Liver lipid accumulation (fatty liver) is an early step in the development of drug-induced, alcoholic (ASH) and non-alcoholic steatohepatits (NASH) that may progress into cirrhosis and hepatocellular carcinoma.
A wealth of animal studies and in vitro models have elucidated molecular mechanisms associated with NASH, whereas translation of these findings to effective therapeutics for humans, remains an unmet medical need. In the effort to establish more predictive and human-relevant models for fatty liver disease/steatosis, a microengineered Liver-Chip was developed to include hepatocytes, liver sinusoidal endothelial cells (LSECs), Kupffer, and stellate cells for more accurate representation of the in vivo tissue. The Liver-Chip has the potential for long-term maintenance of cell viability to enable repeated drug exposure and exhibited hepatic functions that recapitulate in vivo metabolic capabilities. The Liver-Chip has well-characterized toxicology endpoints sensitive for cell-specificity over time and is capable of demonstrating the diverse mechanisms of drug-induced liver injury. The model incorporates relevant cell-ECM interactions, a hepatocyte and LSEC interface, with relevant cytoarchitecture and physiological flow. Liver-specific functions were measured for all three species and demonstrated maintenance of in vivo relevant levels of functionality including albumin secretion, CYP450 enzyme activity, and gene expression of certain markers that demonstrated improved function over conventional monolayer models. We evaluated the ability of the human Liver-Chip to respond to steatosis inducers (e.g., free fatty acid, glucose and ethanol).