INJECTABLE, TUNABLE CO-DELIVERY THERAPEUTIC IMPLANT TO REDUCE AIRWAY STENOSIS

Project Summary Laryngeal injury, defined as glottic mucosal ulceration or granulation or subglottic granulation/stenosis, leads to respiratory failure and requires intensive care unit (ICU) admission. More than 55,000 adults are treated daily in ICUs and 13-20 million worldwide require intubation each year. Current treatment often requires multiple surgeries with or without tracheostomy. Recently, adjuvant glucocorticoid use has been reported, as they are known to improve airway inflammation. However, these treatments require repeated injections with an interval varying from every week to 5 weeks with a total of 3 to 25 injections, which is a significant burden to the patients. Therefore, there is a critical unmet need in delivering glucocorticoid non-invasively in a dose-controlled manner to the lesion. In addition, investigation into the tracheal microbiome suggests a contributing role of laryngotracheal microbiota to mucosal inflammation and the pathogenesis of tracheal stenosis. We will develop a novel injectable co-delivery implant that can deliver glucocorticoid and antimicrobial over time either in a sustained release fashion or in a laser-light activated approach effectively for 6 weeks in a leporine preclinical model. Our in vivo preliminary work showed minimal immune responses from the injectable implant in the leporine upper airway after 6-week implantation. In the first aim, we will optimize our injectable co-delivery implant drug delivery system for the ex vivo trachea tissues and measure any local immune response in healthy leporine. In the second aim, we will employ the implant in a trachea injury model to quantify its healing impacts compared to no treatment or single glucocorticoid and antimicrobial injections. Simultaneously, the upper respiratory microbiome will be analyzed to determine the microbiome changes and the efficacy in reducing bacteria utilizing our implants compared to a single glucocorticoid injection. This work lays the foundation for optimized, dose controllable therapeutic delivery to the airway and improved drug delivery.