Engineering biomimetic lung-on-a-chip systems: Recapitulating air-liquid interface, dynamic breathing, and alveolar microenvironments for disease modeling

The lung is a vital organ for gas exchange. Its microstructure is complex and changes in its physiology are crucial to human health. Lung disease is one of the leading causes of death worldwide, with new cases emerging every year. This highlights the urgent need to develop advanced preclinical models. While animal studies have long been valuable for drug development, there are inherent differences between animal and human pathophysiology. This has led to the development of three-dimensional (3D) microphysiological systems. In particular, the lung-on-a-chip (LOC) platform offers significant advantages by reproducing the alveolar microenvironment-a biphasic air-liquid environment, providing mechanically responsive, periodic stretching to simulate dynamic respiration under controlled microfluidic conditions. This review systematically explores the cellular components inherent in natural lung tissue (such as lung epithelial cells, endothelial cells, and fibroblasts) and its physiology, establishing design criteria for constructing bionic LOC systems. We critically evaluate state-of-the-art LOC architectures for simulating toxicological responses in conditions such as pneumonia, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (PF) and lung cancer. Ultimately, we provide a framework that addresses the limitations of existing LOC technologies, focusing future development efforts on critical areas that are essential for achieving predictive, clinically relevant models. This provides a roadmap for next-generation organ-on-chip platforms that combine engineering innovations with translational lung medicine, with the potential to transform drug discovery and personalized disease modeling. • LoC replicate alveoli, breathing mechanics and ALI, outperforming animals. • Unifies NSCLC & SCLC-on-chip with clinical translation and quantitative readouts. • Ventilation mechanics predict NSCLC TKI response; PLGA/IGF-1 shows resistance. • Actionable methods: ALI, cyclic stretch, vascular/immune co-culture; tox & trials.