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Direct sampling mass spectrometry (MS) has been advancing aggressively, showing immense potential in translating MS into the clinical field. Unlike traditional MS analysis involving extensive sample preparation and chromatographic separation, quick and simple procedures with minimal sample pretreatment or purification became available with direct sampling. An overview of the development in this field is provided, including some representative ambient ionization and fast extraction methods. Quantitative applications of these methods are emphasized and their efficacy are highlighted from a clinical aspect; non-quantitative applications in clinical analysis are also discussed. This review also discusses the integration of direct sampling MS with miniature mass spectrometers and its future outlook as an emerging clinical tool for point-of-care analysis. [ABSTRACT FROM AUTHOR]

Vinylidene carbenes (C3H2) are of high interest to interstellar, combustion, and organic chemistry. Due to their high instability, the direct experimental investigation of their chemical reactivity has rarely been achieved. Herein, we report a first study on the reactions of cyclopropenylidene (c-C3H2) with protonated alkyl amines in the gas phase using a home-built ion trap mass spectrometer. The high gas-phase basicity (GB) of (1A1) c-C3H2 (calculated as 920 kJ mol−1) facilitates the formation of a proton-bound dimer with protonated amines as the first step in the reaction. The dimer can stay as it is or rearrange to a covalent product. The formation of the covalent complex is highly exothermic and its yield is affected by the GB of alkyl amines. The highest yield (82%) was achieved when the GB of the amine was slightly lower but comparable to that of c-C3H2. Our results demonstrate a new reaction pathway of c-C3H2, which has long been considered as a “dead end” in interstellar carbon chemistry. [ABSTRACT FROM AUTHOR]

Bacteria colonies were analyzed using paper spray ionization coupled with a portable mass spectrometer. The spectra were averaged and processed using multivariate analysis to discriminate between different species of bacteria based on their unique phospholipid profiles. Full scan mass spectra and product ion MS/MS data were compared to those recorded using a benchtop linear ion trap mass spectrometer. [ABSTRACT FROM AUTHOR]

Mass spectrometers are complex instrumentation systems where ions are transferred though different pressure regions and mass-analyzed under high vacuum. In this work, we have investigated the impact of the gas flows that exit almost universally in all pressure regions. We developed a method that incorporates the dynamic gas field with the electric field in the simulation of ion trajectories. The scope of the electro-hydrodynamic simulation (EHS) method was demonstrated for characterizing the ion optical systems at atmospheric pressure interfaces. With experimental validation, the trapping of the externally injected ions in a linear ion trap at low pressure was also studied. Further development of the EHS method and the knowledge acquired in this research are expected to be useful in the design of hybrid instruments and the study of ion energetics. [ABSTRACT FROM AUTHOR]

Tandem mass spectrometry (MS/MS) plays an essential role in modern chemical analysis. It is used for differentiating isomers and isobars and suppressing chemical noise, which allows high precision quantitation. The MS/MS analysis has been typically applied by isolating the target precursor ions, while disregarding other ions, followed by a fragmentation process that produces the product ions. In this study, configurations of dual linear ion traps were explored to develop high efficiency MS/MS analysis. The ions trapped in the first linear ion trap were axially, mass-selectively transferred to the second linear ion trap for MS/MS analysis. Ions from multiple compounds simultaneously introduced into the mass spectrometer could be sequentially analyzed. This development enables highly efficient use of the sample. For miniature ion trap mass spectrometers with discontinuous atmospheric pressure interfaces, the analysis speed and the quantitation precision can be significantly improved. [ABSTRACT FROM AUTHOR]

An ambient method for rapid monitoring and quantitation of drugs of abuse in dried blood spots was developed using paper spray tandem mass spectrometry (PS-MS). [ABSTRACT FROM AUTHOR]

Paper spray (PS) ambient ionization is implemented using a portable mass spectrometer and applied to the detection of alkyl quaternary ammonium salts in a complex oil matrix. These salts are commonly used as active components in the formulation of corrosion inhibitors. They were identified in oil and confirmed by their fragmentation patterns recorded using tandem mass spectrometry (MS/MS). The cations of alkyl and benzyl-substituted quaternary ammonium salts showed characteristic neutral losses of CnH2n (n carbon number of the longest chain) and C7H8, respectively. Individual quaternary ammonium compounds were detected at low concentrations (＜1 ng μL−1) and over a dynamic range of ∼5 pg μL−1 to 500 pg μL−1 (ppb). Direct detection of these compounds in complex oil samples without prior sample preparation or pre-concentration was also demonstrated using a home-built miniature mass spectrometer at levels below 1 ng μL−1. [ABSTRACT FROM AUTHOR]

The state-of-the-art in two new ambient ionization methods for mass spectrometry, desorption electrospray ionization (DESI) and paper spray (PS), is described and their utility is illustrated with new studies on tissue imaging and biofluid analysis. DESI is an ambient ionization method that can be performed on untreated histological sections of biological tissue in the open lab environment to image lipids, fatty acids, hormones and other compounds. Paper spray is performed in the open lab too; it involves electrospraying dry blood spots or biofluid deposits from a porous medium. PS is characterized by extreme simplicity and speed: a spot of whole blood or other biofluid is analyzed directly from paper, simply by applying a high voltage to the moist paper.Both methods are being developed for use in diagnostics as a means to inform therapy. DESI imaging is applied to create molecular maps of tissue sections without prior labeling or other sample preparation. Like other methods of mass spectrometry imaging (MSI), it combines the chemical speciation of multiple analytes with information on spatial distributions. DESI imaging provides valuable information which correlates with the disease state of tissue as determined by standard histochemical methods. Positive-ion data are presented which complement previously reported negative-ion data on paired human bladder cancerous and adjacent normal tissue sections from 20 patients. These data add to the evidence already in the literature demonstrating that differences in the distributions of particular lipids contain disease-diagnostic information. Multivariate statistical analysis using principal component analysis (PCA) is used to analyze the imaging MS data, and so confirm differences between the lipid profiles of diseased and healthy tissue types. As more such data is acquired, DESI imaging has the potential to be a diagnostic tool for future cancer detection in situ; this suggests a potential role in guiding therapy in parallel with standard histochemical and immunohistological methods.The PS methodology is aimed at high-throughput clinical measurement of quantitative levels of particular therapeutic agents in blood and other biofluids. The experiment allows individual drugs to be quantified at therapeutic levels and data is presented showing quantitative drug analysis from mixtures of therapeutic drugs in whole blood. Data on cholesterol sulfate, a new possible prostate biomarker seen at elevated levels in diseased prostate tissue, but not in healthy prostate tissue in serum are reported using paper spray ionization. [ABSTRACT FROM AUTHOR]

The design and operation of an annular array of parallel, miniature rectilinear ion traps (RITs) is discussed. Stereolithography apparatus (SLA), a previously validated method for ion trap fabrication, was applied here to construct an array of mass analyzers and their mounting hardware. Two versions of the array were tested, using either six or twelve stretched RITs (x0= 1.66 mm, y0= 1.33 mm, z= 16.66 mm) mounted in parallel about the circumference of a circle with the interior and exterior x-electrode planes oriented tangential to the inner and outer annulus rings, respectively. The arrangement of the ion traps is such that the ions are radially ejected just above the throat of a centrally located electron multiplier detector into which they are accelerated. The mass analyzer array was mounted in a custom vacuum manifold. The resolution, mass-to-charge ratio (m/z) range, and MS/MS capabilities were tested using electrospray ionization (ESI). The devices were tested in two configurations: (i) separate ion sources for each trap, and (ii) a single ion source for the entire array. [ABSTRACT FROM AUTHOR]

Non-polar solvents like hexane allow ionization of insoluble drugs, peptides, nucleotides and phospholipids as solids from paper. Ambient ionization is achieved simply by application of a high voltage to the wet paper. Transport and ionization mechanisms are discussed, including the possibility of field desorption from dendritic structures formed on the paper. [ABSTRACT FROM AUTHOR]

Ambient ionization using a low-temperature plasma (LTP) probe combined with tandem mass spectrometry (MS/MS) allows detection and quantitation of melamine in milk powder, whole milk and other products at levels down to low ppb in analysis times of a few tens of seconds. [ABSTRACT FROM AUTHOR]

The accumulation and deposition of amyloid fibrils, also known as amyloidosis, in tissues and organs of patients has been found to be linked to numerous devastating neurodegenerative diseases. The aggregation of proteins to form amyloid fibrils, however, is a slow pathogenic process, and is a major issue for the evaluation of the effectiveness of inhibitors in new drug discovery and screening. Here, we used microdroplet reaction technology to accelerate the amyloid fibrillation process, monitored the process to shed light on the fundamental mechanism of amyloid self-assembly, and demonstrated the value of the technology in the rapid screening of potential inhibitor drugs. Proteins in microdroplets accelerated to form fibrils in milliseconds, enabling an entire cycle of inhibitor screening for Aβ40 within 3 minutes. The technology would be of broad interest to drug discovery and therapeutic design to develop treatments for diseases associated with protein aggregation and fibrillation., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Single-cell mass spectrometry (MS) is an essential technology for sensitive and multiplexed analysis of metabolites and lipids for cell phenotyping and pathway studies. However, the structural elucidation of lipids from single cells remains a challenge, especially in the high-throughput scenario. Technically, there is a contradiction between the inadequate sample amount ( i.e. a single cell, 0.5-20 pL) for replicate or multiple analysis, on the one hand, and the high metabolite coverage and multidimensional structure analysis that needs to be performed for each single cell, on the other hand. Here, we have developed a high-throughput single-cell MS platform that can perform both lipid profiling and lipid carbon-carbon double bond (C[double bond, length as m-dash]C) location isomer resolution analysis, aided by C[double bond, length as m-dash]C activation in unsaturated lipids by the Paternò-Büchi (PB) reaction and tandem MS, termed single-cell structural lipidomics analysis. The method can achieve a single-cell analysis throughput of 51 cells per minute. A total of 145 lipids were structurally characterized at the subclass level, of which the relative abundance of 17 isomeric lipids differing in the location of C[double bond, length as m-dash]C from 5 lipid precursors was determined. While cell-to-cell variations in MS 1 -based lipid profiling can be large, an advantage of quantifying lipid C[double bond, length as m-dash]C location isomers is the significantly improved quantitation accuracy. For example, the relative standard deviations (RSDs) of the relative amounts of PC 34:1 C[double bond, length as m-dash]C position isomers in MDA-MB-468 cells are half smaller than those measured for PC 34:1 as a whole by MS 1 abundance profiling. Taken together, the developed method can be effectively used for in-depth structural lipid metabolism network analysis by high-throughput analysis of 142 MDA-MB-468 human breast cancer cells., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

As a major class of mammalian lipids, phosphatidylcholines (PCs) often contain mixtures of structural isomers, resulting from different lipogenesis pathways. Profiling PCs at the isomer level, however, remains challenging in lipidomic settings, especially for characterizing the positions of fatty acyls on the glycerol backbone ( sn -positions) and the locations of carbon-carbon double bonds (C[double bond, length as m-dash]Cs) in unsaturated acyl chains. In this work, we have developed a workflow for profiling PCs down to sn - and C[double bond, length as m-dash]C locations at high coverage and sensitivity. This capability is enabled by radical-directed fragmentation, forming sn -1 specific fragment ions upon collision-induced dissociation (CID) of bicarbonate anion adducts of PCs ([M + HCO 3 ] - ) inside a mass spectrometer. This new tandem mass spectrometry (MS/MS) method can be simply incorporated into liquid chromatography by employing ammonium bicarbonate in the mobile phase without any instrument modification needed. It is also compatible with the online Paternò-Büchì reaction and subsequent MS/MS for the assignment of C[double bond, length as m-dash]C locations in sn -1 fatty acyl chains of unsaturated PCs. The analytical performance of the workflow is manifested by identification of 82 distinct PC molecular species from the polar extract of bovine liver, including quantification of 19 pairs of sn -isomers. Finally, we demonstrate that five pairs of PC sn -isomers show significant compositional changes in tissue samples of human breast cancer relative to controls, suggesting a potential for monitoring PC sn -isomers for biomedical applications., (This journal is © The Royal Society of Chemistry 2019.)

Leaf spray mass spectrometry is explored as a fast and simple way for direct analysis of sweet glycosides in fresh untreated Stevia leaves without sample pretreatment. In this technique, a fresh triangular piece of Stevia leaf serves as both sample and substrate. Application of a butanol : methanol : water mixture and a high voltage to intact leaf material produces a high electric field at the tip of the leaf. This results in field emission of charged droplets containing the glycosides. The resulting dry ions are detected by mass spectrometry and confirmed by tandem mass spectrometry and exact mass measurements. A comparison between leaf spray and other ambient ionization methods which are successful for screening glycosides in Stevia leaves--desorption electrospray ionization, low temperature plasma and paper spray--shows that leaf spray produces the highest quality spectra. It is also extremely easy to implement with no need for nebulizing gas or sample preparation and is suited to semi-quantitative determinations. The potential for the application of leaf spray mass spectrometry to direct and rapid screening of plant materials is here realized in the case of Stevia sweet glycosides.

A simple and efficient ambient ionization method based on paper spray combined with tandem mass spectrometry allows rapid detection and quantitation of various contaminants (clenbuterol, melamine, plasticizer and sudan red) in various foodstuffs (e.g., meat, milk, sports drinks and chili powder).

Paper spray mass spectrometry is applied to oncology drugs in fresh whole blood samples supported on filter paper substrates instead of dry blood as done previously. Addition of the coagulant alum clotted the blood and allowed for immediate sample analysis. The coagulant did not interfere with the function of the paper spray nor did it add features to the mass spectra. Quantitative analysis of therapeutic drugs in the blood was achieved utilizing internal standards which were pre-spotted onto the filter paper. Eight oncology drugs were examined, with lower limits of detection ranging between 0.5 and 17 ng mL(-1) and linear dynamic ranges greater than two orders of magnitude. Inter-day accuracies of quality controls for pazopanib ranged from 102 to 118%, with imprecisions of 9 to 13%. This one-step method requires 10 μL of blood, a drop of solvent, and takes 45 seconds per trial. These results indicate applicability to point-of-care therapeutic drug monitoring in a clinical setting.

A new ambient ionization method--leaf-spray mass spectrometry--is used to detect allergenic urushiols directly from poison ivy (T. radicans) leaves with no sample preparation. These simple measurements show all the urushiols previously reported using liquid chromatography mass spectrometry methods. Tandem mass spectrometry analysis of the leaf spray ions confirms the identifications. Enhanced detection of some urushiols was achieved in the negative mode with the addition of chloride anions to the spray solvent.

We describe a rapid in situ method for detecting agrochemicals on the surface or in the tissue of fruit using a portable mass spectrometer equipped with an ambient ionization source. Two such ionization methods, low temperature plasma (LTP) and paper spray (PS), were employed in experiments performed at a local grocery store. LTP was used to detect diphenylamine (DPA) directly from the skin of apples in the store and those treated after harvest with DPA were recognized by MS and MS/MS. These data therefore allowed ready distinction between organic and non-organic apples. DPA was also found within the internal tissue of purchased apples and its distribution was mapped using LTP. Similarly, thiabendazole residues were detected on the skin of treated oranges in a grocery store experiment in which paper spray was performed by wiping the orange surface with a moist commercial lens wipe and then applying a high voltage to ionize the chemicals directly from the wipe. The handheld mass spectrometer used in these measurements is capable of performing several stages of tandem mass spectrometry (up to MS(5)); the compounds on the fruit were identified by their MS/MS fragmentation patterns. Protonated DPA (m/z 170) produced a characteristic MS(2) fragment ion at m/z 92, while thiabendazole was identified by MS(3) using precursor to fragment ion transitions m/z 202 →m/z 175 →m/z 131. These particular examples exemplify the power of in situ analysis of complex samples using ambient ionization and handheld mass spectrometers.

Low-temperature plasma (LTP) permits direct ambient ionization and mass analysis of samples in their native environment with minimal or no prior preparation. LTP utilizes dielectric barrier discharges (DBDs) to create a low power plasma which is guided by gas flow onto the sample from which analytes are desorbed and ionized. In this study, the potential of LTP-MS for the detection of pesticide residues in food is demonstrated. Thirteen multi-class agricultural chemicals were studied (ametryn, amitraz, atrazine, buprofezin, DEET, diphenylamine, ethoxyquin, imazalil, isofenphos-methyl, isoproturon, malathion, parathion-ethyl and terbuthylazine). To evaluate the potential of the proposed approach, LTP-MS experiments were performed directly on fruit peels as well as on fruit/vegetable extracts. Most of the agrochemicals examined displayed remarkable sensitivity in the positive ion mode, giving limits of detection (LOD) for the direct measurement in the low picogram range. Tandem mass spectrometry (MS/MS) was used to confirm identification of selected pesticides by using for these experiments spiked fruit/vegetable extracts (QuEChERS, a standard sample treatment protocol) at levels as low as 1 pg, absolute, for some of the analytes. Comparisons of the data obtained by direct LTP-MS were made with the slower but more accurate conventional LC-MS/MS procedure. Herbicides spiked in aqueous solutions were detectable at LODs as low as 0.5 microg L(-1) without the need for any sample preparation. The results demonstrate that ambient LTP-MS can be applied for the detection and confirmation of traces of agrochemicals in actual market-purchased produce and in natural water samples. Quantitative analysis was also performed in a few selected cases and displayed a relatively high degree of linearity over four orders of magnitude.

Low temperature plasma (LTP) ionization is an ambient plasma ionization method that permits the direct mass analysis of samples in their native atmospheric environment with little or no sample preparation. In this work, the low temperature plasma probe is used in the direct and rapid mass spectrometric analysis of aqueous phase samples including biofluids (saliva, urine, and hair extract). A detailed trace qualitative examination of 14 drugs of abuse has been performed. The relative standard deviation on average was approximately 16% for the LTP analysis of the drugs of abuse standards. Eleven of the fourteen drugs of abuse were detected in the low ng mL(-1) (3 pg absolute detection) to the mid microg mL(-1) (approximately 30 ng absolute detection) concentration range. One drug, cannabidiol, could not be detected until supplemental heating of the substrate was incorporated into the experimental protocol. The addition of supplemental heating improved the detection limits by at least an order of magnitude to approximately 0.5 ng mL(-1) to 0.5 microg mL(-1) (1.5 pg-1.5 ng absolute) for twelve of the fourteen drugs of abuse, so extending the linear dynamic range which for most analytes was four orders of magnitude. Quantitative capabilities were evaluated using the particular example of benzoylecgonine in urine by employing a deuterated internal standard. Matrix effects observed during the analysis of the drugs in complex biological fluids are also discussed. In addition, low temperature plasma ionization was applied to the examination of real (not spiked) biological samples and these results were confirmed using standard LC/MS methodology. The main advantages observed for this ambient desorption/ionization technique include the capabilities for direct analysis of liquid surfaces for in situ detection and the remarkable sensitivity in the examination of the drugs of abuse investigated here. The disadvantages of the method include the modest quantitative accuracy making LTP most useful as a rapid but semi-quantitative screening method.

Mass spectrometry allows rapid chemical analysis of untreated samples in the ambient environment. This is a result of recent rapid progress in ambient ionization techniques. The most widely studied of these new methods, desorption electrospray ionization (DESI), uses fast-moving solvent droplets to extract analytes from surfaces and propel the resulting secondary microdroplets towards the mass analyzer. This review of DESI and other ambient methods centers on the accompanying chemical processes. Manipulation of the chemistry accompanying ambient ionization can be used to optimize chemical analysis, including molecular imaging. Solvent effects, geometry effects, electrochemical processes and mechanisms are covered. Extensions of the methodology to solution-phase analysis, to stand-off detection and to therapeutic drug analysis using miniature mass spectrometers are also treated.

A low temperature plasma ambient ionization source, coupled to a portable mass spectrometer (Mini 10.5), is used for the determination of melamine contamination in whole milk and related materials. Thermally assisted desorption and ionization of the analyte was achieved with the plasma probe. The small size, low power consumption and capability for direct sampling without pretreatment makes plasma ionization an appropriate ionization method for use with a handheld mass spectrometer. The standard discontinuous atmospheric pressure interface used to connect atmospheric pressure ion sources to mass spectrometers (Gao et al., Anal. Chem., 2008, 80, 4026-4032) was modified by using supplementary pumping to increase the ion transfer efficiency. Whole milk, fish, milk powder and other complex matrices spiked with melamine were placed on glass slides close to the vacuum inlet and analyzed without sample pretreatment. Quantitation in complex matrices was achieved using MS/MS of protonated melamine m/z 127 to yield the characteristic fragment ion of m/z 85. Analysis rates of two samples per minute, levels of melamine as low as 250 ng/mL in whole milk (below the regulatory level in the US of 1 ppm (1 microg/mL) or the European level of 2.5 ppm (microg/mL)), a linear dynamic range of 0.5-50 microg/mL and a relative standard deviation of ca. 7.6-16.2% were achieved. The importance of melamine to public health and the prior lack of a rapid, sensitive and yet highly specific field analysis method add to the relevance of this study.

Ambient ionization using a low-temperature plasma (LTP) probe combined with tandem mass spectrometry (MS/MS) allows detection and quantitation of melamine in milk powder, whole milk and other products at levels down to low ppb in analysis times of a few tens of seconds.

In this paper, we have constructed a low temperature plasma (LTP) probe using dielectric barrier discharge (DBD) and employed it for the detection of explosives on a variety of substrates under ambient conditions. Upon discharge, a transient, low-temperature non-equilibrium plasma comprising ions, electrons and metastable atoms are generated between the electrodes. Three common explosives, 2,4,6-trinitrotoluene (TNT), hexahydro-1,3,5-trinitro-1,3,5-trinitro-1,3,5-triazine (RDX), and pentaerythritol tetranitrate (PETN), were directly desorbed and ionized from solid surfaces, followed by subsequent analysis using the mass spectrometer in the negative ion mode. Limits of detection (LODs) were 500 fg for TNT, 1 pg for RDX, and 500 fg for PETN. The reliability of the method was characterized by a successful analysis of a mixture of the three explosives. The ion source also allowed direct detection of trace explosives on both conductive and non-conductive substrates, thus expanding the applicability of low temperature plasma desorption mass spectrometry.