PROJECT SUMMARY – Effects of Wound Dressing’s Vapor and Gas Permeability on Ischemic Ulcer Healing Ischemic PAD ulcers caused by arterial insufficiency of the lower extremities are extremely difficult to heal with basic therapy and require special treatments. But even after the perfusion to the lower limbs is surgically restored, the healing of severe ulcers remains a major medical problem due to the depth of the lesion, age and inflammation-related changes in tissue regenerative capacity, and the tendency of the wound to become infected. Secondary infection of ischemic ulcers is the main cause of lower limb amputations in patients with PAD. To reduce the risk of infection, traditional therapies keep the wound as dry as possible using dressings and topical agents that rapidly absorb exudate, but excessive drying complicates wound healing, especially during a period when blood flow to the capillary bed is still compromised. There is a critical need to develop a new dressing that protects the wound from infection while providing an optimal microenvironment for fast and uncomplicated recovery of ischemic ulcers. We created a novel wound dressing made of biopolymer nanofibers using electrospinning with a minimal concentration of synthetic fiber-forming additives and have tested it in clinical trials treating II-degree thermal burns. Our dressing accelerated regeneration and prevented the growth of pathogenic microflora in the wound. The material also has a high water vapor transmission rate and air permeability, allowing free air access and removal of excess water vapor from the wound surface. In this proposal, we will test the hypothesis that enhanced water vapor and gas permeability of nanofibrous wound dressing (NWD) improves the healing of ischemic ulcers. This hypothesis will be tested through two specific aims, whereby we will first quantify the effects of porosity, thickness, and average nanofiber diameter on the permeability properties of NWDs. By altering the manufacturing parameters, we will produce NWDs with the same chemical composition but different structures, allowing a range of permeabilities for gas and vapor. Second, we will determine the influence of NWD permeability properties on ischemic wound healing in a preclinical DOCA+high-cholesterol ischemic flap swine model. Ischemic wounds will be created as full-thickness bipedicle cutaneous flaps with silicone sheeting to prevent reattachment and reperfusion. This will simulate the conditions of poor blood supply to the wound, while DOCA and western diet will account for the hypertensive inflammatory state typical for PAD patients. This project will demonstrate whether the wound healing process can be improved by managing the water vapor and gas permeability of the wound dressing and help determine the optimal NWD parameters for treating ischemic ulcers. The development of novel concepts for wound care that provide fast and uncomplicated recovery of ischemic ulcers will have substantia...