Respiratory Organ-on-a-Chip for Disease Modeling: From Architecture to Functional Integration.

Respiratory diseases remain a leading cause of morbidity and mortality worldwide and arise from tightly coupled multicellular interactions that occur under continuous airflow and cyclic mechanical strain. However, the platforms most commonly used to study these processes, animal models and conventional 2D cell cultures, frequently decouple the variables that govern human pathophysiology, thereby limiting mechanistic resolution and translational predictability. Respiratory organ-on-chips (ROCs) aim to bridge this gap by reconstituting key structural, mechanical, and microenvironmental features of the human respiratory system in controllable, human-relevant settings, enabling quantitative interrogation of disease dynamics and therapeutic responses. Guided by respiratory anatomy and region-specific functions as design principles, this review integrates ROC architectural strategies with core functional modules and synthesizes how these engineering decisions shape biological performance and translational relevance across inflammation, infection, fibrosis, injury, and cancer. We further examine progress toward industrial translation and propose a decision-making framework that aligns disease-specific research questions with system integration requirements while identifying key technical bottlenecks.