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COVID-19 and Other Lung Conditions to be Tested on a 3D Lung-on-a-Chip

A 3D lung-on-a-chip model of the distal lung and alveolar structures has been developed by Brigham and Women's Hospital researchers. The aim is to gain a deeper understanding of respiratory diseases such as asthma, COPD, influenza, pneumonia, and most recently COVID-19.

The researchers are currently investigating how COVID-19 virus particles migrate across the airways and interact with pulmonary cells. This new chip model allows researchers to investigate how different COVID-19 therapies, such as remdesivir, affect virus replication.

The study was published under title “Reversed-engineered human alveolar lung-on-a-chip model” in PNAS.

“We present a physiologically important human pulmonary alveoli model here. A three-dimensional porous hydrogel made of gelatin methacryloyl with an inverse opal structure is bonded to a compartmentalized polydimethylsiloxane chip in this alveolar lung-on-a-chip platform. “The inverse opal hydrogel structure has well-defined, interconnected pores that are strikingly similar to human alveolar sacs,” the researchers write.

“Functional epithelial monolayers are easily formed by populating the sacs with primary human alveolar epithelial cells. The system incorporates a cyclic strain to enable biomimetic alveolar lung breathing events, allowing researchers to examine pathological effects such as those caused by cigarette smoking and extreme acute respiratory syndrome coronavirus 2 pseudoviral infection.

“Our research demonstrates a novel method for in vitro reconstitution of functional human pulmonary alveoli, which should pave the way for further research into related physiological and pathological events in the human distal lung".

Y. Shrike Zhang, PhD, associate bioengineer in the Brigham's Department of Medicine and Division of Engineering in Medicine, said, "We believe it is a true breakthrough." “This is a first-of-its-kind in vitro model of the human lower lung that can be used to evaluate a variety of biological mechanisms and therapeutic agents, including antiviral drugs for COVID-19 research,” says the researcher.

Understanding and designing therapies for COVID-19 necessitates time and resource-intensive human clinical trials. Researchers will be able to test drugs even quicker and help identify the drug candidates most likely to succeed in clinical trials with improved laboratory models, such as the lung-on-a-chip.

This technology was created by Zhang and colleagues to mimic the biological characteristics of the human distal lung. Previous models relied on flat surfaces and were frequently made of plastic materials that did not account for the curvature of the alveoli and were much stiffer than human tissue. Researchers used materials that were more reflective of human alveolar tissue to construct this new model, which stimulated cell growth inside these 3D spaces.

The 3D alveolar lung effectively developed cells over several days, and these cells adequately populated airway surfaces, according to researchers who tested the model's effectiveness. Scientists discovered that the alveolar lung model resembled the human distal lung more closely than previous 2D models thanks to genome sequencing. Furthermore, the lung-on-a-chip model successfully induced human breaths at the normal frequency.

Zhang's research team plans to use this technology to study a wide variety of pulmonary disorders, including multiple lung cancers, in addition to COVID-19. To mimic the effects of smoking on the lungs, researchers let smoke seep into the model's air chambers before simulating a breathing event, which moved smoke deeper into the lungs. They then assessed the effect of the smoke and the damage it did to the cells.

According to Zhang, while this breakthrough has the potential to greatly expand the possibilities for researching and treating pulmonary diseases, it is still in its early stages. The alveolar lung-on-a-chip currently only includes two of the 42 cell types found in the lung. Researchers plan to add more cell types to the model in the future to make it more clinically reflective of human lungs.

Zhang plans to investigate how COVID-19 variants migrate across the airways and affect pulmonary cells as well as COVID-19 therapies in the future. He assumes that by combining this model with other 3D organs such as the intestines, researchers will be able to learn more about how oral drugs affect cells in the lower lungs.

Zhang also plans to use this technology in the future to better understand and treat emerging infectious diseases.

“When it comes to COVID-19, we've had very short development timelines. We can easily research and test therapeutics in urgent circumstances where clinical trials are limited if we have these models on hand in the future,” Zhang explained.

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