Human small airway-on-a-chip: A novel microphysiological system to model lung inflammation, accelerate drug development and enable inhalational toxico-analysis

Development of new therapeutics for lung inflammatory and infectious diseases, and advancement in our understanding of inhalational toxico-pathology have been hindered by challenges to study organ-level complexities of human lung in vitro. Here, we applied a microengineering technological approach known as 9organ-on-chip9 to create a human lung small airway-on-a-chip that supports full differentiation of a pseudostratified mucociliary bronchiolar epithelium from normal or diseased donors underlined by a functional microvascular endothelium. Small airway chips lined with chronic obstructive pulmonary disease (COPD) epithelia recapitulated features of the disease including selective cytokine hypersecretion, increased neutrophil recruitment, and clinical exacerbations by exposure to pathogens. Using this robust in vitro method, it was possible to detect synergistic tissue-tissue communication, identify new biomarkers of disease exacerbation, and measure responses to anti-inflammatory compounds that inhibit cytokine-induced recruitment of circulating neutrophils. Importantly, by connecting the small airway chip to a custom-designed electromechanical instrument that 9breathes9 whole cigarette smoke in and out of the chip microchannels, we successfully recreated smoke-induced oxidative stress, identified new ciliary micropathologies, and discovered unique COPD-specific molecular signatures. Moreover, this platform revealed a subtle ciliary damage triggered by acute exposure to electronic cigarette. Thus, the human small airway-on-a-chip offers a powerful complement to animal models for studying human lung pathophysiology.