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Lung-on-a-chip leads to new insights on pulmonary diseases

ANN ARBOR, Mich.—A new "lung-on-a-chip" developed at the University of Michigan mimics the fluid mechanics of the real thing on a plastic wafer just bigger than a quarter. It allows researchers to grow lung airway cells that act more like they're in a human body instead of a Petri dish.

Biomedical engineers used the device to show that the respiratory crackles stethoscopes pick up in patients with diseases including asthma, cystic fibrosis, pneumonia and congestive heart failure aren't just symptoms, but may actually cause lung damage.

A paper on the findings is published in the Nov.12 early edition of the Proceedings of the National Academy of Sciences.

"Our lung-on-a-chip causes the cells to really become lung-like in terms of function and protein secretion. They form the tight tissue connections that they do in the human lung. That doesn't happen in a dish. This device gives you the convenience and control of a dish but in physical conditions that are more like the body," said Shuichi Takayama, associate professor of biomedical engineering and principal investigator on this study.

Takayama believes this is the first lung-on-a-chip. It's the same size as the part of the lung it simulates, the smallest airway branches.

The researchers were able to recreate the sound of respiratory crackles on the chip. And they measured and watched the destruction associated with the crackling on the surrounding cells.

The crackling is the sound of a breath of air opening airways that are clogged with thick fluid plugs. The fluid plugs form more frequently in patients with lung diseases that block the production of a fluid-thinning protein or narrow the airways. The plugs burst when air expands the lungs during breathing.

Doctors have considered the crackling sound more as a symptom or red flag, explained Dr. James Grotberg, a co-author of the study who is a professor of biomedical engineering in the College of Engineering and the Medical School.

Now, the plugs that cause the crackles appear to be a cause in addition to an effect.

"We've shown that these liquid plugs are injurious, particularly when they rupture" Grotberg said. "The rupture sends a very strong stress wave onto the cells. What's interesting is that the forces from the rupture are large in one place and small in another and those two places are close to each other. So you have a very steep gradient in forces and that's what shreds the cells."

To the surrounding cells, the bursts are like little sticks of exploding dynamite, Grotberg said.

The lung-on-a-chip that allowed the scientists to demonstrate this is made of two rubber sheets with a groove etched across their length. Their grooved sides are stuck together, with a porous sheet of polyester between them. The polyester allows the device to function as two separate chambers.

Engineers flooded both chambers with nourishing liquid while they were growing the lung cells in the device. Then, they emptied the top chamber to simulate an airway. That's when the lung cells started to develop further than they do in a dish. They formed tighter tissue bonds and secreted airway proteins as if they were part of a real lung.

Once the cells were sufficiently developed on the chip, Takayama and his colleagues did the control part of the experiment. They ran liquid through the chip channels and then air before testing to see if the lung cells were still healthy. They were.

Then they turned on the "microfabricated plug generator," which was connected to the cell culture chamber on the same chip. The plug generator is a vial of liquid into which the scientists pump air in such a way that drops of liquid enter the mock airways of the chip and eventually burst. They tested for periods of 10 minutes and found that at least 24 percent of the cells had died after persistent exposure to bursting liquid plugs. They observed more cell damage with more frequent plug bursts.

Takayama is also an associate professor of macromolecular science and engineering. The paper is called "Acoustically detectable cellular-level lung injury induced by fluid mechanical stresses in microfluidic airway systems." Co-authors include Biomedical Engineering Research Fellow Dongeun Huh, Biomedical Engineering Senior Research Fellow Hideki Fujioka, Biomedical Engineering Research Fellow Yi-Chung Tung, Post-doctoral researcher Nobuyuki Futai, and Adjunct Professor of Internal Medicine Robert Paine III.

Michigan Engineering:

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A liquid plug travels through the lung-on-a-chip device and bursts, simulating respiratory crackles in an actual lung airway.

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