Engineering human multi-organ tissue chip niches for drug absorption, distribution, metabolism, excretion and toxicity prediction.

Predicting human drug responses in vitro remains a central challenge in drug development. Animal models have shown limited accuracy in recapitulating human drug absorption, distribution, metabolism, excretion and toxicity, which arise from coordinated activities across multiple organs. Multi-organ-on-a-chip systems (mOoCs) are a class of promising new approach methodologies that can reconstruct these inter-organ processes. Existing mOoCs have demonstrated proof of concept for inter-organ coupling but translation-ready systems remain out of reach. Two key challenges persist: how to preserve the distinct biochemical and biomechanical niches of each organ while enabling controlled exchange between them, and how to develop mOoCs into robust translation-ready systems. In this Review, we first summarize progress in niche-preserving engineering strategies developed within single-organ systems and outline how these components are integrated to reconstruct multi-organ niches. We then highlight scalable manufacturing and multimodal readouts as the basis for making mOoCs into robust, reproducible and data-rich technologies for drug response evaluation. In the future, the resulting human-relevant datasets are expected to interface with artificial intelligence workflows to accelerate next-generation drug discovery.