Lung-on-a-chip lights up to model damage caused by smoking

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Harvard scientists have developed an instrument that smokes cigarettes in the same way a human does, and runs the smoke through a lung-on-a-chip to model the effects on health(Credit: Wyss Institute at Harvard University)

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Over the last few years, scientists have been able to recreate accurate models of human organs by embedding living tissue onto chips, allowing them to study the effects of drugs and diseases without testing on animals or humans. Versions of these organs-on-chips have so far been developed to mimic the heart, lungs, intestines and placenta. Now a team at Harvard has designed a device that smokes cigarettes and sends the smoke through a human lung small airway-on-a-chip to examine just how the habit damages health.

It's no secret that smoking is harmful, but it's been hard to study its effects on chronic obstructive pulmonary disease (COPD), a disease that leaves sufferers short of breath thanks to inflammation of the small airways in the lung. Replicating how tobacco smoke causes and exacerbates the illness doesn't work with traditional petri dish-based cell cultures since they can't "breathe" the toxins in, and animal responses differ too much from our own. Even in human clinical studies, a variety of variables between different people muddy the waters too much for a clear picture.

Enter the lung-on-a-chip. Researchers previously made a chip model of diseased heart cells in order to study new treatments, and in a similar vein, last year a team at the Wyss Institute at Harvard modeled lung airways exhibiting COPD and asthma. Building on that project, the researchers have now designed a machine that smokes cigarettes in a very human-like manner, and hooked it up to organs-on-chips lined by human lung small airway cells so the smoke interacts with these cells in a realistic way.

"In order to translate observed breathing patterns and smoking behavior into biological effects, we combined the small airway-on-a-chip with a smoking machine that burns cigarettes and a microrespirator that inhales and exhales small volumes of cigarette smoke and fresh air in and out of the epithelium-lined channel in programmable intervals mimicking true smoking behavior," explains Richard Novak, co-author of the study.

The cells used in the models were isolated from both healthy individuals and suffers of COPD. After both were exposed to heavy tobacco smoke, the team was able to study the differences between healthy and COPD airways more accurately, and with far fewer other factors interfering.

"We identified a COPD-specific signature by comparing gene expression changes in COPD-derived chips exposed or not exposed to smoke and subtracting the changes that we see in chips made from healthy lung chips," says first author, Kambez H. Benam. "This type of analysis could lead to future biomarkers, drug targets and possibly more personalized approaches to COPD in the future."

Armed with this knowledge, the researchers believe they can determine the cell types, cellular functions and genes that are affected by smoking, and how that varies between healthy and COPD-afflicted lungs.

The airway cells seen through a microscope, including the cilia that transport mucus(Credit: Wyss Institute at Harvard University)

"The power of the technology is that it allows us to directly analyze the effect of a stimulus, in this case smoke exposure, on lung in what might be thought of as an in vitro human 'pre-clinical' study," says lead researcher, Donald Ingber. "This is hard to do in a standard human clinical study where one compares patients with a history of smoking versus those who do not smoke because all of the patients have different histories, backgrounds and patterns of exposure to the stimulus."

The instrument also allowed the team to study the effects smoking has on cilia, which transport mucus in the airways, and in future, could be used to test the toxicity of products like e-cigarettes.

The research was published in the journal, Cell Systems, and the team discusses the project in the video below.

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