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bioRxiv · 10.64898/2026.06.01.729429

Interstitium-mimicking porous alveolar membranes enable physiologic aerosol transport and distinct acute-chronic lung injury responses

Choi, J.·Zhang, S.·Jalili, A.·Kohls, A.·Maeng, W.-Y.·Azam, S.·Liu, W.·Varghese, B.·Zhao, Y.·Ren, X.·Liu, S.·Zheng, S.-Y.
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Abstract

Barrier membranes govern transport and mechanochemical coupling in lung-on-chip systems but typically exhibit low open porosity, limited pore interconnectivity, and diffusion distances exceeding native thin septal regions. An interstitium-mimicking, alveolus-shaped poly({varepsilon}-caprolactone) membrane is developed using dual-templated nonsolvent-induced phase separation followed by controlled enzymatic pore enlargement. The resulting architecture achieves [~]40% total porosity with 97% pore interconnectivity and incorporates a locally thinned dome region ([~]2.5 {micro}m). This structure sustains cyclic deformation while increasing oxygen diffusivity fivefold compared with conventional Transwell(R) membranes under both acellular and epithelial-endothelial co-culture conditions. Integrated into an air-liquid interface platform, the membrane enables direct aerosol deposition and quantitative interrogation of cross-barrier mass transfer. Using carbonaceous nanoscale particulate matter as a model inhaled aerosol, controlled exposure induces dose-dependent oxidative, inflammatory, and genotoxic responses. Matched cumulative dose studies reveal distinct biological trajectories: acute high-dose exposure produces rapid cytotoxic stress and barrier disruption, whereas chronic low-dose exposure preserves viability yet promotes sustained DNA repair and genome-maintenance programs. Compartment-resolved analysis and therapeutic intervention further demonstrate the platforms utility for spatial and translational interrogation of lung injury. By restoring physiologically relevant diffusion distance, interconnectivity, and strain responsiveness, the interstitium-mimicking membrane advances lung-on-chip design toward functional replication of alveolar transport dynamics for studying lung injury and barrier dysfunction.

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Choi, J., Zhang, S., Jalili, A., Kohls, A., Maeng, W.-Y., Azam, S., Liu, W., Varghese, B., Zhao, Y., Ren, X., Liu, S., Zheng, S.-Y.. 2026-06-04. Interstitium-mimicking porous alveolar membranes enable physiologic aerosol transport and distinct acute-chronic lung injury responses. https://doi.org/10.64898/2026.06.01.729429

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