Lung fibrosis, as one of the major post-COVID complications, is a progressive and ultimately fatal disease without a cure. Here, we introduce an organ- and disease-specific in vitro mini-lung fibrosis model equipped with non-invasive real-time monitoring of cell mechanics as a functional readout. To establish an intricate multi-culture model under physiologic conditions, we developed a biomimetic ultrathin basement (BETA) membrane (<1 μm) with unique properties, including biocompatibility, permeability, and high elasticity (<10 kPa) for cell culturing under air-liquid interface (ALI) and cyclic mechanical stretch conditions. The human-based triple co-culture fibrosis model, which includes epithelial and endothelial cell lines combined with primary fibroblasts from idiopathic pulmonary fibrosis (IPF) patients established on the BETA membrane, is integrated into a millifluidic bioreactor system (CIVIC) with dose-controlled aerosolized drug delivery, mimicking inhalation therapy. We show the real-time measurement of cell/tissue stiffness (and compliance) as a clinical biomarker of the progression/attenuation of fibrosis upon drug treatment, which was confirmed for inhaled Nintedanib -an FDA-approved anti-fibrosis drug. The mini-lung fibrosis model allows the combined longitudinal testing of pharmacodynamics and pharmacokinetics of drugs, which is expected to enhance the predictive capacity of preclinical models and hence facilitate the development of approved therapies for lung fibrosis. This article is protected by copyright. All rights reserved.
- Doryab, A.
- Taskin, M. B.
- Stahlhut, P.
- Groll, J.
- Schmid, O.
Keywords
- aerosolized drug delivery
- biomimetic membrane
- cell mechanics
- cyclic mechanical stretch
- in vitro lung fibrosis model
