Mass Spectrometers

First conceived in 1912, many technical improvements have since advanced the mass spectrometer to the modern set of instruments we know today, contributing many discoveries to the areas of proteomics, metabolomics, pharmacology, forensics, environmental science and more. Improvements such as multiple mass analyzers, ion trapping and coupling to instruments such as gas and liquid chromatographers have expanded what can be analyzed with higher sensitivities and throughput. Research in diverse fields can now enjoy a variety of mass spectrometer choices that, although complex and specialized, can still be categorized by some of its core components: ionization method, type of mass analyzer, and instrument combination. Here we list some established and common considerations for many mass spectrometer systems.

Ionization Methods:

• Electron Ionization (EI) - an electron beam collides with volatile samples to produce radical precursor ions. These precursors can undergo further fragmentation into smaller ions that will produce unique and reproducible patterns for identification of the compound. Also known as electron impact ionization, EI is robust and relatively inexpensive.
  
• Chemical Ionization (CI) - an electron beam first ionizes reagent gas (such as methane), which in turn ionizes and fragments the gaseous sample analytes. CI is a softer ionization method and leaves more precursor ions than EI. Selection of a suitable reagent gas is important for this process.
  
• Matrix Assisted Laser Desorption Ionization (MALDI) - Sample analytes co-crystallized within a matrix are irradiated with a laser pulse, desorbing and vaporizing both sample and matrix. Predominantly singly charged matrix ions are produced and in turn ionize analytes. MALDI is a type of soft ionization and generates mostly precursor ions. Depending on the analyte, different matrixes are used, such as sinapinic acid, a-CHCA, and DHB.
  
• Electrospray Ionization (ESI) - Samples pass through a high voltage spray emitter, dispersing as charged aerosolized droplets. They eventually enter the mass analyzer as finely separated droplets containing an average of one analyte ion or less. Because ESI converts a liquid phase sample to gas phase, this method is used in liquid chromatography-mass spectrometry (LC-MS), and commonly used in proteomic analyses. Typical solvents used with ESI are volatile organics, such as methanol and acetonitrile.
  
• Inductively coupled plasma mass spectrometry (ICP) - Using oscillating electric and magnetic fields, argon gas becomes inductively coupled plasma. Aerosolized samples, upon interaction with the plasma, becomes gaseous and ionized. ICP-MS systems (typically quadrupole analyzers) are useful in elemental analyses such as in detecting metals and trace elements.
  

Mass Analyzers:

• Time of flight (TOF) - Ions are accelerated from the source (through a linear tube or reflection) to a detector, which detects the flight time of the ion. Given a set kinetic energy, the mass/charge ratio (m/z) of the ions are determined based on the time it takes to move across a set distance. Common TOF mass spectrometer combinations include gas chromatography TOF (GC-TOF), MALDI-TOF, and TOF with one or several quadrupoles.
  
• Quadrupole - Four parallel cylindrical rods produce an oscillating electric field that is used to separate ions based on their trajectories. By varying the applied voltages, only ion particles within a desired range of m/z can successfully reach the detector. Quadrupole-based systems are used with liquid chromatography (LC-MS) and can also be connected in series or paired with other mass analyzers in hybrid mass spectrometers. Triple quadrupoles used in tandem mass spectrometry (MS/MS) consist of two mass filter quadrupoles and a collision cell.
  
• Quadrupole Ion Trap - A ring-shaped electrode or modified quadrupoles generate oscillating and static electric fields that traps ions within a 3-dimensional space. While trapped, ions can be selected for future fragmentation and detection. The scanning abilities and high sensitivity of quadrupole ion traps make them ideal in coupling to liquid chromatography (LC-MS) and tandem mass spectrometry (MS/MS).
  
• Fourier transform ion cyclotron resonance (FTICR) - Strong magnetic fields are used to trap ions in 2-D and an electric field adds a third dimension of space. Trapped ions oscillate at frequencies inversely proportional to their m/z; this frequency is measured non-destructively by image current detection plates. These signals undergo Fourier transform to generate a mass sepctrum with very high resolutions.
  
• Orbitrap Ion Trap - A central spindle-like electode enclosed within an outer barrel-like electrode traps analyte ions in an orbital oscillation around the center. The frequency of oscillation is detected non-destructively, undergoing Fourier transform to generate m/z spectra. The orbitrap is highly accurate and is used in LC-MS and MS/MS systems, often accompanied by other mass analyzers and fragmentation modules.

Mass Spectrometer Combinations:

• Tandem Mass Spectrometry (MS/MS) - In MS/MS, precursor ions undergo one round of mass/charge selection, followed by one or more rounds of ion fragmentation, separation and detection. It is highly specific with high detection limits and low chemical noise, allowing for both qualitative and quantitative analysis of complex compounds. In LC-MS, MS/MS systems are coupled to a liquid chromatography (HPLC or UHPLC) workflow for sequencing complex molecules such as polypeptides and oligosaccharides.
  
• Gas chromatography - Mass spectrometry (GC-MS) - GC-MS systems feature a gas chromatograph directly coupled to a mass spectrometer for the precise identification and quantification of volatile or thermally stable compounds. GC-MS applications include environmental, food, forensic, physiological, biochemical, and clinical analyses and in the characterization of new compounds. GC-MS mass analyzer options include TOF, high resolution TOF, triple quadrupole, ion trap, and tandem MS.
  
• Liquid chromatography - Mass spectrometry (LC-MS) - LC-MS utilizes HPLC- or UHPLC-based separation of dissolved samples prior followed by accurate structural identification with mass spectrometry. Ionization methods such as ESI, APCI, APPI and MALDI, bridges the interface from liquid phase into gaseous ions. LC-MS systems are routinely used in many biomedical applications such as proteomics, metabolomics, pharmacokinetics, and drug development.
  LC-MS instruments utilize quadrupole, TOF, ion trap, orbitrap, hybrid and tandem configurations of mass analyzers.