Simulation study of a new racetrack FAIMS analyzer to achieve both high-resolution and high-sensitivity.

A new racetrack field-asymmetric waveform ion mobility spectrometry (r-FAIMS) analyzer was developed in this study by combining the existing planar FAIMS (p-FAIMS) and cylindrical FAIMS (c-FAIMS). The ion inlet and outlet regions of r-FAIMS were consisted of a half of c-FAIMS, respectively, and these c-FAIMS were further connected by two p-FAIMS to form a racetrack shaped FAIMS. With such FAIMS working electrode configuration, the ions entering the r-FAIMS can be focused and separated in the first c-FAIMS section, be further separated in the p-FAIMS section with high-resolution, be focused and separated again in the final c-FAIMS section and eventually enter the mass spectrometer or other analyzers for analysis. Detailed simulation by using SIMION software with the default FAIMS user program showed that the ion focusing effect in the first c-FAIMS section ensures the ions entering the following p-FAIMS section as a compact ion packet. This effectively decreases the ion loss caused by Coulomb repulsion and thermal diffusion in p-FAIMS section as compared to the ions being introduced into the p-FAIMS gap randomly in the conventional design. As a result, the ion transmission efficiency of r-FAIMS is at least 3.3-fold higher than the single p-FAIMS under the operating conditions used in this study. The ion trajectory simulation results also showed that the resolving power of r-FAIMS is about the sum of the resolving powers for its c-FAIMS and p-FAIMS sections. The resolving power of r-FAIMS is at least 3.6-fold higher than the single c-FAIMS under the operation conditions used in this study. Therefore, the r-FAIMS can realize both high-resolution and high-sensitive ion mobility separation.

Quantification and evaluation of ion transmission efficiency in two-stage vacuum chamber miniature mass spectrometer.

Miniature mass spectrometer is more compact and portable than traditional commercial mass spectrometry, with more potential for application outside the laboratory. However, a miniature mass spectrometer is less sensitive than a commercial instrument, limiting its application scenarios. The ion transmission efficiency of the instrument is an essential factor affecting the sensitivity. Still, there are few works of literature on the quantitative study of the ion transmission efficiency of each component from a systematic perspective. In this paper, the Faraday cup coupled with a microcurrent signal testing instrument was used to measure the ions generated by nanoelectrospray ionization (nano-ESI), which have successfully gone through several components. Then the ion transmission efficiency of each component was quantified. Results showed that the front lens had the highest ion transmission efficiency of 39.7%, whereas the inlet and skimmer had the lowest ion transfer efficiency of 0.8% and 17.1%. Next, the influence of control parameters on ion transmission efficiency of critical components was investigated. If optimized, the ion funnel and the skimmer had the potential to improve their transmission efficiency by 120% and 79%, respectively. This paper shows the decreasing intensity distribution of ions in the whole transmission process and the transmission efficiency of each component, which can guide for improving the sensitivity of the miniature mass spectrometer.

Will the Digital Mass Filter Be the Next High-Resolution High-Mass Analyzer?

Mass filter operation in higher stability zones is known to provide better resolution. Unfortunately, for sine driven instruments, higher stability zone operation reduces the accessible mass range and increases the degenerative effects of fringe fields. Conversely, digitally driven mass filters do not suffer from loss of mass range, and the fringe field effects do not increase significantly by switching stability zones because the AC voltage is always constant and the DC voltage is always zero. This work catalogues 12 stability zones that are accessible with the new digital waveform generation technology. These zones have theoretical baseline resolving powers that range from 22 to 1 300 000 with pseudopotential well depths that range from 3.5 to 43 V. Operation in higher stability zones also has the advantage of aligned axial stability wells. That alignment maximizes the pseudopotential well depth for each higher stability zone, making them more than an order of magnitude greater than the standard ∼0.2 V well of a sine filter operating in the first stability zone at unit resolution. Increased pseudopotential well depth correlates with better ion transmission and sensitivity. Our theoretical examination suggests that the digital mass filter can obtain both high resolution and high sensitivity with essentially unlimited mass range.

Electrospray Ionization Inside the Ion Inlet Tube: Multijet Mode Operation.

We investigated the electrospray ionization inside the narrow channel of the ion inlet tube. An insulating emitter capillary made of fused silica with a 0.2 mm outer diameter was inserted into the ion inlet tubes with a 0.5 and 0.6 mm inner diameter to aspirate all the charged droplets. A custom-made ion inlet tube with two side holes near its entrance is used to observe the spraying condition. The spray current is measured and monitored during the MS acquisition using isolation amplifiers. Because the emitter is cylindrically surrounded in close proximity by the metallic inner wall, it is difficult to obtain a stable and symmetric Taylor cone with its apex at the center of the emitter. Instead, a stable operation under a flow rate of 1-4 µL/min is found to be in the form of a multicone-jet mode with two or more Taylor cones anchoring around the rim of the emitter. The emitted charged droplet jets are dragged from hitting the wall by the fast-flowing air inside the inlet tube. Comparison with the typical cone-jet and multijet mode operated several millimeters outside the inlet capillary shows signal enhancements for protein standards.

Contrast modes in a 3D ion transmission approach at keV energies.

We present options for visualizing contrast maps in 3D ion transmission experiments. Simultaneous measurement of angular distributions and flight time of ions transmitted through self-supporting, single-crystalline silicon foils allows for mapping of intensity and different energy loss moments. The transmitted projectiles were detected mainly for random beam-sample orientation using pulsed beams of He ions and protons with incident energies 50 and 200 keV. Differences in contrast, observed when varying the projectile type and energy, can be attributed to sample nuclear and electronic structure and bear witness to impact parameter dependent energy loss processes. Our results provide a base for interpretation of data obtained in prospective transmission studies when for example using a helium ion microscope.

Column bleed in the analysis of highly polar substances: an overlooked aspect in HRMS.

To close the "analytical gap" in the liquid chromatographic (LC) analysis of highly polar substances, two techniques which have been suggested earlier were tested in terms of retention factors and detection limits: hydrophilic interaction liquid chromatography (HILIC) and mixed-mode chromatography (MMC). A substance mix of 55 analytes ranging from logD - 8.2 to 3.4 and 17 different LC columns, also comprising additional reversed-phase columns were used. Contrary to most reversed-phase columns, column bleed has been identified as an important factor, which may cause serious restrictions during high-resolution mass spectrometric detection (HRMS). We found that highly abundant background masses continuously eluting from the columns heavily influence ion transmission to the detector. As a result, the linear dynamic range as well as the sensitivity decreases and thus limits the HRMS applicability of some columns. We therefore recommend a thorough investigation of ion transmission during HRMS method development. This will help to maintain the high potential of HRMS in terms of qualitative and quantitative screening analysis.

Ion Manipulation in Open Air Using 3D-Printed Electrodes.

Ambient ionization techniques provide a way to sample materials via creation of ions in the air. However, transferring and focusing of these ions is typically done in the reduced pressure environment of the mass spectrometer. Spray-based ambient ionization sources require relatively large distances between the source and mass spectrometer inlet for effective desolvation, resulting in a small fraction of the ions being collected. To increase the efficiency of ion transfer from atmosphere to vacuum, 3D-printed focusing devices made of conductive carbon nanotube doped polymers have been designed and evaluated for ion focusing in air. Three main classes of electrodes are considered: (i) conic section electrodes (conical, ellipsoidal, and cylindrical), (ii) simple conductive and non-conductive apertures, and (iii) electrodes with complex geometries (straight, chicane, and curved). Simulations of ion trajectories performed using the statistical diffusion simulation (SDS) model in SIMION showed a measure of agreement with experiment. Cross-sectional images of ion beams were captured using an ion detecting charge-coupled device (IonCCD). After optimization, the best arrangements of electrodes were coupled to an Agilent Ultivo triple quadrupole to record mass spectra. Observations suggest that electrode geometry strongly influences ion trajectories in air. Non-conductive electrodes also assisted in focusing, due to charge buildup from ion deposition. We also observed minimal spreading of the ion packet after exiting the focusing electrodes indicating that atmospheric collisions do not reduce collimation of the beam. The study suggests that high pressures need not be viewed as a hindrance to ion transport, but as a potentially useful force.

In vivo range verification in particle therapy.

Exploitation of the full potential offered by ion beams in clinical practice is still hampered by several sources of treatment uncertainties, particularly related to the limitations of our ability to locate the position of the Bragg peak in the tumor. To this end, several efforts are ongoing to improve the characterization of patient position, anatomy, and tissue stopping power properties prior to treatment as well as to enable in vivo verification of the actual dose delivery, or at least beam range, during or shortly after treatment. This contribution critically reviews methods under development or clinical testing for verification of ion therapy, based on pretreatment range and tissue probing as well as the detection of secondary emissions or physiological changes during and after treatment, trying to disentangle approaches of general applicability from those more specific to certain anatomical locations. Moreover, it discusses future directions, which could benefit from an integration of multiple modalities or address novel exploitation of the measurable signals for biologically adapted therapy.

Numerical simulation of ion transport in an atmosphere-to-vacuum interface taking into account gas dynamics and space charge.

A two-step approach was developed for the study of ion transport in an atmospheric pressure interface. In the first step, the flow in the interface was numerically simulated using the standard gas dynamic package ANSYS CFX 15.0. In the second step, the calculated fields of pressure, temperature, and velocity were imported into a custom-built software application for simulation of ion motion under the influence of both gas dynamic and electrostatic forces. To account for space charge effects in axially symmetric interfaces an analytical expression was used for the Coulomb force. For all other types of interfaces, an iterative approach for the Coulomb force computation was developed. The simulations show that the influence of the space charge is the main contributor to the loss of ion current in the heated capillary. In addition, the maximum ion current which can be transmitted through the heated capillary (0.58 mm inner diameter and 58.5 mm length) is limited to ∼6 nA for ions with m/z = 508 Da and with reduced ion mobility 1.05 cm2V-1s-1. This limit remains practically constant and independent of the ion current at the entrance of the capillary. For a particular ion type, this limit depends on its m/z ratio and ion mobility.

Maximizing Ion Transmission in Differential Mobility Spectrometry.

We provide modeling and experimental data describing the dominant ion-loss mechanisms for differential mobility spectrometry (DMS). Ion motion is considered from the inlet region of the mobility analyzer to the DMS exit, and losses resulting from diffusion to electrode surfaces, insufficient effective gap, ion fragmentation, and fringing field effects are considered for a commercial DMS system with 1-mm gap height. It is shown that losses due to diffusion and radial oscillations can be minimized with careful consideration of residence time, electrode spacing, gas flow rate, and waveform frequency. Fragmentation effects can be minimized by limitation of the separation field. When these parameters were optimized, fringing field effects at the DMS inlet contributed the most to signal reduction. We also describe a new DMS cell configuration that improves the gas dynamics at the mobility cell inlet. The new cell provides a gas jet that decreases the residence time for ions within the fringing field region, resulting in at least twofold increase in ion signal as determined by experimental data and simulations. Graphical Abstract ᅟ.

Increased Ion Transmission for Differential Ion Mobility Combined with Mass Spectrometry by Implementation of a Flared Inlet Capillary.

Differential ion mobility spectrometry (DIMS) is capable of separating components of complex mixtures prior to mass spectrometric analysis, thereby increasing signal-to-noise and signal-to-background ratios on millisecond timescales. However, adding a DIMS device to the front end of a mass spectrometer can reduce the signal intensity of subsequent mass spectrometric analysis. This is a result, in part, of ions lost due to inefficient transfer of ions from the DIMS device through the aperture leading into the mass spectrometer. This problem of transferring ions can be at least partially corrected by modifying the front end of the inlet capillary leading to the vacuum of the mass spectrometer. The inner diameter of the ion-sampling end of the inlet capillary was enlarged by drilling into the face. This results in a conical flare at the front end of the capillary, while the other end of the capillary remains unmodified. These flared capillaries allow for a greater number of ions from the DIMS device to be sampled relative to the unmodified standard capillary. Four flare dimensions were tested, differing by the angle between the wall of the flare and the outer wall of the inlet capillary. All flared capillaries showed greater signal intensity than the standard capillary with a DIMS device present without reducing the resolving power. It was also observed that the signal intensity increased as the flare angle decreased. The flared capillary with the smallest flare angle showed greater than a fivefold increase in signal intensity compared with the standard capillary. Graphical Abstract ᅟ.

Golf ball-assisted electrospray ionization of mass spectrometry for the determination of trace amino acids in complex samples.

During the electrospray ionization (ESI) process, ions move through a heated capillary aperture to be detected on arrival at a mass analyzer. However, the ESI process creates an ion plume, which expands into an ion cloud with an area larger than that of the heated capillary aperture, significantly contributing to an ion loss of 50% due to coulombic repulsion. The use of DC and RF fields to focus ions from the ion source into the vacuum chamber has been proposed in the literature, but the improvement of ion transmission efficiency is limited. To improve ion transmission, in this study we propose a novel method using a home-made golf ball positioned between the ion source and the inlet of the mass analyzer to hydrodynamically focus the ions passing through the golf ball. The ion plume produced by the ESI process passes through the golf ball will reduce the size of the ion cloud then be focused and most of them flowed into the mass analyzer. Therefore, the sensitivity will be improved, the aim of this investigation is to study the enhancing of the signal using golf ball-assisted electrospray ionization liquid chromatography tandem mass spectrometry (LC-MS/MS) to determine 20 trace amino acids in complex samples, including tea, urine and serum. The results showed that the analytical performance of the determination of the 20 amino acids in tea, urine and serum samples using the home-made golf ball-assisted ESI source is better than that of a commercial ESI source. The signal intensities of the 20 amino acids were enhanced by factors of 2-2700, 11-2525, and 31-342680 in oolong tea, urine and serum analyses, respectively. The precision of the proposed method ranged from 1-9%, 0.4-9% and 0.4-8% at low, medium and high concentration levels of amino acids, respectively. The home-made golf ball-assisted ESI source effectively increased the signal intensity and enhanced the ion transmission efficiency and is also an easy, convenient and economical device. This technique can be applied to the analysis of trace compounds in complex matrices.

Numerical analysis of ion-funnel transmission efficiency in an API-MS system with a continuum/microscopic approach.

A multi-step numerical approach is used to analyze the efficiency of an ion-funnel to transport ions over a wide range of m/z. A continuum approach based on the solution of the Navier-Stokes equations is applied to model the gas flow through a capillary connecting the atmospheric and subatmospheric sections of a mass spectrometer. A microscopic, fully kinetic approach based on the solution of the Boltzmann equation is used to examine the ion and gas transport through an ion-funnel kept at a 0.1-3 Torr pressure to the quadrupole section kept at a 0.01 Torr pressure. In addition to aerodynamic drag, the developed approach takes into account the combined effect of the DC field driving the ions downstream toward the funnel exit, the rf field confining the ions in radial direction, and the space charge causing ion repulsion. The sensitivity of the ion transmission to the gas pressure in the ion-funnel, the rf, and the total ion current injected to the funnel from capillary nozzle is shown. Graphical Abstract ᅟ.