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IBM Team, Still Active in Sequencing, Shows Fabrication of Nanopore Arrays with Embedded Electrodes

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NEW YORK (GenomeWeb) – A year after Roche terminated its collaboration with IBM to develop a solid-state nanopore sequencer, IBM researchers continue to publish results from their nanopore-related research on single-molecule sensing and motion control, device manufacture using silicon technology, and nanofluidics.

"We have diversified our nanobiotechnology research portfolio, but DNA nanopore/nanochannel sequencing is still on our radar," Gustavo Stolovitzky, director of the translational systems biology and nanobiotechnology program at the IBM Thomas J. Watson Research Center in Yorktown Heights, New York, told In Sequence via email.

He said IBM scientists are "actively pursuing projects that are relevant to sequencing and other nanobiotechnology solutions" and are "in discussions with potential partners" for commercializing technologies they developed for DNA sequencing.

Most of the techniques developed by the group are already patented, and additional patent applications have been filed. IBM has "complete freedom of action with respect to these patents" at this point, he said.

Earlier this month, Stolovitzky and colleagues published a method for fabricating arrays of nanopores with embedded metal electrodes in the journal Nanoscale. The paper, which acknowledges support from Roche, "paves the way to manufacturable solid-state pores with embedded electrodes for nanopore sequencing and other applications," Stolovitzky said.

Specifically, his team generated arrays of nanopores 55 nanometers thick and about 18 nanometers in diameter through a silicon dioxide membrane with three embedded 5-nanometer layers of titanium nitride, which serve as electrodes. "This design will allow for the creation of an electric field in the nanopore that can be used for translocation control and sensing," he explained.

Rather than drilling the nanopores one by one, for example with the electron beam of a transmission electron microscope, they used a technique called reactive ion etching, or RIE, allowing them to use full-size wafer substrates throughout the fabrication process. In addition, RIE is compatible with a wide range of semiconductor processing steps.

Unlike drilling, RIE also avoids the problem of short-circuiting the embedded metal layers, which leads to a leakage current between the layers. While the yield of unshortened electrodes was 99 percent for RIE-based pores, it was less than 10 percent for TEM-drilled pores.

Using the RIE approach, the researchers were able to routinely produce 121 arrays of 11 by 11 three-metal nanopores, starting with a 200-millimeter wafer. "The achievement of RIE-based nanopore array production at a wafer scale is of great significance towards high-throughput parallel processing in DNA sequencing as well as other single-molecule applications," the authors noted.

"This is very impressive fabrication," said Marija Drndić, a professor at the University of Pennsylvania's department of physics and astronomy, though she cautioned that "the successful operation of these devices will be even more challenging." Last year, her group published a paper on fabricating graphene nanoribbon-nanopore sensors using a TEM in a mode that helped to prevent electron beam-induced damage.

To test the function of their nanopores, the IBM researchers threaded double-stranded DNA through them under a voltage and monitored the ion current signal through an individual pore. They found that the DNA dwell times were similar to those observed previously for silicon nitride pores without embedded metal layers.

They also applied a voltage to one of the embedded metal electrodes but found that it did not alter the dwell time or current blockage of the DNA, which they said was expected because the pore diameter is much bigger than the diameter of the DNA.

For DNA sequencing, the pore size will need to be smaller, and the researchers showed that they can reduce the diameter to about 7 nanometers, which Stolovitzky said is "within the realm of what would enable a pore with embedded electrodes to be functional."

One option to further decrease it is to reduce the thickness of the overall membrane. "Our current efforts are focused on reducing the pore size to dimensions close to the diameter of double-stranded DNA and exploring the possibility of controlling the movement of charged molecules inside the nanopore," the authors concluded.

Besides the Nanoscale paper, the IBM scientists have published a number of other articles on their nanopore and nanochannel research this year, "and there are a few more interesting papers in the pipeline," Stolovitzky said, which will "make inroads into the problem of sensing nucleotides."

A recent publication in Nanotechnology, for example, explored the use of nanochannels and a transversal electric field to control the motion of DNA inside the channel, and a paper in Scientific Reports earlier this year showed that the transport of DNA through a nanopore can be modulated by a self-assembled monolayer with functional groups on the pore surface.

"While doing this work, and with the expertise developed in our lab, we started to work on other technologies in proteomics and nucleic acids, which will enable on-chip sample preparation at small sample volumes," Stolovitzky said, though he was unable to reveal details at this time.

It is unclear who might commercialize the technologies developed by the IBM group for nanopore sequencing following Roche's departure from its partnership with IBM last year.

Genia, which was acquired by Roche earlier this year, has developed a nanopore sensing platform that uses semiconductor fabrication processes but it currently works with protein nanopores, not solid-state nanopores.

Oxford Nanopore Technologies is commercializing a nanopore platform, called MinIon, that employs protein pores, but the company is also conducting research into solid-state nanopores at an R&D group in the US it opened almost three years ago.

Illumina has also said it is pursuing nanopore sequencing, and other sequencing platform vendors might do so, as well. Notably, one of the two lead authors of the IBM Nanoscale article listed his current address as Illumina, and another author now appears to work at Ion Torrent, which is owned by Thermo Fisher.

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