PROJECT SUMMARY In the US, one out of eight people suffers from hearing loss. Common causes of hearing loss are age, frequent exposure to loud noise, genetic disorders, and more. Hearing loss is often accompanied by other medical conditions such as higher rate of depression, social isolation, and cognitive decline (e.g., dementia). Many diverse and novel therapeutic methods are developed to treat hearing loss, but one common challenge that they all share is how to safely deliver therapeutics to the inner ear. Often, non-invasive methods to deliver drugs to the inner ear cannot penetrate the inner ear’s barriers, and consequently, only a small fraction of the drug reaches its target. Alternatively, invasive surgical methods such as direct injection to the inner ear could potentially cause damage to the cells that populate the inner ear. Although rodent models vastly expanded our understanding of hearing loss and its treatment at a molecular level, rodent models are less suitable to address the drug delivery problem. This is due to the fact that the size of the rodent’s inner ear, and the thickness of its protective barriers do not match the human’s, therefore, evaluation of the translational potential of new drug delivery methods using rodent models is challenging. To address this gap, we would like to advocate for the use of the pig as a translational animal model to study non-invasive drug delivery strategies to the inner ear. Pigs are large animal models, and their size, anatomy, intelligence, and genetics are by far closer to humans than rodents. Consequently, the pig is becoming a popular animal model and it is commonly used in cardiovascular research, wound healing, organ transplantation, nutritional studies, and more. In general, pigs are readily available for research as they are a popular form of livestock, and in the US alone, over 100 million pigs are slaughtered annually. Here, to establish the pig as a large animal model to study local delivery to the inner ear, we will: (i) Validate an ex-vivo porcine RWM model for drug permeability studies. (ii) Develop a method to deliver therapeutics to the middle and inner ear of the porcine model. Technically, we will utilize tissue clearing and labeling techniques together with advanced microscopy to image the whole porcine inner ear with cellular resolution. This methodology facilitates the biodistribution of drugs in the tissue. Overall, the success of these goals will open future avenues for testing minimally invasive drug delivery methods to the inner ear and studying in-vivo drug delivery in a big animal model.