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Tiny Plumbing

Michael Shuler is a 57-year-old, lanky chemical engineering professor who has nurtured a side interest in biological processes since junior high school. By 1989 he had become interested in toxicity testing, and he had been pondering the unreliability of conventional cell cultures when an idea occurred to him: could you make a cell culture that replicates the journey through the various organs? He recognized it as a chemical engineering problem: glass chambers lined with different types of cells and hooked up via tubes to each other and to a pump that sent fluid through them would far more realistically simulate a body, and tests employing them might predict what happens in living animals much more accurately.

After several months, Shuler and students had constructed a bench-top conglomeration of cells and plumbing providing a crude working model of a set of mammalian organs. It sort of functioned, but Shuler knew there was a big problem with its fidelity: almost all of the chemistry in the body takes place in tissues packed with minute canals and chambers, where critical reactions hinge on the ability of various chemicals to concentrate in some places and diffuse in others, depending in part on the microscopic geography. Mixing everything up in big beakers would distort that delicate balance. Plus, at this size the system wouldn’t be practical or cheap enough for large-scale testing.

Meanwhile, molecular biologist Greg Baxter had just joined Cornell’s Nanobiotechnology Center as a research scientist. His specialty was microfluidics-essentially, microscopic plumbing on a chip. On his second day he buttonholed Shuler at his lab, wondering if he had any projects that could benefit from ultraminiaturization. Funny you should ask, said Shuler.

It took just two meetings to hammer out the basic chip design and a year to produce the first prototype. To build one of the devices, the researchers carve minute trenches that look like faint scratches into a thumbnail-sized silicon chip; these trenches serve as fluid-carrying pipes. Producing microfluidic features on chips for testing chemical reactions and imitating biological processes is not new. But by combining their skills in chemical engineering and microfabrication, Shuler and Baxter add a significant twist: they’ve engineered the sizes, lengths, and layout of all the trenches in an attempt to closely duplicate the fluid flows and chemical exposures that cells experience in real organs.

The trenches act as surrogate blood vessels, carrying chemicals within and between the chip’s ersatz organs, which are themselves composed of trenches that are tightly spiraled or snaked into dense clots roughly half a centimeter wide. Thousands of living cells are fixed to the floor of each organ’s trenches. A brick-sized external pump circulates a nutrient-rich fluid-a stand-in for blood-through the chip. When a test compound is added to the fluid, its silicon journey is roughly analogous to what it would undergo in a live mammal, thanks to 13 years of fiddling with each organ’s size, pattern, and interconnects, and with the sizes and shapes of the various trenches. “We wanted the cells’ environment to be as realistic as possible, from the delivery of nutrients and the removal of waste products to the mechanical stresses that it experiences,” says Shuler.

After a test compound has circulated through the chip for several hours, the cells in the chip are monitored, either with a microscope or via embedded sensors that can test for oxygen and other indicators. Do the cells absorb the compound? Does it sicken or kill them? As in an actual animal, each organ or tissue plays a specific role in the chip. The liver and gut break some compounds down into smaller molecules, for example, while the fat-jammed not only with cells, but also with a spongelike gel-often retains compounds, allowing them to leak out later. A “target” organ or tissue is usually included to demonstrate the ultimate effects of the compound; this might be a cancer tumor, or an especially vulnerable tissue, such as the lung’s, or bone marrow.

The chips, of course, will have to be extensively tested before drug firms will use them widely. Still, early signs are encouraging. Shuler ran one experiment with naphthalene, a compound used in mothballs and pesticides. Excessive exposure causes lung damage, but you wouldn’t know it from standard cell-culture tests. That’s because the culprit isn’t naphthalene itself but rather two chemicals produced by the liver when it breaks naphthalene down. If you knew that and splashed those by-products directly on lung cells in culture, you’d observe such a severe response that you’d conclude even slight exposure to naphthalene is extremely dangerous. But that’s wrong, too; as it turns out, fat cells yank much of the toxic compounds out of the system. Shuler’s chip convincingly mimics this chain of events, yielding a realistic measure of the damage.

Such precise simulation promises to help drug companies improve their screening of drug candidates-and waste less time and money on those that will ultimately fail animal tests. According to Baxter, the chips are ready for such an application right now, and six large companies are currently talking to Hurel about adopting the technology. Shuler, aided by a team of students and collaborators at Cornell and elsewhere, is working on further shrinking and automating the technology. The goal: a sheet-of-paper-sized bank of 96 chips that plugs into a robotic lab setup that very rapidly adds test drugs and monitors the results. The system could not only replace conventional cell cultures but also reduce a reliance on animal experiments, in which researchers must use a great number of animals to test different doses of a drug, and must monitor those animals over time to pick up subtle side effects. “We’re talking about running a test in one or two days that would take months with animals,” says Shuler. Shuler projects a per-chip production price of about $50 complete with cells, compared to the hundreds or even thousands of dollars it takes to acquire and maintain a single lab animal.

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Tagged: Biomedicine

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