Threat identification for mass spectrometer system

Details Threat identification for mass spectrometer system Threat identification for mass spectrometer system

2002-01-08

2004-11-23

Wells, Nikita (Department: 2881)

Radiant energy

Ionic separation or analysis

C250S282000, C342S093000, C375S227000

Reexamination Certificate

active

06822222

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to mass spectrometry, mass spectrometers and applications thereof.
BACKGROUND OF THE INVENTION
Mass spectrometers provide a fundamental tool of experimental chemistry and have proven useful and reliable in identification of chemical and biological samples. Mass spectrometry is a technique used to determine the masses of molecules and specific fragmentation products formed following vaporization and ionization. Detailed analysis of the mass distribution of the molecule and its fragments leads to molecular identification. The combination of specific molecular identification and extreme sensitivity makes molecular spectroscopy one of the most powerful analytical tools available.
However, the typical mass spectrometer is confined to the laboratory or other fixed sites due to its relatively large size and weight, as well as its high power and cooling requirements. Thus, mass spectrometer technology has not been used as a field portable detection system. Other impediments to field use include the requirements for large amounts of fluids to collect and process samples. Field samples are often much smaller in quantity and detection of such small samples is often essential (for example, in the case of detection of a chemical or biological agent that is lethal at small doses). In addition, typical scanning mass spectrometers have high data acquisition times, which is also inconsistent with field use. Also, stationary and level mounting configurations of typical mass spectrometers are inconsistent with adaptation to field use. Rapid and frequent placement and replacement of a sample is often inconsistent with the vacuum design of the typical stationary mass spectrometer.
FIG. 1
is a schematic representation of a particular type of mass spectrometer, the linear time-of-flight (“TOF”) mass spectrometer. Pulsed ultraviolet laser
10
is used to simultaneously desorb and ionize an analyte
12
from a probe
14
. The laser
10
is triggered by a digital oscilloscope
16
, which simultaneously marks the time, or otherwise initiates a timer. A potential difference across an extraction region serves to accelerate the ions into a drift region (typically on the order of 1 m in length) as shown. As they pass through the drift region, the ions disperse in time, with their flight times proportional to the square root of their respective masses. An ion detector
18
at the end of the drift region records the ion signals on a digital oscilloscope
16
, thus providing detection times.
If there are ions of different masses, the different flight times will give rise to a number of detection times. The trigger time and the one or more detection times thus provide one or more flight time intervals which, as noted, are related to the mass of the ion. The mass of the ion is related to the flight time interval t as follows:
m
=2(
eV
)(
t/D
)
2
where D is the drift region as shown in FIG.
1
and eV is the acceleration energy imparted by the potential difference in the extraction region.
Different masses are thus determined based on the different flight times t of the ions. The TOF mass spectrometer thus records the entire mass spectrum for every ionization event that occurs to the analyte
12
. Unlike other types of mass spectrometers, a TOF mass spectrometer does not rely on a scanning mass analyzer and therefore does not experience loss of signal due to scanning. The TOF mass spectrometer is also one of the simplest chemical analyzers, comprising principally an ion source, field-free tube for a drift region, and an ion detector, as shown in FIG.
1
.
In addition, the TOF mass analyzer is particularly suited to measure the mass of biomolecular ions by using matrix-assisted laser desorption/ionization (“MALDI”). With MALDI, the analyte
12
is mixed with an appropriate organic matrix, inserted into the ionization region (for example, in the region occupied by probe
14
of FIG.
1
), and desorbed from the surface into the TOF drift region D. The matrix absorbs radiative energy from the laser
10
and undergoes a phase change from solid to gas. During the phase change, the analyte gains a H+ ion and is thus accelerated by the potential difference in the extraction region, in the manner described above. MALDI treatment is particularly advantageous for ionization of larger molecules because the matrix provides a buffer between the energy of the laser and the sample. This prevents the larger molecules from being broken into small fragments, where analysis of these larger fragments simplifies the identification of the analyte.
Although ions produced by MALDI can be measured on a variety of mass spectrometers, a TOF mass spectrometer is particularly qualified for MALDI applications because it has no theoretical upper mass limit Thus, MALDI is especially suited to the desorption of the larger macromelocules required for the application of chemotaxonomic methods. Larger mass ions, such as proteins and fragments of DNA strands, are still readily processed since they only take more time to reach the detector. Consequently, both the absence of any scanning requirement and an unlimited mass range make TOF mass spectroscopy a popular method for biomolecular analysis using MALDI.
For example, recent development of TOF mass spectroscopy using MALDI has included the detection of biological weapons whose mass signatures are often found in the 10 to 100 kDa range. Another valuable application is its ability to identify peptides and proteins with very high specificity and sensitivity. This area has led to the commercial development of TOF mass spectrometers for drug development in the pharmaceutical industry. Such applications indicates that TOF mass spectrometers are also well suited for biological threat detection of mid-range toxins (on the order of 1000 to 50,000 Da) in which subfemtomole sensitivity is required.
The resolution that arises from the lack of scanning has been exploited in the laboratory for many years, and the additional advantages that arise due to the TOF mass analyzer's ability to measure the mass of biomolecular ions by using MALDI has been exploited for approximately 10 years. However, the linear TOF mass spectrometer is inconsistent with use as a field portable detection system. One problem associated with adapting a linear TOF mass spectrometer includes limitations relating to mass resolution. Mass resolution of the linear TOF mass spectrometer is expressed in time units as t/2)t, where t is the total flight time and )t is the peak width of each TOF mass peak in the recorded spectrum. (The peak width arises principally from a small spread of energy (eV ∀ U
o
) imparted to ions of the same mass by the potential difference.) Therefore, assuming a constant peak width)t for each ion packet (group of ions having the same mass, with the mentioned energy spread), a longer total flight time will produce a larger dispersion between ions of different masses and thus increased resolution. Accordingly, many linear TOF mass spectrometers have used long drift regions to maximize mass resolution. A long drift region, of course, is incompatible with use as a field portable detection system.
A variation of the linear TOF mass spectrometer, known as the reflector or reflectron TOF mass spectrometer, is as shown in FIG.
2
. Like the mass spectrometer of
FIG. 1
, a laser
10
desorbs and ionizes an analyte
12
, which is accelerated by the potential difference V across the extraction region and into the drift region. However, the ions travel into a reflector or reflectron region at the end of the drift region, which applies a voltage that increases linearly with distance that the ion penetrates the reflectron region (as shown in
FIG. 2
a
). The ion reflector or reflectron generally comprises a series of equally spaced conducting rings that form a retarding/reflecting field in which the ions penetrate, slow down gradually, and reverse direction, thereby reflecting the ion's trajectory back along the incoming path, as shown in FIG.
2
. Ions of a

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