In situ-Like Aerosol Inhalation Exposure for Cytotoxicity Assessment Using Airway-on-Chips Platforms
Shani Elias‐Kirma, Arbel Artzy‐Schnirman, Prashant Das, Metar Heller-Algazi, Netanel Korin, Josué Sznitman
Abstract
Lung exposure to inhaled particulate matter (PM) is known to injure the airway epithelium via inflammation, a phenomenon linked to increased levels of global morbidity and mortality. To evaluate physiological outcomes following PM exposure and concurrently circumvent the use of animal experiments, in vitro approaches have typically relied on traditional assays with plates or well inserts. Yet, these manifest drawbacks including the inability to capture physiological inhalation conditions and aerosol deposition characteristics relative to in vivo human conditions. Here, we present a novel airway-on-chip exposure platform that emulates the epithelium of human bronchial airways with critical cellular barrier functions at an air-liquid interface (ALI). As a proof-of-concept for in vitro lung cytotoxicity testing, we recapitulate a well-characterized cell apoptosis pathway, induced through exposure to 2 µm airborne particles coated with αVR1 antibody that leads to significant loss in cell viability across the recapitulated airway epithelium. Notably, our in vitro inhalation assays enable simultaneous aerosol exposure across multiple airway chips integrated within a larger bronchial airway tree model, under physiological respiratory airflow conditions. Such efforts deliver in situ-like aerosol deposition outcomes where patterns depend on respiratory flows across the airway tree geometry and gravitational orientation, as corroborated by concurrent numerical simulations. Our airway-on-chips not only highlight the need to replicate inhalation exposure processes more accurately, such platforms open opportunities towards advanced in vitro exposure assays for preclinical cytotoxicity and drug screening applications.