When you take a breath of air, it embarks on a complicated journey, beginning at the base of the tree's stump and moving downward through increasingly smaller branches, eventually ending up in the leaves.

But instead of leaves, there are tiny air sacs called alveoli, of which each lung contains millions. Wrapped around the alveoli are miniature blood vessels called capillaries. The intersection between each alveolus and its capillaries is extremely important. First of all, it's the site of gas exchange, the critical process in which oxygen from the lungs is traded for carbon dioxide from the blood. But its also an avenue for the two-way transport, between the lungs and the rest of the body, of fluids, immune cells, nutrients and other chemicals, including drugs and environmental toxins.

Understanding how this complex, microscopic intersection works is a big goal in biomedical engineering. It could lead to improved methods for testing drugs that enter the body through the respiratory system, and help reveal how our lungs deal with nanoparticles, which are becoming increasingly popular ingredients in consumer products like crack-resistant paints, stain-repellent fabrics and cosmetics. Now, researchers say they have built a realistic model of the alveolar-capillary boundary, using real human lung and vascular cells to simulate the life-like interaction of two different organ tissues for the first time.

In recent years, scientists have made gains in recreating precise real-life physiological conditions that affect tissue behavior. Using techniques originally invented to make microscopic etchings in computer chips, various research groups have created miniature 3D models of blood vessels, muscle and other organ tissues. In 2007, a group at the University of Michigan modeled the lungs' tiniest airways, carving microscopic channels, which were used to simulate real-life fluid and air flow, into an elastic material called polydimethylsiloxane (PDMS). The biomedical community called the device a lung-on-a-chip.

These models are limited, however, since they involve only a single tissue, while real organs usually contain multiple tissues that collaborate to perform unique functions. But now, researchers led by Donald Ingber, the director of Harvard University's Wyss Institute for Biologically Inspired Engineering, have taken the lung-on-a-chip one step further, creating the first device to demonstrate the interaction of two separate tissues, in this case respiratory and vascular. The model is also the first to incorporate the rhythmic pressure changes that occur in our chests as we breathe. "Some people have put different cell types next to each other to look at transfer of chemicals and hormones. But what we've done is to basically have a tissue–tissue interface, and we've added the physical microenvironment that is so critical for tissue function," Ingber says.

To replicate the alveolus-capillary barrier, Dongeun Huh, a biomedical engineer at Harvard, created two microscopic channels in a tiny chamber of PDMS. A 10-micron-thick (a micron is a millionth of a meter) porous barrier separates the two channels. The researchers grew human cells on both sides of that barrier, placing alveolar tissue on one side and vascular tissue on the other. Huh and his colleagues then ran fluid through the vascular channel to simulate continuous blood flow through the capillaries, and flowed air through the alveolar side, mimicking real-life conditions in the lung.

The researchers simulated life-like breathing by applying vacuum pressure to adjacent chambers on both sides of the tissue-containing chamber. Reducing the pressure to sub-atmospheric levels, which is what happens when we inhale, caused the tissues in the device to stretch. This stretching is neglected in traditional cell cultures used for drug testing, Ingber says, even though it is vital to the system. "Breathing all the time affects the viability and function of the organ, similar to how tension on muscle affects muscle growth, as we all know from lifting weights," he explains.

With this model, critical interactions between two organ tissues can be observed in real time, another reason future iterations could be useful in research and in medicine. "It's really easy to image and look at, so you can tell what's going on—something you couldn't do very easily if you actually tried to look in the lung itself, in a body," says Shuichi Takayama, a biomedical engineering professor at the University of Michigan. Takayama helped pioneer the lung-on-a-chip concept, but was not part of this study.

Ingber says the next step is to identify the specific needs in the biomedical and pharmaceutical industries. Then, he says, the device could take several forms-—it's low-cost, can be mass-produced, and one day could even be personalized with a patient's own cells, which could be crucial for patients with specific lung conditions. "If we could shortcut the need for animal studies, use human cells and get organ-level type functionality," he says, "that could be huge savings of time and money."

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