Liver‐on‐Chip Models as Miniaturized Platforms for In Vitro Hepatotoxicity Testing

Humans are routinely exposed to various exogenous compounds that ultimately reach the liver, the major site for xenobiotic metabolism and detoxification, making it most vulnerable to their toxic effects. Therefore, a systemic toxicity assessment of all xenobiotics must be conducted before human exposure to understand their potential toxic mechanism, determine a safe exposure limit, and mitigate the risk of adverse health outcomes. Traditional animal models and 2-D models have long served as the cornerstone of toxicology, but they have less human-relevant toxicity prediction ability. As a consequence, they frequently miss xenobiotic toxicities that are later determined on human exposure. To promote 3Rs strategy (Reduce, Refine, and Replace) and advance NAMs (new approach methodologies)/NGRA (next-generation risk assessment), there is a revolutionary advancement toward human-centric in vitro platforms for hepatotoxicity testing of diverse compounds. In the past few years, advancements in microfabrication, microfluidics and toxicology research have made liver-on-chip (LoC), a valuable platform for hepatotoxicity risk assessment. LoC, a miniaturized platform with various advanced components, has the potential to recapitulate the complex physiological hepatic microenvironment, including heterogeneous multicellular interactions, dynamic flow, and metabolic zonation, thereby bridging critical translational gaps of conventional testing models. This review explores the state-of-the-art LoC models for liver toxicity assessment of various exogenous compounds, particularly pharmaceutics, herbal compounds, and environmental pollutants. The review discusses advancements in chip design, co-culture methods, and liver toxicity detection techniques, along with commercially available LoCs. Finally, we conclude with challenges and future research directions for LoCs in hepatotoxicity assessment.