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Due to a more physiological reproduction of the in vivo situation, liver‐on‐a‐chip devices in recent studies have shown higher sensitivity and accuracy for hepatotoxicity testing compared to traditional in vitro liver models. In this context, this work presents an original microfluidic device mimicking 3D hepatic cords organized radially, like in the liver lobule. Ten cell‐culture chambers seeded at a high density are disposed with a parallelized flow that emulates blood flow from the portal triad to the central vein in the liver lobule. Using this device, on‐chip differentiation of human HepaRG‐Hepatoblast (HepaRG‐HB) to HepaRG‐Hepatocytes (HepaRG‐HC) has been studied in terms of self‐organization capabilities, bile canaliculi formation and albumin expression. Our results indicate that due to the design of the cell culture chamber, which mechanically constrains tissue proliferation, and the physiologically relevant microfluidic flow condition used during tissue development, the HepaRG‐HBs in the device can proliferate, self‐organize, and spontaneously differentiate in a DMSO free medium forming long, directional bile canaliculi. On the contrary, under the same conditions, differentiated HepaRG‐HC is observed to aggregate without long bile canaliculi and form tissues resembling traditional HepaRG‐HC cultures. © 2024 Institute of Electrical Engineers of Japan. Published by Wiley Periodicals LLC. [ABSTRACT FROM AUTHOR]

Microphysiological systems (MPSs) have attracted increasing attention as a method for simulating in vitro drug efficiency. In particular, the interaction between liver and intestine tissues is one of the primary targets since they are closely involved in drug absorption and metabolism. However, most of the intestine-liver MPSs reported previously require pumps, electrodes, and porous membranes for co-culture of cells and evaluation of intestinal permeability (i.e., Trans-Epithelial Electrical Resistance, TEER), requiring complex manufacturing processes and operations. In this study, we report an all-polydimethylsiloxane (PDMS) co-culture microfluidic device, connecting microchamber-based paracellular transport assay on gut microtissues to liver tissues matured on the same device. On one side of the device, HepaRG cells are confined within thin parallel grooves that induce their differentiation into hepatocytes. The other side of the device is connected with microchannels to the liver side and includes the gut tissues, organized above microchambers. Such microchambers allow the evaluation of paracellular permeability by fluorescence imaging. Thanks to the microfluidic device we investigated changes in intestinal permeability induced by differentiated hepatocyte excretion and found that Caco-2 permeability was decreased when co-culture with HepaRG. Due to its simplicity and straightforward implementation, this method is anticipated as an innovative and efficient approach to assess tissue barrier function in multi-organ on-chip experiments.