Abstract

The thin air-blood barrier, smallest functional unit of the lung, is the main responsible for oxygen retrieval through gas exchange. Recapitulating its complexity and integrity in vitro is key to develop models aiming at predicting drug safety and efficacy, as well as to investigate the mechanisms underlying lung disease. With that purpose, we have integrated different elements of the lung microenvironment (<5 µm thin porous basement membrane, 3D-breathing motion) with human alveolar cells employing the AlveoliX lung-on-chip technology. 

In this work, we recapitulate various applications focused on inflammation, safety, and efficacy testing. Cells were treated with different proinflammatory or cytotoxic triggers such as bacterial lipopolysaccharide and CdCl2, leading to barrier breakdown and proinflammatory cytokine release. In addition, we present an inhalation model for commonly used nanoparticles (ZnO) which showed the relevance of the dynamic setting in toxicology studies. Finally, we present a disease model based on the coculture of alveolar epithelial cells and lung fibroblasts, which enables efficacy studies for antifibrotic compounds. 

Our findings suggest that integrating alveolar-mimicking mechanical cues and cell complexity is relevant to recapitulate lung in vivo-like responses. Therefore, the AX lung-on-chip is a promising tool for studying molecule toxicity, safety, and efficacy testing in a preclinical setting.