In this work, a “brick” size miniature mass spectrometer (28 cm × 21 cm × 16 cm) was developed and characterized, which was enabled by the development of a new frequency scanning technique. Different from the conventional voltage scanning method or the digital waveforms used on a digital ion trap, a sinusoidal frequency scanning technique was developed to drive the linear ion trap of the brick mass spectrometer (BMS). Both an in-vacuum plasma ionization source and an electrospray ionization source were coupled with this BMS for the analyses of volatile and nonvolatile samples. Stability diagram, sensitivity, mass resolution, and mass range of the BMS were explored. This new frequency scanning technique could not only reduce the size and power consumption of a miniature mass spectrometer but also improve its analytical performances, especially in terms of mass range and resolution. Analogous to the development of cell phones, this BMS would be an important step from “brick” mass spectrometer to “cell” mass spectrometer.

Previously, a continuous atmospheric pressure interfaced miniature mass spectrometer was developed in our lab. The continuous atmospheric pressure interface improves system robustness, stability, and scan speed, but it also results in limited ion transfer efficiency and reduced mass resolution. To solve these problems, a miniature ion funnel was designed and integrated into the miniature mass spectrometer for the first time. Besides ion transfer efficiency, dimension and power consumption of the ion funnel also need to be considered throughout the design process. After a systematic optimization, the designed miniature ion funnel could increase ion transfer efficiency by more than 10 times, while lowering the background pressure of ion trap by ∼2 times. As a result, sensitivity and mass resolution of the second generation miniature mass spectrometer were improved by 20 times and ∼2 times, respectively, while maintaining its high scan speed and stability. A sensitive and robust mini-MS, capable of coupling with ambient ionization sources would meet the needs of many on-site chemical analysis applications, such as in food, drug, and agricultural administrations, forensic science, homeland security, and etc.

•A rapid method has been developed for determination of enterotoxins on protein-level based on membrane electrospray ionization mass spectrometry (MESI-MS). This method is able to be used for direct analyses of clinical samples without pretreatment.Toxigenic bacterial pathogens play important role in enteric infections which remain a major cause of morbidity around the world. Although many methods have been reported for detection of enterotoxins, rapid analyses of AB5 enterotoxins on protein-level in real samples is still challenging. A rapid quantitative method was developed in this study to determine bacterial AB5 enterotoxins targeting at their unique peptides using membrane electrospray ionization mass spectrometry (MESI-MS). Precursor/product-ion pairs of peptides HDDGYVSTSISLR (HR), TPNSIAAISMEN (TN), MASDEFPSMCPADGR (MR) and AVNEESQPECQITGDRPVIK (AK) unique to enterotoxins Ctx, LT, Stx1 and Stx2 respectively were used for both toxin identification and quantitative analysis. The methodologies were validated including sensitivity, accuracy, precision and recovery in detection of simulated real samples. Larger scaled real sample detections with statistical analysis demonstrated that target peptides in developed enterotoxins analyses method are reliable.Download high-res image (78KB)Download full-size image

Typically dealing with practical samples with very complex matrices, ambient ionization mass spectrometry suffers from low detection sensitivity. In this study, molecular imprinting technology was explored and integrated with the membrane electrospray ionization (MESI) method for direct sample analyses. By enriching targeted analytes on molecularly imprinted membranes (MIMs), improvement (by 10- to 50-fold) in the limit of quantitation could be achieved, compared to conventional nanoelectrospray ionization methods or other ambient ionization methods. MIMs were prepared by cross-linking a synthesized molecularly imprinted polymer layer onto a polyvinylidene difluoride (PVDF) membrane. The characteristics of MIM in recognizing target analytes were investigated and verified. Experiments showed that MIM-ESI could provide satisfactory performances for direct quantification of targeted analytes in complex samples using mass spectroscopy (MS), and the quantitative performance of this methodology was validated. With the capability of target enrichment, the uses of MIM-ESI MS in different application fields were also demonstrated, including food safety, quantification of drug concentrations in blood, pesticide residues in soil, and antibiotic residues in milk.

•An electro-kinetic assisted electrospray ionization source (EK-ESI) is proposed and characterized.•Analytes could be separated preliminarily based on their electrophoretic mobility during the electrospray process.•Proteins could be ionized readily at neutral pH using EK-ESI.In this work, an electro-kinetic assisted electrospray ionization (EK-ESI) source is proposed and characterized. In EK-ESI, an additional auxiliary electric field is introduced in the liquid flow of a nano-ESI. While traveling forward in the electrospray flow, charged analytes also experience a reverse electric field, which pushes them backwards. As a result, analytes could be separated preliminarily based on their electrophoretic mobility during the electrospray process. Experiments show that EK-ESI can reduce charge competition effects in the ESI source and increase biomolecule detection sensitivities. It was also found that EK-ESI effectively ionizes proteins in a relatively mild solvent condition, which does not require the addition of acids or salt buffers into the solvent. As a proof-of-concept study, a very rough separation effect was observed in this study, further experiments and theoretical study will be carried out to enhance its performances.

With the increasing demands of molecular structure analysis, several methods have been developed to measure ion collision cross sections within Fourier transform (FT) based mass analyzers. Particularly in the recent three years since 2012, the method of obtaining biomolecule collision cross sections was achieved in Fourier transform ion cyclotron resonance (FT-ICR) cells. Furthermore, similar methods have been realized or proposed for orbitraps and quadrupole ion traps. This technique adds a new ion structure analysis capability to FT-based mass analyzers. By providing complementary ion structure information, it could be used together with tandem mass spectrometry and ion mobility spectroscopy techniques. Although many questions and challenges remain, this technique potentially would greatly enhance the ion structure analysis capability of a mass spectrometer, and provide a new tool for chemists and biochemists.

Previously, we have demonstrated the feasibility of measuring ion collision cross sections (CCSs) within a quadrupole ion trap by performing time–frequency analyses of simulated ion trajectories. In this study, an improved time–frequency analysis method, the filter diagonalization method (FDM), was applied for data analyses. Using the FDM, high resolution could be achieved in both time- and frequency-domains when calculating ion time–frequency curves. Owing to this high-resolution nature, ion-neutral collision induced ion motion frequency shifts were observed, which further cause the intermodulation of ion trajectories and thus accelerate image current attenuation. Therefore, ion trap operation parameters, such as the ion number, high-order field percentage and buffer gas pressure, were optimized for ion CCS measurements. Under optimized conditions, simulation results show that a resolving power from 30 to more than 200 could be achieved for ion CCS measurements.

It is known that the ion collision cross section (CCS) may be calculated from the linewidth of a Fourier transform ion cyclotron resonance (FT-ICR) mass spectral peak at elevated pressure (e.g., ∼10−6 Torr). However, the high mass resolution of FT-ICR is sacrificed in those experiments due to high buffer gas pressure. In this study, we describe a linewidth correction method to eliminate the windowing-induced peak broadening effect. Together with the energetic ion–neutral collision model previously developed by our group, this method enables the extraction of CCSs of biomolecules from high-resolution FT-ICR mass spectral linewidths, obtained at a typical operating buffer gas pressure of modern FT-ICR instruments (∼10−10 Torr). CCS values of peptides including MRFA, angiotensin I, and bradykinin measured by the proposed method agree well with ion mobility measurements, and the unfolding of protein ions (ubiquitin) at higher charge states is also observed.

•An economic in-source desolvation method was developed for miniature mass spectrometers.•2–5 fold signal-noise-ratio improvements could be achieved.•Limit of detection of the miniature mass spectrometer could also be improved.Miniature mass spectrometers could meet the on-site chemical analysis requirements in applications such as space exploration, homeland security, etc. However, miniaturization of a mass spectrometer would sacrifice its performance due to simplified instrumentation and limitations on power and size. In this study, in-source desolvation capability was developed for a miniature mass spectrometer. Similar to the conventional in-source fragmentation technique, the in-source desolvation is more gentle, which is designed to fragment clusters and droplets other than ions. In-source desolvation could effectively help the desolvation of droplets generated by electrospray ionization, and both signal intensity and signal-to-noise ratio of a mass peak could be increased. As a result, sensitivity improvement could be achieved for the miniature mass spectrometer. Compared to the desolvation techniques used on a lab-scale instrument (heated interface, desolvation gas, for instance), the in-source desolvation method is more suitable and economic for a miniature mass spectrometer.Figure optionsDownload full-size imageDownload high-quality image (80 K)Download as PowerPoint slide

Space charge effects play important roles in ion trap operations, which typically limit the ion trapping capacity, dynamic range, mass accuracy, and resolving power of a quadrupole ion trap. In this study, a rhombic ion excitation and ejection method was proposed to minimize space charge effects in a linear ion trap. Instead of applying a single dipolar AC excitation signal, two dipolar AC excitation signals with the same frequency and amplitude but 90° phase difference were applied in the x- and y-directions of the linear ion trap, respectively. As a result, mass selective excited ions would circle around the ion cloud located at the center of the ion trap, rather than go through the ion cloud. In this work, excited ions were then axially ejected and detected, but this rhombic ion excitation method could also be applied to linear ion traps with ion radial ejection capabilities. Experiments show that space charge induced mass resolution degradation and mass shift could be alleviated with this method. For the experimental conditions in this work, space charge induced mass shift could be decreased by ~50%, and the mass resolving power could be improved by ~2 times at the same time.

A miniature capillary electrophoresis mass spectrometry (CE/MS) system has been developed in this work. A 100% electrical driven miniaturized CE device was integrated with a miniature MS instrument, which has a discontinuous atmospheric pressure interface (DAPI) for coupling with atmospheric pressure ionization sources. A nanoelectrospray ionization (nano-ESI) source was developed with a sheath liquid interface for coupling the miniature CE and the MS system. A systematic characterization and optimization of the analytical performance have been done. The analysis of isobaric peptides and avoiding charge competition effects in nano-ESI sources have been demonstrated.

The ability of rapid biomarker quantitation in raw biological samples would expand the application of mass spectrometry in clinical diagnosis. Up until now, the conventional chromatography–mass spectrometry method is time-consuming in both sample preparation and chromatography separation processes, while ambient ionization methods normally suffer from sensitivity. The membrane electrospray ionization (MESI) introduced in this study could not only achieve sensitive biomolecule quantitation, but also minimize the sample handling process. As a unique feature of MESI, both vertical and horizontal chemical separations could be achieved in real-time. With the capability of mass-selectively minimizing matrix effects from salts, small molecules, and macromolecules, ultrasensitive detection of cytochrome C (>500-fold sensitivity improvement) in raw urine samples was demonstrated in less than 20 min.

To understand the role and function of a biomolecule in a biosystem, it is important to know both its composition and structure. Here, a mass spectrometric based approach has been proposed and applied to demonstrate that collision cross sections and high-resolution mass spectra of biomolecule ions may be obtained simultaneously by Fourier transform ion cyclotron resonance mass spectrometry. With this method, the unfolding phenomena for ubiquitin ions that possess different number of charges have been investigated, and results agree well with ion mobility measurements. In the present approach, we extend ion collision cross-section measurements to lower pressures than in prior ion cyclotron resonance (ICR)-based experiments, thereby maintaining the potentially high resolution of Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS), and enabling collision cross section (CCS) measurements for high-mass biomolecules.

In this study, an energetic hard-sphere ion–neutral collision model was proposed to bridge-link ion collision cross section (CCS) with the image current collected from a high-resolution Fourier transform ion cyclotron resonance (FT-ICR) cell. By investigating the nonlinear effects induced by high-order electric fields and image charge forces, the energetic hard-sphere collision model was validated through experiments. Suitable application regions for the energetic hard-sphere collision model, as well as for the conventional Langevin and hard-sphere collision models, were also discussed. The energetic hard-sphere collision model was applied in the extraction of ion CCSs from high-resolution FT-ICR mass spectra. Discussions in the present study also apply to FT-Orbitraps and FT-quadrupole ion traps.

The demand for on-the-spot analysis is met by a miniature mass spectrometer which is preferred to be robust, stable, as small as possible and capable of analyzing different samples by coupling with various ionization methods. However, largely constrained by the atmospheric pressure interface (API), these aspects are difficult to be realized in one system. Herein, we describe the development of a new miniature mass spectrometer with balanced performance. The miniature mass spectrometer is small in size (30 × 30 × 18 cm) but has a continuous API, which was achieved by high-pressure ion trap operation and maximized ion transfer efficiency with the utilization of a differential pumping system. The miniature mass spectrometer was characterized and optimized in terms of stability, sensitivity, mass range, mass resolution and scan speed. Rapid analysis of mixtures was demonstrated by coupling the miniature mass spectrometer with the ambient ionization technique of paper spray. This is the smallest miniature mass spectrometer to date, which has a continuous API.

The concept and method for mass selective ion transfer and accumulation within quadrupole ion trap arrays have been demonstrated. Proof-of-concept experiments have been performed on two sets of ion trap arrays: (1) a linear ion trap with axial ion ejection plus a linear ion trap with radial ion ejection; (2) a linear ion trap with axial ion ejection plus a linear ion trap with axial ion ejection. In both sets of ion trap arrays, ions trapped in the first ion trap could be mass selectively transferred and accumulated into the second ion trap, while keeping other ions reserved in the first ion trap. Different operating modes have been implemented and tested, including transferring all ions, ions within a selected mass range, ions with a mass-to-charge ratio of 1, and randomly selected ions. Unit mass resolution for ion transfer and ∼90% ion transfer efficiency has been achieved. A new tandem mass spectrometry scheme for analyzing multiple precursor ions in a single sample injection has been demonstrated, which would improve instrument duty cycle and sample utilization rate (especially for very limited samples), potentially facilitate applications like single cell analyses, and improve electron transfer dissociation efficiency.

In this study, a method for measuring ion collision crosssections (CCSs) was proposed through time–frequency analysis of ion trajectories in quadrupole ion traps. A linear ion trap with added high-order electric fields was designed and simulated. With the presence of high-order electric fields and ion-neutral collisions, ion secular motion frequency within the quadrupole ion trap will be a function of ion motion amplitude, thus a function of time and ion CCS. A direct relationship was then established between ion CCS and ion motion frequency with respect to time, which could be obtained through time–frequency analysis of ion trajectories (or ion motion induced image currents). To confirm the proposed theory, realistic ion trajectory simulations were performed, where the CCSs of bradykinin, angiotensin I and II, and ubiquitin ions were calculated from simulated ion trajectories. As an example, differentiation of isomeric ubiquitin ions was also demonstrated in the simulations.

Space charge effects play important roles in the performance of various types of mass analyzers. Simulation of space charge effects is often limited by the computation capability. In this study, we evaluate the method of using graphics processing unit (GPU) to accelerate ion trajectory simulation. Simulation using GPU has been compared with multi-core central processing unit (CPU), and an acceleration of about 390 times have been obtained using a single computer for simulation of up to 105 ions in quadrupole ion traps. Characteristics of trapped ions can be investigated at detailed levels within a reasonable simulation time. Space charge effects on the trapping capacities of linear and 3D ion traps, ion cloud shapes, ion motion frequency shift, mass spectrum peak coalescence effects between two ion clouds of close m/z are studied with the ion trajectory simulation using GPU.

Correction for ‘Ion collision cross section analyses in quadrupole ion traps using the filter diagonalization method: a theoretical study’ by Ting Jiang et al., Phys. Chem. Chem. Phys., 2016, 18, 12058–12064.

In this study, an energetic hard-sphere ion–neutral collision model was proposed to bridge-link ion collision cross section (CCS) with the image current collected from a high-resolution Fourier transform ion cyclotron resonance (FT-ICR) cell. By investigating the nonlinear effects induced by high-order electric fields and image charge forces, the energetic hard-sphere collision model was validated through experiments. Suitable application regions for the energetic hard-sphere collision model, as well as for the conventional Langevin and hard-sphere collision models, were also discussed. The energetic hard-sphere collision model was applied in the extraction of ion CCSs from high-resolution FT-ICR mass spectra. Discussions in the present study also apply to FT-Orbitraps and FT-quadrupole ion traps.

Previously, we have demonstrated the feasibility of measuring ion collision cross sections (CCSs) within a quadrupole ion trap by performing time–frequency analyses of simulated ion trajectories. In this study, an improved time–frequency analysis method, the filter diagonalization method (FDM), was applied for data analyses. Using the FDM, high resolution could be achieved in both time- and frequency-domains when calculating ion time–frequency curves. Owing to this high-resolution nature, ion-neutral collision induced ion motion frequency shifts were observed, which further cause the intermodulation of ion trajectories and thus accelerate image current attenuation. Therefore, ion trap operation parameters, such as the ion number, high-order field percentage and buffer gas pressure, were optimized for ion CCS measurements. Under optimized conditions, simulation results show that a resolving power from 30 to more than 200 could be achieved for ion CCS measurements.

It is known that the ion collision cross section (CCS) may be calculated from the linewidth of a Fourier transform ion cyclotron resonance (FT-ICR) mass spectral peak at elevated pressure (e.g., ∼10−6 Torr). However, the high mass resolution of FT-ICR is sacrificed in those experiments due to high buffer gas pressure. In this study, we describe a linewidth correction method to eliminate the windowing-induced peak broadening effect. Together with the energetic ion–neutral collision model previously developed by our group, this method enables the extraction of CCSs of biomolecules from high-resolution FT-ICR mass spectral linewidths, obtained at a typical operating buffer gas pressure of modern FT-ICR instruments (∼10−10 Torr). CCS values of peptides including MRFA, angiotensin I, and bradykinin measured by the proposed method agree well with ion mobility measurements, and the unfolding of protein ions (ubiquitin) at higher charge states is also observed.