Chip-Scale PCR

Founded in 1999, today Fluidigm has over 100 employees and subsidiaries in Europe, Japan and Singapore. Last year, the company introduced its second product platform, the Biomark System for gene expression using quantitative real-time PCR. Based on integrated fluidic circuit technology, the Biomark System enables nanofluidic manipulation and mixing of reagents and samples in a faster-throughput, lower-cost and easier to use platform. Compared to 384-well microplates, the Biomark provides 2,304 parallel data points, uses only 11,500 microliters, performs 2,304 reactions and runs 48 assays against 48 samples each with only 96 pipetting steps per 2,304 reactions, according to the company.

As Fluidigm CEO Gajus Worthington described it, “One of our commercial chips, the 48.48 Dynamic Array, has over 2,300 vials, over 4,500 wells, over 7,000 valves and over 20,000 channels on a single chip that is about half the size of a credit card. We really believe that we are unrivaled in microfluidics in our ability to both miniaturize and integrate, and that means miniaturize all of the basic fluidic components that you need to do sophisticated and complex fluid handling and then integrate them onto a chip at extremely high density.” According to Mr. Worthington, “What this does is really two things: we can implement standard chemistries, like Taqman for real-time quantitative PCR and radically increase the throughput by having a chip that does thousands of real-time quantitative PCR reactions. . . . The other thing we’ve done with our fluid handling is do things in the microformat that you can’t do any other way—implement chemistries or assays for which there is no macroscopic analogue.” As an example, he cited Fluidigm’s 12.765 Digital Array for digital PCR that can provide absolute quantitation. “Real-time quantitative PCR gives you a relative measurement of gene expression, but certainly not an absolute measurement and it certainly does not go down to single copies, which is what this chip can do.”

Fluidgm’s first product, introduced in 2002, was the TOPAZ system for protein crystallography employing automated free interface diffusion. For its first product, the company chose a small, fragmented market, where it could learn without the stakes being too high. With the Biomark PCR system, the company is taking on well-established providers such as Applied Biosystems and Roche. Fluidigm management includes several Applied Biosystems veterans. “The Biomark System is about $260,000 for the complete system, and you can think of the chips as being about 10 cents per data point,” Mr. Worthington explained, comparing the system to an estimated datapoint cost of around 60 cents or 70 cents for conventional PCR systems.

Fluidigm has installed BioMark PCR systems at MedImmune, Eisai and the Howard Hughes Medical Research Institute. The Fred Hutchinson Cancer Research Center and the Chinese University of Hong Kong are also using it. “Those [users] are really important to us because they’re doing research sort of similar to academic labs in that sense, but they’re really directed at molecular diagnostics and their intent is to be able to use our platform to test patients,” noted Mr. Worthington. Future applications of the Biomark platform will include single cell analysis and protein analysis.

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