A Lung Alveoli-on-a-Chip with Highly Porous Membranes for Modeling Pulmonary Toxicity of Nanoscale Coal Dust

The human lung alveolar microenvironment is highly susceptible to inhaled nanoparticles such as coal dust, air pollution particulate matter, and virus-containing aerosols, yet existing in vitro models inadequately recapitulate the physiological barriers and mechanical dynamics of the lung. Here, we present a lung alveoli-on-a-chip system featuring a highly porous (up to 40%) alveolus-shaped polymer membranes that closely mimics the structural, mechanical, and transport properties of the human alveolar capillary interface under air–liquid interface (ALI) culture condition. This engineered membrane facilitates efficient gas and nanoparticle diffusion while supporting long-term co-culture of primary epithelial and endothelial cells with sustained viability and barrier integrity. Leveraging this platform, we systematically evaluated the toxicity of nano-scale coal dust, revealing dose-dependent increases in reactive oxygen species production, pro-inflammatory cytokine secretion, epithelial-endothelial barrier disruption, and DNA double-strand breaks. Notably, therapeutic screening identified vitamins C and E as well as ibuprofen as partial mitigators of coal dust-induced cytotoxicity and inflammation. These findings demonstrate the utility of this advanced lung alveoli-on-chip platform as a physiologically relevant model for respiratory toxicology and as a preclinical tool for evaluating inhaled environmental hazards and therapeutic interventions.