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University of Chicago Team Develops 'SlipChip' for Digital PCR Apps


By Ben Butkus

A team of scientists from the University of Chicago has developed a microfluidic-based consumable chip for a number of life sciences applications, and has demonstrated its use in digital PCR applications, according to a research paper to be published this month.

The technology, which they have dubbed SlipChip, is simply constructed and inexpensive, and thus may enable digital PCR to become a routine procedure in laboratories or resource-limited settings, according to the researchers.

As such, the scientists are currently seeking industrial collaborators to help commercialize SlipChip for various applications, including digital PCR, one of the researchers said this week.

The SlipChip was developed in the laboratory of Rustem Ismagilov, a professor of chemistry at the University of Chicago. As described in a paper published last year in Lab on a Chip, it is a microfluidic device that can perform multiplexed biological reactions without pumps or valves.

The device comprises two plates in close contact: A bottom plate containing wells preloaded with reagents, and a top plate that acts as a lid for the reagent wells. SlipChip also contains a fluidic path composed of ducts in the bottom plate and wells in the top plate, which connect to each other only when the top and bottom plate are aligned in a specific configuration, thus allowing samples and reagents to mix in discrete volumes, according to the article.

This configuration is useful for several research applications, including simple fluidic handling and manipulation in nanoliter- to picoliter-scale volumes; protein crystallization; cell culture; and immunoassays, Feng Shen, a postdoctoral research assistant in Ismagilov's lab, wrote in an e-mail to PCR Insider.

According to Shen, the technology is especially conducive to digital PCR which, at its core, involves partitioning a sample into uniform, nanoscale reaction volumes, which allows the amplification and quantification of increasingly smaller amounts of genetic material, even single transcripts or nucleic acids from single cells.

The lab developed the SlipChip platform around two years ago, Shen said. Meantime, he was working with physician researchers to design an easier-to-use device or platform for molecular diagnostics.

"I thought and still believe now that the SlipChip is a perfect tool for molecular diagnostics both in clinical labs and in resource-limited settings," Shen said. "After carefully analyzing the unmet need, [we] have spent around two years to develop SlipChip platforms for high-throughput multiplex PCR and digital PCR.

"Digital PCR requires a large number of compartments in small volumes," Shen said. "The SlipChip perfectly fulfills this requirement. It can generate tens of thousands of nanoliter to picoliter reaction compartments by a simple slipping without any complex manipulation systems, such as pumps or valves."

In contrast, most digital PCR platforms to date have involved complex fabrication, valve-controlled microfluidic chips, pneumatics, or other pumping mechanisms to produce microdroplet emulsions. These solutions, while all viable, can be expensive , which could prohibit their use in everyday research labs, Shen and colleagues argue in another research paper set to publish this month in Lab on a Chip.

In the new paper, the researchers describe how SlipChip is used for dPCR applications. "The fluidic path for introducing the sample combined with the PCR mixture was formed using elongated wells in the two plates of the SlipChip designed to overlap during sample loading," the researchers wrote.

"This fluidic path was broken up by simple slipping of the two plates that removed the overlap among wells and brought each well in contact with a reservoir preloaded with oil," thereby simultaneously generating 1,280 reaction compartments each with a volume of 2.6 nL. After thermal cycling, the researchers could measure end-point fluorescence intensity to detect the presence of nucleic acid.

Shen and colleagues also tested the performance of their technology by quantitatively measuring Staphylococcus aureus DNA. As they diluted the concentration of this DNA, the fraction of positive wells (i.e., wells containing detectable DNA) decreased as expected. Notably, the researchers saw no cross-contamination when different pre-loaded primers were used to screen a sample to identify the presence of pathogens.

In their paper, the researchers discuss at length how SlipChip should be compatible with a number of amplification chemistries, including isothermal techniques such as loop-mediated amplification, recombinase polymerase amplification, nucleic acid sequence-based amplification, transcription-mediated amplification, helicase-dependent amplification, rolling circle amplification, and strand-displacement amplification.

They also discuss incorporating real-time PCR and multi-color probes, such as TaqMman and molecular beacons.

Shen said that the group is focusing primarily on "applying different strategies to further extend the dynamic range of detection." In addition, "in order [for SlipChip] to be widely available for laboratories and field applications, we are working on fabricating [it] with plastic materials," Shen said. The current SlipChip is made from glass.

Other priorities include testing different thermal cycling conditions, Shen added.

As for commercial prospects, Shen directed PCR Insider to a PCT patent application filed by the University of Chicago on behalf of the researchers in March. This is the first published patent application that specifically mentions the technology by name; however, it appears that Ismagilov and other members of the lab have previously filed applications or been awarded patents related to various microfluidic techniques incorporated by SlipChip.

Shen said that the researchers are currently seeking industrial collaborators "to optimize and mass produce" SlipChip for different applications. In the meantime, the researchers plan to continue to test clinical samples using SlipChip to provide proof of principle for its potential use in diagnostic applications.