Abstract Chronic and non-healing wounds, caused by diseases and physical injuries, are a major medical problem worldwide. Wound dressings are important components for wound treatment. They have been extensively developed to simultaneously obtain various capabilities which facilitate (1) hemostasis, (2) bacterial prevention, (3) thermal insulation, (4) exudate absorbability, and (5) cell/moisture retention in injured or damaged tissues. Despite many encouraging results, current wound dressings still struggle to possess all of the desired properties. Physical stimulations using ultrasound, negative pressures, hydrotherapy and electricity have been also reported as supplements to wound dressing for promoting healing rate. Yet, all of these adjuvant approaches are still at immature stages with limited applications in clinical settings. Nanofiber mats have appeared to be an appealing platform for wound dressing. Due to their inherent nanostructures with high surface-to-volume ratio and high porosity, the mats enable an enhanced hemostasis, excellent retention of cells and moisture, and high absorption of exudate. Hypothetically, a hybridization of nanofiber dressings with physical stimulations such as ultrasound and electrical therapies will provide a synergistic effect to significantly promote wound healing. In this regard, The PI has recently developed a new bioresorbable and biocompatible piezoelectric polymer of poly-L-lactide acid or PLLA (PNAS, 115 (5) 909-914, 2018), which can convert mechanical deformation into useful electricity for stimulating wound healing. Here we propose for the first time a unique approach, utilizing a new biodegradable piezoelectric nanofiber scaffold of PLLA, which is subjected to acoustic-pressure of non- invasive ultrasound (US), to enhance wound healing. Our main hypothesis/scientific premise is that the piezo-PLLA nanofibers under applied US will generate useful surface charge which together with excellent wound-healing properties of the nanofibers will create a synergistic effect to suppress bacterial infection, facilitate exudate drainage, promote proliferation of fibroblasts and enable rapid formation of collagen for re- epithelialization, consequently promoting wound healing. To demonstrate this premise, the project will have three specific aims; Aim 1 is to characterize piezoelectric surface charge, generated by the electrospun PLLA nanofiber mat under applied US in vitro. Aim 2 is to assess activities of fibroblast and epithelial-cells on the piezoelectric PLLA nanofiber mat with ultrasound stimulation and other wound dressing properties of the nanofibers in vitro. And aim 3 is to demonstrate the use of this nanofiber mat and applied US for promoting healing of full-thickness skin wound in vivo.