Mass spectrometry for neurosurgery: Intraoperative support in decision-making.

Ambient ionization mass spectrometry was proved to be a powerful tool for oncological surgery. Still, it remains a translational technique on the way from laboratory to clinic. Brain surgery is the most sensitive to resection accuracy field since the balance between completeness of resection and minimization of nerve fiber damage determines patient outcome and quality of life. In this review, we summarize efforts made to develop various intraoperative support techniques for oncological neurosurgery and discuss difficulties arising on the way to clinical implementation of mass spectrometry-guided brain surgery.

Protein analysis by desorption electrospray ionization mass spectrometry.

This review presents progress made in the ambient analysis of proteins, in particular by desorption electrospray ionization-mass spectrometry (DESI-MS). Related ambient ionization techniques are discussed in comparison to DESI-MS only to illustrate the larger context of protein analysis by ambient ionization mass spectrometry. The review describes early and current approaches for the analysis of undigested proteins, native proteins, tryptic digests, and indirect protein determination through reporter molecules. Applications to mass spectrometry imaging for protein spatial distributions, the identification of posttranslational modifications, determination of binding stoichiometries, and enzymatic transformations are discussed. The analytical capabilities of other ambient ionization techniques such as LESA and nano-DESI currently exceed those of DESI-MS for in situ surface sampling of intact proteins from tissues. This review shows, however, that despite its many limitations, DESI-MS is making valuable contributions to protein analysis. The challenges in sensitivity, spatial resolution, and mass range are surmountable obstacles and further development and improvements to DESI-MS is justified.

Long-chain polyunsaturated lipids associated with responsiveness to anti-PD-1 therapy are colocalized with immune infiltrates in the tumor microenvironment.

The programmed cell death protein-1 (PD-1) is highly expressed on the surface of antigen-specific exhausted T cells and, upon interaction with its ligand PD-L1, can result in inhibition of the immune response. Anti-PD-1 treatment has been shown to extend survival and result in durable responses in several cancers, yet only a subset of patients benefit from this therapy. Despite the implication of metabolic alteration following cancer immunotherapy, mechanistic associations between antitumor responses and metabolic changes remain unclear. Here, we used desorption electrospray ionization mass spectrometry imaging to examine the lipid profiles of tumor tissue from three syngeneic murine models with varying treatment sensitivity at the baseline and at three time points post-anti-PD-1 therapy. These imaging experiments revealed specific alterations in the lipid profiles associated with the degree of response to treatment and allowed us to identify a significant increase of long-chain polyunsaturated lipids within responsive tumors following anti-PD-1 therapy. Immunofluorescence imaging of tumor tissues also demonstrated that the altered lipid profile associated with treatment response is localized to dense regions of tumor immune infiltrates. Overall, these results indicate that effective anti-PD-1 therapy modulates lipid metabolism in tumor immune infiltrates, and we thereby propose that further investigation of the related immune-metabolic pathways may be useful for better understanding success and failure of anti-PD-1 therapy.

Ambient ionization mass spectrometry applied to new psychoactive substance analysis.

In the past decade a plethora of drugs with similar effects to controlled psychoactive drugs, like cannabis, amfetamine (amphetamine), or lysergic acid diethylamide, have been synthesized. These drugs can collectively be classified under the term new psychoactive substances (NPS) and are used for recreational purposes. The novelty of the substances, alongside the rapid rate of emergence and structural variability, makes their detection as well as their legal control highly challenging, increasing the demand for rapid and easy-to-use analytical techniques for their detection and identification. Therefore, interest in ambient ionization mass spectrometry applied to NPS has grown in recent years, which is largely because it is relatively fast and simple to use and has a low operating cost. This review aims to provide a critique of the suitability of current ambient ionization techniques for the analysis of NPS in the forensic and clinical toxicology fields. Consideration is given to analytical performance and ease of implementation, including ionization efficiency, selectivity, sensitivity, quantification, analyte chemistry, molecular coverage, validation, and practicality.

Recent advances in mass spectrometry techniques for atmospheric chemistry research on molecular-level.

The Earth's atmosphere is composed of an enormous variety of chemical species associated with trace gases and aerosol particles whose composition and chemistry have critical impacts on the Earth's climate, air quality, and human health. Mass spectrometry analysis as a powerful and popular analytical technique has been widely developed and applied in atmospheric chemistry for decades. Mass spectrometry allows for effective detection, identification, and quantification of a broad range of organic and inorganic chemical species with high sensitivity and resolution. In this review, we summarize recently developed mass spectrometry techniques, methods, and applications in atmospheric chemistry research in the past several years on molecular-level. Specifically, new developments of ion-molecule reactors, various soft ionization methods, and unique coupling with separation techniques are highlighted. The new mass spectrometry applications in laboratory studies and field measurements focused on improving the detection limits for traditional and emerging volatile organic compounds, characterizing multiphase highly oxygenated molecules, and monitoring particle bulk and surface compositions.

The development and application of matrix assisted laser desorption electrospray ionization: The teenage years.

In the past 15 years, ambient ionization techniques have witnessed a significant incursion into the field of mass spectrometry imaging, demonstrating their ability to provide complementary information to matrix-assisted laser desorption ionization. Matrix-assisted laser desorption electrospray ionization is one such technique that has evolved since its first demonstrations with ultraviolet lasers coupled to Fourier transform-ion cyclotron resonance mass spectrometers to extensive use with infrared lasers coupled to orbitrap-based mass spectrometers. Concurrently, there have been transformative developments of this imaging platform due to the high level of control the principal group has retained over the laser technology, data acquisition software (RastirX), instrument communication, and image processing software (MSiReader). This review will discuss the developments of MALDESI since its first laboratory demonstration in 2005 to the most recent advances in 2021.

Characterization of effective phytochemicals in traditional Chinese medicine by mass spectrometry.

Traditional Chinese medicines (TCMs) have been widely used in clinical and healthcare applications around the world. The characterization of the phytochemical components in TCMs is very important for studying the therapeutic mechanism of TCMs. In the analysis process, sample preparation and instrument analysis are key steps to improve analysis performance and accuracy. In recent years, chromatography combined with mass spectrometry (MS) has been widely used for the separation and detection of trace components in complex TCM samples. This article reviews various sample preparation techniques and chromatography-MS techniques, including the application of gas chromatography-MS and liquid chromatography-MS and other MS techniques in the characterization of phytochemicals in TCM materials and Chinese medicine products. This article also describes a new ambient ionization MS method for rapid and high-throughput analysis of TCM components.

Thermal desorption ambient ionization mass spectrometry for emergency toxicology.

In the emergency department, it is important to rapidly identify the toxic substances that have led to acute poisoning because different toxicants or toxins cause poisoning through different mechanisms, requiring disparate therapeutic strategies and precautions against contraindicating actions, and diverse directions of clinical course monitoring and prediction of prognosis. Ambient ionization mass spectrometry, a state-of-the-art technology, has been proved to be a fast, accurate, and user-friendly tool for rapidly identifying toxicants like residual pesticides on fruits and vegetables. In view of this, developing an analytical platform that explores the application of such a cutting-edge technology in a novel direction has been initiated a research program, namely, the rapid identification of toxic substances which might have caused acute poisoning in patients who visit the emergency department and requires an accurate diagnosis for correct clinical decision-making to bring about corresponding data-guided management. This review includes (i) a narrative account of the breakthrough in emergency toxicology brought about by the advent of ambient ionization mass spectrometry and (ii) a thorough discussion about the clinical implications and technical limitations of such a promising innovation for promoting toxicological tests from tier two-level to tier one level.

Recent advances in entirely hand-held ionization sources for mass spectrometry.

Ambient ionization mass spectrometry (AIMS) has been developing explosively since its first debut. The ionization process was hence able to be achieved under atmospheric pressure, facilitating on-site field analysis in a variety of areas, such as clinical diagnosis, metabolic phenotyping, and surface analysis. As part of the ambitious goal of making MS a general device that can be used in everyday life, lots of efforts have been paid to miniaturize the ionization source. This review discusses avant-garde sources that could be entirely hand-held without any accessories. The structure and applications of the devices are described in detail as well. They could be expediently used in real-time and on-site analysis, presenting a great future potential for the routinizing of MS.

Development of a rapid-fire drug screening method by probe electrospray ionization tandem mass spectrometry for human urine (RaDPi-U).

Drug screening tests are mandatory in the search for drugs in forensic biological samples, and immunological methods and mass spectrometry (e.g., gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry) are commonly used for that purpose. However, these methods have some drawbacks, and developing new screening methods is required. In this study, we develop a rapid-fire drug screening method by probe electrospray ionization tandem mass spectrometry (PESI-MS/MS), which is an ambient ionization mass spectrometry method, for human urine, named RaDPi-U. RaDPi-U is carried out in three steps: (1) mixing urine with internal standard (IS) solution and ethanol, followed by vortexing; (2) pipetting the mixture onto a sample plate for PESI; and (3) rapid-fire analysis by PESI-MS/MS. RaDPi-U targets 40 forensically important drugs, which include illegal drugs, hypnotics, and psychoactive substances. The analytical results were obtained within 3 min because of the above-mentioned simple workflow of RaDPi-U. The calibration curves of each analyte were constructed using the IS method, and they were quantitatively valid, resulting in good linearity (0.972-0.999) with a satisfactory lower limit of detection and lower limit of quantitation (0.01-7.1 ng/mL and 0.02-21 ng/mL, respectively). Further, both trueness and precisions were 28% or less, demonstrating the high reliability and repeatability of the method. Finally, we applied RaDPi-U to three postmortem urine specimens and successfully detected different drugs in each urine sample. The practicality of the method is proven, and RaDPi-U will be a strong tool as a rapid-fire drug screening method not only in forensic toxicology but also in clinical toxicology.

Rapid identification of antibiotic residues in bovine kidney using coated blade spray-mass spectrometry.

The use of certain antibiotics in food-producing animals is allowed in Europe following Regulation (EU) 2017/625. However, use could result in antibiotic residues in foodstuffs of animal origin. Maximum residue limits (MRLs) are in place to protect consumers. For monitoring purposes, animal matrices are tested to verify their compliance with these MRLs. Initially, matrices of (slaughtered) food animals are screened, often using a microbiological assay. Faster screening tests for antibiotics would be an advantage for control laboratories. Therefore, the present study describes, for the first time, the use of coated blade spray (CBS) followed by direct mass spectrometry (MS) analysis for the screening of tetracyclines, sulfonamides, quinolones, and macrolides residues from the renal area of intact bovine kidneys. An optimized workflow using two different desorption/ionization solutions per blade allowed screening of target compounds within 1 min per sample. The proof-of-principle of the CBS-MS method is validated according to (EU) 2021/808, presenting CCß screening values of 0.1 × MRL for 43 analytes, 0.5 × MRL for 4 analytes, and 2.5 µg kg-1 for the prohibited substance dapsone, respectively. The developed method was successfully applied to seven official control samples of bovine kidneys. One of these samples was found to be positive using the CBS-MS method, which was confirmed as a true positive by LC-MSMS analysis. The developed method demonstrates that CBS devices can directly extract and analyze kidney samples for food safety testing.

Magnetic particle spray mass spectrometry for the determination of beta-blockers in plasma samples.

Magnetic particle spray mass spectrometry (MPS-MS), an innovative ambient ionization technique proposed by our research group, was employed to determine beta-blockers in human plasma samples. A dispersive solid phase extraction of atenolol, metoprolol, labetalol, propranolol, nadolol, and pindolol was carried out using magnetic molecularly imprinted polymer (M-MIP) particles that were attached to the tip of a metal probe, which was placed in the mass spectrometer inlet. A solvent (1% formic acid in methanol) was dispensed on the particles, and the Taylor cone was formed around them (in high voltage). The analytes were desorbed/ionized and determined by a triple quadrupole mass spectrometer. M-MIP was synthesized with oxprenolol as a pseudo-template, demonstrating good selectivity to beta-blockers compared with no-analog molecules, with an adsorption process occurring in monolayers, according to isotherm studies. Kinetic experiments indicated chemisorption as the predominant M-MIP/analyte interaction. The analytical curves were linear (R2 > 0.98), and the limit of quantification was 3 µg L-1 for all the analytes. Limits of detection ranged from 0.64 to 2.41 µg L-1. Precisions (relative standard deviation) and accuracies (relative error) ranged from 3.95 to 21.20% and -17.05 to 18.93%, respectively. MPS-MS proved to be a simple, sensitive, and advantageous technique compared with conventional approaches. The analyses were fast, requiring no chromatographic separation and without ionic suppression. The method is aligned with green chemistry principles, requiring minimal sample, solvent, and sorbent amounts. MPS-MS successfully integrates sample preparation and ambient ionization mass spectrometry and holds great potential for application with other sorbents, samples, and analytes.

Influence of Solvent Relative Permittivity in Swab Spray Mass Spectrometry.

The influence of solvent properties on ion generation by swab spray ionization was investigated. The ability of a variety of solvents of different relative permittivity, surface tension, and viscosity to form a stable and reproducible electrospray was examined. It is demonstrated that in swab spray ionization, a crucial balance between solvent composition, applied potential, and the solvent flow fed to the swab head must be maintained. The solvent composition was found to significantly affect the shape of the Taylor cone and the emerging cone jet, which eventually have an impact on the resulting ion yield. The results indicate that the relative permittivity of solvents measured under standard conditions is the main factor governing jet shaping, and consequently, the ionization efficacy. Short jets, which are required for maximum ion yield, were observed for solvents with relative permittivity εr higher than 25. Solvents exhibiting lower relative permittivity required the addition of 20% to 60% methanol to limit the jet length and to avoid the ineffective dripping pulsation. The observed effects were compared to conventional electrospray ionization and paper spray ionization.

Paper Spray Mass Spectrometry with On-Paper Electrokinetic Manipulations: Part-Per-Trillion Detection of Per/Polyfluoroalkyl Substances in Water and Opioids in Urine.

We developed a simple, paper-based device that enables sensitive detection by mass spectrometry (MS) without solid phase extraction or other sample preparation. Using glass fiber filter papers within a 3D printed holder, the device employs electrokinetic manipulations to stack, separate, and desalt charged molecules on paper prior to spray into the MS. Due to counter-balanced electroosmotic flow and electrophoresis, charged analytes stack on the paper and desalting occurs in minutes. One end of the paper strip was cut into a sharp point and positioned near the inlet of a MS. The stacked analyte bands move toward the paper tip with the EOF where they are ionized by paper spray. The device was applied to analysis of PFAS in tap water with sub part-per-trillion detection limits in less than ten minutes with no sample pretreatment. Analysis of opioids in urine also occurs in minutes. The crucial parameters to enable stacking, separation, and MS ionization of both positively and negatively charged analytes were determined and optimized. Experimental and computational modeling studies confirm the electrokinetic stacking and analyte transport mechanisms. On-paper separations were carried out by stacking analyte bands at different locations depending on their electrophoretic mobility, achieving baseline separation in some cases.

Analysis of human skin sebum and animal meats by heat pulse desorption/mass spectrometry using proximity corona discharge ionization.

Recently, we have developed heat pulse desorption/mass spectrometry (HPD/MS). In HPD/MS, a heated N2 gas pulse was directed to the sample surface and desorbed analytes were mass analyzed by corona discharge ionization/mass spectrometry using an Orbitrap mass spectrometer. In this work, HPD/MS was applied to the analysis of skin surface components sampled from the forehead, nose, and jaw of three volunteers. It was found that various kinds of biological compounds such as squalene, free fatty acids, wax esters, triacylglycerols, and amino acids were detected. The simultaneous detection of compounds with a wide range of proton affinities suggests that the occurrence of consecutive proton transfer reactions is less likely to occur in the present experimental system. This is mainly due to the short distance of 1.5 mm between the tip of the corona needle and the inlet of the mass spectrometer (i.e., proximity corona discharge ion source). Under this condition, the transition time of the primary reactant ions (e.g., H3O+) from the tip of the corona discharge needle to the ion sampling orifice is roughly estimated to be ∼20 µs. This value nearly corresponds to the reaction lifetime of exoergic proton transfer reactions with a rate constant: ∼10-9 cm3 s-1 for the analytes of 1 ppm. Accordingly, analytes with concentrations less than 1 ppm would be ionized semi-quantitatively by the present method, making this method highly suitable for the rapid analysis of samples composed of complex mixture of compounds, e.g., non-target lipidomics.

Routine analysis of pesticides in foodstuffs: Emerging ambient ionization mass spectrometry as an alternative strategy to be on your radar.

Pesticides residues in foodstuffs are longstanding of great concern to consumers and governments, thus reliable evaluation techniques for these residues are necessary to ensure food safety. Emerging ambient ionization mass spectrometry (AIMS), a transformative technology in the field of analytical chemistry, is becoming a promising and solid evaluation technology due to its advantages of direct, real-time and in-situ ionization on samples without complex pretreatments. To provide useful guidance on the evaluation techniques in the field of food safety, we offered a comprehensive review on the AIMS technology and introduced their novel applications for the analysis of residual pesticides in foodstuffs under different testing scenarios (i.e., quantitative, screening, imaging, high-throughput detection and rapid on-site analysis). Meanwhile, the creative combination of AIMS with high-resolution mass analyzer (e.g., orbitrap and time-of-flight) was fundamentally mentioned based on recent studies about the detection and evaluation of multi-residual pesticides between 2015 and 2021. Finally, the technical challenges and prospects associated with AIMS operation in food industry were discussed.

Characterization of ginsenoside structural isomers from mixtures using in situ methylation with direct analysis in real-time ionization tandem mass spectrometry.

Characterization of structural isomers of bioactive molecules is important for recognizing their functions, but it has been challenging due to their highly similar structures. As the main bioactive constituents of Panax ginseng, ginsenosides have different structural isomers attributed to the aglycone structure and glycosylation sites as well as stereochemistry of sugar groups attached. This work demonstrated a simple and robust in situ methylation reaction with tetramethylammonium hydroxide (TMAH) using ambient ionization source of direct analysis in real time (DART) to characterize saponin structural isomers. The DART ion source provides favorable conditions to methylate hydroxyl groups of ginsenoside instantaneously with TMAH, and it can ionize the methylated products at the same time. Methylated ginsenoside stereoisomers even with subtle structure differences generated very different mass signals from full-scan MS and tandem MS. High-resolution mass spectrometry aided the assignment of molecular structures of the various precursor and fragment ions from different ginsenosides, which provided structural information for both the aglycone skeleton and the sugar moieties in ginsenosides. The presented method was successfully used for the identification of ginsenosides in Panax ginseng, and saponin isomers were characterized without the need for chromatographic separation and/or tedious offline sample pretreatment.

Advances in Mass Spectrometry-Metabolomics Based Approaches.

Highly selective and sensitive analytical techniques are necessary for microbial metabolomics due to the complexity of the microbial sample matrix. Hence, mass spectrometry (MS) has been successfully applied in microbial metabolomics due to its high precision, versatility, sensitivity, and wide dynamic range. The different analytical tools using MS have been employed in microbial metabolomics investigations and can contribute to the discovery or accelerate the search for bioactive substances. The coupling with chromatographic and electrophoretic separation techniques has resulted in more efficient technologies for the analysis of microbial compounds occurring in trace levels. This book chapter describes the current advances in the application of mass spectrometry-based metabolomics in the search for new biologically active agents from microbial sources; the development of new approaches for in silico annotation of natural products; the different technologies employing mass spectrometry imaging to deliver more comprehensive analysis and elucidate the metabolome involved in ecological interactions as they enable visualization of the spatial dispersion of small molecules. We also describe other ambient ionization techniques applied to the fingerprint of microbial natural products and modern techniques such as ion mobility mass spectrometry used to microbial metabolomic analyses and the dereplication of natural microbial products through MS.

Analysis of Pesticide Residues on Fruit Using Swab Spray Ionization Mass Spectrometry.

The vast quantity and high variety of pesticides globally used in agriculture entails considerable risks for the environment and requires ensuring the safety of food products. Therefore, powerful analytical tools are needed to acquire qualitative and quantitative data for monitoring pesticide residues. The development of ambient ionization mass spectrometry methods in the past two decades has demonstrated numerous ways to generate ions under atmospheric conditions and simultaneously to reduce the need for extended sample preparation and circumvent chromatographic separation prior to mass analysis. Swab spray ionization enables the generation of ions directly from swabs via the application of high voltage and solvent flow. In this study, swab sampling of fruit surfaces and subsequent ionization directly from the swab in a modified electrospray ion source was employed for the screening and quantitation of pesticide residues. Aspects regarding sample collection, sampling efficacy on different surfaces, and swab background are discussed. The effect of solvent composition on pesticide-sodium adduct formation and the suppression of ionization by the background matrix have been investigated. Furthermore, a novel approach for the quantitation of pesticide residues based on depletion curve areas is presented. It is demonstrated that swab spray ionization is an effective and quick method for spectral library-based identification and the quantitative analysis of polar contact pesticide residues on food.

Portable mass spectrometry system: instrumentation, applications, and path to 'omics analysis.

Mass spectrometry (MS) is an information rich analytical technique and plays a key role in various 'omics studies. Standard mass spectrometers are bulky and operate at high vacuum, which hinder their adoption by the broader community and utility in field applications. Developing portable mass spectrometers can significantly expand the application scope and user groups of MS analysis. This review discusses the basics and recent advancements in the development of key components of portable mass spectrometers including ionization source, mass analyzer, detector, and vacuum system. Further, major areas where portable mass spectrometers are applied are also discussed. Finally, a perspective on the further development of portable mass spectrometers including the potential benefits for 'omics analysis is provided.