Project Summary Pressure ulcers affect 2.5 million people in the United States and cost the healthcare system an estimated 11.6 billion dollars annually. A major percentage of affected individuals are over sixty-five years of age and this number is growing rapidly in the United States. A greater incidence of immobility, vascular disease and diabetes is commonly seen in aged populations and places them at an increased risk for developing pressure ulcers. Thus, there is a pressing need to develop new therapies that will effectively treat pressure ulcers in the aged. With prior NIA support, we have found that aging is characterized by the progressive loss of critical molecular and cellular pathways responsible for normal wound healing, specifically hypoxia-inducible factor 1-alpha (HIF- 1α). We have also identified that these changes can be reversed using an FDA-approved small molecule drug, deferoxamine (DFO). Building on our preliminary data, we will first define the aberrations of HIF-1α in healthy, unwounded skin from young and aged patients (Specific Aim 1). We will then confirm the HIF-1α signaling dysfunction in pressure ulcers using biopsy specimens from both young and aged patients. (Specific Aim 2). To define the alterations in hypoxia signaling within the skin cells of young versus aged patients, we will subject the collected tissue for protein analysis and single cell sequencing. We will then determine the optimal delivery system for DFO through both intact stratum corneum as required for treating pressure ulcers in a porcine model (Specific Aim 3). This large animal model is selected since porcine skin has significant similarities to the human skin. Our results will validate the effectiveness of our drug delivery system and provide a novel strategy to deliver other hydrophilic small molecule drugs across intact human skin. Taken together, this pre-clinical study will lay the groundwork for a pilot human trial targeted at treating pressure ulcers with the transdermal DFO delivery system, which will for the first time provide a pharmacologic therapy to treat pressure ulcers in aged patients.