Modular Liver-on-a-Chip Platform for Accelerating Toxicological Applications: A Case Study of Triphenyl Phosphate Hepatotoxicity.

Organ-on-a-chip technology can improve human relevance in toxicity testing. However, meeting toxicological evaluation requirements remains challenging, particularly with respect to controlled flow dynamics, usability, and biological replicates. We present a modular, tubing-free liver-on-a-chip platform with a clamping cartridge and software-controlled recirculation that enables 12 parallel channels and reproducible recirculating concentrations. Using the hepatotoxic chemical triphenyl phosphate, the platform enhanced hepatic function compared with static culture, showing higher cytochrome P450 1A2, 3A4, and 2E1 mRNA expression and increased metabolite formation. Exposure to 10 μM triphenyl phosphate altered urea, lactate dehydrogenase, and aspartate aminotransferase levels with responses occurring at lower measured concentrations on-chip than in plate-based cultures. RNA sequencing revealed pathway-level perturbations consistent with triphenyl phosphate-induced hepatotoxicity, including spliceosome and inflammatory signaling pathways. These results demonstrate advances in the toxicological application of organ-on-a-chip platforms, improving toxicity assessment through enhanced flow fidelity and parallel biological replicates.