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NuGen's Digital Microfluidics-based Mondrian SP Promises Automated Library Prep with Low DNA Input


By Julia Karow

This article has been updated from a previous version to include additional comment from NuGen Technologies.

Aiming to automate next-gen sequencing library preparation while reducing the amount of input DNA, NuGen Technologies recently launched the Mondrian SP System.

The benchtop instrument uses digital microfluidics technology from Advanced Liquid Logic and promises to produce Illumina sequencing libraries from as little as 1 nanogram of starting DNA using NuGen's Ovation SP Ultralow Library Systems kit.

NuGen began taking orders for the Mondrian in December and officially launched it at the Advances in Genome Biology and Technology meeting in February after shipping the system to a number of customers, including the Genome Institute at Washington University, the European Molecular Biology Laboratory in Heidelberg, and Rutgers University. The company is not disclosing how many instruments it has sold so far.

Last summer, NuGen and ALL announced an exclusive partnership, under which NuGen is commercializing ALL's digital microfluidics cartridge technology, instrumentation, and software and both companies are collaborating with the Broad Institute to develop methods for the cartridge (IS 8/30/2011). The initial focus, the firms said at the time, would be on next-generation library prep protocols for Illumina sequencing platforms.

ALL's technology moves sub-microliter droplets around in a disposable microfluidic cartridge, with no need for any pumps, valves, or channels. It relies on so-called electrowetting, where a droplet spreads out on a hydrophobic surface when a voltage is applied between the droplet and an electrode, which changes the droplet's surface hydrophobicity.

The cartridge contains an array of insulated surface electrodes that control the size and movement of the droplets. Each cartridge can be configured for different sample prep applications and can process up to eight samples at a time.

Users load the cartridge with a multichannel pipette, insert it into the Mondrian SP workstation and select a run protocol, which takes on the order of about three hours. The system mixes, incubates, and transports sample and reagent droplets and takes the product to a collection port for retrieval.

At the moment, the Mondrian, which has a list price of $22,500 in the US, supports only Illumina sequencing platforms, but NuGen plans later this year to add support for the Ion Torrent platform, according to Alan Dance, the company's vice president of marketing.

Consumables prices differ depending on the application and volume purchased but "will be similar to equivalent manual procedures," a NuGen spokesperson told In Sequence.

Right now, the instrument runs with NuGen's Ovation SP Ultralow Library Systems and Encore Rapid SP Library Systems kits, as well as with New England Biolabs NEBNext DNA Sample Prep library reagents. These reagents and protocols allow customers to prepare libraries for DNA sequencing, RNA-seq, ChIP-seq, digital gene expression, "and other applications," Dance said.

In addition, a kit for strand-specific RNA-seq called the Encore SP Complete RNA-seq Library System will be "coming soon," according to the company's website.

The Ovation SP Ultralow Library System in particular allows users to start with as little as 1 nanogram of DNA, NuGen said. However, two steps at the end of that workflow — PCR enrichment of the purified library and library quantification — currently still take place off the instrument. On a poster presented at the AGBT meeting, the company showed data using between 10 picograms and 30 nanograms of sonicated genomic input DNA.

The Mondrian SP offers several advantages over other library prep automation platforms, according to Dance. The system is simple to operate and can be installed by the user, and because it has few moving parts, it is "highly reliable" and requires "minimal maintenance."

The instrument will likely compete with liquid handling systems that are used for library prep automation, for example PerkinElmer/Caliper's Sciclone NGS Workstation, IntegenX's Apollo 324, or Beckman Coulter's SPRIworks systems.

According to Elaine Mardis, director of technology development and co-director at the Genome Institute at Washington University, which has had the Mondrian since early January, the instrument has the potential for using a "much lower" amount of input DNA and fewer reagents than typical library preparation methods, and promises to be less error-prone than manual library construction.

The quality of the Mondrian libraries appears to be "comparable" to manually prepared libraries, she said.

In terms of throughput, other approaches might be faster than the Mondrian, she said, since a single lab technician can make "a large number" of libraries manually in a day, and several hundred with automation.

During a presentation at AGBT, Mardis said that her lab has so far used the Mondrian to construct libraries from between 12.5 and 100 nanograms of input DNA from bacteria. It is currently testing the Ovation SP Ultralow Library Systems kit, which has an option for multiplexing through barcoding.

Clinical sequencing projects in particular will require the construction of libraries from small amounts of starting material, she said, citing a prostate cancer project as an example where she and her colleagues had only 20 nanograms of DNA available from a laser capture microdissection.

Researchers at the EMBL in Heidelberg have also been using the Mondrian, which they have had since December, for low input DNA samples. According to Vladimir Benes, head of the institute's genomics core facility, after some initial issues that were quickly resolved by NuGen, the instrument and protocols have been "very robust, reproducible, and extremely efficient."

One of the first tests, for example, yielded almost 2 micrograms of a genomic DNA library from 50 nanograms of starting material, and his team has not seen any problems with cross-contamination.

The costs associated with the technology are "OK, considering we're getting very good libraries from samples that would be hard to process otherwise" because of the small amount of DNA available, he said.

Rutgers University has had the Mondrian for more than six months, and the instrument has performed "flawlessly" from the beginning, according to Andy Brooks, director of the Bionomics Research and Technology Center. His group has been using the system primarily to prepare clinical samples and to validate next-gen sequencing protocols they plan to run in a CLIA laboratory. For example, they have created sequencing libraries for several targeted gene panels.

NuGen stressed, however, that its instrument is for research use only and that the company does not market it for use in CLIA laboratories.

According to Brooks, the main advantages of the system are its "simplicity and robust performance." He said he was skeptical initially about the library prep costs involved, "but given the workflow advantages and the outstanding success rate, the actual cost of generating libraries, especially for critical samples, is actually less compared to other approaches that are a lot more labor intensive."

For high-throughput library production for discovery research, though, his lab uses the Caliper Sciclone, which "can handle large numbers of libraries for a variety of technologies," including NuGen chemistries, he said.

Asked whether NuGen is planning to develop the Mondrian SP for applications other than next-generation sequencing library preparation, Dance said that the company "recognizes the value of digital microfluidics for microarray sample preparation applications."

Have topics you'd like to see covered in In Sequence? Contact the editor at jkarow [at] genomeweb [.] com.