Human 3D airway models to explore in vivo inhalation

Human 3D airway models are promising models for safety and efficacy evaluation of compounds targeting the airways. The two most important reasons are (1) the models are fully differentiated and functional (incl. metabolism activity, mucus production and cilia beating) and (2) they are cultured at air-liquid interface, allowing exposure to gasses, vapours, aerosols and particles via air (relevant exposure). Healthy and diseased airway tissue (asthma, COPD) are available. Some models include cells from the upper respiratory tract (nasal tissues, larynx and trachea), where the highest impact of inhaled compounds is. We explored the use of 3D airway models, including MucilAir™, for toxicity testing, e.g. the COMET assay, cell viability and tissue and cell membrane integrity. Substances were applied to the models in droplets. Tissue and membrane integrity, cell viability and ciliary beating were affected by exposure to chemical compounds. A dose-related response was found in the COMET assay with methyl methane sulfonate and we found a low and reproducible background level. Exposure of the MucilAir™ model to benzo[a]pyrene, silicon dioxide or ceriumdioxide nanoparticles did not show an increase in COMET formation. For benzo[a]pyrene, this is likely to be related to the exposure concentration and duration. Our preliminary results indicate that the MucilAir™ model may be a suitable model for safety testing, including genotoxicity and acute toxicity. In the future, we will further assess the applicability of these models for safety and efficacy testing by exposure through the air and comparison with in vivo inhalation data. Ultimately, these models may be useful in the safety evaluation of pharmaceuticals and chemicals.