Advances in Inhalation Pathophysiology Research Based on Organ-on-a-Chip Platforms

Inhalation represents a primary entry route for airborne pollutants, aerosols, pathogens, and therapeutic agents. Their pathological impacts depend on a complex interplay of physical transport, deposition patterns, cellular crosstalk, mechanical forces, and localized microenvironmental responses. However, traditional 2D cell cultures and animal models fall short in mimicking these human-specific microenvironments, particularly due to the lack of air-exposed barriers, dynamic fluid flow, physiological motion, and precise aerosol dosage control. Respiratory organ-on-a-chip technologies address these limits by integrating air–liquid interfaces, microfluidic perfusion, and tissue-specific mechanics. In this review, we examine the principles of inhaled exposure, disease mechanisms across the respiratory tract, and recent advances in chip design and exposure delivery. We highlight key applications in modeling respiratory infections, chronic inflammatory and fibrotic diseases, airway injury, and carcinogenesis. Finally, we discuss critical requirements for translational impact, emphasizing that advanced model complexity must be supported by accurate dosimetry, robust tissue validation, and defined contexts of use.