CELIA M. HENRY,C&EN WASHINGTON

SMALL STUFF Taylor holds a micro quadrupole mass spectrometer, which is mounted on a vacuum flange. Courtesy of SteveTaylor

In terms of their size, analytical instruments have followed a trajectory similar to computers, which started as behemoths that filled a room and now come in versions that fit in the palm of the hand. That's the way it has been with mass spectrometers--at least for the mass analyzer. Such small instruments could find use in environmental monitoring, space applications, and clinical diagnostics. A half-day symposium at Pittcon described the current state of miniature mass spectrometers.

Most types of mass analyzers have been miniaturized. However, R. Graham Cooks of Purdue University, the symposium organizer, said in his opening remarks that time constraints did not allow him to schedule people to talk about every type of these. The mass analyzers described at the symposium included cylindrical ion-trap, quadrupole, and time-of-flight instruments. Magnetic-sector and ion-cyclotron resonance instruments, which have also been miniaturized, were not included.

In addition, Cooks lamented that he could not include researchers who are working on shrinking other aspects of the overall system, such as vacuum pumps. These ancillary devices account for the largest portion of the overall system, and making truly miniaturized systems will require addressing the size of these components.

J. Michael Ramsey, a chemist at Oak Ridge National Laboratory, led off the symposium with his "philosophy of miniaturization." Ramsey has been a key figure in the development and widespread acceptance of microfluidics. People have been concerned, he said, about a loss in performance in miniaturized instruments relative to their conventional counterparts.

"Most people want to make something small and cheap and maintain performance," Ramsey told C&EN. "The success of microfluidics and the lab-on-a-chip technology has caught everyone's attention and made people think about miniaturizing other devices."

Although miniaturized mass spectrometers are most often considered for field applications, Ramsey thinks they will also find use in the research laboratory.

Miniaturization is not simply repackaging existing mass analyzers, Ramsey told the audience. Instead, it is a reduction in the fundamental length scales of the devices. He believes that microfabrication--techniques such as those used in the semiconductor industry--will eventually play a major role in the miniaturization of mass analyzers.

Cylindrical ion traps lend themselves particularly well to miniaturization because of their ease of manufacture. Cooks and Ramsey both described miniature ion traps. Cooks's ion trap has a radius of 2.5 mm, whereas Ramsey described ion traps with a radius of 0.5 mm. Those values compare with a radius of 1.0 cm in a commercial ion-trap instrument.

Machining a cylindrical ion trap is as easy as running a drill bit through a piece of sheet metal, Ramsey said. However, his group may have reached the lower limit of the size that can be achieved that way. He thinks that making even smaller ion traps will require moving to microfabrication techniques. He suspects that such techniques would allow the ion traps to be mass-produced consistently.

THE ION TRAPS can be used in arrays and operated either separately or together, depending on whether a single detector or multiple detectors are used. When the ion traps are operated independently, each ion trap can be operated at a different mass-to-charge ratio (m/z). When they are operated in parallel, they are set to the same m/z value, which helps compensate for any loss of trap capacity. Ramsey said an array of n traps, where the radius of each trap equals r₀/n, should provide the same performance as one trap with a radius of r₀. He described an array of ion traps that consisted simply of seven 1-mm holes bored in a metal circle the size of a U.S. quarter.

One of the problems that Ramsey and his coworkers initially ran into was "jitter" in the spectrum when they tried to average multiple spectra. They have attacked that problem using double resonance frequencies, which are already known to improve resolution in conventional ion traps, Ramsey said. These nonlinear resonance frequencies are harmonics of the fundamental resonance frequencies.

"The bottom line," Ramsey said, "is that signal averaging is now possible."

Ara Chutjian of the Jet Propulsion Laboratory and California Institute of Technology in Pasadena, Calif., described a miniaturized quadrupole mass spectrometer (QMS) intended for applications in space. The instrument consists of a 4 3 4 array of rods, giving nine quadrupole regions that can--like the ion-trap arrays--be operated either together or independently.

When Chutjian and his group started working on the miniaturized mass spectrometer, they considered the different types of mass analyzers to see which would be amenable to space applications. They decided that only quadrupoles and ion traps would be suitable. "At first, we wanted to stay away from magnetic instruments in space applications," he said, "because of the relatively large mass of magnetic materials and the fact that, without additional shielding, your magnetic field can interfere with somebody else's instrument on a crowded platform."

CLOSE QUARTERS The Oak Ridge cylindrical ion trap in its housing. Courtesy of J. Michael Ramsey

The quadrupole array now aboard the International Space Station has a mass range of 1 to 150 amu and a resolution of 0.5 amu. The instrument is scheduled to be put into action as a leak detector outside the ISS later this month, Chutjian said.

For space applications, size really does matter. The system that Chutjian and his coworkers designed is about the size of a shoebox, including the electronics and vacuum system. The electronics occupy a large portion of the total system, but the quadrupole mass analyzers themselves are only 5 cm long.

The small mass analyzers are compatible with preconcentration techniques such as membrane inlets, and Ramsey, Cooks, and Chutjian each described membrane inlets for their systems. Such preconcentration improves the sensitivity of the instruments. In addition, the membrane inlet allows one to interface to a liquid sample. It also reduces the pumping requirements, making it practical to use smaller vacuum pumps.

On Chutjian's instrument, the combination of a gas chromatograph and preconcentrator has made it possible to detect 80 ppb of benzene. The signal was high enough that he thinks he could see as low as 10 ppb of benzene.

Chutjian is also working on a system that can be used for Martian soil samples, looking especially for prebiotic species. The major challenge is the sampling device. Chutjian's group, in collaboration with Thorleaf Research in Santa Barbara, Calif., has devised microsampling probes with pneumatic cylinders to drive the probe into the ground.

Another QMS described at the symposium may be the smallest mass spectrometer ever made. Steve Taylor, an electrical engineer at the University of Liverpool, in England, described a QMS constructed using microfabrication techniques.

To make the microfabricated QMS, a silicon substrate is patterned and etched with V-shaped grooves to hold two of the electrodes, which are rods made of metal-coated glass fibers. A nonmetallized rod is used as an insulating spacer. The process is repeated, and the two halves are assembled to form the quadrupole. The rods are 0.5 mm in diameter and 10 to 30 mm long. In addition to making a single quadrupole, it is also possible to make an array of nine quadrupoles on a silicon wafer. The quadrupoles, whether alone or arrayed, have a stable mass range of 150 amu.

THE BEST RESOLUTION so far is just over 1 amu peak width at mass 84 (Kr) measured at 10% peak height, and the best sensitivity is in the 10- to 100-ppm range. Unfortunately, Taylor said, the resolution is not as high as he would like, but work is ongoing to address the issue. Because of its small size, the microfabricated QMS performs well at slightly elevated pressures, which could open up new application areas, particularly in the field of process monitoring.

Robert J. Cotter of Johns Hopkins University described work on miniaturizing time-of-flight mass spectrometers. Because he is interested in bioagent detection and clinical diagnostics based on proteomics (for example, protein biomarkers for cancer), Cotter needs an instrument with a wide mass range, which time of flight can provide. His instrument is not as small as the ion traps. The portion of the instrument where the ions are separated is approximately 7.5 cm long, compared with 1 m for conventional time-of-flight instruments.

According to Cotter, it has been assumed that miniaturizing mass spectrometers will result in a loss of performance. In some respects that is true, he said, but sensitivity is actually better for smaller instruments in time of flight. However, one of the limitations in miniaturizing time-of-flight instruments is that the resolving power decreases.

Time-of-flight mass spectrometers are fairly simple instruments. They consist of the ion source, a drift region (where the ions are separated), and a detector. Why then, Cotter asked, are they so difficult to miniaturize One reason is that the resolution depends on the amount of time the ions spend in the drift region. That time can be increased by lengthening the tube. However, Cotter pointed out, when you are trying to miniaturize, that's going the wrong way. Alternatively, the time can be increased by lowering the accelerating voltage. But this has the effect of reducing sensitivity at higher masses and exacerbating the effects of the initial kinetic energy distribution.

Cotter used the miniaturized time-of-flight instrument to acquire the mass spectrum of adrenocorticotropic hormone. The resolving power increased for higher m/z fragments of the peptide. Cotter also showed mass spectra for cytochrome c, spores with peptide biomarkers for Bacillus globigii, and an oligonucleotide mixture. "The performance is not up to that of a $400,000 instrument," Cotter said, "but we think we can maintain most of the performance." The largest mass measured to date with the miniaturized time-of-flight instrument has been a 66-kDa bovine serum albumin.

Cotter described a method called mass-correlated acceleration (MCA) for further improving the performance of time-of-flight mass spectrometry. In this method, a time-dependent voltage is applied to a second stage in the source region. MCA allows ions to be focused at high resolution across a broad mass range. The method has already been demonstrated on a conventional time-of-flight instrument [J. Am. Soc. Mass Spectrom., 13, 135 (2001)]. Cotter and his group are starting to test it for a smaller time-of-flight instrument. However, right now that smaller instrument is a conventional instrument with the flight tube removed. The next step is to move to the miniaturized instrument.

The factors that are preventing the entire system from being shrunk are components such as the electronics and the vacuum pumps. Cooks showed a picture of a miniature ion-trap mass spectrometer being used in the field that required a cart. There's a "tendency for the instrument to bulk up," he said. The independent power supply constituted half of the weight.

One after another, the speakers reiterated that, until the ancillary parts of the system are also reduced in size, it won't do much good to continue to shrink the mass analyzer. Only when those accessories are also available in small packages will these tiny mass spectrometers be ready to hit the big time.

Chemical & Engineering News
Copyright © 2002 American Chemical Society

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Chemical & Engineering News
Copyright © 2002 American Chemical Society