Microphysiological Systems: Transforming Biomedical and Clinical Research.

The pharmaceutical industry continues to face a critical translational bottleneck, with the majority of drug candidates failing in clinical trials despite promising preclinical results, largely due to the limited predictive power of conventional in vitro systems and animal models. Microphysiological systems (MPS), including organ-on-chip and organoid-on-chip platforms, have emerged as transformative human-relevant technologies capable of recapitulating organ-level structure, function, and disease dynamics under precisely controlled microenvironments. By integrating advances in microfabrication, biomaterials, stem cell and organoid biology, microfluidics, and real-time sensing, MPS enables physiologically faithful modeling of tissue interfaces, mechanical forces, metabolic processes, and inter-organ communication. Recent progress has led to robust organ-specific platforms, interconnected multi-organ systems, and body-on-chip models that support systemic pharmacokinetic and pharmacodynamic studies. Concurrently, regulatory recognition through the FDA Modernization Acts and accelerating international standardization efforts have positioned MPS as a validated new approach for drug development and safety assessment. Despite these advances, challenges related to cell sourcing, tissue heterogeneity, scalability, statistical rigor, and protocol standardization remain. This review synthesizes the technological foundations, biological applications, regulatory landscape, and emerging challenges of MPS, emphasizing the need to quantify and harness biological heterogeneity rather than eliminate it.