Abstract Pressure ulcers (PUs) are a common and painful health condition, particularly among people who are elderly or physically impaired. PUs can affect at least 3 million adults in the U.S. and lead to more than 60,000 patients with PUs dying from these ulcers each year. Poor tissue regeneration causes substantial morbidity and is the most crucial risk factor for specific extremity amputation. Primarily, peripheral neuropathy and endothelial dysfunctions attribute to PUs. There is lacking regimens that effectively enhance tissue regeneration in pressure- damaged tissue regeneration patients. Many patients still face limb amputation and increased mortality. There is an unmet yet urgent medical need to develop novel regimens to enhance pressure-ulcer healing and prevent the recurrence of PU injury healing. We propose this research to tackle this poorly addressed problem. To overcome this obstacle, we have developed a group of “novel hormonal therapeutics,” stable chimeric albumin (Alb)- or IgG Fc (Fc)-hormones fusions (Alb- or Fc-hormones) biologics and stable hormones-based nanomedicines. These engineered stable fusions of biologics or nanomedicines will exhibit prolonged bioactivity and efficacy in vivo compared with wild-type hormones. These stable analogs may hold promise for treating pressure ulcers themselves. However, we reason that highly durable hormonal fusion biologics or slow-release formulas for nanomedicines (i.e., hormonal therapeutics) will be essential for clinical success because pressure ulcers usually require extended treatments. Our nontoxic hormonal therapeutics will also reduce potential systemic side effects. Based on this understanding, we hypothesize that delivering highly durable Alb- or Fc- hormone fusion biologics (novel hormonal therapeutics) will be a promising strategy to enhance tissue regeneration in numerous pressure patients. This project aims to create stable hormonal therapeutics and study their therapeutic efficacies alone or with adult adipose stem cells (ASCs) or induced pluripotent stem cells (iPSCs) to heal chronic PUs. Specific Aims: (Aim 1) Generate novel hormonal therapeutics with potent and effective bioactivity on keratinocytes and endothelial cells (KECs). (Aim 2) Investigate the effects of novel hormonal therapeutics on reprogramming of KECs from ASCs or iPSCs in vitro and in rodent models. (Aim 3) Determine the efficacy of combination regimens (novel hormonal regimens plus ASCs or iPSCs) in improving PU tissue regeneration using a PU rodent model and conduct toxicity studies. Significance: Our novel therapies allow us to rapidly test whether they suppress PUs specifically to improve patients with PUs. After this study, we will identify safe and effective anti-PU regimens ready for preclinical development (e.g., toxicity and PK studies), which will be addressed during Phase II. We expect this work strongly supports future SBIR Phase II to make this work to be an effective and first-in-class thera...