Lung-on-a-chip Provides New Insights into Pulmonary Diseases

It allows investigators to grow lung airway cells that act more like they behave in a human body than they do in 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 are not just symptoms, but may actually cause lung damage.

Developed at the University of Michigan (Ann Arbor, MI, USA), the lung-on-a-chip 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. Both chambers are flooded with nourishing liquid while the lung cells were growing in the device. Then, the top chamber is emptied to simulate an airway and the lung cells continue to develop forming tissue bonds and secreting airway proteins as if they are part of a real lung.

Prof. Suichi Takayama from the department of biomedical engineering at the University of Michigan and his colleagues ran liquid through the chip channels and then air before testing to verify that the lung cells were still healthy. 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.

"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 [Petri] dish. This device gives you the convenience and control of a dish but in physical conditions that are more like the body,” said Prof. Takayama.

The investigators 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, which form more frequently in patients with lung diseases, block the production of a fluid-thinning protein or narrow the airways. The plugs burst when air expands the lungs during breathing.

Doctors have always considered the crackling sound more as a symptom but now it appears that the plugs that cause the crackles are a cause in addition to an effect. "We [have] shown that these liquid plugs are injurious, particularly when they rupture” said Dr. James Grotberg, professor of biomedical engineering in the University of Michigan College of Engineering and the Medical School. "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 [is] what shreds the cells.”

To the surrounding cells, the bursts are like little sticks of exploding dynamite, according to Prof. Grotberg.

The study's findings were published in the November 12, 2007, early edition of the journal Proceedings of the U.S. National Academy of Sciences (PNAS).


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