Model systems and integration strategies to capture human biology

Modelling human biology is difficult precisely because many of the responses that matter most emerge not within a single tissue or cell type, but at the boundaries where matrix, immune and systemic signals converge in ways that are hard to recreate in isolation. Conventional in vitro systems and animal studies have advanced our understanding of many physiological processes, but they still consistently fall short at these interfaces. In this Review, we discuss how engineered materials, organoids, microphysiological systems and computational models can be used together to build more informative human model systems. We first consider engineered materials as tools for controlling the local environment around cells, including matrix composition, stiffness, geometry, transport and time-dependent cues. We then examine organoids, assembloids and microphysiological system platforms, with emphasis on functional benchmarking, vascularization, immune integration, maturation, reproducibility and biological variation across donors and conditions. Finally, we discuss computational models, including spatial atlases, generative models and digital twins, as tools for organizing measurements, testing mechanisms and improving prediction. A key insight is that no current platform fully closes the loop between sensing, tissue modelling, computational calibration and feedback-guided intervention. The central challenge now is to build models whose complexity is justified by the human question they are designed to answer.