Breathing, Full Volume Pulmonary Deposition Model to Transform Development of Aerosol Therapeutics - PROJECT SUMMARY The biggest translational hurdle to advancing inhaled therapeutic and vaccine systems is predicting how they will work in the lung. Predictions are challenged by the complex variability of airway structure and motion, the tremendous surface area, and the highly coupled physical phenomena of orally inhaled and nasal drug products (OINDPs). Given the high degree of complexity, there remain no preclinical tools capable of measuring spatial deposition of an entire OINDP dose under simulated breathing conditions. Without knowing where aerosols deposit in each individual, predictions of how well the therapeutic will work once there are severely insufficient. This dearth of realistic in vitro models leads to a complete lack of high throughput screening approaches to new inhalation therapies and creates significant challenges to establishing efficacy, toxicity, and/or bioequivalence (BE) of OINDPs. Given this major bottleneck, pulmonary drug delivery remains a low pipeline priority, despite the overwhelming potential to directly treat a plethora of respiratory diseases. To address this, our lab has created a multiscale dynamic preclinical tool to spatial measure deposition as a function of patient-specific breathing, anatomy, and disease state. Coined the “total inhalable deposition in an actuated lung” (TIDAL) model, this platform leverages advances in additive manufacturing to recreate spatial aerosol collection efficiencies across the five lung lobes. Our overall goal in this project is to realize the potential of the TIDAL tool as an effective measure of inhaled deposition to address outstanding issues in inhalation therapeutics. In Aim 1, we will validate healthy an adult TIDAL prototype with clinical dosimetry benchmarks for aerosols of different average aerodynamic diameters and breathing profiles and identify an optimal upper airway. In Aim 2, we will develop advanced features of the TIDAL model to capture interpatient variability, including aspects of airway disease and altered ventilation. In Aim 3, we will upgrade the TIDAL model to include representative humidity and mucosal mimicry to effectively evaluate DPI products. Progressing in parallel, these aims will yield 1) a novel, integrated preclinical tool to measure spatial deposition and improve predictions of inhalation efficacy (and/or toxicity), 2) broad correlations between regional deposition, BE, and existing in vitro measures, and 3) a platform technology that can support therapeutic development for a wide range of respiratory patients and disease pathologies. The integrated multiscale features of TIDAL within a single physical mode of the entire lung volume will enable the first experimental quantification of how patient geometry, disease, breath maneuver, and aerosol size combine to dictate lung response, leading to a transformative step-change in inhalation therapeutic approaches. The project will catalyze new OINDP model creations and transform opportunities in inhalation medicine.
