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Mechanically tuned Lung-on-a-Chip device to model pathology and drug screening for lung disease

Periodic Reporting for period 1 - MECH-LoC (Mechanically tuned Lung-on-a-Chip device to model pathology and drug screening for lung disease)

Reporting period: 2018-10-15 to 2020-10-14

The need for improved lung models.
Chronic obstructive pulmonary diseases (COPD), like emphysema or chronic bronchitis, affect about 10% of the population, reducing the quality of life for affected patients. To better understand these diseases and to screen potentially efficient drugs, appropriate lung models need to be developed. The current models, based on 2D cell culture or living animal studies, are however quite limited in physiological relevance.
Lungs allow oxygen to pass from the air into the blood stream and carbon dioxide to pass from the blood to the air. This exchange of gas works because the walls between the air sacs and blood vessels are very thin and selective to what crosses (“semi-permeable membrane”) with each breath. Lungs are constantly undergoing mechanical stress during breathing, making the elasticity of the membrane a crucial parameter for understanding lung diseases. The aim of this MSCA project was to build a miniature lung device (microfluidic organ-on-chip) with a more mechanically relevant membrane for cell growth and function to replace, reduce and refine animal models of human disease.
Design of lung models with more mechanically relevant properties.
State of the art lung-on-chip devices model the lung using two chambers, one filled with air and the other with liquid, separated by a semi-permeable membrane, typically modelled by a thin silicon polymer layer (ref 1,2). Cells are grown on one or both sides of the membrane to reproduce a liquid-air interface. This type of device is suitable for measuring gas exchange, metabolite concentrations, or to screen new drugs. Here, soft membrane surfaces were designed entirely from natural elastic proteins (the same proteins that cells naturally secrete and grow on in the body). Protein membranes were shown to be semi-permeable, mechanically responsive (elastic) and biocompatible for cell growth, indicating a greater versatility than commonly used silicon polymers for use as model drug testing platforms. Membranes were integrated into flexible microfluidic chips with perfusable chambers, offering the option to cyclically inflate and deflate the membrane to replicate breathing. This work revealed opportunities to tailor membrane elasticity, suggesting the potential to create devices with physiological and disease-matched mechanical profiles. Scientific results and fundamental microfluidic concepts were exploited and disseminated to a diversity of audiences in the form of detailed protocols and application notes (microfluidic cell culture and perfusion), university lectures, a webinar, market survey, conference presentations, EU science fair demonstrations and science-at-home activities.

1. Huh, D. et al. “Reconstituting organ-level functions on a chip.” Science 328, 1662-1668, 2010.
2. Stucki, A.O. et al. “A lung-on-a-chip array with an integrated bio-inspired respiration mechanism.” Lab Chip 15, 1302-1310, 2015.
Impact and implications: advancing beyond the current state of the art.
Conventional cell culture is carried out under largely static conditions, i.e. in the absence of mechanical forces such as stretch, compression and shear stress from fluid flow, that are found in the body and act continuously on cells. Advances in microfluidics, and in particular with miniature organ-on-chip devices, offer a powerful alternative to study the lung membrane, providing a more realistic 3D cell culture environment and the potential to reduce the number of animal studies. Microfluidic cell culture chambers shrink the surface that the cells grow on to the order of a millimeter wide and reduce the volume of growth medium (liquid nutrients) required to keep the cells alive. Microfluidic fluid handling allows the perfusion of medium over the cells at a controlled flow rate, allowing study of precise shear stress on cells. It also can be used to apply tension (stretch) to thin membrane surfaces that cells are grown on, providing a more life-like environment for cells in the laboratory.
More physiologically relevant models, in this case, by including mechanically-responsive natural materials, will open the door to more realistic studies of disease progression and drug studies, including personalized therapeutic strategies. The stretchable, perfusable lung model created in this work offers promise as a more realistic platform to study the effect of drugs on lung and other cells, and can be adapted to study the immune response to infections like pneumonia and the toxicity of tiny particles of pollution in the air.