Organ-on-a-Chip Models for Drug Toxicity Screening

Abstract

Organ-on-a-chip (OoC) microphysiological systems recapitulate human organ-level physiology within microfluidic devices, offering superior predictive validity for drug toxicity screening compared to conventional two-dimensional cell culture and animal models. This study developed and validated four OoC platforms -- liver-on-a-chip (hepatotoxicity), heart-on-a-chip (cardiotoxicity), kidney-on-a-chip (nephrotoxicity), and a multi-organ body-on-a-chip integrating all three-- using human iPSC-derived organoids under physiological flow conditions. Twenty-four compounds with known clinical toxicity profiles (8 hepatotoxicants, 8 cardiotoxicants, 8 nephrotoxicants) were screened across all platforms at six concentrations spanning 0.1-100x Cmax. The liver-on-a-chip correctly identified 87.5% of known hepatotoxicants (7/8) at clinically relevant concentrations (1-10x Cmax) with 91.7% specificity -- substantially outperforming static 2D HepG2 culture (62.5% sensitivity). The heart-on-a-chip detected 100% of hERG-mediated QT prolonging compounds through real-time calcium transient imaging and field potential duration measurement. The integrated body-on-a-chip revealed two metabolite-mediated toxicities (liver-generated toxic metabolites causing kidney or cardiac injury) missed by single-organ platforms, demonstrating the unique value of multi-organ crosstalk modelling. These findings establish OoC platforms as regulatory-grade alternatives to animal toxicity testing aligned with FDA Modernization Act 2.0.