In Vitro Lung Fibrosis Model: Real-Time Measurement of Cell Mechanics and testing of drugs
Publication of Ali Doryab and Otmar Schmid (Schmid Lab, LHI) in Advanced Materials
Lung fibrosis, or “lung scar” is a chronic disease characterized by excessive fibroblast proliferation, abnormal extracellular matrix deposition, stiffening of alveolar lung tissue, and ultimately loss of lung function. The lack of curative therapies for lung fibrosis not only leads to a high disease burden in the population but also implies significant socio-economic expenses.
Scientists at the Institute of Lung Health and Immunity (LHI, Helmholtz Munich), led by Ali Doryab and Otmar Schmid- together with the Department of Functional Materials in Medicine and Dentistry (University of Würzburg, Germany) - have now developed an organ- and disease-specific in vitro mini-lung fibrosis model. This model also features non-invasive real-time monitoring of cell/tissue stiffness for direct and clinically relevant diagnostics of fibrosis progression upon drug treatment. This allows for combined longitudinal monitoring of drug efficacy (pharmacodynamics) and drug concentration in the blood (pharmacokinetics).
Imitating the processes in the lung during inhalation therapy
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, was integrated into a millifluidic bioreactor system (CIVIC).
This mini-lung fibrosis model closely mimics the microenvironment of the alveolar cells during inhalation therapy in patients through:
- A Cyclic In Vitro Cell-stretch (CIVIC) millifluidic system to culture cells at the air-liquid interface (ALI) with medium (“blood”) perfusion and cyclic mechanical stretch (“breathing”)
- A novel ultrathin, highly permeable, and highly elastic BETA membrane that provides direct interaction between cells on both sides of the membrane
- A novel non-invasive method to monitor cell mechanics (tissue stiffness) during therapeutic intervention
- Aerosolized drug delivery mimicking drug delivery during inhalation therapy
Why is this such a breakthrough?
Current preclinical models of lung fibrosis are either too simplistic (in vitro models) or hampered by species differences (in vivo models). One of the most significant challenges for current in vitro models is the lack of scaffolds (basement membranes) mimicking the conditions in the lung accurately enough. The ultrathin, highly elastic, and delicate architecture of the alveolar tissue has to withstand continued mechano-elastic stress due to breathing-induced cyclic stretch.
This group developed an artificial basement membrane overcoming these challenges, populated it with three key effector cells of lung fibrosis, and demonstrated its clinical relevance by predicting that the orally applied fibrosis drug Nintedanib would be more effective as inhalation therapy. This finding is consistent with preclinical in vivo data but has not yet been confirmed by clinical studies. It is expected that this model will improve the predictive ability of preclinical models and facilitate the development of approved therapies for lung fibrosis.
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