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People with liver disease often have to wait years for a transplant. While they wait, five of them die of liver failure every day. If liver disease could be treated with drugs instead, transplants could be eliminated. But liver disease has been hard for medical researchers to study outside the body. Now, as this ScienCentral News video reports, one nanotechnologist has built a liver on a chip.

A High-Priced Present

Best friends Harvey Davis and Vincent Betts have shared a lot during their 15-year friendship, especially a love of golf. Since 2001, they have also shared Betts' liver.

In the early 1990s, Davis, a 53-year-old third grade teacher from Kingston, New York, was diagnosed with hepatitis C, the leading cause of liver failure, and the major reason for liver transplants. By 1999, his health had begun to deteriorate seriously, and he was added to the national waiting list for a liver transplant. But as he became "pretty much bedridden" and no donor liver had become available, Betts stepped in and offered him part of his own healthy liver. "It was hard to see him getting sicker and knowing that it wasn’t very good odds for him," recalls Betts, 39, a real estate agent. "I just felt like that was the thing to do."

As a live liver donor, Betts underwent an operation during which his healthy liver was surgically split in two. One half was transplanted immediately into Davis to replace his failing liver. Relying on the liver's remarkable regenerative powers inside the body, both halves continued functioning while re-growing to their normal size.

Unfortunately, not everyone on the transplant waiting list is as lucky as Davis. Successful recipients can wait for months or even years for a donor liver, and with the number of people waiting far outnumbering donors, about 25,000 Americans die each year from liver failure while awaiting transplants. As there is no widely used assist device like the dialysis machine for kidney patients, transplantation is the only hope for patients with hepatitis C, liver cancer, or other liver diseases. Currently, more than 17,000 people are waiting for a liver transplant in the United States alone.

With his new healthy liver, Davis felt better immediately. "I never really thought I wouldn't make it," he says, "because of the way Vince volunteered." Betts was not so fortunate: he had to recuperate from his difficult and painful operation. "It's like getting hit by a freight train," Betts recalls.

Treatment, Not Transplant

Vincent Betts and Harvey Davis enjoy a day on the golf course.
Biomedical researchers are working hard to find an alternative to such a traumatic gift of life, which is so hard on donors and on their families who have to witness their ordeal. One day, tissue engineers might be able to simply grow a new liver in a laboratory for patients like Davis, from only a few cells of a healthy liver. "I had jokingly said to a lot of people that before long they'll be able to grow these organs on Petri dishes," Betts remembers.

One researcher investigating that possibility has been tissue engineer Linda Griffith, director of the Biotechnology Process Engineering Center at MIT. Griffith and her research team had hoped to be able to take a single donor organ liver, use it to grow new livers in the lab, and make them available to perhaps a hundred patients. But along the way Griffith had another idea: to build "physiological models" so that they might help them to better understand liver diseases. "If we can head off and prevent organ transplants, it'll be much better for the patient than if we build an organ to put in them after they get really, really sick," Griffith says.

Liver disease is very hard to study, because once liver cells are outside the body, they lose their ability to become infected. So researchers have had trouble developing drugs to treat hepatitis C and other liver diseases. Instead, Griffith and her team have built a tiny three-dimensional silicon scaffold that, combined with a few liver cells, becomes a miniature liver on a chip, smaller than a dime. Once the chip is attached to a circulation system, "we flow fluid through the tissue, just like blood would flow through in the body," Griffith explains. "Then we can use a microscope to study the cells and understand what's happening in the tissue."

Griffith's liver chip consists of two very thin, peanut-shaped pieces of silicon in a plastic housing. The silicon has little "wells" or tiny channels that have been chemically modified to give liver cells from rats a place to anchor themselves. Once sealed tightly inside the housing, the chip is placed inside a bioreactor that sets up a flow of fluid containing oxygen and nutrients. As the fluid flows through the chip, it helps to recreate an environment for the liver cells as similar as possible to the body's—controlling temperature, humidity and the concentrations of oxygen and carbon dioxide, keeping the cells alive with the necessary nutrients, and fostering tissue reorganization. Within a few days, the cells have sorted themselves and begun to assemble into the patterns found in nature.

Griffith believes her "liver on a chip" could help develop drugs for liver disease. And because the human liver is sensitive to everything from drugs to viruses, the chip, which contains up to 1.5 million functional liver cells, amounts to a microscopic biosensor for environmental hazards. Under the aegis of MIT's Institute for Soldier Nanotechnologies, Griffith's team is developing a portable version of their manmade liver. In the future, built into soldiers' uniforms, the liver on a chip could help detect chemical or biological warfare agents.

Meanwhile, the liver on a chip's original mission, to come up with treatments for liver disease, appeals to patients like Harvey Davis. "It takes away all the anxiety of worrying whether someone will donate, worrying that somebody has to die for you to live, or worrying that you may not make it to get your liver."

This research appeared in the 2003 issue of Molecular Therapy and the 2002 issue of Tissue Engineering. It was funded by the Defense Advanced Research Projects Agency (DARPA) and the U.S. Army Research Office.

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