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How do you screen a billion biological samples a day? BioTrove Inc. in Cambridge, Mass., hopes to achieve that extraordinary throughput by processing droplets as small as .5 nanoliters in enormous batches.
Founded in 1997, the MIT spinoff has developed the Living Chip, a 3×5-inch rectangle or 6-inch circular honeycomb of silicon micromachined with as many as 100,000 holes. The chip’s matrix of channels, each about 300 microns in diameter and 500 microns deep, serves as a miniature, massively parallel system for screening genes, isolating enzymes, engineering proteins or discovering drugs.
The Living Chip functions like 100,000 tiny test tubes working in parallel, explained Robert Hess, BioTrove’s vice president of business development. While Hess said that a billion samples per day is not practical yet, future Living Chips could be made with a million .5 nanoliter chambers. Ten of those megamatrixes running a hundred screens a day would screen a billion samples.
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He said the Living Chip system is ready to help scientists find, for example, the most active enzyme in a sea full of slightly different strains. The process works like this: A researcher dips the Living Chip into a solution filled with tens of thousands of randomly mutated enzymes. At the proper dilution, a different strain of enzyme will, on average, end up in each chamber.
How does the sample stay in the channel, which has neither a top nor a bottom? Hess, a molecular biologist, said that the interior of each hole is coated with hydrophilic material, which has a strong affinity for water, that holds the enzyme-bearing fluid in place via surface tension. At the nanoscale, that tension is stronger than gravity. Also, the top and bottom edges of the chip are layered with hydrophobic material that repels water so that samples in adjacent chambers don’t contaminate each other.
To analyze or screen the prepared array of enzymes, another Living Chip would be dipped into a fluid filled with reagent chemicals or molecules. When the second chip is stacked on top of the first, the two tiny drops in each aligned chamber touch and mix.
BioTrove’s stackable grids of tiny chambers could also be used to study individual cells or investigate proteins. “Our system essentially enables you to perform as many as a million tiny experiments simultaneously,” Hess said. BioTrove believes its parallel process offers an order of magnitude increase in bulk screening, while also reducing the volume of reagents needed per screen.
Speeding up biotech research with high volume screening and more accurate identification of targets is critical for the industry, Hess said, because every day of a drug discovery program can cost a company $1 million or more.
To streamline the process of high throughput screening some companies are using microarrays of biomaterials deposited into tiny wells on flat surfaces. PerkinElmer Inc., for example, is marketing a microplate coated with a hydrogel for researching proteins.
Aclara BioSciences has a microfluidic device it calls Arteas that is somewhat similar to BioTrove’s Living Chip, though it has only 96 much-larger microwells that interconnect with secondary reservoirs for running assays.
Other companies such as Caliper Technologies Corp. are building microfluidic lab-on-a-chip devices like its LabChip system.
Hess said that BioTrove’s business model is not just to sell its Living Chips, but also to perform screening services for other biotech companies using its proprietary system, which will also include robotic handling and imaging systems.
He also pointed out that Living Chips are meant to serve as a storage medium for a library of small molecules, genes or cells as well as a platform for research and discovery.
Typically, such libraries of compounds are stored in hundreds or thousands of microplates. Cataloging and retrieving such samples for later study can be time consuming and a logistical headache.
With Living Chips, Hess said, entire libraries of drug-like compounds, cell cultures, genes or assay reagents can be stored and accessed more easily. They can also be duplicated to another Living Chip for safekeeping and redundancy.
Hess said that the company is also developing techniques for synthesizing or growing specific cells, proteins, drugs or other biomolecules directly within the Living Chip.
Felicia Gentile, president of BioInsights, a biotech research firm in Redwood City, Calif., said she thinks that BioTrove’s Living Chips “may be the next generation microplate,” but noted that working with such small volumes of material poses other challenges. Such tiny amounts of fluid are prone to evaporation, she said, and may not be effective for certain kinds of reactions requiring a certain level of reagents.
She also noted that the buzz around high throughput screening technologies that started five years ago has yet to pay big dividends. Moreover, she said that throughput is only part of the equation: “You need good quality data” to make any assay valuable.
The director of high throughput screening for a leading European pharmaceutical company, who asked not to be identified, just completed a pilot study using BioTrove’s chips last week. He said that the chips effectively identified small molecule targets that had been screened in a previous assay by the company.
“We were pleasantly surprised,” the director said, adding that the company now plans to extend the research agreement with BioTrove.