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Teams Pursue Lab-On-A-Chip Strategies with Eyes on Genomic, Dx Applications

By Andrea Anderson

NEW YORK (GenomeWeb News) – As lab-on-a-chip technology expands from research to more diagnostic applications, some researchers are working to develop more portable lab-on-a-chip technology with integrated optical detection systems, while other developers are focusing on expanding the range of applications possible for existing systems.

"In a lab-on-a-chip you are trying to squeeze a whole laboratory on a tiny chip substrate," Giulio Cerullo, a researcher with the National Laboratory for Ultrafast and Ultraintense Optical Science in Milan, told GenomeWeb Daily News. "The hope is to get much more accurate and faster recording of results," he added, while simultaneously curbing the amount of reagent required.

Cerullo coordinated a European Union-funded research team comprised of academic and industry investigators, dubbed the HIBISCUS consortium, which used laser writing to customize commercially available lab-on-a-chip models sold by the Netherlands-based microfluidics company LioniX. Their goal: creating optical sensors on the chip itself — an advance that they say could open the door to more extensive use of lab-on-a-chip technology in a clinical setting.

Lab-on-a-chip systems typically employ microfluidics to move samples through channels carved into small glass, silicon, or plastic chips. While these systems simplify many processes and decrease reagent requirements, Cerullo argues that the need for "off chip" visualization methods may offset the benefits of this miniaturization. "This, of course, is not portable," he said.

The consortium decided to tackle what Cerullo calls the "last bit of integration that was missing, which was the optics," using a femtosecond laser to process commercial lab-on-a-chips, creating so-called waveguides to direct light through channels on the chip so that small changes in sample composition could be detected using an optical interferometer.

Cerullo says such processing should be compatible with a range of commercial lab-on-a-chip platforms. "You don't need to change the way the chip is manufactured," he said, arguing that "any application for which you can use this lab-on-a-chip, I think, can in principle benefit from our technology."

For instance, he said, the consortium used the approach to sense up to 40 DNA fragments separated by capillary electrophoresis — an application that might by useful in a diagnostic setting for identifying stretches of DNA associated with disease risk, Cerullo noted.

Although the three-year HIBISCUS project, which was done in conjunction with investigators at LioniX, Zebra Biosciences, and High Q Laser, wrapped up last November, Cerullo and his colleagues are trying to secure funding to support additional research in this area.

Collaborators at LioniX are now considering making chips with the waveguide built into them, Cerullo said, while those at Zebra Biosciences are reportedly developing commercial diagnostic kits for amplifying, separating, and detecting DNA fragments of interest.

Cerullo said he's open to discussing the HIBISCUS chip processing method with other lab-on-a-chip companies, explaining that he'd eventually like to see portable cartridges in which the entire lab-on-chip reaction and detection takes place.

"Our main interest is to promote this technology," he said. "We believe that this could be a real advance."

Is It a Necessary Advance?

Despite Cerullo's enthusiasm for applying his laser-based chip method for modifying existing lab-on-a-chip platforms, not everyone seems convinced that this type of processing is necessary — at least at the moment.

For example, Chris McNary, chief commercialization officer and former CEO of RainDance, told GWDN that his company's RainStorm technology, based on microdroplet rather than microfluidic technology, has been optimized over several years and may be difficult to retrofit to a different architecture.

For his part, Agilent electrophoresis marketing and support manager Knut Wintergerst noted that integrated, portable platforms such as those pursued by the European consortium are of interest for research areas that require portability, including forensics, pathogen detection, and so on.

But Wintergerst noted that Agilent's own focus at present is to develop platforms with as wide a range of applications as possible. For example, he noted that the company's Bioanalyzer platform, first introduced in 1999, is used for everything from DNA and RNA quality control to assays focusing on proteins or whole cells.

Agilent also sees areas such as barcoding and next-generation sequencing as hot areas of development for lab-on-a-chip platforms, Wintergerst said. Earlier this year, the company launched a PCR-based lab-on-a-chip for identifying fish species based on DNA profiles that combines the technology of the Agilent 2100 Bioanalyzer with its DNA Fish Species ID Ensemble and restriction fragment length decoder software.

So while Cerullo and his colleagues pursue optical integration, other lab-on-a-chip developers are coming out with ways to optimize and expand their current product lines to support basic genetic and genomic research and prepare for what many see as an inevitable translation of this research into clinical care.

Caliper Life Sciences President and CEO Kevin Hrusovsky told GWDN that his company is keen to continue developing devices for genomic research and related diagnostics — particularly chips to aid high-throughput sequencing. He noted, for instance, that next-generation sequencing is among the fastest growing areas for the company's LabChip GX, which is used for DNA quality analyses and control, among other things.

Meanwhile, Hrusovsky said the Caliper's next-generation chip, unveiled at the AGBT meeting in February, expands on the capabilities of the LabChip GX and now includes quality control and sample preparation and separation capabilities. In particular, he explained, the chip allows for targeted selection of DNA of a specific size range by preparing the sample on the chip and diverting DNA that's too big or too small to a waste well.

The new LabChip XT likely won't ship commercially until July or August of this year, Hrusovsky said, noting that several large sequencing centers are already using Caliper technology in their sequencing pipelines.

Caliper announced a partnership with Pacific Biosciences this February, though Hrusovsky said the company also is in talks with other sequencing companies to make sure its chips are compatible with a range of high-throughput sequencing platforms.

"We feel it's important to continue our relationships across all the sequencing companies," Hrusovsky said, explaining that Caliper has invested a great deal in coming up with next-generation sample preparation solutions. "We really want to be agnostic to all of the different companies."

He also emphasized robotics, automation, miniaturization, and integration as key areas of interest for Caliper in the future.

Likewise, both Fluidigm and RainDance are currently marketing lab-on-a-chip technology for use in conjunction with sequencing or other types of genome analyses.

For example, McNary noted that RainDance's enrichment for targeted resequencing chip is frequently employed as a follow-up tool for genome-wide association studies, allowing researchers to hone in on loci of interest and do a "very deep informatics dive."

He emphasized that the same sort of enrichment system is also compatible with second- and third-generation sequencing platforms as well as studies aimed at characterizing regions of the genome containing rare variants.

RainDance announced a strategic agreement with Applied Biosystems in February to co-market the RainDance RDT 1000 chip with the Applied Biosystems' SOLiD sequencing system.

Still others, such as University of California at San Diego researcher Kun Zhang, are working on a cheap, disposable lab-on-a-chip device with the functionality of a cell sorter.

Like Cerullo, Zhang told GWDN that he hopes to build a microfluidics device with a built-in optical detection system for a range of applications, including microbiome studies.

But he and his colleagues are relying on a different approach to achieve this optical integration: they aim to develop a lens directly on the chip employing liquids with specific refractive indexes and creating optical fibers on the chip that are compatible with simple light sources.

Jumping Into Dx

In addition to such research-centered genomics applications, many are already starting to introduce lab-on-a-chip technology tailored to more diagnostic applications.

RainDance's McNary, in particular, emphasized the diagnostic potential of lab-on-a-chip systems, noting that his company's technology is used as part of genetic screening panels at some medical genetic testing centers.

While RainDance systems are still limited to research use and applications in the medical genetics community, he said the company is preparing for an eventual foray into more clinical settings.

"We're ready to move into diagnostics," McNary said, noting that the company is waiting for regulatory oversight and reimbursement to catch up with the technology.

In addition, McNary hopes to see RainDance technology applied to treatment design down the road — for example, to aid in single-cell analyses, small-molecule screening, or pharmacokinetic studies. "We don't see that as being far off," he said.

Caliper, meanwhile, has already lined up a partnership with the molecular testing company Access Genetics to market its LabChip GX system for molecular diagnostics.

"We absolutely believe that some of the most important value occurs once you go into molecular diagnostics or clinics and hospitals," Caliper's Hrusovsky agreed. He believes regulatory and reimbursement issues get ironed out as a by-product of the technology transitioning into clinical settings.

And the companies are not alone in their pursuit of diagnostic devices. Fluidigm is working on microfluidics-based products with research and diagnostic applications as well, including chips used for gene expression, copy number, and SNP studies.

As GWDN sister publication PCR Insider reported in March, Leiden University's human genetics department is using the Fluidigm Access Array system for genetic diagnosis studies. The company also is pursuing an integrated fluidic circuit-based system for non-invasive detection of fetal aneuploidy.

Claros Diagnostics, meanwhile, is launching lab-on-a-chip devices for diagnosing prostate cancer, while the non-profit company Diagnostics for All is exploring ways to offer lab-on-a-chip-based diagnostic tools to developing countries at cut-rate prices.

For his part, though, Cerullo believes lab-on-a-chip diagnostics will ultimately rely, at least in part, on the sorts of integrated optical systems that he and his colleagues have been pursuing with their laser-based chip processing methods.

"Once you make detection part of the lab-on-chip, you have miniaturization of an entire analytical laboratory," he said in a statement. "It will open the door to many exciting applications, especially much faster, on-the-spot medical diagnosis."

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