Radiant energy – Ionic separation or analysis – Ion beam pulsing means with detector synchronizing means
Reexamination Certificate
2000-06-07
2003-02-11
Lee, John R. (Department: 2881)
Radiant energy
Ionic separation or analysis
Ion beam pulsing means with detector synchronizing means
Reexamination Certificate
active
06518568
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to time-of-flight (TOF) mass spectrometers and, in particular, to a mechanism for improving the quality of mass spectra obtained from a TOF mass spectrometer. The invention also relates to a method for improving mass resolution in such TOF instruments in which the initial velocity distribution of ions dominates other mechanisms, such as spatial and temporal distributions, that normally result in loss of mass resolution.
2. Background Information
The use of mass spectrometers in determining the identity and quantity of constituent materials in a gaseous, liquid or solid specimen or sample has long been known. Mass spectrometers or mass filters typically use the ratio of the mass of an ion to its charge, m/z, for analyzing and separating ions. The ion mass m is typically expressed in atomic mass units or Daltons (Da) and the ion charge z is the charge on the ion in terms of the number of electron charges e.
In recent years, the development of an ionization technique for mass spectrometers known as matrix-assisted laser desorption ionization (MALDI) has generated considerable interest in the use of TOF mass spectrometers and in improvements of their performance. MALDI is particularly effective in ionizing large biological molecules (e.g., peptides and proteins, carbohydrates and oligonucleotides), as well as other types of polymers.
The TOF mass spectrometer provides an advantage for MALDI analysis by simultaneously recording ions over a broad mass range, which is the so-called multichannel advantage. At the same time, it has become common to utilize a method for improving mass resolution in a TOF mass spectrometer (i.e., time-lag focusing) which compromises the multi-channel advantage because it is mass-dependent. That is, the magnitude of the time delay between ionization and ion extraction used to provide first-order velocity focusing depends upon mass, so that only a portion of the mass spectrum is in first-order focus.
Mass spectrometers are analytical instruments which determine chemical structures through measurement of the masses of intact molecules and structure-specific fragments. Mass spectrometers consist of a mechanism for ionizing molecules (i.e., an ionization source) so that they can be analyzed by movement, manipulation or selection in some combination of static or dynamic electric and/or magnetic fields (mass analyzer) before arriving at a detector. Common ionization sources include electron ionization (EI), chemical ionization (CI),fast atom bombardment (FAB), electrospray ionization (ESI) and matrix-assisted laser desorption ionization (MALDI). Mass analyzers include magnetic sector (B), quadrupole (Q), quadrupole ion trap (QIT), Fourier transform mass spectrometers (FTMS) and time-of-flight (TOF).
The simplest time-of-flight mass spectrometer consists of a short ion source region of length s (shown in
FIG. 1
) and a longer drift region D. Ions formed in the source are accelerated by the high electrical field E defined by the potential difference V between the front (i.e., grid) and rear (i.e., backing plate) of the ion source. Then, the ions enter the length of the drift region D (or flight tube) with kinetic energies eV=½ mv
2
and velocities v=(2 eV/m)
½
which are different for each mass m. The resultant mass spectrum (shown in
FIG. 2
) is obtained by recording the flight times of ions reaching the detector, with time, t, being approximated by:
t
=
(
m
2
eV
)
1
/
2
D
The earliest known time-of-flight mass spectrometers, see Stephens, W. E.,
Phys. Rev
., vol. 69, p. 691, 1946; U.S. Pat. No. 2,612,607; Keller, R.,
Helv. Phys. Acta
., vol. 22, p. 386, 1949, had very poor mass resolution (i.e., the ability to distinguish ions having nearly the same mass at different flight times). This arises because the actual flight time, t, of an ion reflects uncertainties in the time of ion formation, t
0
, and the initial position, s, and kinetic energy, U
0
, of an ion prior to acceleration:
t
=
(
2
m
)
1
/
2
eE
[
(
U
0
+
eEs
)
1
/
2
∓
U
0
1
/
2
]
+
(
2
m
)
1
/
2
D
2
(
U
0
+
eEs
)
1
/
2
+
t
0
Later, an instrument that addressed the effects of initial temporal, spatial and kinetic energy (or velocity) distributions achieved considerably improved mass resolution. See Wiley, W. C., et al.,
Rev. Sci. Instrumen
., vol. 26, pp. 1150-57, 1955. In this instrument, an ion extraction pulse with a fast rise-time minimized the temporal distribution, while a dual-stage source (see
FIG. 3
) provided first-order space focusing when the detector was located at a distance:
d
=
2
σ
3
/
2
[
1
s
0
1
/
2
-
2
s
1
s
0
1
/
2
(
σ
1
/
2
+
s
0
1
/
2
)
2
]
wherein:
&sgr;=s
0
+(E
1
/E
0
)s
1
, and E
0
and E
1
are the electric fields in the two regions s
0
and s
1
of the dual-stage source, respectively.
The so-called space-focus plane (d) is independent of mass. That is ions of all masses achieve first-order focusing at this location for given values of E
0
, E
1
, s
0
and s
1
. In addition, it is also possible, using specific values of E
0
, E
1
, s
0
and s
1
to achieve second-order, mass-independent focusing. First-order kinetic energy (velocity) focusing is achieved using a time delay between the ionization pulse and the extraction pulse, a scheme known as time-lag focusing. See U.S. Pat. No. 2,685,035.
Time-lag focusing is mass-dependent, with the optimal time delay for velocity focusing being different for each mass. Hence, methods used to obtain mass spectra utilize a boxcar approach in which the time-lag is scanned in each successive time-of-flight recording cycle. A time-of-flight (TOF) instrument based upon the design of this instrument is disclosed by Wiley, W. C., et al.,
Science
, vol. 124, pp. 817-20, 1956.
More recently, the development of methods that form ions directly from surfaces using fast pulse lasers and ion beams has generally reduced both the temporal and spatial distributions associated with ion formation, obviating the need for pulsed ion extraction. In these static TOF instruments, ion reflectrons, see Mamyrin, B. A., et al.,
Sov. Phys. JETP
, vol. 37, p. 45, 1973, provide a simple and mass-independent method for energy focusing.
However, pulsed ion extraction has been employed in instruments utilizing infrared laser desorption, see Van Breeman, R. B., et al.,
Int. J. Mass Spectrom. Ion Phys
., vol. 49, pp. 35-50, 1983, and Cotter, R. J.,
Biomed. Environ. Mass Spectrom
., vol. 18, pp. 513-32, 1989; pulsed ion beams, see Olthoff, J. K., et al.,
Anal. Chem
., vol. 59, pp. 999-1002, 1987; and matrix-assisted laser desorption, see Spengler, B.,
Anal. Chem
., vol. 67, pp. 793-96, 1990, as methods of ionization.
It is known to employ a time-delayed focusing scheme, which is operationally similar to that of the instrument of U.S. Pat. No. 2,685,035, to compensate for relatively broad ionization pulses and/or to enable observation of ions fragmenting over a long time period. See Cotter, R. J.,
Biomed. Environ. Mass Spectrom.
Subsequently, others have reported extraordinary improvements in MALDI mass spectra using pulsed ion extraction. See Whittal, R. M., et al,
Anal. Chem
., vol. 67, pp. 1950-54, 1995; Brown, R. S., et al.,
Anal. Chem
., vol. 67, pp. 1998-2003, 1995; and Vestal, M. L., et al.,
Rapid Commun. Mass Spectrom
., vol. 9, pp. 1022-50, 1995. Time-lag focusing, time-delayed extraction, and delayed extraction have been used to describe this method which is employed on modern MALDI time-of-flight mass spectrometers. Similar to the instrument of U.S. Pat. No. 2,685,035, such newer instruments utilize dual-stage extraction sources in which the first extraction field is pulsed, although there are some differences in which the source element is pulsed.
As shown in
FIG. 4
, the instrument of U.S. Pat. No. 2,685,035 uses a grounded ion source plate (Ue=0V), and a negative-going voltage pulse (Ua=−64V after a suitable delay) at the inte
Cotter Robert J.
Kovtoun Viatcheslav V.
Eckert Seamans Cherin & Mellott , LLC
Houser Kirk D.
Johns Hopkins University
Lee John R.
Smith II Johnnie L
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