Mass spectrometers, one of the principal instruments for investigating chemical composition, operate by separating ions according to their mass/charge ratio by transmitting them through a magnetic and electrical field. The ions are initially created from molecules through a destructive process such as collision or laser irradiation and are evaluated after separation by an integrated detector.
The initial concept of mass spectrometry (MS) was ignited in the late 1890s, came to realization during the 20th century, and continues to evolve in the 21st century. The key milestones in the development of mass spectrometry are described below.
In 1921, the instrument that we now consider to be the first mass spectrometer (although it was then known as the ‘parabola spectrograph’) was constructed by J.J. Thomson. Thomson was the renowned British physicist who had some years earlier discovered the electron. Within the span of a few years, MS had become an established method for the separation of ions on the basis of their mass, although there was to be little significant development of the technique until the 1940s.
It was during the 1940s that MS began to move away from its academic origins to find use in more practical applications such as nuclear isotope enrichment and the study of the composition of petroleum.
In 1941, John Hipple designed the first portable mass spectrometer which was marketed by Westinghouse Electric. However, this model did not seem to catch the imagination of scientists, and was not a commercial success.
In 1943, the Consolidated Engineering Corporation (CEC) became the first company to achieve market success in the MS field, initially selling the CEC Model 21-101 mass spectrometer to the Atlantic Refining Corp. (Philadelphia, PA).
In 1946, the first time-of-flight (TOF) mass analyzer was developed by W. Stephens of Pennsylvania. TOF MS involves acceleration of ions through an electric field of known strength, which confers the same kinetic energy to all ions of equal charge. By measuring the time taken for a particle to reach the detector, the mass/charge ratio of particles can be calculated.
In 1948, the first mass spectrometer to use electron ionization (EI), the MS-2, was launched by Vickers in Manchester, England.
Also in 1948, the first ion cyclotron mass spectrometer, known as the Omegatron, was developed at the University of Minnesota. This spectrometer incorporated a dual inlet with a changeover valve for rapid sample switching.
During the early 1950s, the mass spectrometer was still extremely restricted in terms of its resolution limits. However, the instruments developed during this time may be considered the forerunners of today’s popular and ubiquitous benchtop models.
In 1953, Wolfgang Paul and Helmut Steinwedel initiated development of the quadrupole mass analyzer (and quadrupole ion trap). In such a device, ions are separated by use of a quadrupolar electrical field consisting of both direct current and radiofrequency components. Quadrupole instruments are currently very popular, with sales exceeding the total of all other types of mass spectrometer.
In 1956, Roland Gohlke and Fred McLafferty initiated the trend of coupling the mass spectrometer to other techniques by developing gas chromatography-mass spectrometry (GC-MS). Model 12-101 using GC-MS with a TOF mass spectrometer was developed by the Bendix Aviation Corporation and allowed mixtures to be analyzed without prior time-consuming separation.
Also in 1956, MS was first used to identify an organic compound by breaking down the molecule to form positive, negative and neutral fragments.
1960 saw the first use of the quadrupole mass spectrometer as a residual gas analyzer.
In 1964, W.M. Brubaker, P. Michael Uthe, and Robert Finnigan at EAI developed the first commercially available quadrupole mass spectrometer residual gas analyzer.
In 1965, the first pre-packaged magnetic sector incorporating a helium enrichment jet separator was developed by R. Ryhage of the Karolinska Institute and sold by LKB instruments.
In 1967, the first magnetic double-focusing GC-MS, the PerkinElmer Model 270, was introduced.
In 1968, the technique of electrospray ionization (ESI) at atmospheric pressure was investigated by Malcolm Dole and colleagues. This advance was important to the biological future of MS, although the technique would not be routinely used for two more decades.
During the 1970s, a number of important modifications to MS were developed, including Fourier-transform, secondary ionization, plasma desorption, laser desorption, thermal desorption, spark source, and glow discharge MS.
In 1974, Fourier-transform ion cyclotron resonance was introduced.
In 1976, Hewlett-Packard (HP) introduced the world’s first integrated, digital benchtop GC-MS system, the 5992. The 5992 also featured the world’s first true hyperbolic chromium-molybdenum alloy (Cr-Mo) quadrupole mass filter.
In 1982, Bruker Spectrospin in Switzerland began successfully installing the first Fouriertransform ion cyclotron resonance (FT-ICR) mass spectrometry systems, drawing on Bruker’s existing expertise in NMR and superconducting magnet technology.
In 1983, the first commercial ion-trap system was introduced by Finnigan MAT (San Jose, CA), originally intended as a GC detector. In this instrument, a scanning radio frequency causes ions of increasing mass-to-charge ratio to become successively unstable. Today, ion trap instruments are common in GC detectors, LC-MS detectors and standalone mass spectrometers.
In 1985, the technique known as matrixassisted laser desorption/ionization (MALDI) was developed by Koichi Tanaka of Shimadzu Corp.
In 1987, PerkinElmer SCIEX introduced the ELAN 500, the first ICP-MS system with platinum cones and an inert sample introduction system.
Also in 1987, Finnigan (later acquired by Thermo in 1990) launched the MAT 90 series of mass spectrometers—the first mass spectrometers on the market completely controlled by computers.
In 1988, the first commercial MALDI-TOF MS instrument, the LAMS- 50K, was launched by Shimadzu. MALDI rapidly became an important technique for analyzing biological samples, and was being used in protein structure studies by the 1990s.
Also during 1988, John B. Fenn published two articles relating to an electrospray technique that revolutionized mass spectrometry. These articles showed that the release of ions could be achieved by spraying a sample using an electrical field so that charged droplets are formed. As the water gradually evaporates from these droplets, freely hovering “stark naked” protein molecules remain. The method came to be called electrospray ionization (ESI).
Finally in 1988, HP introduced the 5971 MSD, the world’s first mass spectrometer to employ a true hyperbolic glass quadrupole.
In 1990, PerkinElmer launched the first turbomolecular-pumped ICP-MS instrument (the ELAN 5000).
In 1992, low-level peptide analysis using MS techniques became possible.
Also in 1992, Shimadzu Corp. launched the Kompact MALDI Series, enabling analyses of a wide range of applications including peptides, proteins, sugars, multiplex fats, nucleotides, pharmaceutical products and metabolites.
By 1993, limited oligonucleotide sequencing had become possible, driven in part by the demands of the Human Genome Project.
By 1996, MS was starting to be linked to HPLC instruments, and MS studies of viruses were beginning.
In 1997, Shimadzu Corp. launched the LCMS-QP8000 with ESI and Atmospheric Pressure Chemical Ionization interfaces.
In 2002, the Nobel Prize in Chemistry was given to three pioneers of techniques for the identification and structural analyses of biological macromolecules. The recipients included Koichi Tanaka (Shimadzu Corp.) for his development of MALDI and John B. Fenn, who was recognized for the development of ESI.
Also in 2002, Shimadzu Corp. announced and launched the laser ionization quadrupole ion trap time-of-flight mass spectrometer AX IMA-QIT.
In 2005, the technique known as Direct Analysis in Real Time (DART) was patented. DART is based on the atmospheric pressure interactions of long-lived electronic excited-state atoms or vibronic excited-state molecules with the sample and atmospheric gases.
In 2006, Shimadzu Corp. launched AXIMA-TOF2TM, the next generation in MALDI CID MS-MS, a TOF-TOF mass spectrometer with high-energy MS-MS.
Also in 2006, Waters Corporation introduced the SYNAPT High-Definition MS (HDMS) system at the American Society of Mass Spectrometry annual meeting in Seattle. The HDMS system analyzes ions by their size, shape and charge, in addition to mass.
Finally in 2006, Agilent introduced its innovative GeneSpring MS software to facilitate biomarker discovery from mass spectrometry data.
In 2008, Waters Corp. launched the SYNAPT MS system; a next-generation, quadrupole acceleration, time-of-flight (QA-TOF) mass spectrometry platform, designed to generate high quality, comprehensive data from complex biological samples.
Also in 2008, Agilent introduced the first mainstream mass spectrometer to break the femtogram-detection barrier.
In 2009, Thermo Fisher Scientific Inc. launched the LTQ Velos, the industry’s fastest and most-sensitive ion trap mass spectrometer, increasing both scan speed and resolution.
In 2010, Bruker obtained the first in vitro diagnostic CE mark for its MALDI-TOF-based microbial identification workflow solution, the IVD MALDI Biotyper. This system is pioneering the advancement of mass spectrometry in clinical diagnostics.
In 2010, Waters Corp. introduced two new mass spectrometers for its Xevo MS platform (the Xevo TQ-S and Xevo G2 QTof) that offer an unequalled combination of separation power with the highest levels of sensitivity for compound identification, quantification and screening.
Future of MS
MS technology is still evolving to meet the latest demands of biotechnology. Innovations include tandem expansions, multiple connections to HPLC and the development of newer, portable systems. It is predicted that MS will remain the keystone of modern chemical analysis, as well as the ultimate chromatography detector.