PROJECT ABSTRACT Juvenile Onset Recurrent Respiratory Papillomatosis (JORRP) is a rare disease in children that causes papillomatous legions on the glottis (voice box) leading to significant airway obstructions and difficulties with eating, speech, and breathing. The current treatment is surgery and, to minimize surgical damage, diseased cells are usually left behind in surgery and regrow. This leads to a vicious cycle of regrowth and repeated surgical intervention, with some children requiring as many as 12 surgeries each year. In an analogous HPV eye infection, ocular conjunctival papilloma legions are managed with eye drop delivery; however, there are currently no equivalent options for direct topical therapeutic delivery to the glottis. Unfortunately, pediatric preclinical drug delivery models are notably absent in the field, including those that might enable development of customized pediatric inhalation therapies. There is a significant remaining challenge to develop high-throughput, integrated preclinical models that accurately predict drug transport within the unique physiology of pediatric patients, especially in regions of high mobility such as the glottis. The overall objective of this work is to engineer a first-in-kind experimental pediatric “breathing pharyngeal” model, allowing us to directly establish spatial drug deposition profiles in pediatric-specific airways under realistic breathing conditions. This design-driven objective will require integration of pediatric imaging, automation, and tissue-mimicry, combining discrete engineering design approaches to create critical experimentally capacity for drug transport studies under accurate physiological movement. In Aim 1, we will develop analogous in silico and in vitro dynamic glottis models. We will employ novel computational fluid particle dynamics (CFPD) modeling techniques capturing glottis motion. We will vary patient geometry, air flow rates, and particle sizes, creating a library of aerosol deposition profiles and trends. These simulations will complement and inform the in vitro model development; we will integrate technological engineering designs with patient airway replicas utilizing motorized, flexible glottis sections in line with a particle collection impactor to quantify particle deposition. In Aim 2, we will increase particle delivery to the glottis by leveraging CFPD modeling to identify promising parameters with the greatest probability of successful targeting and subsequently replicate and interrogate the simulations in vitro. We will incorporate cellularized hydrogels into the model to ensure disease development and physiological environments are accurately represented, varying thickness and including a complex cellular co-culture will ensure accurate mimicry of physiological and disease development. This project will result in the generation of 1) novel dynamic pediatric glottis computational models, 2) a preclinical tool to establish pediatric aerosol delivery...