A microfluidic liver-like model for antiepileptic drugs hepatotoxicity evaluation

Drug-Induced Liver Injury (DILI) is the leading cause of late-stage drug failure and withdrawal of medications from the market. This underscores the urgent need for newin vitroliver models that better recapitulate physiologically relevant conditions and provide controlled physical and biochemical parameters for drug toxicity testing. While advanced, complex liver-on-a-chip systems have been in use for some years, this study presents a simplified microfluidic model for technically comparing static and dynamic culture conditions using a hepatocyte-like cell line for drug toxicity testing. In this study, a dual-compartment microfluidic device comprising a dynamic flow channel and a cell culture chamber was designed to mimic the liver's microstructure. The device's membrane-based design enabled the investigation of cell-media interactions and replication of hepatic Disse space, with comparisons made between static and dynamic conditions. The chip design was evaluated using computational models of glucose consumption and shear stress, which yielded an optimal flow rate of 50 μL/h. HepG2 cells cultured within the chip were assessed via live/dead staining and metabolic function assays, including responses to three antiepileptic drugs at physiological doses, to evaluate hepatotoxicity. Under dynamic conditions, cell viability and function improved significantly, simulating a continuous supply of nutrients and oxygen, as well as mechanical shear stress signaling. Among the tested drugs, sodium valproate (500 μM) induced the least hepatotoxicity, whereas carbamazepine and phenytoin led to a ∼60% reduction in hepatic function over one week. Although structurally and functionally less complex than existing liver-on-a-chip platforms, these findings suggest that this liver-chip platform is a simple yet useful tool for drug screening and hepatotoxicity assessment.