From mice to microchips: Organ-on-a-chip technology as a paradigm shift in drug discovery, disease modeling, and personalized medicine

Organ-on-a-chip (OoC) technology is an interdisciplinary platform that combines microfluidics, micro-electromechanical systems, tissue engineering, and human cell biology to recapitulate the structural and physiological complexity of native human organs within centimetre-scale microdevices. The persistent failure of conventional two-dimensional cell culture and animal models to predict human drug responses—reflected in clinical attrition rates exceeding ninety percent—has driven urgent demand for more predictive in vitro systems. OoC platforms address this gap by reconstituting functional tissue–tissue interfaces such as the alveolar–capillary unit, hepatic sinusoid, renal proximal tubule, intestinal villus, and blood–brain barrier within perfused microchannels exposed to physiologically relevant mechanical cues including cyclic strain, shear stress, and electrical pacing. This review provides a comprehensive account of the architecture, working principles, fabrication strategies, and pharmaceutical applications of OoC systems. Detailed mechanistic descriptions of lung-, liver-, heart-, kidney-, gut-, blood–brain barrier-, skin-, and tumour-on-a-chip models are presented, along with multi-organ body-on-a-chip platforms enabling integrated pharmacokinetic–pharmacodynamic studies. The commercial landscape (Emulate, MIMETAS, TissUse, CN Bio, Hesperos), regulatory milestones including the United States Food and Drug Administration Modernization Act 2.0 (2022) and FDA acceptance of Liver-Chip data in investigational new drug applications, and challenges relating to standardization, polydimethylsiloxane-mediated drug absorption, vascularization, and scale-up are critically discussed. Integration with induced pluripotent stem cells, artificial intelligence, and multi-omics technologies positions organ-on-a-chip as a cornerstone of New Approach Methodologies and the future of precision pharmaceutical research.