1.1. Mass Spectrometry
A mass spectrometer is described as the smallest weighing scale in the world ever used.1 Mass spectrometry (MS) is a unique technique that has an interdisciplinary nature, which freely crosses the borders of physics, chemistry and biology. Mass spectrometry makes a great scientific tool due to its capabilities to determine the mass of large biomolecular complexes, individual biomolecules, small organic molecules as well as single atoms and their isotopes. Right from the time of its invention in the first decade of the 20th century, mass spectrometry has undergone tremendous improvements in terms of its sensitivity, resolution and mass range. It currently finds applications in all scientific disciplines such as chemistry, physics, biology, pharmacology, medicine, biochemistry and bio-agro-based industry.

Introduction of “soft” ionization sources such as electrospray ionization (ESI) by J.B. Fenn et al.2 and matrix-assisted laser desorption/ionization (MALDI) by M. Karas et al.3 in 1980s revolutionized mass spectrometry as it offered the capability to analyze large intact biomolecules. As such MS became an irreplaceable tool for the biological sciences. The development of both ESI and MALDI made possible the ionization of smaller biomolecules such as drugs and metabolites as well larger biomolecules such as lipids, peptides and even proteins.2,4 The molecular weight (Mw) ranges we use in this review are defined as follows. The low Mw range includes elements and molecules from 1 to 500 Da. Molecules with Mw between 500 and 2000 Da fall in the medium Mw range. All molecules with Mw > 2000 Da are considered to be part of the high molecular weight class. It goes beyond the scope of this review to cover all developments in MS. Rather this review focuses on one of the latest, rapidly developing innovations in MS namely mass spectrometric imaging (MSI). This young technique takes benefit from all methodological and technological developments in general MS over the last decades. Over the last twenty years MSI has transformed from an esoteric, specialist technology studied by few researchers only to a technique that now finds itself at the center stage of mainstream MS. Over the last years the technology has matured to find applications in many different areas, with instrument developments taken up by all MS instrument manufacturers resulting in a rapid rise of the number of research groups active in this area. A thorough review of the area is therefore timely and needed to offer a starting point for all newcomers to the field. In this paper we describe and review approximately 20 years of MSI developement from the perspective of its application to biomedical imaging. We will emphasize the key research steps and pitfalls that determine the outcome of biological applications of this relatively new label free biomolecular imaging technique in life sciences.

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Mass spectrometric imaging for biomedical tissue analysis.

Ambient Sampling/Ionization Mass Spectrometry: Applications and Current Trends

Since our last comprehensive review on multi-dimensional mass spectrometry-based shotgun lipidomics (Mass Spectrom. Rev. 24 (2005), 367), many new developments in the field of lipidomics have occurred. These developments include new strategies and refinements for shotgun lipidomic approaches that use direct infusion, including novel fragmentation strategies, identification of multiple new informative dimensions for mass spectrometric interrogation, and the development of new bioinformatic approaches for enhanced identification and quantitation of the individual molecular constituents that comprise each cell's lipidome. Concurrently, advances in liquid chromatography-based platforms and novel strategies for quantitative matrix-assisted laser desorption/ionization mass spectrometry for lipidomic analyses have been developed. Through the synergistic use of this repertoire of new mass spectrometric approaches, the power and scope of lipidomics has been greatly expanded to accelerate progress toward the comprehensive understanding of the pleiotropic roles of lipids in biological systems.

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Multi-dimensional mass spectrometry-based shotgun lipidomics and novel strategies for lipidomic analyses.

1. Scope of this Review 2270 2. Ambient Ionization Techniques 2272 2.1. Solid−Liquid Extraction-Based Techniques 2272 2.1.1. Desorption Electrospray Ionization (DESI) 2272 2.1.2. Desorption Ionization by Charge Exchange (DICE) 2277 2.1.3. Easy Ambient Sonic-Spray Ionization (EASI) 2278 2.1.4. Liquid Micro Junction Surface Sampling Probe (LMJ-SSP) 2279 2.1.5. Liquid Extraction Surface Analysis (LESA) 2279 2.1.6. Nanospray Desorption Electrospray Ionization (nanoDESI) 2280 2.1.7. Desorption Atmospheric Pressure Photoionization (DAPPI) 2280 2.2. Plasma-Based Techniques 2281 2.2.1. Direct Analysis in Real Time (DART) 2282 2.2.2. Flowing Atmospheric-Pressure Afterglow (FAPA) 2286 2.2.3. Low Temperature Plasma (LTP) & Dielectric Barrier Discharge Ionization (DBDI) 2286 2.2.4. Chemical Sputtering/Ionization Techniques 2287 2.3. Two-Step Thermal/Mechanical Desorption/ Ablation (Non-Laser) Techniques 2288 2.3.1. Neutral Desorption Extractive Electrospray Ionization (ND-EESI) 2288 2.3.2. Beta Electron-Assisted Direct Chemical Ionization (BADCI) 2288 2.3.3. Atmospheric Pressure Thermal Desorption-Secondary Ionization (AP-TD/SI) 2289 2.3.4. Probe Electrospray Ionization (PESI) 2289 2.4. Two-Step Laser-Based Desorption Ablation Techniques 2290 2.4.1. Laser-Based Hybrid Techniques Coupled to ESI or Plasma Ionization 2290 2.4.2. Laser Electrospray Mass Spectrometry (LEMS) 2292 2.4.3. Laser Ablation Atmospheric Pressure Photoionization (LAAPPI) 2293 2.4.4. Laser Ablation Sample Transfer 2293 2.5. Acoustic Desorption Techniques 2294 2.5.1. Laser-Induced Acoustic Desorption (LIAD) 2294 2.5.2. Radiofrequency Acoustic Desorption Ionization (RADIO) 2295 2.5.3. Surface Acoustic Wave-Based Techniques 2295 2.6. Multimode Techniques 2296 2.6.1. Desorption Electrospray/Metastable-Induced Ionization (DEMI) 2296 2.7. Other Techniques 2296 2.7.1. Rapid Evaporative Ionization Mass Spectrometry (REIMS) 2296 2.7.2. Laser Desorption Ionization (LDI) 2297 2.7.3. Switched Ferroelectric Plasma Ionizer (SwiFerr) 2297 2.7.4. Laserspray Ionization (LSI) 2297 3. Remote Sampling 2298 3.1. Nonproximate Ambient MS 2298 3.2. Fundamentals of Neutral/Ion Transport 2298 3.3. Transport of Neutrals 2298 3.4. Transport of Ions 2299 4. Future Directions 2300 Author Information 2300 Corresponding Author 2300 Author Contributions 2300 Notes 2300 Biographies 2300 Acknowledgments 2301 References 2301

Mass Spectrometry: Recent Advances in Direct Open Air Surface Sampling/Ionization

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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Mass spectrometry imaging under ambient conditions.

Latent fingerprints (LFPs) potentially contain more forensic information than the simple identification of the subject; they may contain evidence of contacts with explosives or substances of abuse. Chemical information can also be useful in resolving overlapping LFPs from different individuals. We used desorption electrospray ionization mass spectrometry in an imaging mode to record compound-specific chemical fingerprints.

/pdf/latent-fingerprint-chemical-imaging-by-mass-spectrometry-bkda0zjc18.pdf

Latent fingerprint chemical imaging by mass spectrometry.

Brain tissue biopsies are required to histologically diagnose brain tumors, but current approaches are limited by tissue characterization at the time of surgery. Emerging technologies such as mass spectrometry imaging can enable a rapid direct analysis of cancerous tissue based on molecular composition. Here, we illustrate how gliomas can be rapidly classified by desorption electrospray ionization-mass spectrometry (DESI-MS) imaging, multivariate statistical analysis, and machine learning. DESI-MS imaging was carried out on 36 human glioma samples, including oligodendroglioma, astrocytoma, and oligoastrocytoma, all of different histologic grades and varied tumor cell concentration. Gray and white matter from glial tumors were readily discriminated and detailed diagnostic information could be provided. Classifiers for subtype, grade, and concentration features generated with lipidomic data showed high recognition capability with more than 97% cross-validation. Specimen classification in an independent validation set agreed with expert histopathology diagnosis for 79% of tested features. Together, our findings offer proof of concept that intraoperative examination and classification of brain tissue by mass spectrometry can provide surgeons, pathologists, and oncologists with critical and previously unavailable information to rapidly guide surgical resections that can improve management of patients with malignant brain tumors.

https://cancerres.aacrjournals.org/content/canres/72/3/645.full.pdf

Classifying human brain tumors by lipid imaging with mass spectrometry

Desorption electrospray ionization mass spectrometry for lipid characterization and biological tissue imaging.

Development of methods for rapid distinction between cancerous and non-neoplastic tissues is an important goal in disease diagnosis. To this end, desorption electrospray ionization mass spectrometry (DESI-MS) imaging was applied to analyze the lipid profiles of thin tissue sections of 68 samples of human prostate cancer and normal tissue. The disease state of the tissue sections was determined by independent histopathological examination. Cholesterol sulfate was identified as a differentiating compound, found almost exclusively in cancerous tissues including tissue containing precancerous lesions. The presence of cholesterol sulfate in prostate tissues might serve as a tool for prostate cancer diagnosis although confirmation through larger and more diverse cohorts and correlations with clinical outcome data is needed.

Allison L. Dill

Papers

Mass spectrometry imaging under ambient conditions.

Latent fingerprint chemical imaging by mass spectrometry.

Classifying human brain tumors by lipid imaging with mass spectrometry

Desorption electrospray ionization mass spectrometry for lipid characterization and biological tissue imaging.

Cholesterol Sulfate Imaging in Human Prostate Cancer Tissue by Desorption Electrospray Ionization Mass Spectrometry