Short Specialist Review Time-of-ight mass spectrometry

Robert J. Cotter
Johns Hopkins University School of Medicine, Baltimore, MD, USA

1. Introduction
Time-of-ight (TOF) mass spectrometers were introduced in the 1940s (Stephens, 1946; Cameron and Eggers, 1948) and commercialized in 1955 (Wiley and McLaren, 1955). Regarded for many years as instruments with low mass range and low resolving power, TOF mass spectrometers were rediscovered following the introduction of ionization techniques capable of ionizing biological macromolecules including proteins and peptides, oligosaccharides, glycolipids and other glycoconjugates, and polynucleotides. Thus, they have become important for proteomics not only in their ability to obtain molecular weights of intact proteins but also for obtaining amino acid sequences of peptides and for locating and characterizing posttranslational modications.

2. Mass analysis and mass range

The basic TOF mass spectrometer consists of a small source region s, a longer drift length D and a detector (Figure 1a). Ions are formed in the source by any number of ionization techniques that have included electron ionization (EI) (Wiley and McLaren, 1955), chemical ionization (CI) (Futrell et al ., 1968), plasma desorption mass spectrometer (PDMS) (Torgerson et al ., 1974), laser desorption (LD) (Van Breemen et al ., 1983), matrix-assisted laser desorption/ionization (MALDI) (Karas and Hillenkamp, 1988; Tanaka et al ., 1988), and electrospray ionization (ESI) (Verentchikov et al ., 1994). Ions of all masses m are then accelerated as they exit the source to nal kinetic energies 1 mv 2 = eV , where e is the charge on an electron 2 and V is the voltage across the source. The ions then travel through a drift length at velocities v , which are constant but different for each mass, before striking the detector. The TOF for an ion is then given by t= m 2eV
1/2

(2s + D)

m 2eV

1/2

(1)

In theory, the mass range of such an instrument is unlimited. For current instruments using MALDI, detectors limit the mass range, as the efciency for conversion

2 Core Methodologies

Source

Drift tube

Detector

(a) Single-stage reflectron

s0

s1

L1

d L2
(b) RF ion guide Ion storage volume

Dual-stage reflectron

(c)

Figure 1 Basic congurations of time-of-ight mass spectrometers: (a) a simple linear TOF mass analyzer with a single-stage ionization source, (b) a reectron TOF mass analyzer with a dualstage ion extraction source, and (c) an orthogonal acceleration mass analyzer with a quadrupole ion guide and a dual-stage reectron

of incoming ions to an electron cascade by electron multipliers and channel plate detectors depends upon ion velocity. That velocity is slower for higher mass ions and is the reason that current instruments operate at high (generally 20 kV) accelerating voltages. At the same time, cryo-cooled superconducting tunneling junction (SJT) (Hilton et al ., 1998) detectors are now providing megadalton detection, but at lower time resolution.

3. Spatial, energy distributions and mass resolution

The expression for mass resolving power: m/ m = t/2 t indicates that this will be only as good as our ability to parse the time measurement into very small time intervals. The boxcar method used by early commercial instruments (which

Short Specialist Review

enabled recording of only one time interval in each TOF cycle) (Holland et al ., 1983) was capable of resolving time intervals ranging from 10 to 40 ns. Today, fast analog-to-digital converters (transient recorders, waveform recorders, and digital oscilloscopes) have digitization rates up to 8 Gsample s1 , corresponding to time intervals of 125 ps. When single ion counting is used, time-to-digital converters (TDCs) provide an accuracy of 200500 ps. Mass resolution is also affected by the initial conditions of ions. For example, ions formed at different distances between the back of the source and the extraction grid will have different kinetic energies as they leave the source, and therefore different velocities and different TOFs. This is because an initial spatial distribution is effectively a different distance s, and a different energy due to acceleration eV = eEs, where E is the electric eld in the source. Ions may, of course, have different kinetic energies before or as a result of ionization. This initial kinetic energy distribution U 0 means that ions will have different nal energies as well: eV + U0 . The effects of both of these are given in a more complex TOF equation: t= (2m)1/2 D (2m)1/2 1/2 + (U0 + eEs)1/2 U0 eE 2 (U0 + eEs)1/2 (2)

The rst term is the time in the source and includes the so-called turn-around time (Wiley and McLaren, 1955), since the initial velocity component along the ight path may be in the forward or reverse direction. The second term is the time in the ight tube and reects the nal energy. While the turn-around time is important in gas phase ionization methods, such as EI, it is generally not in methods such as MALDI in which ions are formed on a surface. The effects of the initial spatial distribution are the easier of the two to correct. Ions formed about a small distance s + s will be focused to rst order at a distance d = 2s from the source, the so-called space-focus plane. Because this distance is not far enough from the source to enable sufcient mass/time dispersion and achieve good resolving power, it is more common to use a dual-stage extraction source (Figure 1b), in which the eld strength E 1 in the second region s 1 is much greater than that E 0 in the rst s 0 . In this case, the space focus is given by 2s1 1 d = 2 1/2 1/2 1/2 1/2 s0 1/2 + s0 s0
2

(3)

where = s0 + (E1 E0 )s1 . In addition, it is possible to achieve better (second order) focusing for an optimal set of parameters.

4. Time-lag focusing and delayed extraction

The greatest challenge for achieving high resolving power is the simultaneous focusing of the initial spatial and energy distributions. The time-lag focusing method of Wiley and McLaren introduced a delay time between the ionizing

4 Core Methodologies

electron beam pulse forming the ions and the extraction pulse accelerating them from the source. During that time, ions with larger forward velocity would move closer to the extraction grid, so that they would receive less energy from acceleration than slower moving ions. Prior to the development of MALDI this approach was used for infrared laser desorption (IRLD) (Van Breemen et al ., 1983; Tabet and Cotter, 1984). Laser microprobes (Hillenkamp et al ., 1975) and PDMSs (Torgerson et al ., 1974) relied on the fact that ions formed directly from a surface would have a very minimal spatial distribution, so that correction of the kinetic energy could be accomplished, without pulsed extraction, using a reectron (see below). Following the introduction of MALDI7 (Karas and Hillenkamp, 1988; Tanaka et al ., 1988) there was a return of interest in pulsed extraction methods (Whittal and Li, 1995; Brown and Lennon, 1995; Vestal et al ., 1995), which have produced very high mass resolutions. While known commonly as delayed extraction, King et al . (1995) have termed this approach velocity-space correlated focusing because the spatial distribution at the time of the extraction pulse (which is absent initially) is derived entirely from the initial velocities (energies). Time-lag focusing and the more recent pulsed extraction methods are generally accomplished with dual-stage extraction and are all mass dependent. Because the velocity distributions will be different for different masses, motion during the delay period will be different. Thus, either the delay time or the ratio E 1 /E 0 is different for each mass. Over many years a number of dynamic methods have been developed, including impulse eld focusing (Marable and Sanzone, 1974), postsource pulsed focusing (Kinsel and Johnston, 1989), velocity compaction (Muga, 1988), and dynamic-eld focusing (Yefchak et al ., 1989). Mass-correlated acceleration, developed more recently (Kovtoun et al ., 2002), takes advantage of the fact that heavier ions enter the second region later than lighter ions and dynamically changes the eld E 1 by raising the ight tube voltage. In many cases, it is found that focusing in the middle mass range (50006000 Da) produces reasonable focus throughout the useful mass range for MALDI.

5. Reectrons and postsource decay

Mamyrin and coworkers rst reported their reectron or ion mirror in 1973 (Mamyrin et al ., 1973). Shown in Figure 1b, this mass analyzer incorporates a retarding electric eld that reverses the direction of the ions. The device works to correct for an initial kinetic energy spread because the higher velocity ions penetrate more deeply into the reectron and take longer to turn around. For a single-stage reectron: t= m 2eV
1/2

[L1 + L2 + 4d]

(4)

where L1 and L2 are the drift paths toward and away from the reectron, and d is the penetration depth. The single-stage reectron (Tang et al ., 1988) provides rst order energy focusing, while the dual-stage reectron (an example is shown

Short Specialist Review

in Figure 1c) can provide second order focusing. A quadratic reectron (Mamyrin, 1994) provides (in theory) innite order focusing, that is, the ight time is independent of energy, but the nonlinear eld along the center axis also includes off-axis eld lines that cause divergence of the ion beam and loss of transmission. When an ion of mass m 1 originating from the source dissociates to form a fragment m 2 in the ight tube, its ight time through a single-stage reectron is t= m1 2eV
1/2

L1 + L2 + 4

m2 d m1

(5)

This offers the opportunity to select a given precursor ion m 1 using an electronic gate in the ight tube L1 and to record the ight times of all the product ions m 2 , a method generally referred to as postsource decay (PSD) (Kaufmann et al ., 1994). Focusing is poorer for lower mass product ions that do not approach the optimal penetration depth, a problem that is generally addressed by acquiring multiple spectral segments at reduced reectron voltage. The curved-eld reectron (CFR) (Cornish and Cotter, 1993; Cornish and Cotter, 1994) eliminates the need for stepping the reectron voltage, focusing the entire product ion mass range simultaneously. Though this reectron uses a nonlinear eld, it is closer to the constant eld reectron than to the quadratic, so that high ion transmission is maintained.

6. Orthogonal acceleration
The development of orthogonal acceleration (oaTOF) mass spectrometers has not only provided a means for achieving high mass resolution but has also provided the opportunity to utilize continuous ionization sources, most notably electrospray ionization. The rst such instrument by Dawson and Guilhaus (1989) used an EI source and extraction into a linear TOF mass analyzer, while a later instrument by Mirgorodskaya et al . (1994) used an ESI source with a reectron. Essential to the operation of the instrument (and to its ultimate mass resolution) is the collimation of the ion beam into a storage volume (Figure 1c) so that the remaining component of the velocity spread is directed along a single axis. Ions are then extracted orthogonal to that axis, using space focusing to correct for any width in the collimated beam. While a collimated beam can be achieved by passing the beam through a small orice, much better transmission can be achieved using a quadrupole, hexapole, or octapole ion guide (Krutchinsky et al ., 1998). With such a conguration, the mass analyzer is effectively isolated from the source and has no memory of the initial conditions of the ions. Thus, multiple sources can be used, as can atmospheric pressure sources such as electrospray and atmospheric pressure MALDI (AP MALDI) (Laiko et al ., 2000).

7. Hybrid instruments
The development of oaTOF mass spectrometers has provided the opportunity for a very successful tandem (hybrid) conguration that combines a quadrupole mass

6 Core Methodologies

RF ion guide

Collision cell

Ion storage volume

MS1: quadrupole mass filter

MS2: oaTOF

(a) Quadrupole ion trap

L1

d L2
(b)

Figure 2 Hybrid instruments: (a) a tandem quadrupole/time-of-ight mass spectrometer with an RF ion guide and collision chamber, and (b) a tandem ion trap/time-of-ight mass spectrometer

analyzer in the rst stage and an orthogonal TOF as the second mass analyzer (Figure 2a) (Shevchenko et al ., 1997; see also Article 10, Hybrid MS, Volume 5). In a tandem experiment, the rst mass analyzer is generally used to pass a precursor mass while the second mass analyzer scans its product ion spectrum; thus, the quadrupole is an appropriate mass lter as the rst stage while the TOF analyzer provides the multichannel advantage for recording the product ion spectrum. The mass/charge range of quadrupoles is more limited than the TOF, but is nicely compatible with the multiply charged ions from an electrospray source, which it accommodates using an RF ion guide as described above. An additional quadrupole provides a low energy collision-induced dissociation (CID) chamber for inducing fragmentation. Because fragmentation of multiple-charged ions is generally accompanied by charge reduction, product ions may have considerably higher m/z than their precursors, but this is easily accommodated by the TOF analyzer. An additional advantage is that selection of the precursor ion mass is much better than it is on the TOF/TOF instruments described below. A conguration utilizing an electrostatic ion trap (see Article 9, Quadrupole ion traps and a new era of evolution, Volume 5) with the TOF mass spectrometer was introduced by Chien and Lubman (1994), and was also intended to provide compatibility between a continuous beam ESI source and the pulsed TOF mass analyzer. A trapTOF instrument with a quadratic reectron was reported by

Short Specialist Review

Doroshenko and Cotter (1998). An advantage of the combined ion trap/TOF (Figure 2b) is that one can carry out MSn analyses. While this is possible on an ion trap alone, the recorded spectrum at any stage of MSn on the ion trap/TOF is always a TOF spectrum with higher mass resolution than can be obtained on the trap.

8. Tandem time-of-ight mass spectrometers

The difculties inherent in stepping the reectron voltage for PSD, as well as an interest in providing collision-induced dissociation of larger singly charged ions, has motivated the development of tandem TOF (or TOF/TOF) mass spectrometers. Such instruments are not entirely new; a very simple linear system designed by Jardine et al . (1992) used a voltage step after the collision cell to differentiate the ight times of the product ions. Beussman et al . (1995) and Cotter and Cornish (1993) both reported instruments using two reectrons in a Z geometry in 1993. In the rst instrument, photodissociation of the precursor ion was followed by additional acceleration of the product ions to accommodate the bandwidth of the reectron; in the latter, pulsed CID was followed by a CFR to enable focusing of the product ions. The most recent approaches to TOF/TOF design use a linear, pulsed extraction rst analyzer, a mass selection gate at (or near) the space-velocity focus point, a collision chamber, and a second reectron mass analyzer (Figure 3). These instruments differ in how they address the focusing of product ions in the reectron. Specically, precursor ions of mass m 1 produce product ions m 2 whose kinetic energies are proportional to their masses: (m 2 /m 1 ) eV. Thus, product ion energies can range from the precursor ion energy (typically 20 keV) to a few eV, while single and dual-stage reectrons focus only a fraction of that energy range. In one conguration (Figure 3a), precursor ions are decelerated to 2 keV prior to collision. After the collision, the product ions are pulse extracted from (effectively) a second source, which reaccelerates the ions by an additional 18 keV, so that ions with an energy range from 18 to 20 keV enter the reectron (Medzihradszky et al ., 2000). In a second approach (Figure 3b), precursor ions leave the source and enter the collision chamber at 8 keV and are not decelerated. The product ions (still traveling at the same velocity) enter a eld-free lift cell whose potential is raised (by 19 kV) while the ions are in residence (Suckau et al ., 2003). A third conguration (Figure 3c) uses a CFR to focus all the product ions resulting from 20-keV collisions, obviating the need for decelerating, reextracting, or lifting the product ions (Iltchenko et al ., 2004). These congurations provide much-improved approaches compared with stepping of the reectron voltage, plus the opportunity to locate mass selection at the space-velocity focus point and to carry out CID between the mass analyzers. Interestingly, MS/MS spectra on these instruments are not very different with and without a collision gas, which suggests that the processes are fundamentally the same: PSD or laser induced dissociation producing high internal energies, with fragmentation then aided by the collisions. At the same time, one observes the appearance of (or increases in) internal and single amino acid ions, which may result from a second, collision-induced fragmentation (Medzihradszky et al ., 2000; Iltchenko et al ., 2004; see also Article 4, Interpreting tandem mass spectra of peptides, Volume 5).

8 Core Methodologies

Ion source

Retarding Collision lens cell

2nd source pulsed extraction

Mass selection gate (a) Ion source Collision cell Lift cell

Mass selection gate (b) Ion source Mass selection gate

Collision cell (c)

Figure 3 Tandem time-of-ight mass spectrometers using different approaches for focusing product ions: (a) deceleration prior to collision followed by reacceleration of product ions, (b) potential lifting of product ions, and (c) focusing by a curved-eld reectron

9. Future prospects
There is considerable interest in the development of compact, eld-portable and/or miniaturized mass spectrometers; in this area, the TOF offers the possibility for retaining the same high mass range as its larger, high-performance counterparts (English et al ., 2003). While such instruments are expected to play a signicant future role in proteomics-based, point-of-care diagnostics, it is also clear that there is currently an increasing demand for high-performance instrument for the identication and validation of biomarkers. This includes both high mass resolution and MS/MS capabilities.

Further reading
Cotter RJ (1997) Time-of-Flight Mass Spectrometry: Instrumentation and Applications in Biological Research, American Chemical Society: Washington DC, ISBN 0-8412347-4-4. Kinter M and Sherman NE (2000) Protein Sequencing and Identication Using Tandem Mass Spectrometry, ISBN 0-4713224-9-0.

Short Specialist Review

Siuzdak G (2003) The Expanding Role of Mass Spectrometry in Biotechnology, ISBN 0-97424510-0. Warscheid B, Jackson K, Sutton C and Fenselau C (2003) MALDI analysis of Bacilli in spore mixtures by applying a quadrupole ion trap time-of-ight tandem mass spectrometer. Analytical Chemistry, 75, 56085617.

References
Beussman DJ, Vlasak PR, McLane RD, Seeterlin MA and Enke CG (1995) Tandem reectron time-of-ight mass spectrometer utilizing photodissociation. Analytical Chemistry, 67, 39523957. Brown RS and Lennon JJ (1995) Mass resolution improvement by incorporation of pulsed ion extraction in a matrix-assisted laser desorption/ionization linear time-of-ight mass spectrometer. Analytical Chemistry, 67, 19982003. Cameron AE and Eggers DF Jr (1948) An Ion Velocitron. The Review of Scientic Instruments, 19, 605. Chien BM and Lubman DM (1994) Analysis of the fragments from collision-induced dissociation of electrospray-produced peptide ions using a quadrupole ion trap storage/reectron time-ofight mass spectrometer. Analytical Chemistry, 66, 16301536. Cornish TJ and Cotter RJ (1993) A curved eld reectron for improved energy focusing of product ions in time-of-ight mass spectrometry. Rapid Communications in Mass Spectrometry: RCM , 7, 10371040. Cornish TJ and Cotter RJ (1994) A curved eld reectron time-of-ight mass spectrometer for the simultaneous focusing of metastable product ions. Rapid Communications in Mass Spectrometry: RCM , 8, 781785. Cotter RJ and Cornish TJ (1993) A tandem time-of-ight (TOF/TOF) mass spectrometer. Analytical Chemistry, 65, 10431047. Dawson JHJ and Guilhaus M (1989) Orthogonal-acceleration time-of-ight mass spectrometer. Rapid Communications in Mass Spectrometry: RCM , 3, 155. Doroshenko VM and Cotter RJ (1998) A quadrupole ion trap/time-of-ight mass spectrometer with a parabolic reectron. Journal of Mass Spectrometry: JMS , 33, 305318. English RD, Warscheid B, Fenselau C and Cotter RJ (2003) Bacillus spore identication via proteolytic peptide mapping with a miniaturized MALDI TOF mass spectrometer. Analytical Chemistry, 75, 68866893. Futrell JH, Tiernan TO, Abramson FP and Miller CD (1968) Modication of a Time-of-Flight Mass Spectrometer for Investigation of Ion-Molecule Reactions at Elevated Pressures. The Review of Scientic Instruments, 39, 340345. Hillenkamp F, Unsold E, Kaufmann R and Nitsche R (1975) Laser microprobe mass analysis of organic materials. Nature, 256, 119. Hilton GC, Martinis JM, Wollmann DA, Irwin KD, Dulcie LL, Gerber D, Gillevet PM and Twerenbold D (1998) Impact energy measurement in time-of-ight mass spectrometry with cryogenic microcalorimeters. Nature, 391, 672675. Holland JF, Enke CG, Allison J, Stults JT and Pinkston JD (1983) Mass spectrometry in the chromatographic time frame. Analytical Chemistry, 65, 997A1112A. Iltchenko S, Gardener B, English RD and Cotter RJ (2004) Tandem time-of-ight mass spectrometry with a curved eld reectron. Analytical Chemistry, 76, 19761981. Jardine DR, Morgan J, Alderdice DS and Derrick PJ (1992) A tandem time-of-ight mass spectrometer. OMS, Organic Mass Spectrometry, 27, 10771083. Karas M and Hillenkamp F (1988) Laser desorption ionization of proteins with molecular masses exceeding 10,000 Daltons. Analytical Chemistry, 60, 22992301. Kaufmann R, Kirsch D and Spengler B (1994) Sequencing of peptides in a time-of-ight mass spectrometer: evaluation of postsource decay following matrix-assisted laser desorption ionisation (MALDI). International Journal of Mass Spectrometry and Ion Processes, 131, 355385.

10 Core Methodologies

King TB, Colby SM and Reilly JP (1995) High resolution MALDI-TOF mass spectra of three proteins obtained using space-velocity correlation focusing. International Journal of Mass Spectrometry and Ion Processes, 145, L1L7. Kinsel GR and Johnston MV (1989) Post source pulse focusing: a simple method to achieve improved resolution in a time-of-ight mass spectrometer. International Journal of Mass Spectrometry and Ion Processes, 91, 157176. Kovtoun SV, English RD and Cotter RJ (2002) Mass correlated acceleration in a reectron MALDI TOF mass spectrometer: an approach for enhanced resolution over a broad mass range. Journal of the American Society for Mass Spectrometry, 13, 135143. Krutchinsky AN, Loboda AV, Spicer VL, Dworschak R, Ens W and Standing KG (1998) Orthogonal injection of matrix-assisted laser desorption/ionization ions into a time-ofight spectrometer through a collisional damping interface. Rapid Communications in Mass Spectrometry: RCM , 12, 508518. Laiko VV, Baldwin MA and Burlingame AL (2000) Atmospheric pressure matrix-assisted laser desorption/ionization mass spectrometry. Analytical Chemistry, 72, 652657. Mamyrin BA (1994) Laser assisted reectron time-of-ight mass spectrometry. International Journal of Mass Spectrometry and Ion Processes, 131, 119. Mamyrin BA, Karatajev VJ, Shmikk DV and Zagulin VA (1973) Mass reectron. New nonmagnetic time-of-ight high-resolution mass spectrometer. Soviet Physics JETP, 37, 4548. Marable NL and Sanzone G (1974) High-resolution time-of-ight mass spectrometry. Theory of the impulse-focused time-of-ight mass spectrometer. International Journal of Mass Spectrometry and Ion Physics, 13, 185194. Medzihradszky KF, Campbell JM, Baldwin MA, Falick AM, Juhasz P, Vestal ML and Burlingame AL (2000) The characteristics of peptide collision-induced dissociation using a high-performance MALDI-TOF/TOF tandem mass spectrometer. Analytical Chemistry, 72, 552558. Mirgorodskaya OA, Shevchenko AA, Chernushevich IV, Dodenov AF and Miroshnikov AI (1994) Electrospray-ionization time-of-ight mass spectrometry in protein chemistry. Analytical Chemistry, 66, 99107. Muga ML (1988) Velocity compaction time-of-ight mass spectrometer for mass range 100010,000 mu. Analytical Instrumentation, 16, 31. Shevchenko A, Chernushevich I, Ens W, Standing KG, Thomson B, Wilm M and Mann M (1997) Rapid de Novo peptide sequencing by a combination of nanoelectrospray, isotopic labeling and a quadrupole/time-of ight mass spectrometer. Rapid Communications in Mass Spectrometry: RCM , 11, 10151024. Stephens WE (1946) A Pulsed Mass Spectrometer with Time Dispersion. Physical Review , 69, 691. Suckau D, Resemann A, Schuerenberg M, Hufnagel P, Franzen J and Holle A (2003) A novel MALDI LIFT-TOF/TOF mass spectrometer for proteomics. Analytical and Bioanalytical Chemistry, 376, 952965. Tabet JC and Cotter RJ (1984) Laser desorption time-of-ight mass spectrometry of high mass molecules. Analytical Chemistry, 56, 1662. Tanaka K, Waki H, Ido Y, Akita S, Yoshida y and Yoshida T (1988) Protein and polymer analyses up to m/z 100 000 by laser ionization time-of ight mass spectrometry. Rapid Communications in Mass Spectrometry: RCM , 2, 151153. Tang X, Beavis R, Ens W, LaFortune F, Schueler B and Standing KG (1988) A secondary ion timeof-ight mass spectrometer with an ion mirror. International Journal of Mass Spectrometry and Ion Processes, 85, 4367. Torgerson DF, Skowronski RP and Macfarlane RD (1974) New approach to the mass spectroscopy of non-volatile compounds. Biochemical and Biophysical Research Communications, 60, 616621. Van Breemen RB, Snow M and Cotter RJ (1983) Time resolved laser desorption mass spectrometry: I. The desorption of preformed ions. International Journal of Mass Spectrometry and Ion Physics, 49, 3550.

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Verentchikov AN, Ens W and Standing KG (1994) Reecting time-of-ight mass spectrometer with an electrospray ion source and orthogonal extraction. Analytical Chemistry, 66, 126133. Vestal ML, Juhasz P and Martin SA (1995) Delayed extraction matrix-assisted laser desorption time-of-ight mass spectrometry. Rapid Communications in Mass Spectrometry: RCM , 9, 10441050. Whittal RM and Li L (1995) High-resolution matrix-assisted laser desorption/ionization in a linear time-of-ight mass spectrometer. Analytical Chemistry, 67, 19501954. Wiley WC and McLaren IH (1955) Time-of-ight mass spectrometer with improved resolution. The Review of Scientic Instruments, 26, 11501157. Yefchak GE, Enke CG and Holland JF (1989) Models for mass-independent space and energy focusing in time-of-ight mass spectrometry. International Journal of Mass Spectrometry and Ion Physics, 87, 313330.