Lung-on-a-Chip Passes a Crucial Test

Researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University have shown that their "lung-on-a-chip" technology can mimic a life-threatening lung condition. They also report that scientists can uncover new aspects of the disease using the lung chip that would not be found with animal experiments.

The study, published in today's Science Translational Medicine, is the first definitive demonstration that the institute's organ-mimicking chips, which include a gut, a heart, and a kidney, can be used to model a disease and even test candidate drugs.

The lung-on-a-chip device is a clear, flexible thumb-sized block of polymer perforated by two tiny channels separated by a thin membrane. Air flows through one channel, which is lined with human lung cells; a nutrient-rich liquid that acts as a blood substitute flows through the other, which is lined with blood-vessel cells. A vacuum applied to the chip moves the channels to re-create the way human lung tissues physically expand and contract when breathing.

The study, led by Wyss Institute fellow Dongeun Huh, focused on pulmonary edema, a condition in which fluid and blood clots fill the lungs. It can be caused by heart failure as well as the side effects of a common cancer drug. The researchers injected the cancer drug into the blood-vessel-like channel and found that fluid and blood plasma proteins leaked across the membrane into the air channel, similar to the drug's side effect in patients.

This led to two surprising discoveries, says study coauthor and Wyss lead staff scientist Geraldine Hamilton. One was that the immune system, which was not represented in the chip, was not required to cause the leakage side effect as had been previously thought. Second, the team found that when they turned on the vacuum system to create breathing-like movements, the leakage worsened, another unknown aspect of pulmonary edema.

The researchers also show that a GlaxoSmithKline drug candidate could prevent the leakage in the chip system (GSK researchers were also coauthors on the Wyss study). In a separate study in the same issue of Science Translation Medicine, GSK researchers demonstrate in mice with heart failure that their drug can reduce pulmonary edema, helping to validate the chip system, says Hamilton. "The reality is that animals will be required for clinical testing for many years to come, but this moves us a step closer to finding alternatives," she says.

There are skeptics. Organ-on-chip systems lack the typical environment that an organ would be exposed to, such as the various hormones and other molecular cues that are constantly being circulated throughout the body of an organism, says Michael Hayward, a lead scientist at Cranbury, New Jersey-based life sciences company Taconic. Hayward, who specializes in developing animal models of human disease, also notes that most diseases involve many organs, and understanding how different organs interact to cause a disease state would be out of the grasp of a single organ-mimicking device.

Hamilton acknowledges that both industry and regulators are going to want lots of validation of the organ-on-chip technology before using it as an alternative to animals, but the potential benefits of the chip technology are evident in today's study, she says. "Not only do we mimic clinical response, but we also found out something new. This is a glimpse into the effects this could have on drug discovery and development in the future," she says. "Not only could you replace the animal, but you gain further insight."

And one day, they may begin to address the concerns of Hayward and others about the isolated nature of their devices. "Our ultimate goal, which is high risk, is not only to develop disease models but to develop an integrated body-on-a-chip, where we can start to link these organs, moving us a step closer to mimicking the whole human response," she says.