeal) for treatment of non-healing diabetic ulcers.
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