Comprehensive theoretical analysis and experimental exploration of ultrafast microchip‐based high‐field asymmetric ion mobility spectrometry (FAIMS) technique

High‐field asymmetric ion mobility spectrometry (FAIMS) has become an efficient technique for separation and characterization of gas‐phase ions at ambient pressure, which utilizes the mobility differences of ions at high and low fields. Micro FAIMS devices made by micro‐electromechanical system technology have small gaps of the channels, high electric field and good installation precision, as thus they have received great attentions. However, the disadvantage of relatively low resolution limits their applications in some areas. In this study, theoretical analysis and experimental exploration were carried out to overcome the disadvantage. Multiple scans, characteristic decline curves of ion transmission and pattern recognitions were proposed to improve the performance of the microchip‐based FAIMS. The results showed that although micro FAIMS instruments as a standalone chemical analyzer suffer from low resolution, by using one or more of the methods proposed, they can identify chemicals precisely and provide quantitative analysis with low detection limit in some applications. Copyright © 2015 John Wiley & Sons, Ltd.     

Ion mobility spectrometer—field asymmetric ion mobility spectrometer-mass spectrometry

Since the development of electrospray ionization (ESI) for ion mobility spectrometry mass spectrometry (IMMS), IMMS have been extensively applied for characterization of gas-phase bio-molecules. Conventional ion mobility spectrometry (IMS), defined as drift tube IMS (DT-IMS), is typically a stacked ring design that utilizes a low electric field gradient. Field asymmetric ion mobility spectrometry (FAIMS) is a newer version of IMS, however, the geometry of the system is significantly different than DT-IMS and data are collected using a much higher electric field. Here we report construction of a novel ambient pressure dual gate DT-IMS coupled with a FAIMS system and then coupled to a quadrupole ion trap mass spectrometer (QITMS) to form a hybrid three-dimensional separation instrument, DT-IMS-FAIMS-QITMS. The DT-IMS was operated at ~3 Townsend (electric field/number density (E/N) or (Td)) and was coupled in series with a FAIMS, operated at ~80 Td. Ions were mobility-selected by the dual gate DT-IMS into the FAIMS and from the FAIMS the ions were detected by the QITMS for as either MS or MSⁿ. The system was evaluated using cocaine as an analytical standard and tested for the application of separating three isomeric tri-peptides: tyrosine-glycine-tryptophan (YGW), tryptophan-glycine-tyrosine (WGY) and tyrosine-tryptophan-glycine (YWG). All three tri-peptides were separated in the DT-IMS dimension and each had one mobility peak. The samples were partially separated in the FAIMS dimension but two conformation peaks were detected for the YWG sample while YGW and WGY produced only one peak. Ion validation was achieved for all three samples using QITMS.     

Elimination of the helium requirement in high-field asymmetric waveform ion mobility spectrometry (FAIMS): beneficial effects of decreasing the analyzer gap width on peptide analysis

Cylindrical geometry high-field asymmetric waveform ion mobility spectrometry (FAIMS) focuses and separates gas-phase ions at atmospheric pressure and room (or elevated) temperature. Addition of helium to a nitrogen-based separation medium offers significant advantages for FAIMS including improved resolution, selectivity and sensitivity. Aside from gas composition, ion transmission through FAIMS is governed by electric field strength (E/N) that is determined by the applied voltage, the analyzer gap width, atmospheric pressure and electrode temperature. In this study, the analyzer width of a cylindrical FAIMS device is varied from 2.5 to 1.25 mm to achieve average electric field strengths as high as 187.5 Townsend (Td). At these electric fields, the performance of FAIMS in an N(2) environment is dramatically improved over a commercial system that uses an analyzer width of 2.5 mm in 1:1 N(2) /He. At fields of 162 Td using electrodes at room temperature, the average effective temperature for the [M+2H](2+) ion of angiotensin II reaches 365 K. This has a dramatic impact on the curtain gas flow rate, resulting in lower optimum flows and reduced turbulence in the ion inlet. The use of narrow analyzer widths in a N(2) carrier gas offers previously unattainable baseline resolution of the [M+2H](2+) and [M+3H](3+) ions of angiotensin II. Comparisons of absolute ion current with FAIMS to conventional electrospray ionization (ESI) are as high as 77% with FAIMS versus standard ESI-MS.     

Enhancement of mass spectrometry performance for proteomic analyses using highfield asymmetric waveform ion mobility spectrometry (FAIMS)

Remarkable advances in mass spectrometry sensitivity and resolution have been accomplished over the past two decades to enhance the depth and coverage of proteome analyses. As these technological developments expanded the detection capability of mass spectrometers, they also revealed an increasing complexity of low abundance peptides, solvent clusters and sample contaminants that can confound protein identification. Separation techniques that are complementary and can be used in combination with liquid chromatography are often sought to improve mass spectrometry sensitivity for proteomics applications. In this context, high‐field asymmetric waveform ion mobility spectrometry (FAIMS), a form of ion mobility that exploits ion separation at low and high electric fields, has shown significant advantages by focusing and separating multiply charged peptide ions from singly charged interferences. This paper examines the analytical benefits of FAIMS in proteomics to separate co‐eluting peptide isomers and to enhance peptide detection and quantitative measurements of protein digests via native peptides (label‐free) or isotopically labeled peptides from metabolic labeling or chemical tagging experiments. Copyright © 2015 John Wiley & Sons, Ltd.     

Corona Discharge Ionization Source for a Planar High-Field Asymmetric Waveform Ion Mobility Spectrometer

A corona discharge (CD) ionization source was prepared for a planar high-field asymmetric waveform ion mobility spectrometer (FAIMS). The effects of discharge current and discharge distance on ionization efficiency were investigated; and the electric field dependence of the ion injection in the reaction region was studied. The results showed that the discharge current of CD source had good linearity with the intensity of reactant ion peak (RIP), and the RIP intensity increased to a stable level at the discharge distance of >5 mm. An injection electrode was introduced to improve the ionization efficiency. A square-wave voltage applied to the electrode was found to provide optimal performance of ion injection and utilization. The operating parameters of the CD-FAIMS were optimized to achieve trace level detection of dimethyl methylphosphonate (DMMP) sample. The detection limit for DMMP was 0.5 µg/m^3.     

Comparison of experimental and calculated peak shapes for three cylindrical geometry FAIMS prototypes of differing electrode diameters

High-field asymmetric waveform ion mobility spectrometry (FAIMS) separates ions at atmospheric pressure and room temperature based on the difference of the mobility of ions in strong electric fields and weak electric fields. This field-dependent mobility of an ion is reflected in the compensation voltage (CV) at which the ion is transmitted through FAIMS, at a given asymmetric waveform dispersion voltage (DV). Experimental CV, relative peak ion intensity, and peak width data were compared for three FAIMS prototypes with concentric cylindrical electrodes having inner/outer electrode radii of: (1) 0.4/0.6 cm, (2) 0.8/1.0 cm, and (3) 1.2/1.4 cm. The annular analyzer space was 0.2 cm wide in each case. A finite-difference numerical computation method is described for evaluation of peak shapes and widths in a CV spectrum collected using cylindrical geometry FAIMS devices. Simulation of the radial distribution of the ion density in the FAIMS analyzer is based upon calculation of diffusion, electric fields, and the electric fields introduced by coulombic ion-ion repulsion. Excellent agreement between experimental and calculated peak shapes were obtained for electrodes of wide diameter and for ions transmitted at low CV.     

Monte Carlo simulation of ion transport in non-linear ion mobility spectrometry

A program for Monte Carlo simulation of ion transport in non-linear ion mobility spectrometry, also known as field asymmetric ion mobility spectrometry (FAIMS) or differential mobility spectrometry (DMS), has been developed. Simulations are based on elastic collisions between the ions and the gas particles, and take into account the effects of flow dynamics and asymmetric electric fields. Using this program, the separation and diffusion of the ions moving in a planar DMS filtration gap are demonstrated. Ion focusing in a cylindrical filtration gap is also confirmed. A characteristic compensation voltage is found to provide insight for understanding separation in non-linear ion mobility spectrometry. The simulation program is used to study the characteristics of non-linear ion mobility spectrometry, the effect of the carrier gas flow, and the dependence of the compensation voltage and nonlinear mobility coefficient (α) on the applied asymmetric electric field.     

Field asymmetric waveform ion mobility spectrometry studies of proteins: Dipole alignment in ion mobility spectrometry?

Approaches to separation and characterization of ions based on their mobilities in gases date back to the 1960s. Conventional ion mobility spectrometry (IMS) measures the absolute mobility, and field asymmetric waveform IMS (FAIMS) exploits the difference between mobilities at high and low electric fields. However, in all previous IMS and FAIMS experiments ions experienced an essentially free rotation; thus the separation was based on the orientationally averaged cross-sections Omega(avg) between ions and buffer gas molecules. Virtually all large ions are permanent electric dipoles that will be oriented by a sufficiently strong electric field. Under typical FAIMS conditions this will occur for dipole moments >400 D, found for many macroions including most proteins above approximately 30 kDa. Mobilities of aligned dipoles depend on directional cross-sections Omega(dir) (rather than Omega(avg)), which should have a major effect on FAIMS separation parameters. Here we report the FAIMS behavior of electrospray-ionization-generated ions for 10 proteins up to approximately 70 kDa. Those above 29 kDa exhibit a strong increase of mobility at high field, which is consistent with predicted ion dipole alignment. This effect expands the useful FAIMS separation power by an order of magnitude, allowing separation of up to approximately 10(2) distinct protein conformers and potentially revealing information about Omega(dir) and ion dipole moment that is of utility for structural characterization. Possible approaches to extending dipole alignment to smaller ions are discussed.     

Ion peak narrowing by applying additional AC voltage (ripple voltage) to FAIMS extractor electrode

The use of a non-uniform electric field in a high-field asymmetric waveform ion mobility spectrometry (FAIMS) analyzer increases sensitivity but decreases resolution. The application of an additional AC voltage to the extractor electrode (“ripple” voltage, U _ripple ) can overcome this effect, which decreases the FAIMS peak width. In this approach, the diffusion ion loss remains minimal in the non-uniform electric field in the cylindrical part of the device, and all ion losses under U _ripple occur in a short portion of their path. Application of the ripple voltage to the extractor electrode is twice as efficient as the applying of U _ripple along the total length of the device.     

Feasibility of higher-order differential ion mobility separations using new asymmetric waveforms

Technologies for separating and characterizing ions based on their transport properties in gases have been around for three decades. The early method of ion mobility spectrometry (IMS) distinguished ions by absolute mobility that depends on the collision cross section with buffer gas atoms. The more recent technique of field asymmetric waveform IMS (FAIMS) measures the difference between mobilities at high and low electric fields. Coupling IMS and FAIMS to soft ionization sources and mass spectrometry (MS) has greatly expanded their utility, enabling new applications in biomedical and nanomaterials research. Here, we show that time-dependent electric fields comprising more than two intensity levels could, in principle, effect an infinite number of distinct differential separations based on the higher-order terms of expression for ion mobility. These analyses could employ the hardware and operational procedures similar to those utilized in FAIMS. Methods up to the 4th or 5th order (where conventional IMS is 1st order and FAIMS is 2nd order) should be practical at field intensities accessible in ambient air, with still higher orders potentially achievable in insulating gases. Available experimental data suggest that higher-order separations should be largely orthogonal to each other and to FAIMS, IMS, and MS.     

Compensation voltage (CV) peak shapes using a domed FAIMS with the inner electrode translated to various longitudinal positions

High-field asymmetric waveform ion mobility spectrometry (FAIMS) separates ions at atmospheric pressure based on the difference in the mobility of an ion in a strong electric field and in a weak electric field. This field-dependent mobility of an ion is reflected in the compensation voltage (CV) at which the ion is transmitted through FAIMS at an applied asymmetric waveform dispersion voltage (DV). In this report, we show that experimental CV peak shapes using dome tipped inner electrode FAIMS prototypes with inner/outer electrode radii of: (1) 0.2/0.4 cm and (2) 0.4/0.6 cm are a function of the longitudinal position of the inner electrode. Varying the longitudinal position of the inner electrode modifies the electric fields between the surfaces of the hemispherical shaped inner electrode and the outer electrode in the vicinity of the ion outlet. In this region the position-dependent electric field strength (E/N) effectively forms a second tandem FAIMS analyzer region having differing ion separation properties. The final tandem FAIMS separation is the intersection of the CV windows of these two differing FAIMS separations and, therefore, the peak width in the CV scan is dependent on the longitudinal tip displacement (LTD) of the inner electrode. CV scans are shown for a LTD range of 0.14 to 0.4 cm. These scans illustrate that it is possible to control the FAIMS resolution (CV/peak width) from about 1 for the 0.2/0.4 cm electrode set at intermediate longitudinal position to over 10 at the narrowest distance between the inner electrode and the ion outlet.     

Ion trapping at atmospheric pressure (760 Torr) and room temperature with a high-field asymmetric waveform ion mobility spectrometer

A method for the confinement of ions at 760 Torr and room temperature is described. We have recently shown that a cylindrical-geometry high-field asymmetric waveform ion mobility spectrometer (FAIMS), which utilizes an ion separation technique based on the change in ion mobility at high electric fields, focuses ions in two dimensions. This article describes a FAIMS device in which the focusing is extended to three dimensions (i.e. ion trap). Characterization of the ion trap was carried out using a laboratory-constructed time-of-flight mass spectrometer. The half-life of a m/z 380 ion in the trap was determined to be 5 ms.     

Differential Ion Mobility Separations in up to 100 % Helium Using Microchips

The performance of differential IMS (FAIMS) analyzers is much enhanced by gases comprising He, especially He/N₂ mixtures. However, electrical breakdown has limited the He fraction to ~50 %–75 %, depending on the field strength. By the Paschen law, the threshold field for breakdown increases at shorter distances. This allows FAIMS using chips with microscopic channels to utilize much stronger field intensities (E) than “full-size” analyzers with wider gaps. Here we show that those chips can employ higher He fractions up to 100 %. Use of He-rich gases improves the resolution and resolution/sensitivity balance substantially, although less than for full-size analyzers. The optimum He fraction is ~80 %, in line with first-principles theory. Hence, one can now measure the dependences of ion mobility on E in pure He, where ion-molecule cross section calculations are much more tractable than in other gases that form deeper and more complex interaction potentials. This capability may facilitate quantitative modeling of high-field ion mobility behavior and, thus, FAIMS separation properties, which would enable a priori extraction of structural information about the ions.

一种用于高场非对称波形离子迁移谱系统的新型敞开式化学离子源

根据高场非对称波形离子迁移谱(FAIMS)系统的要求, 本文提出了一种新型敞开式直流电晕放电化学离子源. 该离子源主要由内线电极、外筒电极和牵引电极组成, 内、外电极半径分别是0.08、2 mm. 筒壁电极上开有对称的4个槽, 用于通入样品和牵引离子. 质谱实验结果表明, 该离子源能够在敞开环境下很好地离子化丙酮、乙醇、苯胺、N,N-二甲基甲酰胺、甲基磷酸二甲酯(DMMP)、乙酸乙酯、甲酸、乙酸、苯酚等正、负电性物质. 静电计测试实验结果说明该离子源能够稳定地产生离子电流. 通过分析不同时刻的谱图发现, 在不同时间点上产生的主要离子相同, 具有很好的稳定性. 利用感应耦合等离子体(ICP)工艺在硅片上加工了该离子源, 从而验证了该结构可以由微机电系统(MEMS)加工技术实现. 该离子源具有体积小、结构简单、无辐射、工作稳定等特点, 不仅可以满足FAIMS系统的要求, 还可用于敞开式质谱、微型质谱仪、离子迁移谱(IMS)等仪器.     

Field dependence of mobilities for gas-phase-protonated monomers and proton-bound dimers of ketones by planar field asymmetric waveform ion mobility spectrometer (PFAIMS)

The dependence of the mobilities of gas-phase ions on electric fields from 0 to 90 Td at ambient pressure was determined for protonated monomers [(MH+(H2O)n] and proton bound dimers [M2H+(H2O)n] for a homologous series of normal ketones, from acetone to decanone (M=C3H6O to C10H20O). This dependence was measured as the normalized function of mobility alpha (E/N) using a planar field asymmetric waveform ion mobility spectrometer (PFAIMS) and the ions were mass-identified using a PFAIMS drift tube coupled to a tandem mass spectrometer. Methods are described to obtain alpha (E/N) from the measurements of compensation voltage versus amplitude of an asymmetric waveform of any shape. Slopes of alpha for MH+ versus E/N were monotonic from 0 to 90 Td for acetone, butanone, and pentanone. Plots for ketones from hexanone to octanone exhibited plateaus at high fields. Nonanone and decanone showed plots with an inversion of slope above 70 Td. Proton bound dimers for ketones with carbon numbers greater than five exhibited slopes for alpha versus E/N, which decreased continuously with increasing E/N. These findings are the first alpha values for ions from a homologous series under atmosphere pressure and are preliminary to explanations of alpha (E/N) with ion structure.     

Off-axis field approximations for ion traps with apertures

In recent work (Int. J. Mass Spec., vol. 282, pp. 112–122) we have considered the effect of apertures on the fields inside rf traps at points on the trap axis. We now complement and complete that work by considering off-axis fields in axially symmetric (referred to as “3D”) and in two dimensional (“2D”) ion traps whose electrodes have apertures, i.e., holes in 3D and slits in 2D. Our approximation has two parts. The first, E_noAperture, is the field obtained numerically for the trap under study with apertures artificially closed. We have used the boundary element method (BEM) for obtaining this field. The second part, E_{dueToAperture}, is an analytical expression for the field contribution of the aperture.In E_{dueToAperture}, aperture size is a free parameter. A key element in our approximation is the electrostatic field near an infinite thin plate with an aperture, and with different constant-valued far field intensities on either side. Compact expressions for this field can be found using separation of variables, wherein the choice of coordinate system is crucial. This field is, in turn, used four times within our trap-specific approximation.The off-axis field expressions for the 3D geometries were tested on the quadrupole ion trap (QIT) and the cylindrical ion trap (CIT), and the corresponding expressions for the 2D geometries were tested on the linear ion trap (LIT) and the rectilinear ion trap (RIT). For each geometry, we have considered apertures which are 10%, 30%, and 50% of the trap dimension. We have found that our analytical correction term E_{dueToAperture}, though based on a classical small-aperture approximation, gives good results even for relatively large apertures.     

Scaling of the resolving power and sensitivity for planar FAIMS and mobility-based discrimination in flow- and field-driven analyzers

Continuing development of the technology and applications of field asymmetric waveform ion mobility spectrometry (FAIMS) calls for better understanding of its limitations and factors that govern them. While key performance metrics such as resolution and ion transmission have been calculated for specific cases employing numerical simulations, the underlying physical trends remained obscure. Here we determine that the resolving power of planar FAIMS scales as the square root of separation time and sensitivity drops exponentially at the rate controlled by absolute ion mobility and several instrument parameters. A strong dependence of ion transmission on mobility severely discriminates against species with higher mobility, presenting particular problems for analyses of complex mixtures. While the time evolution of resolution and sensitivity is virtually identical in existing FAIMS systems using gas flow and proposed devices driven by electric field, the distributions of separation times are not. The inverse correlation between mobility (and thus diffusion speed) and residence time for ions in field-driven FAIMS greatly reduces the mobility-based discrimination and provides much more uniform separations. Under typical operating conditions, the spread of elimination rates for commonly analyzed ions is reduced from >5 times in flow-driven to 1.6 times in field-driven FAIMS while the difference in resolving power decreases from approximately 60% to approximately 15%.     

Spherical FAIMS: comparison of curved electrode geometries

High-field asymmetric waveform ion mobility spectrometry (FAIMS) can operate at atmospheric pressure to separate gas-phase ions on the basis of a difference in the mobility of an ion at high fields relative to its mobility at low field strengths. Several novel cell geometries have been proposed in addition to the commercially available planar and cylindrical designs. Nevertheless, there is still much to explore about three-dimensional (3-D) curved cell geometries (spherical and hemispherical) and comparison to two-dimensional (2-D) curved geometries (cylindrical). The geometry of a FAIMS cell is one of the essential features affecting the transmission, resolution, and resolving power of FAIMS. Electric fields in a spherical design allow advantages such as virtual potential wells that can induce atmospheric-pressure near-trapping conditions and help reduce ion losses. Curvature of electrodes enables the ions to remain focused near the gap median, which help to improve sensitivity and ion trapping at higher pressures. Here we detail the design and characterization of a novel FAIMS cell having spherical electrode geometry and compare it to hemispherical and cylindrical cells. These FAIMS cells were interfaced with a quadrupole ion trap mass spectrometer in this study. Several structural classes of common explosives were employed to evaluate the separation power of these geometries. FAIMS spectra were generated by scanning the compensation voltage (CV) while operating the mass spectrometer in total ion mode. The identification of ions was accomplished through mass spectra acquired at fixed values of CVs. The performance of FAIMS using cylindrical, hemispherical, and spherical cells was compared and trends identified. For all trials, the best transmission was obtained by the spherical FAIMS cell while hemispherical FAIMS provided the best resolution and resolving power.     

用高场非对称波形离子迁移谱技术快速检测二乙醇胺

采用高场非对称波形离子迁移谱(FAIMS)对二乙醇胺(DEA)进行快速检测分析, 以热解析法进样, 确定了二乙醇胺的离子特征信号, 并与气相色谱-质谱联用仪的检测结果进行了比较. 用聚四氟乙烯(PTFE)扩散管进样, 控制二乙醇胺样品气(DEA与空气的混合气)浓度, 利用FAIMS对不同浓度的二乙醇胺样品气进行检测. 通过对离子特征信号进行量化和重复性分析, 确定了二乙醇胺样品气的检出限为0.02 μg/L, 并建立了FAIMS检测二乙醇胺样品气的离子电流强度积分面积与样品气浓度关系曲线. 为FAIMS应用于现场快速检测二乙醇胺提供了一定的依据.     

Characterization of a miniature, ultra-high-field, ion mobility spectrometer

By combining a multiple micron-gap ion separator with a novel high-frequency separation waveform drive topology, it has been possible to considerably extend the separation field limits employed in Field Asymmetric Ion Mobility Spectrometry (FAIMS)/Differential Mobility Spectrometry (DMS); giving rise to an Ultra-High-Field operational domain. A miniature spectrometer, based around the multi-micron-gap ion separator and ultra-high-field drivers, has been developed to meet the continuing industrial need for sensitive (sub-ppm), broadband and fast (second timescale) response volatile chemical detection. The packaged miniature spectrometer measures 12?×?12?×?15?cm, weighs 1.2?kg and is fully standalone; consisting of the core multi-micron gap ion separator assembly and RF/DC electronic drivers integrated with pneumatic handling/sample conditioning elements, together with ancillary temperature, flow and humidity sensing for stable closed loop operation (under local microprocessor control). The combination of multiple micron-gap ion separators with the novel high-frequency separation waveform drive topology enables ion separations to be performed over scanning electric field ranges of 0 to >75?kV·cm^?1 (0 to >??320 Td at 101?kPa), offering a potential solution to trace and ultra-trace chemical detection/monitoring problems, that conventional IMS and DMS/FAIMS may otherwise find challenging. In this ultra-high field operational regime effective ion temperatures may be ??swept?? from ambient to >1000 K because critically, the effective ion temperature scales to at least the square of the applied field. With this field induced ion heating a controlled manipulation (or switching) of the ion chemistry within the separation channel (the ion drift region) may be invoked. For example, ion fragmentation via thermal dissociation can be induced. Chemical separation and identification is thus derived from the unique kinetic and thermodynamic behavior of ions assessed over a very broad effective temperature range. In addition to describing the novel miniature spectrometer, this paper addresses key aspects of ultra-high-field operation, which render it distinct from traditional ion mobility technologies and principles. In particular, this paper essays a model of ultra-high-field operation and highlights model deviations, whilst providing clear theoretical explanation backed up with experimental evidence.