Liver-on-a-Chip: Applications for clinical modeling of liver disease using microscale systems

Liver-on-a-chip (LOC) systems are tunable, microscale environments that can incorporate additional layers of physiologic complexity in comparison to 2D cell culture. LOCs are an in vitro adjunct and potential alternative to in vivo animal models that utilize human-derived cells, typically embedded in a synthetic device containing natural or engineered materials. This enables LOC models to exhibit a high level of customization per organ, disease, or condition. LOCs typically contain dynamic flow to cells embedded in a series of microchannels within the device. This perturbation aims to recreate mechanobiological forces seen in vivo and encourage cell-to-cell interactions in a 3D environment. These models have proven to be particularly advantageous in modeling organs with complex spatial zonation, such as the liver, as oxygen and nutrient gradients can more accurately be represented under these dynamic conditions. LOC systems have also been proposed to improve the accuracy of drug toxicity screening for clinical applications because they employ human-derived cells in more physiologically relevant conditions. This review will first discuss fabrication techniques and considerations when recreating biological microenvironments. Next, the advances of LOC systems and applications for modeling liver disease and infection will be explored. Finally, current limitations and advances for implementing LOC devices into clinical and commercial settings will be examined.