Researchers say their airway-on-a-chip may help uncover new treatments for COPD.
Image credit: Wyss Institute at Harvard
First study author Kambez H. Benam, of the Wyss Institute for Biologically Inspired Engineering at Harvard University in Boston, MA, and team publish the details of their creation in the journal Cell Systems.
According to the American Lung Association, chronic obstructive pulmonary disease (COPD) affects more than 11 million people in the United States, and it is the third leading cause of death in the country.
While cigarette smoking is not the sole cause of COPD, it is responsible for around 85-90 percent of all cases.
When a person smokes, over time, many of the toxic chemicals inhaled can cause inflammation and an overproduction of mucus in the airways of the lungs. This can obstruct the airways, making it difficult to breathe.
The challenges with current smoke exposure models
Though the general mechanisms behind smoking-induced COPD are understood, the precise way by which smoking damages the lungs has been unclear, largely due to the difficulties in accurately measuring such an effect.
"Because commonly used laboratory animals (e.g., mice, rats) are obligate nose-breathers, their applicability for smoke exposure studies, either from conventional cigarettes or e-cigarettes, is [...] debatable," the authors note.
They add that human clinical trials are the most direct way to measure the effects of smoke exposure, but even those have limitations.
"[...] patient-to-patient variability is a major challenge for understanding of disease biogenesis and biomarker discovery, particularly for heterogeneous disorders like COPD," the researchers explain.
"Therefore, there is a great need for a novel, versatile, and physiologically relevant experimental model that faithfully recapitulates inhaled smoke-induced airway pathologies to study the biological effects of tobacco products."
How does the airway-on-a-chip work?
To meet this need, Benam and colleagues created an airway-on-a-chip - a device made of a clear, flexible rubber consisting of living cells that line the small airways of human lungs.
- Almost 1 in 6 adults in the U.S. currently smoke cigarettes
- Cigarette smoking is the leading cause of preventable death in the U.S., killing more than 480,000 Americans annually
- More than 16 million people in the U.S. are living with a smoking-related disease.
"We call them chips because we adapted computer microchip manufacturing methods to create very small hollow channels that we line with living human cells," notes senior study author Donald Ingber, also of the Wyss Institute for Biologically Inspired Engineering.
The airway cells on the chip have the ability to differentiate, specialize, produce mucus, and develop cilia - hair-like protrusions that move mucus though the airways.
The top channel of the chip is where the airway cells are cultured, the team explains. This channel allows air to pass over the cells. The cells then pass through to a bottom channel that mimics the vascular system.
The chip is connected to a smoke generator developed by the team, which is controlled by computer software to simulate various patterns of smoking; the machine can take a puff of a cigarette, exhale the smoke, and breathe normally in between each puff.
The chip is also connected to a diaphragm-simulating microrespirator, which hauls air and smoke across the airway cells and forces it back out.
Cigarette smoke alters cilia activity
In their study, the team used their device to test the effects of cigarette smoke and e-cigarette vapor on airway cells taken from healthy humans and those with COPD.
When the airway cells were exposed to cigarette smoke, the researchers witnessed alterations to gene expression profiles and pathways that protect against oxidative stress that are comparable with those seen in human smokers.
Additionally, the team identified abnormal cilia activity in the airway cells after cigarette smoke exposure, providing further insight into how smoking damages the lungs.
On exposure to e-cigarette vapor, the team identified changes to cilia function similar to those caused by exposure to cigarette smoke, though there was less evidence that e-cigarette vapor alters oxidative stress-reduction pathways.
System could lead to new COPD treatments
Benam and team say their airway-on-a-chip has many advantages over other models used to assess the effects of smoking on the lungs.
For example, their system can monitor the effects of numerous smoking patterns on airway cells, while in vitro studies have only been able to test the effects of isolated puffs of smoke or cigarette extracts in liquid form.
What is more, the new system addresses the problems of breathing physiology presented by rodent models, and it is able to demonstrate the progression of human disease as a result of smoke exposure.
Importantly, the researchers say their airway-on-a-chip could open the door to new treatments for COPD:
"[...] the smoking human small airway chip method provides a tool for studying airway pathophysiology at multiple system levels and enables true matched comparisons of biological responses to inhaled smoke generated by either whole cigarettes or e-cigarettes.
It also can be used to identify COPD-specific biological responses and discover novel molecular signatures that may serve as potential therapeutic targets or diagnostic biomarkers."
The team now plans to create a more detailed airway-on-a-chip that incorporates different types of airway cells, including immune cells. The team says this may advance understanding of the immune response to smoking.
Additionally, the researchers want to test their system in preclinical trials, with the hope of identifying new therapeutic strategies for COPD.
"This type of research is very high risk; it brings so many stakeholders, chemists, engineers, etc. to the table to think about this model and tackle some of the challenges we have in healthcare and in society," says Benam.