Tools
Mass Spectrometer
Introduction
Mass spectrometry (MS) is a highly effective qualitative and quantitative analytical technique used to identify and quantify a wide range of clinically relevant analytes.[1] When coupled with gas or liquid chromatographs, mass spectrometers expand analytical capabilities to various clinical applications.[2] In addition, due to its ability to identify and quantify proteins, mass spectrometry is an essential analytical tool in the field of proteomics.[3]
Most mass spectrometry data are presented in units of the mass-to-charge ratio (m/z), where m is the molecular weight of the ion (in daltons), and z is the number of charges present on the measured molecule.[4] For small molecules (<1000 Da), there is typically only a single charge; therefore, the m/z value is the same as the mass of the molecular ion.[5] However, when larger molecules such as proteins or peptides are measured, they typically carry multiple ionic charges, and, therefore, the z-value is an integer greater than 1. In these cases, the m/z value is a fraction of the ion's mass.[6]
Sample preparation is crucial for successful mass spectrometry, particularly when analyzing complex matrices commonly encountered in clinical chemistry. This process typically involves one or more of the following steps—protein precipitation followed by centrifugation or filtration, solid-phase extraction, liquid-liquid extraction, affinity enrichment, or derivatization.[7] Derivatization is the process of chemically modifying the target compounds to make them more suitable for analysis by mass spectrometry.[8] This process typically involves the addition of some well-defined functional groups.[9] The goals of derivatization vary depending on the application but typically include increased volatility, greater thermal stability, modified chromatographic properties, greater ionization efficiency, favorable fragmentation properties, or a combination of these.[10]
Mass spectrometers convert molecules into ions, which are then manipulated using electric and magnetic fields.[11] This process requires 3 main components as follows:
- Ion source: A sample is placed into the mass spectrometer, which is then ionized by the apparatus.[12]
- Mass analyzer: Ions are sorted in the device based on their mass-to-charge ratio (m/z).
- Detector: Ions are measured and displayed on the mass spectrum chart.
Atoms and molecules must first be ionized before being accelerated through the mass spectrometer and detected.[13] The sample molecule introduced into the mass spectrometer first gets a positive charge from an ionization source. This positive charge is achieved by removing a valence electron. Alternatively, protons can also be added to create a positive electrical charge. Once ionized, the molecule breaks apart into smaller fragments, then separated according to their mass-to-charge ratio in the mass analyzer.[1] Of note, only the cationic fragments are separated. The neutral species in the mass spectrometer go undetected as they are either absorbed by the apparatus or removed by a vacuum. After the ions are separated, the detector quantifies the ions.[11]
A chart is generated to analyze the mass spectrometer's results, with the mass-to-charge ratio (m/z) on the x-axis and the relative intensity on the y-axis. [12] For a given sample, the most abundant ion in the sample molecule is known as the base peak.[14] This ion is set to 100% on the y-axis for its relative intensity, and all the remaining ion peaks are generated relative to this value. The molecular ion peak is known as the parent peak because it corresponds to the molecular weight of the sample.[15] For example, if the specimen in the mass spectrometer is hexane, the m/z is 86, as the molecular weight of hexane is 86 g/mol. In addition, if there is a peak at m/z=87, this is classified as the m+1 peak because all atoms have various isotopes.[11]
Specimen Requirements and Procedure
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Specimen Requirements and Procedure
Before using the mass spectrometer, a sample must be prepared for ionization, typically by converting it into either a liquid or gaseous phase using chromatography techniques. The 2 types of chromatography procedures that are used to prepare the sample are gas chromatography and liquid chromatography.[16]
Gas Chromatography
Gas chromatography separates components of a mixture of gases and filters the passage of these molecules based on physical characteristics such as shape, size, molecular weight, and boiling point. The sample is diluted and vaporized in the chromatograph, where it is separated. After separation, the gases enter the mass spectrometer for analysis. Notably, a gas chromatography sample must be volatile, meaning it must be capable of entering the gas phase without breaking down in the mass spectrometer.[17]
Liquid Chromatography
Liquid chromatography separates samples based on interactions with the mobile and stationary phases, often depending on polarity. If a component's polarity differs from that of the mobile phase, it migrates more quickly through the chromatography column. The sample is separated into bands of individual components that can be further analyzed in mass spectrometry.[18] Other techniques used for sample preparation include electrospray ionization, which uses high voltages to separate components, and fast atom bombardment, which uses a beam to generate ions from a solid phase.[19][20] The types of samples that can be analyzed within mass spectrometry include proteins, nucleic acids, lipids, and fatty acids.[21]
Testing Procedures
In mass spectrometry, several key components are involved in analyzing a sample.
Ionization
During ionization, atoms are ionized by removing an electron, producing a positive ion known as a cation. Mass spectrometers only analyze positive ions. Cations are formed regardless of the present state of the atoms. For example, this is true even if there is initially a negative ion in the sample, such as fluoride, or an element that does not form ions, such as neon.[22] Inside the mass spectrometer, an electrical field is generated that emits electrons. These electrons return to the electron trap, forming collisions to knock off the electrons to create cations.[23]
The most common form of ionization used in gas chromatography/mass spectrometry (GC/MS) is electron ionization. This method requires a source of electrons in the form of a filament to which an electric potential is applied, typically at 70 eV.[24] The molecules in the source are bombarded with high-energy electrons, resulting in the formation of charged molecular ions and fragments. Molecules break down into characteristic fragments according to their molecular structure.[25] The resulting ions and their relative proportions are reproducible, enabling the qualitative identification of compounds.[26]
Unlike electron ionization in GC/MS, most liquid chromatography/mass spectrometry (LC/MS) ionization techniques are conducted at atmospheric pressure. Electrospray ionization and atmospheric pressure chemical ionization are soft ionization techniques that leave the molecular ion largely intact in the source.[27] Many LC/MS techniques use technologies after the source, in the mass analyzer, to fragment molecules and generate the daughter or fragment ions used in identification.[28] However, ionization techniques in LC/MS produce fragments and, therefore, mass spectra that are somewhat less reproducible between instruments compared to the electron ionization method used in gas GC/MS.[29]
Electrospray ionization uses a combination of voltage, heat, and air to produce successively smaller droplets from the liquid, eluting off a chromatographic column.[30] As the solvent evaporates, the droplets become more concentrated, significantly increasing charge per unit volume. Ions accumulated at the droplet surface desorb from the liquid into the gas phase, allowing these gas phase ions to enter the mass spectrometer for analysis.[31] In addition, complete evaporation of the solvent liberates large ions, such as proteins, producing the necessary gas phase ions for analysis.[32] Atmospheric pressure chemical ionization produces ions using a combination of heat to completely vaporize the sample and plasma produced by an electrical discharge, commonly referred to as a corona discharge.[33] The corona discharge ionizes the evaporated solvent, and through physical interaction with gaseous sample components, including the analytes of interest, positive or negative ions are formed.[34]
Acceleration
All ions undergo acceleration to achieve the same amount of kinetic energy. Cations pass through slits in the mass spectrometer apparatus and accelerate into the ion beam, allowing the mass analyzer to start separating the ions based on the mass-to-charge ratio.[35]
Deflection
A magnetic field deflects the cations based on their mass and charge. Mass and deflection are inversely proportional, whereas charge and deflection are directly proportional. Therefore, ions with a lower mass are deflected more, and ions with a higher positive charge experience greater deflection.[36] This process allows the apparatus to determine the mass-to-charge ratio. The mass-to-charge ratio is denoted by m/z. For example, if an ion has a mass of 120 and a charge of 3+, the m/z ratio is 40. Notably, most ions passing through the mass spectrometer carry a charge of 1+, meaning their mass (or molecular weight) is typically equivalent to the m/z value.[37]
Detection
In mass spectrometry, a detector quantifies the ions and removes certain ones. Positive ions are detected using the apparatus, whereas neutral ions are removed by the vacuum.[38] The most common detection method is the electron multiplier.[39] In this detector, a series of dynodes with increasing potentials are linked. When ions strike the first dynode surface, electrons are emitted. These electrons are attracted to the next dynode, where more secondary electrons are emitted due to the higher potential of subsequent dynodes. A cascade of electrons is formed by the end of the chain of dynodes, resulting in overall signal amplification on the order of 1 million or greater.[40]
Vacuum
Mass spectrometers operate at low pressure, which creates a vacuum effect as there is less probability that ions collide with one another in the apparatus. This environment facilitates the proper separation of cations from the neutral ions, as the vacuum removes the neutral molecules.[41]
Interfering Factors
The primary sources of interference in mass spectrometry typically occur during sample preparation and the measurement of separated ions within the spectrometer. Interference can occur due to inaccurate sample handling when acquiring from patients or improper quality control.[42] Interference alters the concentration of the molecules, which can result in the inaccuracy of the mass spectrometer graph due to potential contaminants or other ions appearing.[43]
Results, Reporting, and Critical Findings
Mass spectrometry produces results for the mass-to-charge ratio of ions in a compound.[2] The results are reproduced on a graph known as a mass spectrum, which plots the relative abundance of ions versus the mass-to-charge ratio.[3] The spectra showcase elements and isotopes to configure a given compound's chemical identity and structure.[14] The graph should be analyzed to deduce the structural quality of the compound based on the mass spectrometer. The graph consists of 3 main components and an additional component depending on the isotopes present in the sample, which are relevant for determining the structure.
- Molecular ion peak (or parent peak): This is the second-highest peak that corresponds directly to the compound in question. The m/z ratio directly correlates to the molecular weight. For example, if hexane is the compound, the m/z ratio is 86, reflecting its molecular weight of 86 g/mol.[44]
- Base peak: This is the ion with the highest relative abundance in the compound out of all the ions in the given sample. The relative intensity of this ion is set to 100%, and all other ion peaks are set relative to this value.[45]
- M+1 peak: This smaller peak corresponds to an isotope in the sample. For example, if the molecular weight of the specimen is 96 g/mol, the m/z ratio is 96. Thus, the m+1 peak is at an m/z of 97. Although it may seem confusing for an ion to have a mass greater than the compound itself, this occurs due to isotopes of elements, such as carbon and hydrogen, contributing to the formation of the m+1 peak.[46]
- M+2 peak: This is another small peak similar to the m+1 peak. Certain elements, such as chlorine and oxygen, have multiple isotopes, which is why these elements in a given compound can result in an m+2 peak.[46]
Clinical Significance
Mass spectrometry is applicable across diverse fields, including forensic toxicology, metabolomics, proteomics, pharma/biopharma, and clinical research. Specific applications of mass spectrometry include drug testing and discovery, food contamination detection, pesticide residue analysis, isotope ratio determination, protein identification, and carbon dating.[47]
Applications of Mass Spectrometry in the Diagnosis of Disease
Mass spectrometers are primarily used in clinical settings to diagnose diseases due to biomarkers. Biomarkers are used in diagnoses, prognoses, and treatment.[48] For example, the enzyme amylase can be used as a biomarker for pancreatitis in disease diagnosis. Similarly, natriuretic peptides are monitored in patients with cardiovascular diseases to predict patient outcomes. Mass spectrometry can be used to examine the metabolic profile of pharmacologic agents to monitor the efficacy of certain therapies.[49]
Mass spectrometers can measure biomarkers, ranging in size from small molecules to large macromolecules.[50] The principle of mass spectrometers also applies to human body samples such as plasma and serum blood, urine, saliva, sweat, and skin secretions.[2] Using liquid or gas chromatography allows for biomarkers to be separated and analyzed in smaller pieces, which optimizes the sensitivity and specificity of the spectrometer. Thus, mass spectrometers thereby improve clinical decision-making.[6] Mass spectrometers analyze a sample and its biomarker profile to diagnose disease. Of note, 2 critical biomarkers are proteins and lipids.[13] In earlier examples, it was stated that enzymes, which are proteins, can be used to detect diseases. Similarly, a lipid panel has often been used to diagnose diseases such as metabolic syndrome.[1]
If the biomarker is a protein, the principles of proteomics can be applied to mass spectrometry.[13] Mass spectrometry has been used to quantify differences between 2 biological states of proteomes, a set of proteins produced in a specific organism. A protein sample is placed into the spectrometer, and the mass of the individual components of the protein is tagged based on the isotopes generated through spectral analyses.[2] The mass spectrometer is useful in this setting because it generates spectral data for proteomes, allowing the human body to analyze proteins in urine and serum.[3]
If the biomarker is a lipid, the principles of lipidomics can be applied to generate a clinical profile for the patient using mass spectrometry.[21] Lipidomics consists of the lipid profile and set of reactions generated within biology. Lipids are used for energy storage and assist in the endocrine regulation of the body system.[51] Mass spectrometry has been used to characterize masses of important ingredients in lipid oxidation reactions, helping quantify the various molecules of lipid reactions and, thus, their biological properties within the human body.[52]
Applications of Mass Spectrometry in COVID-19
During the peak of the coronavirus pandemic, many countries were hindered by inadequate testing due to supply chain shortages and inconsistencies in mass-produced testing kits. Clinical laboratories thus created a method to use mass spectrometry. Nasal swab samples of patients were analyzed using mass spectrometry, and the pattern generated by the spectrum was used to categorize patients if they were COVID-19 positive or negative.[53]
Applications of Mass Spectrometry in Pharmaceuticals
Mass spectrometry plays a crucial role in the analysis of pharmaceutical drugs. The ionization process within the apparatus helps differentiate the molecules that create the drugs. This capability is essential for conducting faster and more accurate screenings during clinical analysis of patient samples, leading to improved drug monitoring and safety.[54]
Applications of Mass Spectrometry in the Analysis of Glycans
Oligosaccharides are molecules formed by associating several monosaccharides linked through glycosidic bonds. Determining the complete structure of oligosaccharides is more complex compared to that of proteins or oligonucleotides. This process involves the determination of additional components as a consequence of the isomeric nature of monosaccharides and their capacity to form linear or branched oligosaccharides.[55] Knowing the structure of an oligosaccharide requires not only the determination of its monosaccharide sequence and its branching pattern but also the isomer position and the anomeric configuration of each of its glycosidic bonds.[56] Advances in glycobiology involve a comprehensive study of the structure, biosynthesis, and biology of sugars and saccharides. Mass spectrometry is emerging as an enabling technology in the field of glycomics and glycobiology.[57]
Applications of Mass Spectrometry in the Analysis of Oligonucleotides
Oligonucleotides, DNA or RNA, are linear polymers of nucleotides. These nucleotides are composed of a nitrogenous base, a ribose sugar, and a phosphate group.[58] Oligonucleotides may undergo several natural covalent modifications, which are commonly present in transfer RNA and ribosomal RNA, or unnatural ones resulting from reactions with exogenous compounds.[59] Mass spectrometry plays a vital role in identifying these modifications and determining their structure and position in the oligonucleotide. This technique allows the determination of the molecular weight of oligonucleotides and, directly or indirectly, their sequences.[60]
Applications of Mass spectrometry in Environmental Analysis
Drinking water testing, pesticide screening and quantitation, soil contamination assessment, monitoring carbon dioxide levels and pollution, and conducting trace elemental analysis of heavy metals leaching.[61]
Applications of Mass Spectrometry in Forensic Analysis
In forensic science, mass spectrometry is used to analyze trace evidence, such as fibers from carpets and polymers found in paints. Mass spectrometry is also essential in arson investigations to detect fire accelerants, confirm drug abuse, and identify explosive residues in bombing investigations.[62]
Quality Control and Lab Safety
When working in the laboratory, it is crucial to exercise caution while preparing samples before introducing the compound into the mass spectrometer for analysis. For example, using the proper measuring tools for accuracy during chromatography is essential.[63] If quality control is not used, resultant peaks may form in the mass spectrum, which does not correspond to ions within the sample.[64]
Operating the mass spectrometer requires safety to be taken into consideration. The mass spectrometer apparatus can have high temperatures, resulting in burns. Thus, it is important not to touch any part of the apparatus while the spectral data is generated. In addition, ionization occurs within the device, so it is essential to be cautious when running a mass spectrometer. Lastly, the samples placed in the spectrometer could be hazardous upon exposure to the skin or inhalation.[65] Thus, wearing the appropriate personal protective equipment, such as safety glasses, long pants, closed-toed shoes, a long lab coat, and gloves, is highly recommended.[66]
Enhancing Healthcare Team Outcomes
Interprofessional communication is essential when using mass spectrometers. For example, if a patient presents to the emergency department after ingesting an unknown compound, lab technicians and pathologists can analyze the patient's sample to identify the components present in the substance. This collaboration enables laboratory professionals to support healthcare workers, including nurses and physicians, in hospital or clinic settings.
In the emergency room, clinicians play a crucial role in fostering this interprofessional environment by sharing the patient's medical history and physical examination findings. This information can help narrow the possible compounds in the patient's sample, facilitating a more accurate and timely diagnosis and treatment plan.
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