Mass spectrometry imaging under ambient conditions.
TL;DR: The role of bioinformatics in acquiring and interpreting the chemical and spatial information obtained through MSI, especially in biological applications for tissue diagnostic purposes is described, and the challenges in ambient MSI are discussed.
Abstract: Mass spectrometry imaging (MSI) has emerged as an important tool in the last decade and it is beginning to show potential to provide new information in many fields owing to its unique ability to acquire molecularly specific images and to provide multiplexed information, without the need for labeling or staining. In MSI, the chemical identity of molecules present on a surface is investigated as a function of spatial distribution. In addition to now standard methods involving MSI in vacuum, recently developed ambient ionization techniques allow MSI to be performed under atmospheric pressure on untreated samples outside the mass spectrometer. Here we review recent developments and applications of MSI emphasizing the ambient ionization techniques of desorption electrospray ionization (DESI), laser ablation electrospray ionization (LAESI), probe electrospray ionization (PESI), desorption atmospheric pressure photoionization (DAPPI), femtosecond laser desorption ionization (fs-LDI), laser electrospray mass spectrometry (LEMS), infrared laser ablation metastable-induced chemical ionization (IR-LAMICI), liquid microjunction surface sampling probe mass spectrometry (LMJ-SSP MS), nanospray desorption electrospray ionization (nano-DESI), and plasma sources such as the low temperature plasma (LTP) probe and laser ablation coupled to flowing atmospheric-pressure afterglow (LA-FAPA). Included are discussions of some of the features of ambient MSI for example the ability to implement chemical reactions with the goal of providing high abundance ions characteristic of specific compounds of interest and the use of tandem mass spectrometry to either map the distribution of targeted molecules with high specificity or to provide additional MS information on the structural identification of compounds. We also describe the role of bioinformatics in acquiring and interpreting the chemical and spatial information obtained through MSI, especially in biological applications for tissue diagnostic purposes. Finally, we discuss the challenges in ambient MSI and include perspectives on the future of the field.
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TL;DR: In the last 15 years, innovations in the field of ambient ionization MS have grown expansively, pushing these technologies far past their point of conception and integrating them into the broader scientific community in creative and stimulating ways.
Abstract: The early 2000s brought a new age in the field of mass spectrometry (MS) with the introduction of ambient ionization MS techniques. As defined by one of its early visionaries, Prof. R. Graham Cooks, ambient ionization refers to \"the ionization of unprocessed or minimally modified samples in their native environment, and it typically refers to the ionization of condensed phase samples in air.\" Since its inception in 2004, many researchers and laboratories have contributed with approaches for sampling and ionization at atmospheric conditions, greatly decreasing experimental complexity and time required for mass spectrometry analyses. In the last 15 years, innovations in the field of ambient ionization MS have grown expansively, pushing these technologies far past their point of conception and integrating them into the broader scientific community in creative and stimulating ways.
268 citations
TL;DR: The MasSpec Pen, a handheld pen-like device that rapidly identifies the molecular profile of tissues using a small volume water droplet and mass spectrometry analysis, is developed and used for ex vivo and in vivo cancer diagnosis of human cancer tissues.
Abstract: Conventional methods for histopathologic tissue diagnosis are labor- and time-intensive and can delay decision-making during diagnostic and therapeutic procedures. We report the development of an automated and biocompatible handheld mass spectrometry device for rapid and nondestructive diagnosis of human cancer tissues. The device, named MasSpec Pen, enables controlled and automated delivery of a discrete water droplet to a tissue surface for efficient extraction of biomolecules. We used the MasSpec Pen for ex vivo molecular analysis of 20 human cancer thin tissue sections and 253 human patient tissue samples including normal and cancerous tissues from breast, lung, thyroid, and ovary. The mass spectra obtained presented rich molecular profiles characterized by a variety of potential cancer biomarkers identified as metabolites, lipids, and proteins. Statistical classifiers built from the histologically validated molecular database allowed cancer prediction with high sensitivity (96.4%), specificity (96.2%), and overall accuracy (96.3%), as well as prediction of benign and malignant thyroid tumors and different histologic subtypes of lung cancer. Notably, our classifier allowed accurate diagnosis of cancer in marginal tumor regions presenting mixed histologic composition. Last, we demonstrate that the MasSpec Pen is suited for in vivo cancer diagnosis during surgery performed in tumor-bearing mouse models, without causing any observable tissue harm or stress to the animal. Our results provide evidence that the MasSpec Pen could potentially be used as a clinical and intraoperative technology for ex vivo and in vivo cancer diagnosis.
264 citations
TL;DR: Recent applications of metabolomics are described and its increasing application to study plant responses to environmental (stress-) factors, including drought, salt, low oxygen caused by waterlogging or flooding of the soil, temperature, light and oxidative stress are described.
Abstract: Metabolomics is one omics approach that can be used to acquire comprehensive information on the composition of a metabolite pool to provide a functional screen of the cellular state. Studies of the plant metabolome include analysis of a wide range of chemical species with diverse physical properties, from ionic inorganic compounds to biochemically derived hydrophilic carbohydrates, organic and amino acids, and a range of hydrophobic lipid-related compounds. This complexitiy brings huge challenges to the analytical technologies employed in current plant metabolomics programs, and powerful analytical tools are required for the separation and characterization of this extremely high compound diversity present in biological sample matrices. The use of mass spectrometry (MS)-based analytical platforms to profile stress-responsive metabolites that allow some plants to adapt to adverse environmental conditions is fundamental in current plant biotechnology research programs for the understanding and development of stress-tolerant plants. In this review, we describe recent applications of metabolomics and emphasize its increasing application to study plant responses to environmental (stress-) factors, including drought, salt, low oxygen caused by waterlogging or flooding of the soil, temperature, light and oxidative stress (or a combination of them). Advances in understanding the global changes occurring in plant metabolism under specific abiotic stress conditions are fundamental to enhance plant fitness and increase stress tolerance. © 2015 Wiley Periodicals, Inc. Mass Spec Rev 35:620-649, 2016.
243 citations
Cites background or methods from "Mass spectrometry imaging under amb..."
...Another study that unravelled the metabolite response of barley to salinity stress compared cultivated and wild barley (Wu et al., 2013b)....
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...In leaves, changes in amino acid metabolism seemed to be critical to develop salt tolerance (Wu et al., 2013b)....
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...…LC–MS sample-preparation protocols, MSI sample preparation is not extensive, and therefore, analyses are commonly performed in situ with ionization techniques (McDonnell & Heeren, 2007; Van Hove, Smith, & Heeren, 2010; Wu et al., 2013a) to ionize and desorb the analytes directly from the tissue....
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...Compared to GC– and LC–MS sample-preparation protocols, MSI sample preparation is not extensive, and therefore, analyses are commonly performed in situ with ionization techniques (McDonnell & Heeren, 2007; Van Hove, Smith, & Heeren, 2010; Wu et al., 2013a) to ionize and desorb the analytes directly from the tissue....
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...Detailed information can be found in other reviews (Table 2) (McDonnell & Heeren, 2007; Masujima, 2009; Van Hove, Smith, & Heeren, 2010; Wu et al., 2013a; Bjarnholt et al., 2014)....
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TL;DR: This chapter provides a glimpse at the current status of the mass spectrometry-based metabolomics field highlighting the opportunities and challenges.
Abstract: The field of metabolomics has witnessed an exponential growth in the last decade driven by important applications spanning a wide range of areas in the basic and life sciences and beyond. Mass spectrometry in combination with chromatography and nuclear magnetic resonance are the two major analytical avenues for the analysis of metabolic species in complex biological mixtures. Owing to its inherent significantly higher sensitivity and fast data acquisition, MS plays an increasingly dominant role in the metabolomics field. Propelled by the need to develop simple methods to diagnose and manage the numerous and widespread human diseases, mass spectrometry has witnessed tremendous growth with advances in instrumentation, experimental methods, software, and databases. In response, the metabolomics field has moved far beyond qualitative methods and simple pattern recognition approaches to a range of global and targeted quantitative approaches that are now routinely used and provide reliable data, which instill greater confidence in the derived inferences. Powerful isotope labeling and tracing methods have become very popular. The newly emerging ambient ionization techniques such as desorption ionization and rapid evaporative ionization have allowed direct MS analysis in real time, as well as new MS imaging approaches. While the MS-based metabolomics has provided insights into metabolic pathways and fluxes, and metabolite biomarkers associated with numerous diseases, the increasing realization of the extremely high complexity of biological mixtures underscores numerous challenges including unknown metabolite identification, biomarker validation, and interlaboratory reproducibility that need to be dealt with for realization of the full potential of MS-based metabolomics. This chapter provides a glimpse at the current status of the mass spectrometry-based metabolomics field highlighting the opportunities and challenges.
225 citations
TL;DR: This review will discuss some key technological developments that have occurred over this time with an emphasis on technologies that will create new avenues for biomarker discovery.
Abstract: The greatest unmet needs in biomarker discovery are those discoveries that lead to the development of clinical diagnostic tests. These clinical diagnostic tests can provide early intervention when a patient would present otherwise healthy (e.g., cancer or cardiovascular disease) and aid clinical decision making with improved clinical outcomes. The past two decades have seen significant technological improvements in the analytical capabilities of mass spectrometers. Mass spectrometers are unique in that they can directly analyze any biological molecule susceptible to ionization. The biological studies of human metabolites and proteins using contemporary mass spectrometry technology (metabolomics and proteomics, respectively) has been ongoing for over a decade. Some of these studies have resulted in exciting insights into human biology. However, relatively few biomarkers have been translated into clinical tests. This review will discuss some key technological developments that have occurred over this time with an emphasis on technologies that will create new avenues for biomarker discovery.
206 citations
Cites methods from "Mass spectrometry imaging under amb..."
...The most commonly applied direct ionization techniques are Desorption Electrospray Ionization (DESI) [45] and Laser Ablation Electrospray Ionization (LAESI) [46], though other iterations are also being developed rapidly [47]....
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References
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TL;DR: The Orbitrap as mentioned in this paper is a mass analyzer based on an electrospray ionization source (ESI) with an outer barrel-like electrode, coaxial with the inner spindlelike electrode and mass/charge values measured from the frequency of harmonic ion oscillations along the axis of the electric field, undergone by the orbitally trapped ions.
Abstract: Research areas such as proteomics and metabolomics are driving the demand for mass spectrometers that have high performance but modest power requirements, size, and cost. This paper describes such an instrument, the Orbitrap, based on a new type of mass analyzer invented by Makarov. The Orbitrap operates by radially trapping ions about a central spindle electrode. An outer barrel-like electrode is coaxial with the inner spindlelike electrode and mass/charge values are measured from the frequency of harmonic ion oscillations, along the axis of the electric field, undergone by the orbitally trapped ions. This axial frequency is independent of the energy and spatial spread of the ions. Ion frequencies are measured non-destructively by acquisition of time-domain image current transients, with subsequent fast Fourier transforms (FFTs) being used to obtain the mass spectra. In addition to describing the Orbitrap mass analyzer, this paper also describes a complete Orbitrap-based mass spectrometer, equipped with an electrospray ionization source (ESI). Ions are transferred from the ESI source through three stages of differential pumping using RF guide quadrupoles. The third quadrupole, pressurized to less than 10(-3) Torr with collision gas, acts as an ion accumulator; ion/neutral collisions slow the ions and cause them to pool in an axial potential well at the end of the quadrupole. Ion bunches are injected from this pool into the Orbitrap analyzer for mass analysis. The ion injection process is described in a simplified way, including a description of electrodynamic squeezing, field compensation for the effects of the ion injection slit, and criteria for orbital stability. Features of the Orbitrap at its present stage of development include high mass resolution (up to 150,000), large space charge capacity, high mass accuracy (2-5 ppm), a mass/charge range of at least 6000, and dynamic range greater than 10(3). Applications based on electrospray ionization are described, including characterization of transition-metal complexes, oligosaccharides, peptides, and proteins. Use is also made of the high-resolution capabilities of the Orbitrap to confirm the presence of metaclusters of serine octamers in ESI mass spectra and to perform H/D exchange experiments on these ions in the storage quadrupole.
1,309 citations
"Mass spectrometry imaging under amb..." refers background in this paper
...Nevertheless the improved resolution of the instrument resolves many isobaric species and increases the amount of chemical information obtained from complex samples although at a cost in terms of signal intensity and/or time (Hu et al., 2005; Manicke et al., 2009a)....
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TL;DR: In DESI as discussed by the authors, electrically charged droplets are directed at the ambient object of interest; they release ions from the surface, which are then vacuumed through the air into a conventional mass spectrometer.
Abstract: A recent innovation in mass spectrometry is the ability to record mass spectra on ordinary samples, in their native environment, without sample preparation or preseparation by creating ions outside the instrument. In desorption electrospray ionization (DESI), the principal method described here, electrically charged droplets are directed at the ambient object of interest; they release ions from the surface, which are then vacuumed through the air into a conventional mass spectrometer. Extremely rapid analysis is coupled with high sensitivity and high chemical specificity. These characteristics are advantageously applied to high-throughput metabolomics, explosives detection, natural products discovery, and biological tissue imaging, among other applications. Future possible uses of DESI for in vivo clinical analysis and its adaptation to portable mass spectrometers are described.
1,307 citations
"Mass spectrometry imaging under amb..." refers background in this paper
...The main DESI mechanism has been summarily described as ‘‘droplet pickup’’ (Cooks et al., 2006)....
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...In ambient ionization (i) the surface is sampled with minimal or no preparation, (ii) ionization occurs externally to the mass spectrometer, and (iii) ions, not the entire sample, are introduced into the mass spectrometer (Cooks et al., 2006)....
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TL;DR: Many of the instrumental developments and methodological approaches responsible for an increasing upsurge in interest in imaging mass spectrometry are reviewed, compare and contrast the information provided by SIMS and MALDI imaging, and discuss future possibilities.
Abstract: Imaging mass spectrometry combines the chemical specificity and parallel detection of mass spectrometry with microscopic imaging capabilities. The ability to simultaneously obtain images from all analytes detected, from atomic to macromolecular ions, allows the analyst to probe the chemical organization of a sample and to correlate this with physical features. The sensitivity of the ionization step, sample preparation, the spatial resolution, and the speed of the technique are all important parameters that affect the type of information obtained. Recently, significant progress has been made in each of these steps for both secondary ion mass spectrometry (SIMS) and matrix-assisted laser desorption/ionization (MALDI) imaging of biological samples. Examples demonstrating localization of proteins in tumors, a reduction of lamellar phospholipids in the region binding two single celled organisms, and sub-cellular distributions of several biomolecules have all contributed to an increasing upsurge in interest in imaging mass spectrometry. Here we review many of the instrumental developments and methodological approaches responsible for this increased interest, compare and contrast the information provided by SIMS and MALDI imaging, and discuss future possibilities.
946 citations
TL;DR: In this paper, the mechanism of ablation of solids by intense femtosecond laser pulses is described in an explicit analytical form, and the formulas for ablation thresholds and ablation rates for metals and dielectrics, combining the laser and target parameters, are derived and compared to experimental data.
Abstract: The mechanism of ablation of solids by intense femtosecond laser pulses is described in an explicit analytical form. It is shown that at high intensities when the ionization of the target material is complete before the end of the pulse, the ablation mechanism is the same for both metals and dielectrics. The physics of this new ablation regime involves ion acceleration in the electrostatic field caused by charge separation created by energetic electrons escaping from the target. The formulas for ablation thresholds and ablation rates for metals and dielectrics, combining the laser and target parameters, are derived and compared to experimental data. The calculated dependence of the ablation thresholds on the pulse duration is in agreement with the experimental data in a femtosecond range, and it is linked to the dependence for nanosecond pulses.
749 citations
"Mass spectrometry imaging under amb..." refers background in this paper
...NIR femtosecond laser pulses are characterized by having very high peak power densities ( 10(14) W/cm(2)) which allows direct non-resonant desorption and ionization of analytes (Gamaly et al., 2002)....
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...NIR femtosecond laser pulses are characterized by having very high peak power densities ( 1014 W/cm2) which allows direct non-resonant desorption and ionization of analytes (Gamaly et al., 2002)....
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TL;DR: In this paper, a process and apparatus which combine infrared laser ablation (LA) with electrospray ionization (ESI) is described, which is called atmospheric pressure mass spectrometry (APMS).
Abstract: The field of the invention is atmospheric pressure mass spectrometry (MS), and more specifically a process and apparatus which combine infrared laser ablation (LA) with electrospray ionization (ESI).
688 citations