Project Summary Treatment of Onychomycosis Utilizing Targeted, Controlled High-Frequency Energy PIs: Laura King and Dan van der Weide The painful and disfiguring fungal infection of the nail, known as onychomycosis, afflicts over 5% of the global population and accounts for 50% of all nail disorders. Not simply a cosmetic disease, onychomycosis is an intractable infection strongly intertwined with diabetes, as diabetic patients are more likely to be susceptible to this fungal infection and those who are infected are more likely to develop serious issues such as foot ulcers, secondary infections, peripheral neuropathy, and even amputation. A substantial, unmet clinical need for safe, effective treatment of onychomycosis exists because current therapies are minimally effective, require daily application, and have significant potential risks. A new therapeutic modality, heating through delivery of High Frequency Energy (HFE), is already successfully treating patients with cancer by killing the offending cells and sparing adjacent tissue through cooling mechanisms. Building upon our previous innovations in HFE, this same technology at much lower powers can be used to treat infections like onychomycosis. Treatment with HFE, as developed with attention to patient-specific time and dose delivery provided by clinicians in their offices, can provide the safe, effective, and efficiently delivered treatment for millions of patients with this challenging, often painful condition and limit its sequelae. In this proposal, Aim 1 will model a range of treatment zone temperatures (47o–50oC) at the simulated nail bed using HFE power and time schedules consistent with clinical treatment (e.g. 5–10 W for 5–30 minutes), and to optimize the placement and orientation of the HFE relative to the infected nail bed. Careful modulation of the treatment times and temperatures will avoid second and third degree burns and spare the nail from damage, while eliminating fungal growth. In Aim 2, an in vitro model of fungal infection will be utilized to demonstrate the ability to inhibit growth of dermatophytes utilizing time and power algorithms guided by the predictive models developed in Aim 1. Using the HFE algorithms and our applicator design, Aim 3 will test the ability of HFE to eliminate dermatophyte growth supported on cadaver nails with a goal of 100% elimination of fungal growth. The computational model will be further refined with the resulting data from this human nail model to optimize the time and temperature algorithm. After further development in a potential Phase II grant, the ultimate goal will be to develop and build a functional prototype based on these results, capable of delivering controlled HFE to the nail bed for repeatable treatment of onychomycosis, to be used in the physician’s office or point-of-care dermatology clinics.