Dec. 3, 2007 -- Researchers have developed tiny colonies of living human liver cells that, together, offer a full-sized artificial liver that can be used to screen new drugs before they're sold.
The model could save pharmaceutical companies money in development and, more importantly, reduce health risks in patients.
Last week for example, the UK's Medicines and Healthcare Products Regulatory Agency suspended the license for the arthritis drug Prexige, which was found to cause serious liver reactions in patients. Toxicity is one of the main reasons drugs get pulled off the market.
"If you had a human liver platform outside the body, you could weed out toxic and other problematic compounds much earlier on in the process of drug discovery and development," said postdoctoral associate Salman Khetani of the Harvard-MIT Division of Health Sciences and Technology. "But in order to do robust screening, you need a model system that maintains the physiologic state of the cells," he said.
Khetani and associate professor Sangeeta Bhatia described the technique in a recent issue of the journal Nature Biotechnology.
So far, developing a liver model that resembles the real thing has been a challenge. Researchers typically use liver cells from laboratory rats, which do not always behave like human liver cells. Or they grow human liver cells for tests, but those often do not survive more than a couple of days. Since people usually take drugs over an extended period of time, scientists need a model system that lasts just as long.
Khetani and Bhatia have created an artificial liver that last several weeks.
"To get the human liver cells to live months to years is the next major challenge in this field," said Khetani.
The researchers built the model using the same mass-production technology manufacturers use to etch and assemble the microscopic components on computer chips. But instead of carving out patterns and arranging wires, Khetani's method arranges cells and proteins on a glass or plastic plate.
Living cells are organized on the plates using a technique called micro-patterning. Nearly 300 liver cells are placed onto 37 islands of proteins and then seeded with other cells called fibroblasts, which give rise to connective tissue. One plate has 24 groupings of the islands, for a total of about 10,000 cells.
Although the plate doesn't look like a liver, it behaves like one. The cells secrete the blood protein albumin, for example, synthesize urea, and produce enzymes that break down drugs and toxins.
Because the cells live for several weeks, the scientists were able to conduct tests using drugs known to be toxic to livers. In one test, the team showed that troglitazone, an anti-diabetic and anti-inflammatory drug removed from the market in 2000 by the FDA, had much higher toxicity levels than two other drugs approved for the same purpose.
"If you can weed out the toxic drugs early on in the process that would really be helpful," said Jennifer Elisseeff, associate professor of biomedical engineering and orthopedic surgery at Johns Hopkins University in Baltimore, Md.
The challenge, she said, is proving to pharmaceutical companies and regulatory agencies that an artificial liver model can predict toxicity just as well or better than a similar animal model.
Khetani's long-term goal is to improve the model so that the cells will live much longer. In the meantime, a startup company called Hepregen has licensed the technique and is working to introduce it into the pharmaceutical marketplace.Related Links:
Tracy Staedter's blog: What the Tech?
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