Lung-on-a-Chip Replicates the Tiny Explosions Inside Diseased Lungs
11.12.07 | 5:30 PM 
Image: Courtesy of Shuichi Takayama
Scientists have modeled the lungs' tiniest airways on a microchip device a little larger than a quarter, providing new insight into lung diseases like pneumonia and cystic fibrosis.
By scientifically reproducing the real crackling sound diseased lungs make when clogged with fluid, the lung-on-a-chip showed that the crackles aren't just a symptom of trouble, they're also a cause.
"The crackles are the sound of liquid plugs rupturing," said Shuichi Takayama, associate professor of biomedical engineering at the University of Michigan. "When the plugs rupture, they damage and even kill the surrounding cells."
It's one of a number of new tissue-engineering methods that more realistically model conditions inside the body. In another example, scientists found that cancer cells act more like cancer in the body growing on a 3-D scaffold than they do smeared on a flat petri dish.
More-realistic cell action improves pharmaceutical research, making drug discovery faster and more likely to make it through human trials. BCC Research predicts the so-called lab-on-a-chip market will grow from $566 million in 2006 to $1.25 billion in 2013.
The lung-on-a-chip is made by culturing actual human lung-tissue cells on a plastic chip laced with microscopic channels. The microfluidics device allows scientists to act like micro-plumbers, selectively exposing cells to various liquids and air.
The research appears in the Nov. 12 edition of the Proceedings of the National Academy of Sciences.
The chip mimics the fluid dynamics in the body's respiratory system. Takayama's tiny plumbing unit models the alveolar ducts, the smallest of the bronchial tubes, which carry air from the environment to the alveolar sacs that exchange carbon dioxide for oxygen.
To make the cells recognize they should behave like airway cells, the scientists provided liquid nutrients (simulating pulmonary fluid) on one end of the cell and exposed the other to air, Takayama said.
The Michigan team modeled an unhealthy lung by using liquid that was missing lung surfactant, which normally reduces surface tension in the bronchial tubes. Without the substance, the fluid sticks in the airways, causing liquid plugs to form. They prevent air from moving along the airway: In other words, the plugs prevent the lung-on-a-chip from breathing.
"Basically, the microfluidic airway tries to clear itself. In so doing, it causes the liquid plug to rupture," he said.
That rupture acts as a tiny explosion in the alveolar duct. Small numbers of pops, which might happen in healthy lungs, didn't damage the cells much. But in conditions that mimicked seriously diseased lungs (100 events in 10 minutes), the mini-explosions damaged the large majority of cells. Takayama noted the ruptures could be a major contributor to lung impairment.
The miniaturization through microfluidic devices will allow us to better understand the microscopic infrastructure that allows complex organisms to function, said Abraham Stroock, an assistant professor in Cornell's School of Chemical and Biomolecular Engineering.
"The lung, as a gas exchanger, is luckily serving our entire body," Stroock said. "We have one pump and then a network of vascular structures that pervade our entire body. Microfluidics help us understand microphysiological details, like the structure inside the lung."
The University of Michigan researchers plan to use the lung-on-a-chip to examine many lung conditions.
"Now that we have a lung-on-a-chip, what would happen if we make the chip smoke?" asked Takayama. Or the chip could be deliberately infected with bacteria, he added. "We can study how we can make lungs better with pharmaceuticals."
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