FDA issued guidance on April 10, 2025 to phase out animal trials in favor of organoids and organ-on-a-chip systems. This pivotal move was swiftly followed by National Institutes of Health (NIH) on April 29, when it inaugurated the Office of Research Innovation, Validation, and Application (ORIVA). The establishment of ORIVA aims to spearhead the advancement of human-centric organ-on-a-chip technologies, marking a major stride toward more accurate, ethical, and efficient research methods in the biomedical field. Compared to traditional 2D cell cultures and animal models, organ-on-a-chip systems enable precise control of hydrodynamic parameters and biomechanical microenvironments. This review systematically elaborates on applications of single-organ, multi-organ, and organoid-on-a-chip technologies in modeling complex diseases, host-microbiome interactions, inter-organ physiological networks, and quantitative prediction of pharmacokinetics, toxicity responses, and personalized therapies. Furthermore, the core challenges in translating these technologies to pharmaceutical development and clinical practice are critically analyzed. With interdisciplinary integration of materials engineering, biosensing, and artificial intelligence, organ-on-a-chip technologies are transcending the limitations of conventional preclinical research. Their strategic value as 'patient surrogates' is poised to accelerate breakthroughs in precision medicine and rare disease treatments.
DOI：10.1093/procel/pwaf058