iPSC-Derived Bronchial Airways-On-Chip for the Assessment of Cytokine Secretion Triggered by Volatile Organic Compounds.

Air quality monitoring currently relies mostly on a combination of epidemiological data and classic experimental data. Our objective was to design an alternative approach for assessing air pollutant risk potential using a specialized platform capable of detecting the cumulative and indirect effects of exposure via the inhaled route. We used a bronchial airways-on-chip (BOC) that captures key physiological features of the human lung. The platform integrates our previously developed device with in vitro differentiated bronchial epithelium derived from induced pluripotent stem cells (iPSCs). This setup is capable of replicating bronchial epithelial exposure to irritants at the air-liquid interface under controlled and reproducible conditions. It comprises the first proof-of-concept design combining a BOC with iPSC-derived bronchial epithelium as an alternative approach toward potential risk assessment of inhaled pollutants. As a representative pollutant, we use benzene, a volatile organic compound (VOC). At low concentrations and short-term exposure, it is not considered acutely harmful, but long-term exposure can result in mutagenic and carcinogenic effects. As air pollutant toxicity is known to be mediated by the respiratory epithelial lining and secretion of cytokines, we demonstrate our system to be sufficiently sensitive to capture increased cytokine secretion corresponding to increasing concentrations of benzene. Of utmost relevance is our finding that a cumulative effect could be detected, only caused by prolonged exposure at low concentrations of benzene, previously shown to be nontoxic in classic short-term in vitro studies. Finally, the cumulative effect could be reversed using a commonly used asthma medication (Montelukast), further supporting the relevance of the setup.