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Mass Spec Device Could Significantly Up Assay Sensitivity, Says Georgia Tech Team


NEW YORK (GenomeWeb) – A team led by researchers at the Georgia Institute of Technology has developed a device that could increase the amount of sample introduced to mass spectrometers and significantly improve instrument sensitivity and signal-to-noise.

Called DRILL (dry ion localization and locomotion), the device links a mass spec system's electrospray ionization (ESI) component to the instrument's inlet using electrodes to manipulate the charged droplets generated via ESI and deliver them more effectively to the mass spectrometry.

The technology was described in a paper published last month in Analytical Chemistry and, in analyses of a stable isotope labeled peptide mixture, improved signal strength of target peptides by as much as 700-fold.

The device tackles a central challenge of ESI mass spec, which is sample loss during the process of ionizing and transferring sample into the mass spectrometer. One of the main ionization modes used in mass spec-based proteomics, ESI uses an electric field to turn a solution containing target analytes like peptides or proteins into charged droplets that can be analyzed by mass spec.

One difficulty of the approach, though, is that it does not create droplets of uniform size. Larger droplets contain a higher proportion of solvent to target analytes, which increases the amount of noise.

"And the more chemical noise you have, the less your detection capability," said Andrei Fedorov, a professor of mechanical engineering at Georgia Tech and senior author on the study.

This, he noted, means that "in theory, it would be preferable to strip all of the solvent molecules from the analytes for these electrospray droplets entering the mass spectrometer, because this dramatically improves the quality of the analysis and the detection capability."

Greater distance between the ESI device and mass spec inlet increases the amount of desolvation, but also leads to a reduction in the amount of sample that makes it into the inlet as the droplet plume produced by ESI expands as it moves outward. Additionally, the smaller, more highly charged droplets are driven to the outer edges of the plume, further contributing to the loss of signal.

With a conventional ESI-MS set up, "we are losing 90 percent of the good stuff," Fedorov said. "So it’s a really important aspect of this whole workflow to be able to capture all of the analytes that are there and to be able to preferentially send to the mass spectrometer droplets that are stripped from the solvent molecules."

The DRILL device manipulates the ESI droplet plume using vortex flow and centrifugal forces to move the bigger droplets to the periphery of the plume while concentrating the smaller droplets with a higher ratio of analyte to solvent to the center of the plume where they will be directed into the mass spec inlet.

Once these smaller droplets have entered the mass spec, the device brings the larger droplets, which have in the meantime seen much of their solvent evaporate, back into the center of the plume and then they, too, are introduced to the mass spectrometer.

"So, essentially, we [do?] two functions at the same time," Fedorov said. "We split the [droplets] upfront into small ones and bigger ones and send the smaller ones to mass spectrometer, which allows us to reduce chemical noise upfront." In addition, he added, "we don't get rid of the bigger droplets because they still do have analytes, even though not as much as the smaller droplets."

In experiments measuring the peptide angiotensin I using a Thermo Fisher Scientific TSQ Vantage instrument, the researchers found the DRILL device improved signal-to-noise ten-fold. Measuring the limit of detection for the same molecule on a Thermo Fisher LTQ Orbitrap, Fedorov and his colleagues found it improved limit of detection by an order of magnitude.

They also tested the device on a mixture of nine stable isotope-labeled peptides that they measured using multiple reaction-monitoring, finding that it improved quantification of eight of the nine peptides with sensitivity increases as much as 700-fold.

Fedorov and his colleagues first conceived of the device in 2007 and have been working on it since that time under several grants from the National Institutes of Health. One of the biggest challenges, he said, was devising a system capable of taking into account the differences not only in droplet size but also charge.

"Anytime droplets of like charge come close together, they repel each other. So that was the biggest challenge — to come up with the appropriate vortex integration and [point at which to] introduce gas into the device and what electric field potential one needs to apply to really be able to divide and conquer this very complex aerosol mist of different droplet sizes that are also charged."

Having worked that out, though, making the device "is not a big challenge," Fedorov said, adding that it would probably cost a lab around $100 to produce.

"All the materials are very basic materials," he said. "There's no very complicated manufacturing process involved."

The device is compatible with any ESI mass spec and is essentially ready for commercialization, Fedorov said.

"It's at the stage right now where you can start to make it and sell it to customers," he said, adding that he and his collaborators had no commercial ambitions themselves but would hope to license the technology to an outside company or startup.

He said that the device has drawn interest from both ion source and mass spectrometer manufacturers but declined to name any specific companies.

The researchers are also doing further development work on the device, including heating the droplets to improve desolvation and exploring other options to improve ion transfer and capture, Fedorov said. "I envision iterations … of this device that further improve but also bring additional modalities to the analysis."