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Techniques & Tools Mass Spectrometry

The Rise of IMS-MS

Give us some background on your interest in ion mobility, particularly when interfaced to mass spectrometry. 

Since its commercial adoption in the 1940s and 1950s, mass spectrometry has continued to progress in new and exciting ways. And I’m particularly excited about any tools or techniques that accelerate scientific research. The marriage of ion mobility (to separate ionized compounds in the gas phase) with mass spec (to identify and detect them) nicely complements the capabilities of chromatographic separation (GC-MS and LC-MS). One advantage is that IMS separation is faster than chromatographic separation by a factor of >1000.

Can you offer some perspective on the history of IMS and IMS-MS?

E. W. McDaniel performed fundamental studies on ion mobilities and ion molecule reactions in gasses during the 1950s and 1960s at Georgia Tech – and these were key to the development of IMS. Francis Karasek at the University of Waterloo first employed atmospheric pressure drift tube ion mobility for analytical applications in the 1970s, and IMS came into widespread use for homeland security and military use for detecting explosives and chemical warfare agents. But the real leader in developing IMS and IMS-MS for analytical uses was Herb Hill at Washington State University (who was previously a postdoc for Karasek). These early IMS systems all employed ion mobility at one atmosphere, so they didn’t require vacuum pumps. Even still, as we entered the 21st century, all commercial IMS were designed for homeland security and military applications.

The first commercial integrated IMS-MS instrument used a traveling wave IMS interfaced to a Q-ToF mass spec, and was introduced by Waters in 2006; the first commercial IMS-MS using a classic drift tube, also interfaced to a Q-ToF, was first offered by Agilent in 2014. Both of these instruments perform ion mobility at reduced pressure (typically at <1 percent of atmospheric pressure) to make it easier to interface the IMS with the high vacuum required by the mass spectrometer (about a billionth of atmospheric pressure). But that inevitably compromises the separation that can be achieved compared with operating the IMS at one atmosphere.

Ching Wu, one of Herb Hill’s PhD students in the 1990s, founded Excellims in 2005 to develop atmospheric pressure high performance IMS (HPIMS) systems for new application areas. In 2006, Excellims introduced an atmospheric pressure drift tube IMS with electrospray ion source (the GA2200) as well as one that could be added to the front of Thermo and other mass spectrometers in 2014 (the MA3100). Excellims also introduced an integrated system that interfaced IMS to their own compact linear ion trap MS/MS instrument in 2019 (the MC3100). 

Because of my interest in combining IMS with MS, I followed developments at Excellims, getting to know Ching and his team. I saw a lot of potential in moving IMS-MS into clinical and point-of-care applications, and therefore agreed to serve as a member of their scientific advisory board in 2018. 

What are the advantages of atmospheric pressure IMS-MS?

Clearly a big advantage of performing IMS at one atmosphere is the improved separation possible with a reasonable length drift tube (hence the term HPIMS or high-performance IMS), as well as eliminating the need for vacuum pumps for the IMS. And that’s why atmospheric pressure IMS is widely used in passenger screening at airports, but not used in other commercial IMS-MS systems.  

By interfacing an atmospheric pressure IMS with a mass spectrometer, you end up with a much more powerful analytical system than IMS alone – you’re able to differentiate compounds that have the same drift time by different masses, as well as identify unknown IMS peaks by their mass spectra. And adding tandem mass spectrometry (MS/MS) to the mix, as on the MC3100, further increases the selectivity as well as the ability to identify unknowns. (For more insights into the central role that such tandem instruments play in modern trace analysis, see here). 

The third advantage of this approach is that it makes two complementary analytical instruments possible: a small, low-cost, stand-alone IMS for field use or rapid screening in point-of-care clinical applications, and then a larger (and more expensive) tandem IMS-MS system, with the same IMS front end, but interfaced to a mass spectrometer, for laboratory studies, method development, and validation of screening performed with the standalone IMS system. 

What are the benefits of HPIMS in clinical diagnostics and disease research?

In my lab at the University of Florida, we have used the Agilent 6560 IMS-MS instrument (with a meter-long drift tube IMS operated at 1/200 of an atmosphere interfaced to a Q-ToF mass spec) for studies in metabolomics, lipidomics, and clinical analysis. We’ve found that the instrument provides many advantages, including rapid analysis (eliminating or dramatically reducing the need for LC separation), reducing interferences, helping identify unknowns, and, in particular, resolving isomers that cannot be resolved by LC or MS alone. For example, we’ve found that IMS can resolve many steroid isomers of interest in antidoping studies of athletes; it can also remove the interference of a Vitamin D isomer in its clinical analysis. But that instrument is big (I like to say 10 foot long and 10 foot tall!) and is priced proportionally. Moving those analyses onto a smaller and less expensive IMS-MS platform, such as the MC3100, would be very attractive. In fact, we have evaluated the Vitamin D assay on the Excellims MA3100 interfaced to a Thermo Orbitrap mass spec.

Another intriguing application area for IMS-MS is breath analysis for clinical applications (everything from routine diabetes monitoring to screening for diseases, such as COVID). And this is clearly an application where the availability of both a stand-alone IMS for rapid point-of-care screening and a laboratory IMS instrument interfaced to a mass spectrometer for method development and validation would be a very powerful combination.

What future developments do you foresee for IMS technology?

I see a lot of potential for IMS for rapid analyses in a variety of application spaces, from quality control to clinical analysis. The availability of a complementary IMS-MS system for developing and validating those applications, and then troubleshooting them when problems arise, could be game changing – particularly if the IMS and IMS-MS systems were well integrated in terms of hardware and software platforms. For many of these applications, front end sampling capabilities (for breath analysis, for instance) and back-end software integration will be key to the widespread acceptance of such technology.

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