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Demands for Simpler, More Streamlined Mass Spec Provide Opening for Miniaturized Devices


NEW YORK (GenomeWeb) – Vendors of mass spectrometry instrumentation have been noting an ongoing shift in customer needs towards smaller, more user-friendly devices. At the American Society for Mass Spectrometry annual meeting last month, several companies said that while instrument performance was still important, users were more and more willing to trade raw analytical power for faster, more streamlined workflows and greater ease of use.

This shift has manifested itself in a variety of ways, ranging from Sciex's efforts to develop "industrial proteomics" workflows around its Swath data independent acquisition technique to Agilent Technologies' release at the ASMS meeting of its small-footprint Ultivo triple quad to Thermo Fisher Scientific's planned release next year of its Cascadion SM Clinical Analyzer, a fully automated mass spec-based clinical system.

Another area that could benefit from this move toward convenience is miniature mass spectrometry, portable instruments that are many times smaller, and cheaper, than conventional laboratory platforms. While still largely confined to the fringes of the life sciences, such instruments could make inroads in various areas, including point-of-care testing, in-surgery analysis, and drug development.

"The idea that a mass spectrometer should be an enormous instrument that continually [measures] higher and higher mass ranges [at] higher and higher mass resolution is perhaps reaching the end of its development," said Graham Cooks, professor of analytical chemistry at Purdue University and an expert in miniature mass spectrometry and mass spec more generally. "Certainly there is a lot of room for small, agile, minimally capable but sufficiently capable mass spectrometers to meet the problem at hand."

Cooks and his colleagues have built handheld instruments weighing around 10 pounds that they are exploring for applications including the analysis of tumor grade and tumor margins during brain cancer surgery. In that case, he noted, the portability of the instrument provides a key advantage in that "you are really forced to do the measurements as close to the patient as possible."

Point-of-care testing is another area where Cooks said he sees great potential down the road for miniaturized mass spec. "I think [first] in hospitals but then further along in physician's offices. There are lots of tests that could be done in those circumstances rather than sending them out," he said.

One of the keys to bringing down the size of a mass spec instrument is removing the high-end vacuum equipment that contributes to much of its bulk, cost, and energy demands. Ion traps are most commonly used in small devices, Cooks said, due to the fact that "you don't have to have an outstanding vacuum to get good data from an ion trap." He noted, though, that researchers have miniaturized instruments like triple quadrupoles, as well.

In terms of performance, mini mass specs offer less sensitive detection by a factor of around four to 10, Cooks said, adding that they also provide less resolution and smaller mass ranges.

Even so, he said, they can be useful for analyzing a wide range of biological molecules. "If by life sciences you mean [analyzing] large intact biomolecules, I would say that is more of a reach," Cooks said. Peptides and a variety of small molecules like drugs and metabolites, however, are amenable to analysis on miniaturized devices.

"Then you start factoring in the ease of use, the price per sample, and the possibilities for [immediate] feedback, where the results of the experiment allow you to determine the next experiment, and so on," he said.

"I don’t believe mini MS should be used for general-purpose work," said Cooks' Purdue colleague Zheng Ouyang, a professor of biomedical engineering and president and founder of Purspec Technologies, a mini mass spec firm he launched in 2015 to commercialize technology developed by his and Cooks' labs.

"The power of the mini MS comes from the streamlined analysis providing direct answers at the site [of analysis]," he said. Such instruments, he added, make most sense as tools "to be used by nurses, physicians, biologists who care about specific biomarkers; not for scientists who want to see everything."

Ouyang noted that Purspec's mini mass specs have m/z ranges of 2,000, which makes them suitable for analysis of biomolecules including peptides and metabolites. The key issue now, he said, is developing extremely simple workflows for measuring target molecules.

"The challenges lie in [developing] fast analyte extraction and preparation using [for instance] cartridge-type technology," he said. "The mini MS should be known for convenience. If the sample prep process requires in-lab procedures, then users are more likely to go with a versatile lab-size MS than a mini MS."

This drive towards convenience has led mini mass spec researchers like Cooks to explore ambient ionization techniques like desorption electrospray ionization (DESI) or paper spray ionization that allow users to avoid conventional liquid chromatography.

Michael Ramsey, a professor of chemistry at the University of North Carolina and an expert in miniature mass spectrometry, has used microfluidic chip-based capillary electrophoresis (CE) for upfront separations in much of his mini mass spec work directed towards life science applications.

"We chose to go the electrophoresis route because we already have a small footprint mass spectrometer, so we'd like a small footprint separation technology," he said.

Ramsey, who is the scientific founder of mini mass spec firm 908 Devices and chair of the company's scientific advisory board, said he sees a number of life science applications where miniaturized instruments could prove useful.

His lab's high-pressure mass spec systems (HPMS), which operate without the vacuum conditions used in conventional systems and can weigh on the order of four pounds, are able to analyze a variety of molecules, including peptides and metabolites. He and his colleagues have also explored, with success, using them for characterization of intact antibodies, which he said could prove useful for QA/QC work in biopharma development.

Mass spectrometry experts "generally want to go for high performance," Ramsey said. But, he added, echoing many of the vendor comments at this year's ASMS, there is a large group of potential users who are not interested in the particulars of the instrumentation but just want the result.

"We're mostly trying to address a measurement problem and sell those instruments to people who want the information and don't care what's inside the box," he said. "And as long as they can get their information at a lower price and as low a footprint as possible, they are happy."

While there is still room for technological advances, the biggest challenge facing the field from a life science perspective is determining what markets and what problems are the best fit, Ramsey said. "While we believe there are many opportunities for miniature MS benchtop analyzers in the life sciences, the best applications for entrance into the market are still being studied."

He cited the example of panels of commonly tested metabolites. "Most of those are pretty high concentrations, are pretty easy to detect," he said. "But once you put something out there, people are going to say, 'Well, what about this metabolite? What about this one?' I think the challenge for us is maybe to identify what is that minimal set of metabolites that would pique people's interest."

Ramsey said work he has done with the Whitehead Institute suggests one possible implementation of miniaturized mass spec. There, researchers have used CE coupled to conventional laboratory mass spec to analyze metabolites of interest from cell lysates. "At [the University of North Carolina] we have done similar experiments using microchip CE coupled to HPMS that would allow for a benchtop metabolite analyzer," he said.

"The problem is that even in large pharma companies that generally have deep pockets, you have impressive centralized mass spectrometry facilities, but, still, the turnaround time on the samples is measured in days if not weeks," he said. "And the cellular biologists would like a more immediate feedback on their experiments."

"So the cellular biologists want to look at the expression or the concentration of a number of these metabolites, and they would like to have devices they can put on their benchtops to do sort of a triage on cellular lysates," Ramsey said.

Since its founding in 2012, 908 Devices' HPMS product lines have focused primarily on military, hazmat, and hydrocarbon processing applications, but it sees great potential for mini mass spec as a life science tool, said Trent Basarsky, vice president and general manager of the company's life sciences business.

"Whether it's in standard cell biology applications or potentially even extending into the diagnostic space, I think there are a lot of differing opportunities," Basarsky added. He declined to say exactly what life science applications 908 Devices is currently exploring with HPMS, but said that he envisioned mini mass spec technology being valuable as a highly targeted approach to answering specific research or clinical questions.

"We have a lot of instrumentation giving us fairly complex answers, and in many situations, folks really do desire an analyzer that gives them an answer, rather than a large data file that they then have to process," he said.

It's not just miniature mass spec firms like 908 Devices that are exploring such possibilities. In fact, perhaps the space's greatest success story thus far comes from Waters, whose QDa Detector is essentially a mini mass spectrometer and has been a major success for the company since it launched in 2013. The device consists of a single-quadrupole mass spectrometer coupled to an LC system and can be used to quantify and confirm the identity of compounds separated via LC.

"I think it's a combination of simplifying the technology and simplifying that user interaction," Basarsky said. "I'm not questioning that there's tremendous value in extremely high horsepower instrumentation. But I do think there are situations where folks can get the answers that they need, but they don't have to be driving a Ferrari to get there. I think that's some of the shifting that we're seeing in the space."