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Fluidigm Mulls Expansion into Diagnostics, Develops Higher-Density Chips

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By Justin Petrone

Fluidigm is developing an array for prenatal diagnosis of chromosomal abnormalities, BioArray News has learned. The project, while nascent, signals that the integrated fluidic circuit maker is interested in expanding eventually beyond its activities in the research market.

Grace Yow, the firm's vice president of manufacturing, discussed the development of a fetal aneuploidy chip during a site visit to South San Francisco, Calif.-based Fluidigm's Singapore office last month. Aneuploidy, or an abnormal number of chromosomes, results in a number of conditions such as Down, Edwards, and Patau syndromes.

Spokesperson Howard High confirmed recently that such a project is underway, but stressed that it was early stage. "Non-invasive prenatal diagnostics is a complex topic," High told BioArray News earlier this month. "We are currently using, as are many researchers around the globe that are pursuing this same goal, existing Fluidigm products such as our 48.770 Digital Array IFC," he said. "We have some other versions of these types of chips that could be useful for this area of research and some of those are being developed in Singapore," High added.

Founded in 1999, Fluidigm makes and sells IFCs embedded in silicone for SNP genotyping, single-cell gene expression, copy-number, and gene-expression studies, high-throughput sequencing sample preparation, and protein crystallization.

The 48.770 Digital Array, launched last year, supports copy number variation studies, DNA library quantitation, and other applications. It is capable of producing 37,000 individual qPCR reactions and provides 48 individual sample inlets.

While it is too soon to tell if Fluidigm will seek to commercialize a test based on the 48.770 Digital Array, which runs on both its BioMark and EP1 systems, High said that Fluidigm is looking for collaborators to aid it in its diagnostic ambitions.

"We are working to find partners to work with in this area because Fluidigm hasn't yet produced a diagnostic product and all the regulatory trials and approval process is complex," he said.

Increasing Density

While Fluidigm's R&D team advances its fetal aneuploidy chip, the company is developing several other new products, beginning with an enhancement of its existing platform. Fluidigm's Dynamic Arrays are currently available in 48.48 and 96.96 formats. The 48.48 chips enable users to run 48 samples in 48 separate assays, producing 2,304 parallel reactions. The 96.96 arrays, meantime, enable users to run 96 samples in 96 assays, setting up 9,216 data points.

According to High, the "next logical extension" for Fluidigm would be a 192.192 Dynamic Array. "As we understand market segments that can use these ever-denser chips, we will make them," High said. "We have produced experiments in our R&D labs that allow our feature sizes to continue to shrink for many more generations." Users of the 192.192 Dynamic Arrays will be able to generate 36,864 data points simultaneously, four times the amount produced by the current 96.96 arrays.

Though the 192.192 chips will increase the number of samples customers can run, some of Fluidigm's clients prefer to run larger numbers of samples against a smaller number of targets. For instance, customers may wish to run 192 samples against 24 or 36 targets. These requirements have encouraged Fluidigm to develop rectangular chips, which differ from the square matrix of its current and previous generations of arrays.

"Using the same density that is available in our current products, but changing the configuration, can be very useful for some market segment where they may have a limited number of markers they want to explore but want a large number of samples to check against those markers," said High.

High cited agbio as a market segment that has requested such formats. Such a customer is Dutch seed producer Enza Zaden, which last year said it selected its BioMark System for genetic engineering and would use its 96.96 Dynamic Arrays to ensure the quality of its feed supply.

Some customers might also require the opposite: an ability to run fewer samples against a very large number of markers. In a previous discussion with BioArray News in August 2009, High cited those conducting single-cell gene expression studies as being interested in such a format.

"In this market segment, cost is not the primary concern," High said at the time. "Here researchers want to study many genes using very little sample," he said. "The ability for maximum utilization off of a rare or small sample will have them tap into the properties of a 192x24 chip, for example" (BAN 8/18/2009).

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Sample Prep and Cell Culture

Beyond density upgrades, Fluidigm is also focusing on several other projects in the area of sample preparation and cell culture. In the sample prep project, Fluidigm is looking to enhance the capabilities of its Access Array platform, which is currently used for library preparation before high-throughput sequencing.

"In our current Access Array IFCs, the chips can … automatically perform the tedious job of sample prep," High said. "In the future, maybe the chips can take raw material and do the separation of elements, the preparation, the mixing, et cetera, automatically in one chip," he said.

Fluidigm is also developing a stem cell chip to meet the needs of a market where its products have received some acceptance. Fluidigm's IFCs are already being used by stem cell researchers for single-cell gene expression studies. In June 2009, the firm said that Shinya Yamanaka of Kyoto University and Toshio Suda of Keio University, both in Japan, had adopted its BioMark platform for use in their studies (BAN 6/30/2009).

Last year, the firm discussed plans to develop a chip to simplify protocols for turning differentiated cells into stem cells, and to reprogram stem cells to redifferentiate in a desired way so that they can be used therapeutically. Current plate-based protocols can take up to 30 days and have 25-percent efficiency (BAN 8/18/2009).

Marc Unger, Fluidigm's chief scientific officer, told BioArray News last year that the chip will be able to simplify the protocol for these processes in one IFC. The current prototype of the chip has 64 chambers with controls to automatically feed cells in the chambers and provide a medium in which the researcher can individually and automatically dose the cells in a chamber with up to 16 different reagents.

Fluidigm is also developing a supporting instrumentation system that will control the elements on the stem cell IFC and allow researchers to modify the composition of the medium delivered to each chamber in the chip over time. The system will also provide time-lapse microscopic images in both transmitted light and fluorescence of the cells so the researchers can consistently monitor the progress of their experiments, Unger said at the time.

High confirmed that the development of the stem cell culture chip is on track. The "multiplexing of reagents will allow for precise reproducible dosing, timed accuracy, food in, waste out, temperature and humidity control, growth, monitoring, et cetera," High said. "It can be used in various cell culture venues," such as stem cell, immunology, and cancer studies," he said. "It sure beats trying to do this in a dish."

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