Choi, J.; Azam, S.; Hisaeda, M.; Liu, S.; Zheng, S.

Understanding how airborne particulates disrupt the alveolar barrier requires in vitro systems that recapitulate both the structure and transport properties of the lung air-blood interface. Here, we report a biodegradable lung alveoli-on-a-chip enabled by porous poly(lactic-co-glycolic acid)/polycaprolactone (PLGA/PCL) membranes with an interconnected porous architecture generated via porogen-assisted phase separation process. The membrane exhibits tunable degradation behavior, allowing progressive increases in surface porosity (~40%) and reduction in thickness during culture, while PCL maintains mechanical integrity under dynamic conditions. These degradation-driven structural changes regulate membrane transport properties, leading to enhanced permeability and supporting the formation of a functional epithelial-endothelial barrier under air-liquid interface (ALI) culture with breathing-mimetic cycling strain. Primary human alveolar epithelial and microvascular endothelial cells formed confluent, junctional monolayers on opposing membrane surfaces, exhibiting stable barrier function and high viability throughout the culture period. As a functional application, the platform was used to assess diesel particulate matter (DPM)-induced alveolar injury. Apical exposure to DPM induced dose-dependent cytotoxicity, increased barrier permeability, elevated reactive oxygen species, and DNA damage in both epithelial and endothelial layers, demonstrating trans-barrier propagation of particulate-induced injury. Pharmacological modulation with roflumilast-N-oxide (RNO), a phosphodiesterase-4 (PDE4) inhibitor, selectively attenuated oxidative stress and inflammatory responses, with limited effects on barrier integrity. Together, this work establishes degradable PLGA/PCL membranes as tunable interface materials for lung-on-a-chip systems, where structural evolution during degradation directly governs transport and barrier function. The resulting platform provides a physiologically relevant approach for studying particulate toxicity and therapeutic modulation at the alveolar interface.