Radiant energy – Ionic separation or analysis
Reexamination Certificate
2004-03-24
2004-10-05
Graybill, David E. (Department: 2827)
Radiant energy
Ionic separation or analysis
C250S283000
Reexamination Certificate
active
06800847
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a micro-channel plate (MCP) detector system, a modified fast gain MCP-detector and a method of operating the same. More specifically, the invention relates to a micro-channel plate detector system with fast variable gain and a method of operating the same, such that an improved dynamic range is achieved.
PRIOR ART
Analyzing all proteins from cells is impossible by today's techniques since the amount of each expressed protein varies over a huge dynamic range. Mass spectrometry, together with other techniques, has shown a lack of the necessary dynamic range, largely due to lack of a detection technique that can detect both the abundant and the very rare proteins within the same mixture. Noteworthy is, that also a separated (LC, gel, etc) sample will display mixtures with overlapping protein species, so the problem with complex mixtures remains also after separation. An ideal mass spectrometer should therefore have single particle sensitivity and a high dynamic range.
FIG. 3
a
shows a fabricated example of a mass spectrometer spectrum, wherein these large variations in amount of each expressed protein are illustrated.
In this document ionization efficiency and transmission from ion source to detector will not be discussed. Designing a mass spectrometric detection is a trade off. Today, a perfect system can only be designed to one of the two extremes: either tailoring the detection for single-ion detection or for high dynamic range. The extreme sensitivity can be achieved by using a high detector gain and digital single-particle pulse counting electronics. High dynamic range can be achieved by using lower gain and analog detection electronics. The problem is that, ideally, both the high sensitivity and the high dynamic range are wanted.
FIG. 1
shows a micro-channel plate (MCP) detector system
10
for a mass spectrometer. A micro channel plate multiplier
12
,
14
consists of a large number of individual electron multiplier channels positioned in parallel typically in the shape of a perforated thin dish. Such a detector system typically comprises two MCP electron multipliers
12
,
14
, each having a gain of approximately 1000. This means that the first MCP
12
converts the incident ion
18
to a number of secondary electrons, which are then further multiplied to give of the order of 1000 electrons at the exit of this first detector. These 1000 electrons are transported to the second MCP
14
situated of the order of millimeters away. The 1000 electrons will impinge on the surface of the second MCP
14
, and a new multiplication process with an amplification of approximately 1000 takes place.
The amplification of the MCP will be temporary degraded (or lost) if too many secondary electrons are drawn from the output of a channel. The degraded gain results in lowered signal-to-noise ratio in the recorded spectrum when using analog-to-digital conversion (ADC) or a dead time after a large peak when using time-to-digital conversion (TDC). Temporary degradation of the gain occurs under two circumstances, either when the gain is high (which is needed for high sensitivity) or when too many ions reaches the MCP within a short period of time (which may be the case for certain ion species in high dynamic range mode).
Therefore it is obvious that trying to detect a sample with large variations of protein concentrations will give rise to just these conditions. In the high gain mode, the rare proteins will be lost since they drown in the highly attenuated signal from the abundant proteins. In the low gain mode, the signal from the rare proteins will be lost since it is too close to the dark current (signal with ion beam turned off) of the MCP.
Hence, there is needed a method that combines the best sides of the low gain and the high gain mode of operating the MCP detector system. There have been shown several ways to provide detector systems having an extended dynamic range.
A detector of this type which has two modes of operation to extend its dynamic range is disclosed by Kristo and Enke in Rev. Sci. Instrum. 1988 vol 59 (3) pp 438-442. This detector comprises two channel type electron multipliers in series together with an intermediate anode. The intermediate anode was arranged to intercept approximately 90% of the electrons leaving the first multiplier and to allow the remainder to enter the second multiplier. An analogue amplifier was connected to the intermediate anode and a discriminator and pulse counter connected to an electrode disposed to receive electrons leaving the second multiplier. The outputs of the analogue amplifier and the pulse counter were electronically combined. A protection grid was also disposed between the multipliers. At high incident ion fluxes, the output signal comprised the output of the analogue amplifier connected to the intermediate anode. Under these conditions a potential was applied to the protection grid to prevent electrons entering the second multiplier (which might otherwise cause damage to the second multiplier). At low ion fluxes, the potential on the protection grid was turned off and the output signal comprised the output of the pulse counter. In this mode the detector was operable in a low sensitivity analogue mode using the intermediate anode and a high sensitivity ion counting mode using both multipliers and the pulse counter, so that the dynamic range was considerably wider than a conventional detector which only use one of these modes. The switching between the two sensitivity levels is in this case performed as a response to the detected signal, i.e. direct feed back.
WO 99/38190 disclose a dual gain detector having two collection electrodes with different areas, whereby the larger electrode is used for detecting at low ion flux and the smaller at high ion flux. In a special embodiment the smaller collection electrode is provided as a grid that is placed between the first and the second MCP.
Soviet Inventors Certificate SU 851549 teaches the disposition of a control grid between two micro channel plate electron multipliers, the potential of which can be adjusted to control the gain of the assembly. This detector is further incorporated in a direct feed back detection system.
However, none of these detector systems represent a system that has the ability to cover the complete ion flux spectra of the proteins in a cell with high accuracy. More specifically, Kristo et al only detects approx. 10% of the ions at low ion fluxes, and both this system and the system disclosed in WO 99/38190 represent static two level systems, which results in lower over all sensitivity.
SUMMARY OF THE INVENTION
Obviously an improved detector system is needed, which provides detection over an improved dynamic range, such that analysis of samples with large variations of protein concentrations, e.g. a cell, may be performed with a mass spectrometer.
The object of the present invention therefore is to provide a new high sensitivity detector system and a method of controlling the same, which overcome the limitations with the prior art devices. This is achieved by the detector system of claim
5
by the method as defined in claim
1
and by the detector of claim
3
.
An advantage with the detector system according to the invention is that a new detector system with fast variable gain and a method of operating the same are achieved.
Embodiments of the invention are defined in the dependent claims.
REFERENCES:
patent: 4977320 (1990-12-01), Chowdhury et al.
patent: 5591969 (1997-01-01), Park et al.
patent: 2002/0182649 (2002-12-01), Weinberger et al.
patent: 2002/0195555 (2002-12-01), Weinberger et al.
patent: 2003/0219731 (2003-11-01), Weinberger et al.
patent: 2004/0079878 (2004-04-01), Vestal et al.
Nielsen, “Biomolecular ions in accelerators and storage rings,” Journal of Physics B: Atomic, Molecular and Optical Physics, Apr. 2004, pp. R-26-R56.*
Westman, A., et al. “MALDI induced saturation effects in chevron microchannel plate detectors” International Hournal of Mass Spectrometry and Ion Processes, Elsev
Amersham Biosciences AB
Graybill David E.
Ji Yonggang
Ronning, Jr. Royal N.
Ryan Stephen G.
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