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First-of-its-Kind Cyclic IMS Promises Unlimited Experimental Opportunities

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Ion mobility spectrometry (IMS) coupled to mass spectrometry (MS) has witnessed significant growth over the last two decades. Driven by increasing IMS sensitivity and capacity with improvements in MS instrumentation, ion mobility MS enables users to rapidly obtain information for molecular structure elucidation, significantly enhancing system peak capacity.

With the launch of the SELECT SERIES Cyclic IMS at ASMS 2019, Waters claims to be providing "limitless experimental potential" for scientists who are seeking a high-performance research-grade time-of-flight MS. There is certainly some hype surrounding the launch: University College London’s Dr Kostas Thalassinos suggests that the instrument will be “transformative for our [protein structural] work.”

To better understand IMS, the benefits this technology provides, and exactly what the SELECT SERIES CyclicTM IMS offers, we spoke to Emma Marsden-Edwards, Principal Product and Customer Relationship Manager at Waters to learn more.

AB: Recently, ion mobility spectrometry (IMS) has become an increasingly popular approach for the structural analysis of ionic species and for mixture separation. Why is this?

Emma Marsden-Edwards (EM-E): IMS is a technique that separates ions by size, shape and charge based upon their mobility in a buffer gas. While often used in standalone devices for rapidly detecting known analytes (for example, specific narcotics and explosives) at airports and remote locations when coupled with MS, it provides an additional orthogonal dimension of separation and some unique and enabling capabilities. IM-MS can be used for separating complex mixtures, such as peptides or metabolites, resolving ions that may be indistinguishable by MS alone, such as positional isomers or diastereoisomers, or to determine structural information. IM also allows the rotationally averaged cross-sectional (CCS) to be determined, and this intrinsic property of an ion can be used for qualitative conformation and identification purposes. IM-MS can also provide insight into the conformational dynamics of a system, enabling characterization of flexibility and folding mechanisms, which is not possible by MS alone. 

AB: What benefits does IMS offer over GC and LC? In what situations might someone choose to adopt IMS rather than GC/LC?

EM-E: That’s a really interesting question. IM  offers the advantage of speed, operating in the millisecond timeframe, fitting perfectly in a nested fashion between the separation timeframe of LC/ GC (secs) and time-of-flight (TOF) (µsec). This means IM is fully compatible with both LC and GC separations and is frequently used in this combination, so rather than choosing to use it instead of GC/LC it’s a way to maximise the information from a single sample analysis. However, the real power of IM is where liquid phase separations are not desirable or even possible, such as MS imaging applications or direct ionization using techniques such as MALDI, DESI and Rapid Evaporative Ionization MS (REIMS).

AB: At ASMS 2019 you announced the launch of the SELECT SERIES CyclicTM IMS. Can you discuss the design process of the product and whether you encountered any challenges during the process?

EM-E: Waters' MS Research has been actively working on developing our travelling wave ion mobility (TWIMS) technology and investigated several innovative ways to improve ion mobility resolution.  The new cyclic geometry was chosen as it offers so many analytical possibilities.  This technology was given the nickname "the race track" and we used Silverstone (British Grand Prix Circuit) as our development project name. The cyclic device provides scalable, high-resolution ion mobility separations with the ability to vary the number of passes through the device until the desired resolution is achieved. In addition, the advanced travelling WAVE technology enables the unique ability to perform ion mobility selection for ion mobility/ion mobility and IMSn experiments. In an IMSn experiment, we use multiple rounds of ion mobility selection, coupled with fragmentation and subsequent ion mobility separation, for detailed structural elucidation studies. A key component of the system is the multifunction TWAVE array where ions are injected into the cyclic device. This device moves the TWAVE voltages, and therefore ions, in a forward, reverse and sideways (orthogonal) direction. It is a critical technology development. There was such demand from customers for us to commercialise this technology that in early 2018 we formed the Waters Advanced Mass Spectrometry group to accelerate the development and commercial introduction. of this unique technology. This team is focused solely upon the delivery of high-performance MS systems for the research market, and in the future additional products will appear under the SELECT SERIES brand. 

Working closely with scientific collaborators we have developed a truly unique next-generation mass spectrometer, showcasing our continuing commitment to innovation.

In the cIMS System the typical drift tube is replaced by a compact cIM device. The cIM device consists of a circular 100 cm path length RF ion guide comprising over 600 electrodes around which T-Waves circulate to provide mobility separation. The circular path minimises instrument footprint whilst providing a longer, higher-mobility resolution separation path. As molecular ions enter the ion guide, they circle around it and with every pass, further separation occurs until they are released into the time-of-flight region and to the mass analyser.

AB: At Waters’ ASMS 2019 press conference Jim Langridge stated that “Currently IMS resolution is a bottleneck” why is this, and how does the CyclicTM IMS overcome the issue?

EM-E: Waters introduced the first commercial IM-MS in 2006 with an IM resolution of 10. The second generation SYNAPT had an improved resolution of 40. Whilst our ion mobility MS platforms have enabled customers to probe their sample further, generate CCS and increase system peak capacity as previously mentioned, the resolution of IM has been a major bottleneck to research scientists pushing the limits of MS across a wide range of applications. This was noted by David Clemmer in a recent publication One of the key current bottlenecksis an improvement in IMS resolution, with very few advances since the turn of the century.”

To address these issues, at ASMS 2019 we introduced the SELECT SERIES Cyclic IMS system, which incorporates our next generation IM technology. The revolutionary cyclic IM device, has a circular path which minimises instrument footprint whilst providing a longer, higher mobility resolution separation path and the device offers a multi-pass capability which can provide significantly higher resolution

AB: The CyclicTM IMS enables researchers to capture IMSn, can you explain what is meant by this and what it provides?

EM-E: In a tandem MS experiment (MS/MS) an ion of interest is separated from a mixture of ions by their characteristic m/z values using a first stage of mass analysis , and the ion(s) of interest are then fragmented e.g. using collision induced dissociation. The resulting product ions are then separated using a second stage of mass analysis, before detection.  This can be done either using two separate mass analysers such as with a Q-Tof instrument where MS1 is performed in the quadrupole and MS2 in the ToF or can be undertaken by two separate stages of mass analysis in the same mass analyser such as with an ion trap.

If you think about an ion trap, they can perform MSn experiments. The selectivity of MSn means that a compound can be mass selected, fragmented, and the resulting fragments further isolated and analyzed to yield structural information about complex molecules in the presence of mixtures. 

In the SELECT SERIES Cyclic IMS, the advanced travelling WAVE cyclic IM device enables the unique ability to perform ion mobility selection, for ion mobility/ion mobility, and IMSn experiments. In an IMSn experiment we use multiple rounds of IM selection, coupled with fragmentation and subsequent IM separation for detailed structural elucidation studies. The mobility device enables selection with a much higher specificity than typically available by mass spectrometry.

AB: A recent Analytical Chemistry paper stated that: “The instrument geometry [of the CyclicTM IMS] provides unique capabilities with the potential to expand the field of protein analysis via IM-MS.” What capabilities does the geometry offer and how can this benefit protein analysis?

EM-E: The cyclic design allows for quadrupole selection of ions coupled with scaleable, high resolution IM separation. The instrument geometry provides fragmentation capabilities before and after the cyclic IM separation stage. This allows specific conformations of proteins to be IM separated, isolated, and then activated by CID to generate collision induced unfolding plots. Alternatively, it allows protein complexes to be activated, separated by IM and then subsequently fragmented to determine sub-unit stoichiometry. In summary, the flexibility and unique functionality of the cyclic design/ geometry provides unique insights into protein structure and function.

Emma Marsden-Edwards was speaking to Ash Board, Editorial Director at Technology Networks.