3D lung-on-a-chip will test therapies and conditions

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First-of-its-kind in vitro model of the human lower lung will allow research into how diseases and conditions affect cell growth and development and provide insight into impact of various drugs.

Globally, lung failure is one of the leading causes of death. Many conditions can affect and damage the lungs, including asthma, chronic obstructive pulmonary disease (COPD), influenza, pneumonia, and, most recently, COVID-19. To better understand respiratory diseases and develop new drugs faster, investigators from Brigham and Women’s Hospital designed a 3D “lung-on-a-chip” model of the distal lung and alveolar structures, the tiny air sacs that take in oxygen as you breathe.

Longevity.Technology: Aging is not kind to the lungs; lung function declines, alveoli can lose their shape and become saggy and the risk for pneumonia increases. The COVID-19 pandemic has put both lungs and aging in the spotlight and made it clear that a geroscience approach, targeting aging processes, is key to improving healthspan, lifespan and disease outcomes. The research community is calling for clinical trials of potential geroprotective therapies that would not only help guard against future pandemics, but begin to address the needs of an aging population; innovative tech, such as the lung-on-a-chip, has an important role to play in both research and trials.

“We believe that it is a true innovation,” said Y Shrike Zhang, PhD, associate bioengineer in the Brigham’s Department of Medicine and Division of Engineering in Medicine. “This is a first-of-its-kind in vitro model of the human lower lung that can be used to test many of the biological mechanisms and therapeutic agents, including anti-viral drugs for COVID-19 research [1].”

Developing lung therapies

Understanding and developing treatments for respiratory diseases and conditions requires human clinical trials, which are time and resource-intensive. With better laboratory models, such as the lung-on-a-chip, researchers may be able to evaluate drugs much faster and help select the respiratory drug candidates most likely to succeed in clinical trials.

Zhang and colleagues developed this technology to mirror the biological characteristics of the human distal lung. Previous models have been based on flat surfaces and often made with plastic materials, which do not incorporate the curvature of the alveoli and are much stiffer than the human tissue. Researchers created this new model with materials more representative of human alveolar tissue and stimulated cell growth within these 3D spaces.

Image shows left: The image shows the lining of alveolar epithelial cells in the sacs under breathing, where white color shows junction protein expressions (ZO-1). Scale bar is 50 um. Right: The image shows angiotensin-converting enzyme 2 (ACE2) expression (red) on the cells in the sac. Scale bar is 50 um. Source: Division of Engineering in Medicine, Brigham and Women’s Hospital

Testing the model

In testing the model’s effectiveness, researchers found that the 3D alveolar lung effectively grew cells over multiple days and that these cells adequately populated airway surfaces. Through genome sequencing, scientists observed that the alveolar lung model more closely resembled the human distal lung than previous 2D models have. Additionally, the lung-on-a-chip model successfully stimulated breaths of air at the normal frequency for humans [2].

Beyond COVID-19, Zhang’s research team intends to use this technology to study a broad range of pulmonary conditions, including damage from smoking and environmental factors.

BWH
The team of the Division of Engineering in Medicine, Brigham and Women’s Hospital

While this innovation holds the potential to vastly expand the possibilities of studying and treating pulmonary diseases, this model is still in its early stages, said Zhang. Currently, the alveolar lung-on-a-chip only incorporates two out of the 42 cell types existing in the lung. In the future, researchers hope to incorporate more cell types into the model to make it more clinically representative of human lungs.

What happens in the future?

Going forward, Zhang also hopes to study how COVID-19 variants may travel through airways and impact pulmonary cells and COVID-19 therapies. He believes that using this model in tandem with other 3D organs, such as the intestines, could enable researchers to study how oral drugs impact cells in the lower lungs. Zhang also hopes that in the future, this technology could be implemented to urgently understand and develop treatments for emerging contagious diseases.

“In terms of COVID-19, we’ve had very minimal timelines for developing therapies. In the future, if we have these models ready in hand, we can easily use them to study and test therapeutics in urgent situations where clinical trials are limited,” said Zhang [1].

As well as being on standby for future pandemics, lungs-on-a-chip will be invaluable in developing therapies for deadly lung conditions that limit lifespan and place an enormous burden on healthcare; COPD alone kills 3 million people globally each year and hospitalises  nearly 16 million people in the US annually. Early prevention and treatment of COPD can help prevent serious lung damage, respiratory problems and even heart failure.

[1] https://www.brighamandwomens.org/about-bwh/newsroom/research-briefs-detail?id=3887
[2] https://www.pnas.org/content/118/19/e2016146118

Images courtesy of Division of Engineering in Medicine, Brigham & Women’s Hospital
Eleanor Garth
Deputy Editor Now a science and medicine journalist, Eleanor worked as a consultant for university spin-out companies and provided research support at Imperial College London and various London hospitals in a former life.

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