Differential mobility spectrometry with nanospray ion source as a compact detector for small organics and inorganics.

Electrospray ionization (ESI) is an important tool in chemical and biochemical survey and targeted analysis in many applications. For chemical detection and identification electrospray is usually used with mass spectrometry (MS). However, for screening and monitoring of chemicals of interest in light, low power field-deployable instrumentation, an alternative detection technology with chemical selectivity would be highly useful, especially since small, lightweight, chip-based gas and liquid chromatographic technologies are being developed. Our initial list of applications requiring portable instruments includes chemical surveys on Mars, medical diagnostics based on metabolites in biological samples, and water quality analysis. In this report, we evaluate ESI-Differential Mobility Spectrometry (DMS) as a compact, low-power alternative to MS detection. Use of DMS for chemically-selective detection of ESI suffers in comparison with mass spectrometry because portable MS peak capacity is greater than that of DMS by 10X or more, but the development of light, fast chip chromatography offers compensating resolution. Standalone DMS provides the chemical selectivity familiar from DMS-MS publications, and exploits the sensitivity of ion detection. We find that sub-microliter-per-minute flows and a correctly-designed interface prepare a desolvated ion stream that enables DMS to act as an effective ion filter. Results for a several small organic biomarkers and metabolites, including citric acid, azelaic acid, n-hexanoylglycine, thymidine, and caffeine, as well as compounds such as dinitrotoluene and others, have been characterized and demonstrate selective detection. Water-quality-related halogen-containing anions, fluoride through bromate, contained in liquid samples are also isolated by DMS. A reaction-chamber interface is highlighted as most practical for portable ESI-DMS instrumentation.

Detection of Radiation-Exposure Biomarkers by Differential Mobility Prefiltered Mass Spectrometry (DMS-MS).

Technology to enable rapid screening for radiation exposure has been identified as an important need, and, as a part of a NIH / NIAD effort in this direction, metabolomic biomarkers for radiation exposure have been identified in a recent series of papers. To reduce the time necessary to detect and measure these biomarkers, differential mobility spectrometry - mass spectrometry (DMS-MS) systems have been developed and tested. Differential mobility ion filters preselect specific ions and also suppress chemical noise created in typical atmospheric-pressure ionization sources (ESI, MALDI, and others). Differential-mobility-based ion selection is based on the field dependence of ion mobility, which, in turn, depends on ion characteristics that include conformation, charge distribution, molecular polarizability, and other properties, and on the transport gas composition which can be modified to enhance resolution. DMS-MS is able to resolve small-molecule biomarkers from nearly-isobaric interferences, and suppresses chemical noise generated in the ion source and in the mass spectrometer, improving selectivity and quantitative accuracy. Our planar DMS design is rapid, operating in a few milliseconds, and analyzes ions before fragmentation. Depending on MS inlet conditions, DMS-selected ions can be dissociated in the MS inlet expansion, before mass analysis, providing a capability similar to MS/MS with simpler instrumentation. This report presents selected DMS-MS experimental results, including resolution of complex test mixtures of isobaric compounds, separation of charge states, separation of isobaric biomarkers (citrate and isocitrate), and separation of nearly-isobaric biomarker anions in direct analysis of a bio-fluid sample from the radiation-treated group of a mouse-model study. These uses of DMS combined with moderate resolution MS instrumentation indicate the feasibility of field-deployable instrumentation for biomarker evaluation.

Selection and generation of waveforms for differential mobility spectrometry.

Devices based on differential mobility spectrometry (DMS) are used in a number of ways, including applications as ion prefilters for API-MS systems, as detectors or selectors in hybrid instruments (GC-DMS, DMS-IMS), and in standalone systems for chemical detection and identification. DMS ion separation is based on the relative difference between high field and low field ion mobility known as the alpha dependence, and requires the application of an intense asymmetric electric field known as the DMS separation field, typically in the megahertz frequency range. DMS performance depends on the waveform and on the magnitude of this separation field. In this paper, we analyze the relationship between separation waveform and DMS resolution and consider feasible separation field generators. We examine ideal and practical DMS separation field waveforms and discuss separation field generator circuit types and their implementations. To facilitate optimization of the generator designs, we present a set of relations that connect ion alpha dependence to DMS separation fields. Using these relationships we evaluate the DMS separation power of common generator types as a function of their waveform parameters. Optimal waveforms for the major types of DMS separation generators are determined for ions with various alpha dependences. These calculations are validated by comparison with experimental data.

Chemical effects in the separation process of a differential mobility/mass spectrometer system.

In differential mobility spectrometry (also referred to as high-field asymmetric waveform ion mobility spectrometry), ions are separated on the basis of the difference in their mobility under high and low electric fields. The addition of polar modifiers to the gas transporting the ions through a differential mobility spectrometer enhances the formation of clusters in a field-dependent way and thus amplifies the high- and low-field mobility difference, resulting in increased peak capacity and separation power. Observations of the increase in mobility field dependence are consistent with a cluster formation model, also referred to as the dynamic cluster-decluster model. The uniqueness of chemical interactions that occur between an ion and cluster-forming neutrals increases the selectivity of the separation, and the depression of low-field mobility relative to high-field mobility increases the compensation voltage and peak capacity. The effect of a polar modifier on the peak capacity across a broad range of chemicals has been investigated. We discuss the theoretical underpinnings which explain the observed effects. In contrast to the result with a polar modifier, we find that using mixtures of inert gases as the transport gas improves the resolution by reducing the peak width but has very little effect on the peak capacity or selectivity. The inert gas helium does not cluster and thus does not reduce low-field mobility relative to high-field mobility. The observed changes in the differential mobility alpha parameter exhibited by different classes of compounds when the transport gas contains a polar modifier or has a significant fraction of inert gas can be explained on the basis of the physical mechanisms involved in the separation processes.

Control of chemical effects in the separation process of a differential mobility mass spectrometer system.

Differential mobility spectrometry (DMS) separates ions on the basis of the difference in their migration rates under high versus low electric fields. Several models describing the physical nature of this field mobility dependence have been proposed but emerging as a dominant effect is the clusterization model sometimes referred to as the dynamic cluster-decluster model. DMS resolution and peak capacity is strongly influenced by the addition of modifiers which results in the formation and dissociation of clusters. This process increases selectivity due to the unique chemical interactions that occur between an ion and neutral gas-phase molecules. It is thus imperative to bring the parameters influencing the chemical interactions under control and find ways to exploit them in order to improve the analytical utility of the device. In this paper, we describe three important areas that need consideration in order to stabilize and capitalize on the chemical processes that dominate a DMS separation. The first involves means of controlling the dynamic equilibrium of the clustering reactions with high concentrations of specific reagents. The second area involves a means to deal with the unwanted heterogeneous cluster ion populations emitted from the electrospray ionization process that degrade resolution and sensitivity. The third involves fine control of parameters that affect the fundamental collision processes, temperature and pressure.

Planar differential mobility spectrometer as a pre-filter for atmospheric pressure ionization mass spectrometry.

Ion filters based on planar DMS can be integrated with the inlet configuration of most mass spectrometers, and are able to enhance the quality of mass analysis and quantitative accuracy by reducing chemical noise, and by pre-separating ions of similar mass. This paper is the first in a series of three papers describing the optimization of DMS / MS instrumentation. In this paper the important physical parameters of a planar DMS-MS interface including analyzer geometry, analyzer coupling to a mass spectrometer, and transport gas flow control are considered. The goal is to optimize ion transmission and transport efficiency, provide optimal and adjustable resolution, and produce stable operation under conditions of high sample contamination. We discuss the principles of DMS separations and highlight the theoretical underpinnings. The main differences between planar and cylindrical geometries are presented, including a discussion of the advantages and disadvantages of RF ion focusing. In addition, we present a description of optimization of the frequency and amplitude of the DMS fields for resolution and ion transmission, and a discussion of the influence and importance of ion residence time in DMS. We have constructed a mass spectrometer interface for planar geometries that takes advantage of atmospheric pressure gas dynamic principles, rather than ion focusing, to minimize ion losses from diffusion in the analyzer and to maximize total ion transport into the mass spectrometer. A variety of experimental results has been obtained that illustrate the performance of this type of interface, including tests of resistance to high contamination levels, and the separation of stereoisomers. In a subsequent publication the control of the chemical interactions that drive the separation process of a DMS / MS system will be considered. In a third publication we describe novel electronics designed to provide the high voltages asymmetric waveform fields (SV) required for these devices as well as the effects of different waveforms.

Pressure effects in differential mobility spectrometry.

A microfabricated planar differential ion mobility spectrometer operating from 0.4 to 1.55 atm in a supporting atmosphere of purified air was used to characterize the effects of pressure and electric field strength on compensation voltage, ion transmission, peak width, and peak intensity in differential mobility spectra. Peak positions, in compensation voltage as a function of separating rf voltage, were found to vary with pressure in a way that can be simplified by expressing both compensation and separation fields in Townsend units for E/N. The separation voltage providing the greatest compensation voltage and the greatest resolution is ion-specific but often occurs at E/N values that are unreachable at elevated pressure because of electrical breakdown. The pressure dependence of air breakdown voltage near 1 atm is sublinear, allowing higher E/N values to be reached at reduced pressure, usually resulting in greater instrumental resolution. Lower voltage requirements at reduced pressure also reduce device power consumption.