Mini mass specs are still looking for an audience

Mass spectrometry is a go-to method for determining which molecules are in a sample. If security officers are faced with an unknown, possibly dangerous, substance, they don’t want to waste time sending samples to a lab and waiting for mass spec results, however. They’d rather be able to take a portable mass spec into the field to get answers quickly.

Efforts to miniaturize mass spectrometers are by no means new. Researchers have been working to fit these powerful instruments into small packages for decades. They’ve succeeded in making small systems for particular applications, but they haven’t succeeded as much in reaching a broader audience.

Miniature mass specs face the challenge of “false expectations” from users, says R. Graham Cooks, a chemistry professor at Purdue University and leader in the field. If people expect a miniature mass spectrometer to give them the same quality data as a high-end lab instrument, they’re going to be disappointed.

“Whenever we make something smaller, we sacrifice some aspect of performance,” says Daniel E. Austin, a chemistry professor at Brigham Young University who has been working on miniature ion traps for over 15 years.

For instance, miniature mass spectrometers—ones about the size of a desktop computer tower—are not going to “win” compared with much larger versions that have more space over which to separate ions, says Zheng Ouyang, professor at Tsinghua University and founder and president of Purspec Technologies, a company focused on commercializing miniature mass specs. The mini versions will have worse resolution, higher detection limits, and worse mass precision.

But scientists aren’t necessarily making miniature mass spectrometers in hopes of outperforming the originals. They’re doing it because they need analytical tools that are speedy and portable.

“There are a lot of potential applications where it’s best if you can make your analysis out in the field,” Austin says. “You need a fast answer or to make a fast decision; the sample is changing quickly; or you need to make lots of samples quickly in a way that’s cumbersome to send back to a lab.” For instance, they might be detecting toxic gases in transportation systems or making environmental measurements in the field.

To improve demand for miniature mass specs, scientists are still working to boost their performance.

In a miniaturized mass spec, the most common type of mass analyzer—the component of the instrument that sorts and separates molecular fragments—is the ion trap. In ion traps, various voltages and frequencies are applied to electrodes to set up fields that confine ions. The smaller the device, the higher the frequencies required to trap ions.

“They’re already fairly compact compared with other mass analyzers,” Austin says. And another benefit is that they can operate at higher pressures than other mass analyzers, so they don’t need a vacuum-pumping system that’s as large and bulky.

Other types of mass spectrometers usually require pumping the system down to low pressures in the range of 0.001 Pa or even lower so that ions can easily fly through the analyzer to the detector. Such pressures are usually achieved with multiple stages of pumping. Ion traps, in contrast, can typically be run at pressures in the 0.1 Pa range.

J. Michael Ramsey, a chemistry professor at the University of North Carolina, Chapel Hill, and another pioneer in miniature mass specs, has succeeded in relaxing the pressure requirements even more. By using micrometer-scale ion traps that he drives at high frequencies, he has been able to operate ion traps at pressures of 133 Pa and even higher, a method he calls high-pressure mass spectrometry.

“That’s saved us a lot of size, weight, and power in the vacuum system,” Ramsey says.

Ramsey’s technology has been licensed and developed by Boston-based 908 Devices. The company sells compact systems for safety and security applications that weigh between 2 and 4 kg, including the pumps and batteries.

“The vacuum system is the single largest component in the system,” says Ed Lee, director of research for portable MS and gas chromatography/MS at PerkinElmer. “Anything you can do to reduce the vacuum requirements is going to yield a smaller instrument. Of course, compromising on the vacuum compromises the performance.”

Jason J. Amsden of Duke University, who’s bucking the ion-trap trend and miniaturizing a magnetic-sector instrument instead, says, “Looking at our instrument, I would say the vacuum pump probably takes up approximately two-thirds” of the overall system. Amsden estimates that his system is about 36 × 50 × 20 cm and weighs between 9 and 14 kg, most of which is the pump.

Part of the problem is that there’s little commercial demand for small vacuum systems, BYU’s Austin says. Until demand picks up, miniature mass specs will use oversized pumps or expensive specialty pumps.

Another area of improvement for miniature mass specs is their sensitivity.

For instance, smaller ion traps hold fewer ions and therefore can detect a narrower range of masses at a time and have potentially lower sensitivity. Ramsey and 908 have overcome these issues by using arrays of ion traps. The arrays increase ion-trapping capacity.

Another approach, Austin says, is to use traps that are extended in one dimension, like linear or toroidal traps. These have an inherently larger trapping capacity because ions can spread out in one dimension while still being trapped in the other two.

Ramsey and 908 also take advantage of this trick, using stretched-length ion traps. Austin also microfabricates linear ion traps on ceramic plates. He lithographically patterns two plates that fit together easily and establishes a trapping potential between them to help ions stay put.

PerkinElmer is interested in Austin’s technology. It already sells a 17-kg, suitcase-sized gas chromatography/miniature mass spec system that uses a toroidal ion trap, called the Torion T-9.

So far the performance of Austin’s microfabricated ion traps “isn’t at the same level as what we have with the toroidal ion trap,” PerkinElmer’s Lee says. “But it’s getting better, and we’re watching the technology.”

Austin would like to shrink PerkinElmer’s system by a factor of two to four. “My group has just focused on the mass analyzer, but the staff at PerkinElmer have all the engineering support to make the rest of the system smaller.”

As improvements to miniature mass spec technology continue to be made, researchers like Cooks hope that commercialization will pick up. Security applications have taken off more than others because the instrument can be programmed with libraries of target compounds. But developers have their sights set on applications such as clinical mass spec.

Purspec’s Ouyang wants to develop a system that makes it simple for people to get answers from their samples.

Ouyang sees the miniature mass spec as a way to personalize drug doses for so-called precision medicine. “A lot of potent drugs have a very narrow therapeutic window and are highly dependent on the metabolism of the person,” he says. He wants to use the instrument to analyze blood or urine samples to get pharmacokinetic and pharmacodynamic information for individuals. “Then you can prescribe the drug with the right dose.”

Ramsey and 908 are likewise eyeing life sciences applications. “We think there are applications for a benchtop, dedicated analyzer that is focused on some subset of metabolites,” Ramsey says. For example, they’ve shown that they can measure phenylalanine in urine in the case of phenylketonuria, a condition in which the ability to metabolize that amino acid is impaired.

For such applications, Ramsey and 908 will combine the miniature mass spec with a chip-based capillary electrophoresis device with an integrated nanoelectrospray emitter developed in the Ramsey lab. That device, called a ZipChip, separates samples and electrosprays them into a mass spectrometer. The current commercial version of the device works with full-size mass specs but has also been successfully coupled to high-pressure mass spectrometry for analytes ranging from amino acids to intact monoclonal antibodies.

“We have an active area of research to develop a small system that could use that capillary electrophoresis chip in conjunction with a miniature spec to address life sciences applications,” says Christopher D. Brown, chief technology officer at 908.

In the life sciences, “maybe the user of interest is a biologist,” Brown says. “They don’t know a whole lot about mass spectrometry, and they don’t really want to know a whole lot about mass spectrometry.” But they would like to get the answer they’re looking for.

There is a market for miniature mass specs, Ouyang says. Companies just need to find it. “This market is different from the one for traditional mass spec. Usually mass spec is done by experienced, well-trained personnel. The miniature mass spec has to be foolproof.”