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Ion-mobility spectrometry–mass spectrometry (IMS-MS), also known as ion-mobility separation–mass spectrometry, is an analytical method that separates gas phase ions based on  their interaction with a collision gas and their masses. In the first step, the ions are separated according to their mobility through a buffer gas in a high pressure ion mobility spectrometer (1 -760 Torr). The separated ions are then introduced into a mass analyzer in a second step where their mass to charge ratios can be determined. This effective separation of analytes makes it a widely applicable method in the analysis of complex samples such as in proteomics and metabolomics.

History
Earl W. McDaniel has been called the father of ion mobility mass spectrometry. In the early 1960s, he coupled a low-field ion mobility drift cell to a sector mass spectrometer.

The combination of time-of-flight mass spectrometry and ion-mobility spectrometry was pioneered in 1963 at Bell Labs. In 1963 McAfee and Edelson published an IMS-TOF combination. In 1967 McKnight, McAfee and Sipler published an IMS-TOF combination. Their instrument included an orthogonal TOF. In 1969 Cohen et al. filed a patent on an IMS-QMS system. The QMS at that time was an improvement compared to the TOFMS, because the TOFMS had a slow electronic data acquisition systems at that time. In 1970, Young, Edelson and Falconer published an IMS-TOF with orthogonal extraction. They seem to have used the same system as McKnight et al. in 1967, incorporating slight modifications. Their work was later reproduced in the landmark book of Mason/McDaniel, which is regarded as the “bible of IMS” by those skilled in the art.

In 1996 Guevremont et al. presented a poster at the ASMS conference about IMS-TOF. In 1997 Tanner patented a quadrupole with axial fields which can be used as a drift cell for IMS separation. He also mentions the combination of these quadrupoles with an orthogonal TOFMS. In 1998 Clemmer developed an IMS-TOF combination, using a co-axial IMS-TOF setup. In 1999 Clemmer developed an IMS-TOF with an orthogonal TOF system. This work led to the development of an ion mobility-quadrupole-CID-TOFMS instrument by Micromass in the UK and ultimately led Micromass / Waters corporation to develop of the worlds first commercial ion mobility-mass spectrometer instrument in 2006. The Synapt, as it is called, incorporates a pre ion mobility quadrupole allowing precursor ion selection prior to IMS separation further enhancing the flexibility of the ion mobility-mass spectrometry combinations. In 2013, Agilent Technologies released the first commercial drift tube ion mobility-mass spectrometer named 6560 with an 80 cm drift tube. Ion funnels are used to improve the ion transmission efficiency. The design thus greatly improved the sensitivity of ion mobility and allowed commercialization.

A variation of IMS-MS is differential ion mobility spectrometry-mass spectrometry (DIMS-MS), in which gas phase ions are separated based on their ion mobility in varying strengths of electric fields. This analytical method is currently being advanced by Gary Glish and the Glish Group.

Instrumentation
The IMS-MS is a combination of an ion-mobility spectrometer and a mass spectrometer. Similar to a mass spectrometer, First the ion mobility spectrometer separates ions according to their mobilities. In a second step the mass spectrometer separates ions according to their mass-to-charge ratio. Such a combination is often referred to as a hyphenated separation or multi-dimensional separation. Ion source- ion mobility spectrometer-mass analyzer

Sample Introduction/Ionization
IM-MS is versatile because samples in different physical states can be anlayzed. Various ion sources that are traditionally used for mass spectrometry are also applicable for IM-MS. Gas phase samples are ionized with techniques such as thermal desorption, radioactive ionization, corona discharge ionization and photo ionization. Electrospray and secondary electrospray (SESI) are common methods for ionizing samples in solution. Solid-phase samples can be ionized with the matrix-assisted laser desorption ionization (MALDI) in source for large mass molecules or laser desorption ionization (LDI) for smaller mass molecules.

Drift-time ion mobility spectrometry (DTIMS),
Drift tube ion mobility does not employ RF voltage which may heat ions, and it can preserve the structure of the ions. The rotationally averaged collision cross section (CCS) which is a physical property of ions reflecting the shape of the ions can be measured accurately on drift tube ion mobility. The resolving power is high (CCS resolution can be higher than 100). Drift tube ion mobility is widely used for structure analysis. It is usually coupled with time-of-flight (TOF) mass spectrometer.

 Temporally-Dispersive Ion Mobility 

Time-dispersive separations are an integral part of contemporary IM-MS and untargeted approaches whereby analysis is conducted with no prior hypothesis or specific molecular targets.(53) This is due to the fact that time dispersion is inherently a comprehensive survey of all signals present within the observation period. This broadband analysis has a drawback in that the sensitivity associated with a single time dispersion event is low, requiring many (10–100) events to be summed in order to obtain statistically significant ion mobility measurements. Such techniques include DTIMS and TWIMS, for which the time-of-flight mass spectrometer(54) and the traveling wave “Solitron”(55) are the analogous MS techniques, respectively. Also included is the overtone mobility spectrometer (OMS) which operates in a similar manner as the radio frequency mass spectrometer described by Bennett.(56)

Travelling-wave ion mobility spectrometry (TWIMS) and field-asymmetric ion mobility spectrometry (FAIMS)

There are different types of ion mobility spectrometers and there are different types of mass spectrometers. In principle it is possible to combine every type of the former with any type of the latter. However, in the real world, different types of ion mobility are coupled with different types of mass spectrometers to achieve reasonable sensitivity (will be discussed later).

Types of IMS-MS include drift tube IMS (DT IMS) or the traditional ion mobility spectrometer, DMS differential mobility spectrometer, a scanable filter, also called FAIMS, and DMA differential mobility analyzer, a scanable filter.

High-field asymmetric-waveform ion-mobility spectrometry (FAIMS or RF-DC ion-mobility spectrometry) is a mass spectrometry technique in which ions at atmospheric pressure are separated by the application of a high-voltage asymmetric waveform at radio frequency (RF) combined with a static (DC) waveform applied between two electrodes. Depending on the ratio of the high-field and low-field mobility of the ion, it will migrate toward one or the other electrode. Only ions with specific mobility will pass through the device. It is well known that the high RF field distort the conformation of the ions, FAIMS thus is a separation technique without reserving the structure of the ions and the CCSs of the ions cannot be measured. Because FAIMS is a mass selector (other ions are excluded), the sensitivity in the scan mode is much lower than that of the drift tube ion mobility (all the ions are analyzed). Therefore, FAIMS is usually coupled with triple quadrupole mass spectrometer which is also ion selection type instrument.

Mass separation
Mass spectrometers: Time‐of‐flight,quadrupole, ion‐trap, ion‐cyclotron, or magnetic‐sector mass spectrometers. Ion mobility cell can be interfaced to other ion mobility cells or to tandem mass spectrometers to produce IMSn–MSm type analyses.

Biochemistry
Small molecules

Lipidomics

Several lipid molecules including phosphatidylcholine, phosphatidylethanolamine, IM-MS analysis of of phospholipid classes. Information regarding the extent of unsaturation, the types of linkage as well as the polar head groupcan be derived from t

Proteomics

Forensics
Drugs/Explosives

Medical
The IM-MS technique can be used for analyzing complex mixtures based on differing mobilities in an electric field. The gas-phase ion structure can be studied using IM-MS through measurement of the CCS and comparison with CCS of standard samples or CCS calculated from molecular modelling. The signal-to-noise ratio is obviously improved because the noise can be physically separated with signal in IM-MS. In addition, isomers can be separated if their shapes are different. The peak capacity of IM-MS is much larger than MS so more compounds can be found and analyzed. This character is very critical for -omics study which requires analyzing as many compounds as possible in a single run. It has been used in the detection of chemical warfare agents, detection of explosives, in proteomics for the analysis of proteins, peptides, drug-like molecules and nano particles.{ } Recently, microscale FAIMS has been integrated with electrospray ionization MS and liquid chromatography MS to rapidly separate ions in milliseconds prior to mass analysis. The use of microscale FAIMS in electrospray ionization MS and liquid chromatography MS can significantly improve peak capacity and signal-to-noise for a range of applications including proteomics, and pharmaceutical analysis.

Recently, gas-phase ion activation methods have been used to gain new insights into complex structures. Collision induced unfolding (CIU) is a technique in which an ion's internal energy is increased through collisions with a buffer gas prior to IM-MS analysis. Unfolding of the ion is observed through larger CCSs, and the energy at which unfolding occurs corresponds partially to noncovalent interactions within the ion. This technique has been used to differentiate polyubiquitin linkages and intact antibodies.