A human airway-on-a-chip microphysiological system for modeling chlorine gas toxicity.

There is a critical need to understand pathophysiological mechanisms involved in injury from acute chlorine gas (Cl2) exposure. Limited information is available regarding the time course and mechanisms of injury after acute Cl2 exposure due to a lack of human clinical data and limited fidelity of pre-clinical animal models. We designed and integrated a Cl2 exposure platform to generate and deliver precise concentrations of Cl2 to a microfluidic human airway-on-a-chip microphysiological system. Chemical, biological, structural, and functional airway-on-a-chip responses to Cl2 exposure were characterized across multiple concentrations, exposure times, and post-exposure timepoints. Transcriptomics and metabolomics analyses delineated key molecular, cellular, and physiological pathways involved in the acute response to Cl2 exposure. This work represents a significant advancement towards high-throughput, human-relevant characterization of pulmonary toxicants and medical countermeasure development, addressing critical gaps in toxicology modeling while reducing reliance on animal studies.