Hepatology and drug development for liver diseases require in vitro liver models. Typical models include 2D planar primary hepatocytes, hepatocyte spheroids, hepatocyte organoids, and liver-on-a-chip. Liver-on-a-chip has emerged as the mainstream model for drug development because it recapitulates the liver microenvironment and has good assay robustness such as reproducibility. Liver-on-a-chip with human primary cells can potentially correlate clinical testing. Liver-on-a-chip can not only predict drug hepatotoxicity and drug metabolism, but also connect other artificial organs on the chip for a human-on-a-chip, which can reflect the overall effect of a drug. Engineering an effective liver-on-a-chip device requires knowledge of multiple disciplines including chemistry, fluidic mechanics, cell biology, electrics, and optics. This review first introduces the physiological microenvironments in the liver, especially the cell composition and its specialized roles, and then summarizes the strategies to build a liver-on-a-chip via microfluidic technologies and its biomedical applications. In addition, the latest advancements of liver-on-a-chip technologies are discussed, which serve as a basis for further liver-on-a-chip research.
Organ-on-a-chip academic research is in its blossom. Drug toxicity evaluation is a promising area in which organ-on-a-chip technology can apply. A unique advantage of organ-on-a-chip is the ability to integrate drug metabolism and drug toxic processes in a single device, which facilitates evaluation of toxicity of drug metabolites. Human organ-on-a-chip has been fabricated and used to assess drug toxicity with data correlation with the clinical trial. In this review, we introduced the microfluidic chip models of liver, kidney, heart, nerve, and other organs and multiple organs, highlighting the application of these models in drug toxicity detection. Some biomarkers of toxic injury that have been used in organ chip platforms or have potential for use on organ chip platforms are summarized. Finally, we discussed the goals and future directions for drug toxicity evaluation based on organ-on-a-chip technology.
The poor metabolic ability of cell lines fails to meet the requirements of an in vitro model for drug interaction testing which is crucial for the development or clinical application of drugs. Herein, we describe a liver sinusoid-on-a-chip device composed of four kinds of transformed cell lines (HepG2 cells, LX-2 cells, EAhy926 cells, and U937 cells) that were ordered in a physiological distribution with artificial liver blood flow and biliary efflux flowing in the opposite direction. This microfluidic device applied three-dimensional culturing of HepG2 cells with high density (10 7 ml −1), forming a tightly connected monolayer of EAhy926 cells and achieving the active transport of drugs in HepG2 cells. Results showed that the device maintained synthetic and secretory functions, preserved cytochrome P450 1A1/2 and uridine diphosphate glucuronyltransferase enzymatic activities, as well as sensitivity of drug metabolism. The cell lines derived device enables the investigation of a drug-drug interaction study. We used it to test the hepatotoxicity of acetaminophen and the following combinations: "acetaminophen + rifampicin," "acetaminophen + omeprazole," and "acetaminophen + ciprofloxacin." The variations in hepatotoxicity of the combinations compared to acetaminophen alone, which is not found in a 96-well plate model, in the device were −17.15%, 14.88%, and −19.74%. In addition, this result was similar to the one tested by the classical primary hepatocyte plate model (−13.22%, 13.51%, and −15.81%). Thus, this cell lines derived liver model provides an alternative to investigate drug hepatotoxicity, drug-drug interaction.
Intracellular calcium dynamics plays an important role in the regulation of vascular endothelial cellular functions. In order to probe the intracellular calcium dynamic response under synergistic effect of wall shear stress (WSS) and adenosine triphosphate (ATP) signals, a novel microfluidic device, which provides the adherent vascular endothelial cells (VECs) on the bottom of microchannel with WSS signal alone, ATP signal alone, and different combinations of WSS and ATP signals, is proposed based upon the principles of fluid mechanics and mass transfer. The spatiotemporal profiles of extracellular ATP signals from numerical simulation and experiment studies validate the implementation of our design. The intracellular calcium dynamics of VECs in response to either WSS signal or ATP signal alone, and different combinations of WSS and ATP signals have been investigated. It is found that the synergistic effect of the WSS and ATP signals plays a more significant role in the signal transduction of VECs rather than that from either WSS signal or ATP signal alone. In particular, under the combined stimuli of WSS and ATP signals with different amplitudes and frequencies, the amplitudes and frequencies of the intracellular Ca dynamic signals are observed to be closely related to the amplitudes and frequencies of WSS or ATP signals.
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