The goal of this proposal is to develop a non-toxic hydrogel to achieve trans-tympanic delivery of therapeutics to treat otitis media (OM). This platform will non-invasively deliver therapeutics across the tympanic membrane to eradicate bacterial infections and curb antimicrobial resistance, while avoiding side effects caused by systemic antibiotic exposure. This proposal builds on our previous work that demonstrated successful eradication of OM through a polymeric hydrogel, by now employing solely biocompatible polymer chemistries (e.g. ones that have obtained approval from the FDA for topical, oral, or intravenous delivery) with safe degradation products. By using these chemistries, we aim to accelerate downstream clinical translation. The project addresses the NIDCD mission by focusing on OM, a key pillar within the Hearing and Balance Program, and on developing new drug delivery systems to the middle ear to treat middle and inner ear diseases. In this project, we will apply our experience in functional material design, mechanics, and nanotechnology to enable the successful development, and eventual deployment, of this new treatment platform. The unique and wide-ranging methods utilized here range from fundamental polymer physics, rheology and mechanics, and small angle scattering to ex vivo and in vivo testing in a chinchilla model. The first aim focuses on reverse engineering the hydrogel structure based on criteria developed from our previous results, to obtain the optimal structure and mechanical properties for effective drug delivery and gel adhesion to the tympanic membrane. The impact of the hydrogel structure and mechanical properties on the trans-tympanic flux, bio-compatibility, and bio-degradation will be investigated for promising formulations in the second aim. The third aim focuses on the best performing formulations, where in vitro studies will assess antimicrobial effectiveness and cytotoxicity, and in vivo assessment in a chinchilla model will evaluate treatment efficacy, pharmacokinetics, and pharmacodynamics. The project will contribute to the mission of NIDCD by providing new treatments that will lead to better health for all, including the 95% of US children affected by acute OM. We will generate new knowledge, both to help treat otitis media and to develop new drug delivery platforms, while improving the delivery, quality, and effectiveness of care for everyone. In the short term, this project will help accelerate downstream translation of research findings into clinical practice by focusing on biocompatible polymer chemistries. In the longer term, this new drug delivery platform has potential to reduce treatment side effects and antimicrobial resistance, while improving treatment efficacy by removing barriers to patient compliance associated with oral therapy.