PROJECT SUMMARY The overall goal of this proposal is to identify a novel preventative approach targeting an oral condition prevalent in the edentulous population. Denture stomatitis caused by the oral fungal pathogen Candida albicans, is a common oral condition prevalent in up to 70% of denture wearers causing severe pain impairing the ability to eat and speak. This debilitating disease tends to be persistent and recurrent as a consequence of the ability of C. albicans to adhere and form biofilms on denture surfaces and associated oral tissue. Despite its prevalence, there are currently no strategies available for the prevention of denture stomatitis. Natural antimicrobial peptides have attracted significant attention due to their broad-spectrum activity and lack of toxicity. Histatin-5 (Hst-5) is particularly attractive as it is potent in killing C. albicans. To that end, we recently designed a bioadhesive hydrogel delivery system specifically for oral topical application and using Hst-5 as a blueprint, we also engineered a novel variant. Our preliminary investigations demonstrated the ability of the peptide variant in preventing C. albicans adherence and biofilm formation on denture acrylic material in vitro. Importantly, by taking advantage of new technological advances in dentistry available to us, we digitally engineered and fabricated a universal intraoral acrylic device for rats. The model was specifically designed to study Candida biofilm formation on installed oral devices, and ensuing tissue infection and inflammation, mimicking clinical denture stomatitis in humans. In this proposal, we aim to demonstrate the clinical utility of the novel formulation against denture stomatitis in an aging rat model. We expect the fulfillment of the aims of this proposal to identify a feasible approach for the prevention of biofilm-associated oral infections, and specifically denture stomatitis, which continues to be a public health problem particularly in the pre-disposed edentulous elderly population.