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Lung failure is a leading cause of death worldwide. Many conditions can affect and damage the lungs, including asthma, chronic obstructive pulmonary disease, influenza, pneumonia, and most recently, COVID-19. To better understand respiratory diseases and develop new drugs faster, researchers at Brigham and Women’s Hospital developed a 3D model of the distal lungs and alveolar structures, the tiny air sacs that hold oxygen when you breathe. With this innovation, researchers are actively studying how COVID-19 virus particles move through the airways and act on lung cells. Specifically, this technology will allow scientists to study how various COVID-19 therapies such as remdesivir affect the replication of the virus. Their results will be published in the Proceedings of the National Academy of Sciences.
“We believe it’s a real innovation,” said Y. Shrike Zhang, Ph.D., associate bioengineer in the Brigham Medical Department and the Department of Medical Engineering. “This is a unique in vitro model of the human lower lung that can be used to test many of the biological mechanisms and therapeutics, including antiviral drugs for COVID-19 research.”
Understanding and developing treatments for COVID-19 requires time-consuming and resource-intensive human clinical trials. With better laboratory models like the lungs on a chip, researchers may be able to evaluate drugs much faster and help select the drug candidates that are most likely to be successful in clinical trials.
Zhang and colleagues developed this technology to mirror the biological properties of the human distal lung. Previous models were based on flat surfaces and were often made of plastic materials that did not take into account the curvature of the alveoli and were much stiffer than human tissue. The researchers created this new model using materials more representative of human alveolar tissue and stimulated cell growth in these 3D spaces.
When testing the effectiveness of the model, the researchers found that the 3-D alveolar lung was effectively growing cells for several days and that these cells adequately colonized the airway surfaces. Through genome sequencing, the scientists observed that the alveolar lung model was more similar to the human distal lung than previous 2D models. In addition, the lung-on-a-chip model successfully stimulated air breathing at the normal human frequency.
Beyond COVID-19, Zhang’s research team intends to use this technology to study a wide range of lung diseases, including various types of lung cancers. To reproduce the effects of smoking on the lungs, the scientists let smoke enter the model’s air chambers and then simulated a breathing event, causing smoke to travel deeper into the lungs. From there, they measured the effects of the smoke and the cell damage it caused.
While this innovation has the potential to greatly expand the possibilities for studying and treating lung diseases, this model is still in its early stages, Zhang said. Currently, the alveolar lung contains only two of the 42 cell types present in the lung on a chip. In the future, the researchers hope to include more cell types in the model to make it more clinically representative of the human lungs.
In the future, Zhang also hopes to study how COVID-19 variants can migrate through the airways and affect lung cells and COVID-19 therapies. He believes that using this model in conjunction with other 3-D organs like the intestine could allow researchers to study how oral drugs affect cells in the lower lungs. Zhang also hopes this technology can be implemented in the future to urgently understand and develop treatments for emerging infectious diseases.
“With regards to COVID-19, we had very minimal schedules for developing therapies. With these models on hand in the future, we can easily use them to study and test therapeutics in urgent situations where clinical trials are limited “said Zhang.
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Di Huang el al., “Reversed-Engineered Human Alveolar Lung-on-a-Chip Model,” PNAS (2021). www.pnas.org/cgi/doi/10.1073/pnas.2016146118 Provided by Brigham and Women’s Hospital
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