A human breathing lung‐on‐a‐chip

Abstract

Here we describe a biomimetic microsystem that reconstitutes the critical functional alveolar‐capillary interface of the human lung and exposes it to cyclic mechanical strain and fluid dynamic forces that mimic breathing and blood flow. This microdevice reproduces complex integrated organ‐level responses to bacteria and inflammatory cytokines introduced into the alveolar space by inducing expression of intercellular adhesion molecule‐1 (ICAM‐1) on the microvascular endothelium surface, adhesion of circulating blood‐borne neutrophils, their transmigration across the capillary‐alveolar interface, and phagocytosis of the infectious pathogens, which can be visualized using real‐time, high‐resolution microscopy. Using this approach, we developed novel nanotoxicology models and revealed that physiological cyclic mechanical strain greatly accentuates toxic and inflammatory responses of the lung to silica nanoparticles by promoting rapid release of toxic reactive oxygen species by alveolar epithelial cells and upregulating endothelial ICAM‐1 expression. Mechanical strain also enhances nanoparticle uptake by the epithelial cells and stimulates their transport into the underlying microvasculature. This mechanically active biomimetic microsystem represents valuable new model systems for in vitro analysis of various physiological functions and disease processes, in addition to providing low‐cost alternatives to animal and clinical studies for drug screening and toxicology applications. This work was supported by grants from NIH and the Wyss Institute for Biologically Inspired Engineering at Harvard University.