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Biomedicine

A Faster Screen for Toxicity

Researchers have made a biochip that could help replace animal testing for new cosmetics and pharmaceuticals.

Drug candidates that seem promising in preliminary laboratory tests often fail once they are tested for toxicity in animals–a waste of time and money for a pharmaceutical company. What’s more, chemical and cosmetics companies are increasingly looking for cheap and efficient ways to test potential products for toxicity problems without resorting to animal testing. Now, researchers have designed a biochip that could screen out compounds with toxicity problems much earlier in the drug-development process. It could also be useful for rapidly screening chemicals and cosmetics for potential toxicity.

Toxic tester: Human liver cells are dotted across the new chip, which can be used to quickly determine if various chemicals, drugs, and drug candidates are toxic. When coupled with another biochip developed earlier by the same researchers, the technology could provide an accurate alternative to animal testing.

Called the DataChip (for data analysis toxicology assay chip), it “allows for a very quick determination of whether a compound is likely to be toxic,” says Jonathan Dordick, a biochemical engineer at the Rensselaer Polytechnic Institute (RPI), in Troy, NY, and cofounder of Solidus Biosciences, a startup that is commercializing the technology. The chip holds a miniature array of more than a thousand 3-D cell cultures, each 20 nanoliters in size, on a glass microscope slide. Each cell culture is able to test the toxicity of a different chemical. The miniaturization allows compounds to be tested in a high-throughput manner, which is important in the early stages of drug discovery, when thousands of drug candidates need to be screened.

Dordick and Douglas Clark, a chemical engineer at the University of California, Berkeley, and cofounder of Solidus Biosciences, describe the DataChip in the December 26 online early edition of the Proceedings of the National Academy of Sciences.

Traditional toxicity testing involves using animals or tissue samples, methods that are time consuming and expensive. Also, European cosmetics companies will be restricted from animal testing starting in 2009, making the need for new in vitro methods even more important.

Several groups are working on liver models for predicting drug toxicity since many compounds are metabolized in the liver. (See “Liver Models Go to Market.”) Even if the drugs themselves aren’t toxic, their metabolites might be. In 2005, the RPI and Berkeley researchers reported developing what the group calls the MetaChip, a chip that mimics how compounds are metabolized by the liver. By combining the two biochips, the researchers say, it could now be possible to accurately predict the toxicity of chemicals and drug candidates without the use of animals.

In the MetaChip, liver enzymes are placed on individual spots on a slide, and the test compounds are placed on those spots to be metabolized by the enzymes. When the MetaChip and the DataChip are sandwiched together, the DataChip can analyze the metabolites produced by the MetaChip and determine whether they are toxic. “The main innovation is coupling a toxicity assay with the metabolism–all done in a high-throughput screen,” says Salman Khetani, a postdoc at MIT and cofounder of Hepregen, a company that’s also developing liver models.

Any type of cell can be included in the DataChip, so “you can be predictive not only against a liver cell, which most technologies now deal with, but go beyond the liver to other organ types,” Dordick says. For example, skin cells could be used to rapidly screen new chemicals and cosmetics for skin toxicity.

The individual cell cultures on the chip are contained within blobs of hydrogel on the glass slide, which allows the human cells to grow in a three-dimensional way. That’s important when mimicking how a compound will affect real tissues in the body, Dordick says.

To be sure, the new technology faces many challenges before it becomes an accurate drug-screening method. For one thing, the DataChip assesses toxicity by looking at how compounds affect cell growth. But growth can also be affected by the cells’ environment, in this case the hydrogel, says Linda Griffith, director of the Biotechnology Process Engineering Center at MIT, whose group is working on liver models that would be used at a later stage in the drug-development process. For example, the researchers tested the DataChip with cells from a breast-cancer cell line, and research from other labs has shown that the mechanical properties of the matrix drive cell signaling and gene expression, Griffith says.

But despite such limitations in drug testing, the new combination of biochips could be useful as an early screening tool for drug candidates. Even more immediate, say the RPI and Berkeley researchers, the combination could provide a quick and easy way to screen cosmetics without animal testing.

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