Overview of microfluidic device designs to mimic the lung-capillary interactions in the alveolus. (Left) (A) Diagram of the nanoparticle exposure to human lung. (B) Alveolar-capillary barrier in vitro. (C) Design and structure of the lung-on-a-chip. (D) Zoom-in showing the artificial alveolar-capillary barrier on the chip. Epithelial and endothelial cells are seeded on opposite sides of a Matrigel barrier. Media was flown through the endothelial channel88. (Top right) (E) Schematic of alveolus Lung-on-a-chip model comprising compartmentalized PDMS microchannels to form an alveolar-capillary barrier. Alveolar epithelial and endothelial cells are co-cultured on porous PDMS membrane coated with ECM. (F) Physiological cyclic strain or ‘breathing’ is generated by applying vacuum to the side chambers95. (G) Schematic diagram of device containing human lung epithelial cells and a low density of NSCLC tumor cells cultured on the upper surface of a porous ECM-coated membrane with an endothelial square cross-sectioned lumen. Physiological breathing motions were also mimicked in this device. (B) Confocal fluorescence micrograph of a cross-section of alveolus chip, showing lung cancer cells (green, anti-GFP), primary lung alveolar epithelial cells labeled with ZO-1 (white). A square cross-section endothelial cells lumen is created on the bottom microchannel and labeled with anti-VE-cadherin (red). (Scale bar, 200 μm)77. Reproduced from ref. 88 with permission from Oxford University Press, copyright 2018. Reproduced from ref. 77 with permission from The American Association for the Advancement of Science, copyright 2012.