Human-Relevant Microphysiological Systems: Evidence for Defined Contexts of Use.

The FDA Modernization Act has accelerated the transition from animal-based testing toward human-relevant new approach methodologies in drug development, shifting attention from technological feasibility to regulatory implementation. Among these approaches, microphysiological systems (MPS) can generate evidence that more directly reflects human physiology, but their regulatory readiness varies substantially across applications. This Review summarizes recent regulatory developments and evaluates the readiness of major organ-specific and multi-organ MPS. Liver MPS have advanced furthest through quantitative benchmarking, industrial adoption and sustained regulatory engagement, whereas kidney, lung, gastrointestinal, tumor, nervous system and multi-organ models remain limited by varying degrees of standardization, independent validation and clearly defined regulatory use. Across applications, major barriers include insufficiently specified contexts of use, limited human benchmark data, inadequate multicenter reproducibility, manufacturing variability and fragmented data infrastructure. We discuss priorities for overcoming these barriers, including performance-based standards, quality-controlled manufacturing, auditable data systems and earlier coordination among technology developers, end users and regulatory authorities. Patient-derived and stem cell-derived models, artificial intelligence and digital twins may further extend the scope of MPS, but their value will depend on transparent validation and integration with complementary evidence. Regulatory adoption is likely to proceed incrementally, with MPS initially supporting defined decisions as complementary evidence and replacing conventional studies when their performance and uncertainty are sufficiently characterized.