Multiple reflection mass analyzer

Abstract

To provide a multireflection time-of-flight type mass spectrometer that includes a mass analyzer having opposing mirror electrodes and focal plane correction electrodes.SOLUTION: Each mirror electrode 12 is elongated generally along a drift direction. A focal plane correction electrode 25 extends along at least a portion of the drift direction in or adjacent to a space between the mirror electrodes. Ions 20 are injected into the mirror electrodes, and potentials provided to the mirror electrodes reflect the ions in a resulting ion beam, causing the ions to follow a zigzag path as the ions drift along the mirror electrodes. Potentials are also provided to the focal plane correction electrode to set a focal plane position of the ion beam to coincide with a detector surface of an ion detector 16 arranged at an end of the ion's path.SELECTED DRAWING: Figure 3

Description

[Technical Field]

[0001] The present invention relates to the field of mass spectrometry, and in particular to time-of-flight mass spectrometry and electrostatic trap mass spectrometry utilizing multiple reflection techniques to extend ion flight paths. [Background technology]

[0002] Various arrangements are known that utilize multiple reflections to extend the flight path of ions in a mass spectrometer. Extending the flight path is desirable for increasing the time-of-flight separation of ions in time-of-flight (ToF) mass analyzers, as it increases the ability to distinguish small mass differences between ions.

[0003] An example of a multi-reflection time-of-flight (MR-ToF) mass analyzer can be found in WO 2013 / 110587. Two parallel, opposing mirror electrodes are elongated in the drift direction (y-direction). Ions are extracted from the ion trap and injected into the mirror electrodes, and then the ions are reflected between the mirror electrodes (z-direction) while drifting relatively slowly along the extended length of the mirror electrodes in the drift direction. Thus, the ions follow a zigzag flight path through the mass analyzer.

[0004] Furthermore, the mirror electrodes are tilted at an angle Θ relative to each other so that their spacing in the z direction decreases as they extend in the drift direction. Ions that begin oscillating between opposing mirror electrodes also drift in the y direction due to the initial tilt at which the ions were injected into the mirror electrodes. The mirror focusing tilt angle Θ reduces the trajectory tilt angle by 2Θ with each oscillation, which includes two reflections. As a result, the drift direction is eventually reversed so that the ions return through the mirror electrodes and are detected by an ion detector located adjacent to the ion trap.

[0005] However, tilted mirror electrodes introduce ToF aberrations because not all ions follow a common path through the mirror electrodes. The finite spread of the beam injection angle causes some ions to drift further down the mirror electrodes than others. Advantageously, reflecting ions back along the mirror electrodes means that when they reach the ion detector, they are once again spatially focused. However, time aberrations are introduced because the oscillation period of the ions decreases as a function of distance along the drift direction as a result of the reduced spacing between the mirror electrodes.

[0006] These ToF aberrations are corrected by using stripe electrodes to modify the average velocity of ions as they traverse between the mirror electrodes as a function of drift position y. The stripe electrodes are shaped to have a width that aligns with the space between the mirror electrodes and varies with drift position y, so that the proportion of the flight path between the mirrors at the potential of the stripe electrodes varies along the drift position. As a result, the average potential, and therefore the average ion velocity, varies as a function of distance along the mirror electrodes. The average field potential increases along the drift direction, so that ions move more slowly the further they drift along the mirror electrodes. This increases the period of oscillation as a function of distance along the drift direction, thereby mitigating the period reduction caused by the focusing mirror electrodes.

[0007] The voltages applied to the stripe electrodes can be adjusted to produce electric fields that offset the ToF aberrations resulting from the angular spread of ions injected into the mirror electrodes. This correction helps to produce substantially equal average oscillation times over multiple oscillations of ions between opposing mirror electrodes, even as the distance between the mirrors changes.

[0008] An alternative MR-ToF analyzer is described in U.S. Patent Application Publication No. 2020 / 0243322. The analyzer includes mirror electrodes that are parallel rather than tilted, so that ions travel along the length of the mirror electrodes at a constant drift velocity and are detected at the end of the mirror electrodes opposite the ion trap into which they are injected. U.S. Patent Application Publication No. 2020 / 0243322 includes stripe electrodes, but for reasons different from those in WO 2013 / 110587, it does not need to correct for ToF aberrations resulting from the tilted mirror electrodes. Instead, a first pair of curved stripe electrodes is used to correct for any curvature in the mirror electrodes. A second pair of stripe electrodes is used to correct for misalignment between the mirror electrodes.

[0009] To achieve high resolution, the mirror electrodes must be fabricated and positioned with very high precision, i.e., with tolerances as low as tens of microns. Small mechanical errors can degrade focus quality and / or tilt the ion focal plane relative to the detector surface, disrupting the achievable resolution. Additionally, the voltages applied to the mirror electrodes must be extremely stable, down to parts per million. These highly stable voltages are required to maintain mass calibration of the mass analyzer, ensuring no jitter when summing multiple mass analyzer iterations and over longer time periods. Mass calibration is required to mitigate the effects of mechanical errors. Calibration involves, for example, adjusting the voltages applied to the mirror electrodes to at least align the focal length of the ion beam to coincide with the detector surface.

[0010] The requirement to provide precise voltages that remain very stable at high voltage levels typically requires high levels of filtering and attenuation, thus necessitating the use of substantial capacitance. As a result, power supplies respond slowly to changes in settings, cannot cope with changes within a scan, and often struggle to provide smooth changes between scans for typical repetition rates in the 100 Hz region. This means that delays are required when switching between operating modes that require the focal plane to be adjusted.

[0011] An additional problem faced by ToF analyzers is that resolution rapidly decreases as the number of ions in the ToF analyzer increases as peaks are scanned. This is because the increased ion density causes space charge effects that shift the focal plane position. The mirror electrode voltage can be increased to counter the focal plane shift and mitigate losses, but this sacrifices maximum resolution. A compromise can be found, but it is better to be able to quickly switch between space charge tolerance levels based on the expected intensity of the measured peak, or to obtain a wider dynamic range of space charge tolerance values ​​by combining several spectra. Unfortunately, as mentioned above, the large capacitance present in the power supply means that the mirror electrode voltage cannot be adjusted in such a short (low millisecond) time frame.

[0012] A special mode of operation for multi-reflection ToF analyzers, called "zoom mode," was described by Verenchikov et al. in the Journal of Applied Solution Chemistry and Modeling, 2017, volume 6, pages 1-22. A deflector placed at the beginning of the ion path through the mirror electrode is switched on to provide a trapping voltage that causes the ions to make multiple passes above and below the mirror electrode. The significantly extended flight path provided a significantly increased resolution up to 500,000, but, as the name suggests, caused a severe narrowing of the mass range that could be scanned.

[0013] The main drawback of zoom mode is that the ToF focal plane position shifts with the number of drift passes. This means that it is difficult to quickly switch between zoom and normal modes, because the mirror electrode voltage shift is not responsive enough to track the switching device behavior. This undermines many potential applications, such as blending unambiguous full MS or MS / MS spectra with high-resolution zoom shots of the target area for isobaric TMT reporter ions, as proposed by McAlister et al. (Anal. Chem., 2012, volume 84, pages 7469-7478). Summary of the Invention

[0014] According to a first aspect, there is provided a method of mass analysis in a multi-reflecting time-of-flight mass spectrometer comprising a mass analyzer having two mirror electrodes and a focal plane correction electrode. Each mirror electrode is elongated generally along the drift direction (y), and each mirror electrode faces the other in the z direction, which is orthogonal to the y direction. The focal plane correction electrode extends along at least a portion of the drift direction within or adjacent to the space between the mirror electrodes.

[0015] The method includes injecting ions into a mirror electrode and providing a potential to the mirror electrode, the potential reflecting ions in a resulting ion beam and causing the ions to follow a zigzag path as they drift along the mirror electrode, and also providing a potential to a focal plane correction electrode to set a focal plane position of the ion beam to coincide with a detector surface of an ion detector located at an end of the path of the ions through the mirror electrode.

[0016] The use of focal plane correction electrodes provides an advantageous method for adjusting the focal plane position of the ion beam. The focal plane correction electrodes can fully or partially correct the focal plane position of the ion beam to coincide with the detector surface of the ion detector. This avoids the problems of using stable, high-potential supplies, which are used to set potentials on mirror electrodes, which can only provide very slow response times. Focal plane correction electrodes have the unique advantage of allowing fine adjustments of the focal plane position to be performed by perturbation fields that require much lower potentials. For example, the focal plane correction electrodes can be set to a potential close to ground. These smaller potentials can be changed rapidly, thereby avoiding any delay between scans. This also ensures that the power supply to the mirror electrodes provides a fixed, unchanging voltage during the scan. This reduces the complexity and cost of the electronics required for the power supply. The potential supplied to the focal plane correction electrodes can have a value between -150 V and +150 V, or between -100 V and +100 V. A further advantage is that the low potential set means that the focal plane correction electrodes have little effect on the ion reflection process, which means that the requirement for a very stable applied potential is even more relaxed.

[0017] Optionally, the method includes providing a potential to the focal plane correction electrode to set an effective length of oscillation of the ions between the mirror electrodes such that the total effective path length of the ions coincides with a focal plane position of the ion beam with a detector surface of the ion detector.

[0018] The method may include adjusting a potential to a focal plane correction electrode during a scan to mitigate drift in the focal plane position of the ion beam away from a detector surface of the ion detector. The potential provided to the focal plane correction electrode may be adjusted during a scan to mitigate drift in the focal plane position of the ion beam away from a detector surface of the ion detector as a function of the number of ions in the mass analyzer. This may be done to mitigate changes in space charge effects resulting from either an increase or decrease in the number of ions in the mass analyzer. The use of focal plane correction electrodes allows rapid shifts in the focal plane position due to space charge effects to be instantly compensated for, thereby extending the dynamic range of the instrument.

[0019] Optionally, the method may include adjusting a potential to the focal plane correction electrode between scans to mitigate drift in the focal plane position of the ion beam away from the detector surface of the ion detector. The potential provided to the focal plane correction electrode may be adjusted between scans to mitigate drift in the focal plane position of the ion beam away from the detector surface of the ion detector as a function of the number of ions in the mass analyzer. This may be done to mitigate changes in space charge effects between scans resulting from either an increase or decrease in the number of ions in the mass analyzer. A scan may be a zoom mode scan preceded by a scan that is not a zoom mode scan. The non-zoom mode scan may include ions completing one pass between the ion source and the ion detector. The zoom mode may include multiple passes of ions between the ion source and the ion detector, i.e., the ion beam is deflected and returns through the mirror electrodes multiple times before being allowed to travel to the ion detector. The use of focal plane correction electrodes allows for fast switching between normal mode and zoom mode, possibly even within a single scan, so that all ions are always in focus during both scans.

[0020] The mirror electrodes may be segmented into electrodes extending in the y-direction and separated in the z-direction. The method may include providing a potential to the focal plane correction electrode by providing a potential to one of the mirror electrodes, the electrode being closest to the space between the mirror electrodes. Alternatively, the method may include providing a potential to a pair of the mirror electrodes, the pair being closest to the space between the mirror electrodes. In this way, the mirror electrodes may also be used to perform the function of the correction electrode. This means that the mass analyzer does not require additional electrodes.

[0021] The mirror electrodes may be tilted at a tilt angle relative to one another such that the spacing between the mirrors in the z-direction decreases as the distance along the y-direction increases. The mass analyzer may also further comprise a time-of-flight correction electrode. The method may further include providing an additional potential to the time-of-flight correction electrode to correct for spread in the time-of-flight of ions along their paths through the mirror electrodes caused by the tilt angle of the mirror electrodes. In such a case, providing a potential to the focal plane correction electrode may include providing a potential and an additional potential to the time-of-flight correction electrode. In this way, the time-of-flight correction electrode may also be used to perform the function of the focal plane correction electrode. This means that the mass analyzer does not require additional electrodes.

[0022] The time-of-flight correction electrode may be supported by a carrier. Providing a potential to the focal plane correction electrode may then include providing a potential and a further potential to the time-of-flight correction electrode, and providing a potential to the carrier. Supplying a potential to both the time-of-flight correction electrode and the carrier ensures that a potential difference between the time-of-flight correction electrode and the carrier is maintained, thereby preserving the time-of-flight correction applied by the time-of-flight correction electrode.

[0023] According to a second aspect, there is provided a method for calibrating a mass analyser in a multi-reflecting time-of-flight mass spectrometer, the mass analyser comprising two mirror electrodes and a focal plane correction electrode, each mirror electrode being elongated generally along a drift direction (y), each mirror electrode facing the other in a z direction, the z direction being orthogonal to the y direction, and the focal plane correction electrode extending along at least a portion of the drift direction within or adjacent to a space between the mirror electrodes.

[0024] The method includes injecting ions into a mirror electrode and providing a potential to the mirror electrode, the potential reflecting ions in a resulting ion beam and causing the ions to follow a zigzag path as they drift along the mirror electrode, the method also includes providing a range of potentials to a focal plane correction electrode, detecting the ions at a detector surface of an ion detector positioned at an end of the ion's path through the mirror electrode, and measuring the resolution of the mass analyzer at each of a plurality of potentials provided to the focal plane correction electrode.

[0025] This allows optimal settings to be found for different scans. Different ions can be used to compile a table of settings. Such a table can be used as a look-up table for subsequent operation of the mass spectrometer.

[0026] Optionally, measuring the resolving power of the mass analyzer at each of a plurality of potentials provided to the focal plane correction electrodes includes measuring the width of the peak corresponding to the number of ions as a function of the m / z ratio of the ions. For example, the full width at half maximum may be measured.

[0027] According to a third aspect, there is provided a multi-reflection time-of-flight mass analyzer comprising two mirror electrodes, each elongated generally along a drift direction (y-direction) away from an ion injection point, and each mirror electrode facing the other in a z-direction, the z-direction being orthogonal to the y-direction. The mass analyzer also comprises a focal plane correction electrode extending along at least a portion of the y-direction within or adjacent to the space between the mirror electrodes. The mass analyzer also comprises a controller configured to operate the mass analyzer according to any of the methods described above.

[0028] Optionally, the two mirror electrodes are tilted at a tilt angle such that the separation between the mirrors in the z direction decreases as the distance along the y direction increases. The mass analyzer may comprise an ion source and an ion detector, both located at the same end of the mirror electrodes.

[0029] The width of the focal plane correction electrode may be substantially the same in the z direction along the length of the focal plane correction electrode in the y direction. The mass analyzer may include a pair of focal plane correction electrodes positioned on either side of a path of the ion beam through the mass analyzer.

[0030] In order that the present invention may be more readily understood, reference will now be made, by way of example only, to the accompanying drawings in which: [Brief explanation of the drawings]

[0031] [Figure 1] 1 is a schematic diagram of a prior art multi-reflecting time-of-flight mass spectrometer. [Figure 2] FIG. 1 is a schematic diagram of the operation of a mass analyzer in zoom mode. [Figure 3] FIG. 1 is a schematic diagram of an embodiment of a multi-reflecting time-of-flight mass analyzer. [Figure 4] FIG. 10 is a schematic diagram of a method for determining the potentials applied to focal plane correction electrodes to optimize resolution. [Figure 5] 10 is a graph showing the variation in resolution due to the focal plane correction electrode potential. [Figure 6]FIG. 10 is a schematic diagram of a further embodiment of a multi-reflecting time-of-flight mass analyzer. [Figure 7] FIG. 10 is a schematic diagram of yet another embodiment of a multi-reflecting time-of-flight mass analyzer. DETAILED DESCRIPTION OF THE INVENTION

[0032] As discussed above, some mass analyzer designs typically utilize multiple reflections to extend the flight path of ions, which is desirable because it increases the time-of-flight separation of ions and therefore increases the resolution in a time-of-flight (ToF) mass analyzer. Figure 1 shows an example of a multi-reflection time-of-flight (MR-ToF) mass analyzer 10. A pair of ion-optical mirrors is provided by two parallel, opposing mirror electrodes 12 elongated in the drift direction (y-direction). Ions 20 are extracted from an ion trap 14 and injected into the mirror electrodes 12. The ions 20 are beam-shaped by a lens / deflector 18 before reflecting from the first mirror electrode 12. The expanding ion beam 20 then strikes a second deflector 19, which sets the final injection angle and collimates the ion beam 20 as much as possible. The ions 20 then undergo multiple reflections between the mirror electrodes 12 (in the z-direction) while drifting relatively slowly along the extended length of the mirror electrodes 12 in the drift (y) direction. Ions 20 therefore follow a zigzag flight path through the mass analyzer 10 .

[0033] Furthermore, the mirror electrodes 12 are tilted relative to one another by an angle Θ (typically about 0.05 degrees) so that their spacing in the z-direction decreases as they extend in the drift direction. The focusing angle Θ reduces the trajectory tilt angle of the ions 20 by 2Θ with each oscillation (each oscillation includes two reflections). As a result, the drift of the ions 20 is eventually reversed, and the ions 20 return through the mirror electrodes 12 and are detected by the ion detector 16 located adjacent to the ion trap 14.

[0034] Because the ions 20 have a smaller spread at the injection angle, the ion beam 20 spreads as it drifts along the mirror electrodes 12. Therefore, the drift length of an ion along the mirror electrodes 12 varies depending on the injection angle of that ion, with ions 20 injected at a steeper angle having a lower velocity component in the y direction and therefore drifting a shorter distance along the mirror electrodes 12 than ions injected at a shallower angle having a higher velocity component in the y direction. A smaller tilt angle Θ acts to cause a spread in the flight times of the ions 20 because ions 20 that drift further along the mirror electrodes 12 experience a narrower gap between the mirror electrodes 12 than ions 20 that drift less far. This results in different flight times for ions 20 with the same m / z ratio but with different injection angles, resulting in a loss of resolution.

[0035] The time-of-flight spread of the ions 20 introduced by the tilted mirror electrodes 12 is addressed by adding a pair of correction electrodes 24 along the length of the drift dimension, one correction electrode 24 positioned above the ion beam 20 and the other correction electrode 24 positioned below the ion beam 20. These correction electrodes 24 are hereinafter referred to as ToF correction electrodes 24 to reflect their function in correcting the time-of-flight spread of the ions 20.

[0036] The edges of each ToF correction electrode 24 have a shape determined by a shape function S(y) corresponding to the time-of-flight spread to be corrected. The shape function may define the width (z-direction) of the ToF correction electrode 24 as a function of position along the drift (y) direction. The ToF correction electrodes 24 modify the electric field in the region where the ions 20 propagate, thus causing additional drift deflection and time-of-flight perturbations to the ions 20. Furthermore, the modification to the electric field can be configured to counter the focusing effect of the mirror electrodes, such that the ToF correction electrodes 24 ensure that all ions 20 have the same time-of-flight from the ion trap 14 to the ion detector 16, regardless of any variations in the starting point y and initial drift velocity v = dy / dt.

[0037] As briefly discussed in the "Background" section, a ToF mass analyzer such as that shown in FIG. 1 can be operated in a zoom mode. FIG. 2 shows a schematic of how this mode of operation works. Ions 20 are injected from the ion trap 14 through a deflector 18 and between the mirror electrodes 12 at a relatively high angle. After a first half-oscillation, the ions 20 pass through a second prism-shaped deflector 19, which reduces the injection angle by approximately half. The oscillating ions 20 then drift up the length of the elongated mirror electrodes and are returned by the set tilt of the mirror electrodes. By the time the ions 20 return to the second deflector 19, the voltage has been switched to a trapping voltage, e.g., between about -150 V and about +350 V, causing the ions 20 to reflect back along the length of the mirror electrodes 12 for a second pass. These reflections continue until the deflector 19 is switched back to the injection / extraction voltage (e.g., about -150V) after a desired number of passes so that the ions 20 can pass through and proceed toward the ion detector 16. For optimal resolution, the number of passes of the ions 20 is made odd, as this allows aberrations caused by deflector reflections to self-correct with each repeat movement. By having the ions 20 make multiple passes above and below the mirror electrodes 12, the ion's path length is significantly extended, providing significantly increased resolution within a much narrower mass range scan.

[0038] However, the focal plane position of the ions 20 shifts with each pass through the mirror electrodes 12. As a result, switching the zoom mode on and off requires large changes in the voltage set on the mirror electrodes 12 to adjust the focal plane position. As mentioned above, the large capacitance inherent in the power supply means that such switching cannot be done quickly, which compromises many potential applications, such as mixing a clear full MS or MS / MS spectrum (e.g., for isobaric TMT reporter ions) with a high-resolution zoom shot of the target area.

[0039] A ToF mass analyzer 10 is shown in Figure 3. The mass analyzer 10 comprises parallel mirror electrodes 12 such that ions 20 make a single pass along the length of the mirror electrodes 12 as they oscillate between them. Ions 20 are injected from an ion trap 14 and pass through a lens / deflector 18, where the ion beam 20 is shaped before reflecting from the first mirror electrode 12. In some embodiments, including this one, the lens / deflector 18 comprises a pair of out-of-plane lenses 18a and a pair of deflectors 18b, which also provide drift focusing.

[0040] Three trajectories are shown for the ion beam 20: 20a corresponds to the trajectory followed by ions 20 implanted at the steepest implant angle, 20b corresponds to the mid-median trajectory, and 20c corresponds to the trajectory followed by ions 20 implanted at the shallowest implant angle.

[0041] The mass analyzer 10 also comprises a correction electrode, i.e. a flat stripe electrode 25, which, in use, is biased with a voltage that affects the oscillation time of ions between the mirror electrodes 12 without spatially deflecting the ion trajectories, thereby shifting the focal plane of the ion beam 20. This correction electrode 25 will be referred to hereinafter as the focal plane correction electrode 25 to reflect its function in correcting the focal plane of the ion beam 20.

[0042] Applying a relatively low voltage, in the range of −100V to +100V, to the focal plane correction electrode 25 substantially shifts the focal plane of the ion beam 20. While FIG. 3 shows parallel mirror electrodes 12 and the ion beam 20 collimated by the drift focusing lens 18b, it is readily apparent that a corresponding focal plane correction electrode 25 could be used in a tilted mirror mass analyzer 10 such as that shown in FIG. 1. An additional focal plane electrode 25 could be located in the space between an existing pair of ToF correction electrodes 24. In either arrangement, a pair of focal plane correction electrodes 25 could be used, one on each side of the ion beam 20. The focal plane correction electrodes 25 could be a pair of metal plates attached via insulators to an electrode carrier, which itself is typically of steel or aluminum construction. The vacuum chamber housing the mass analyzer 10 itself could serve this purpose if manufactured with sufficient precision. Alternatively, the focal plane correction electrodes 25 could be printed on a glass substrate or PCB / ceramic PCB material.

[0043] The low voltage requirements of such focal plane correction electrodes 25 make them suitable for fast voltage switching so that the focal plane of the ion beam can be adjusted on a low millisecond timescale, sufficient for shot-by-shot adjustments. This also makes them applicable for switching between zoom and normal modes of operation, for example, and for rapid switching to accommodate rapidly changing space charge tolerance levels caused when ion densities change rapidly as a peak is scanned.

[0044] The action of the focal plane correction electrodes 25 is to modify the effective distance between two opposing mirror electrodes 12 when the ions 20 are accelerated or decelerated while moving between the mirror electrodes 12 by the focal plane correction electrodes 25 located on both sides of the (yz) plane. The effective length W of one oscillation is osc is the nominal ion velocity

[0045]

number

[0046]

number

[0047] A voltage u (|u|< a ) biased by width w s The focal plane correction electrode 25 adjusts the oscillation period T0 by a quantity

[0048]

number

[0049] The factor of 2 reflects the fact that ions 20 pass through the focal plane correction electrode 25 twice per oscillation. Accordingly, the effective oscillation length W is

[0050]

number

[0051] When ions 20 move from the ion trap 14 to the ion detector 16, with K oscillations between the mirror electrodes 12, the ToF focal plane position changes by a quantity

[0052]

number

[0053]

number

[0054] As mentioned above, achieving an equivalent shift in the ToF focal plane by adjusting the voltage applied to the mirror electrodes 12 is very slow. For example, it can take several seconds for the new voltage to stabilize. Conversely, a low-voltage focal plane correction electrode 25 can operate at a frequency of several kHz. This allows the ToF focal plane position to be adjusted during normal operation without the need for a delay.

[0055] In addition to a stable high voltage source supplying the mirror electrodes 12, which changes very slowly, there are several advantages to using focal plane correction electrodes 25 to correct the ToF focal plane position. For example, an arrangement that adjusts only the voltage supplied to the mirror electrodes 12 would require an individually adjustable voltage for each mirror electrode 12, which would be very expensive. In the present invention, the mirror electrodes 12 can be used to provide coarse adjustment using two stable voltages in conjunction with a resistor chain, and then the focal plane correction electrodes 25 can provide fine focal plane adjustment.

[0056] Additionally, by switching the bias of the focal plane correction electrodes 25 between scans, the mass analyzer 10 can be adjusted for optimal focusing of ion peaks containing different numbers of ions 20 and, therefore, different amounts of space charge. The primary effect of space charge on intense peaks is a reduction in resolution, which can usually be improved by the same mirror electrode voltage tuning adjustment that changes the focal plane position. Thus, a series of scans can sequentially provide the highest resolution for low-abundance, medium-abundance, and high-abundance peaks (or in reverse order), thus covering the full range of peaks in the mass spectrum. The energy acceptance limits of the mass analyzer 10 also often mean that low m / z scans will have slightly different focal plane adjustments than higher m / z scans. The use of the focal plane correction electrodes 25 allows for rapid adjustment of the focal plane position between scans to correct for drift in the focal plane position.

[0057] A further advantage is that it corrects for large shifts in the ToF focal plane position seen in zoom mode, where the flight path of ions 20 is changed by repeatedly sending ions 20 along the mass analyzer 10. The use of focal plane correction electrodes 25 allows for rapid correction of the ToF focal plane position, which can be done within about 1 ms between scans.

[0058] FIG. 4 shows a method 100 for determining the correction voltage to be applied to the focal plane correction electrode 25 to ensure that the focal plane of the ion beam 20 coincides with the ion detector 16, thus optimizing resolution.

[0059] The method 100 begins at 102 where the peak resolution is measured. This can be done by measuring the full width at half maximum of a peak in a single measurement, where a single peak contains many ions, typically about 100. At 104, a determination is made as to whether the resolution is acceptable. If the resolution is not found to be acceptable, the method ends at 106.

[0060] If the resolution is found to be unacceptable, the method proceeds to 108 where an optimum focal plane correction electrode voltage is calibrated by performing a one-dimensional scan of the voltage applied to focal plane correction electrode 25 while measuring the full width at half maximum of a known ion peak, such as an internal calibrant. This may be done by scanning the voltage applied to focal plane correction electrode 25 by ±20 V around the voltage initially set in step 102.

[0061] Step 108 produces data such as that shown in Figure 5, in which measurement resolution is plotted against the voltage set on the focal plane correction electrode 25. Any suitable technique, such as curve fitting, can be used to find the optimum resolution at 110 and the corresponding voltage at 112. The voltage determined in step 112 can then be applied to the focal plane correction electrode 25 during subsequent operation, as shown in step 114.

[0062] This calibration method 100 shown in FIG. 4 can be repeated for different operating modes, such as zoom mode and normal mode. For example, zoom mode can be used for MS / MS analysis of TMT-labeled peptides. Upon fragmentation, these analytes generate TMT reporter ions in multiple channels around m / z 130, requiring >50K resolution to distinguish between different reporter ions. Multiple sample peptides are labeled with different TMT labels and injected together, so being able to distinguish isobaric labels from each other is important. Labeled peptides also generate peptide fragments across a wide mass range. For efficient peptide fragment measurement, a scan can be performed in normal mode, and then a further scan can be performed in zoom mode for high-resolution measurement of challenging TMT reporter ions. Doing this results in two scans in succession, with a shift in the focal plane position between them. The focal plane correction electrode 25 facilitates switching between the optimal voltages for normal and zoom modes to maintain optimal resolution in both modes.

[0063] Further modes of operation are enabled by the use of focal plane correction electrodes 25 to correct the focal plane position. Zoom mode can be rapidly switched on and off so that within a single scan, TMT reporter ions make multiple passes through the mass analyzer 10 in zoom mode, while peptide fragments make only a single pass. This is highly advantageous because it occurs within a single scan and does not waste any ions of either type, but requires very rapid switching of the focal plane correction electrodes 25 within the scan, preferably after the last fragment ion reaches the ion detector 16.

[0064] It was explained above that the focal plane correction electrode 25 of Figure 3 can be used in a tilted mirror mass analyzer 10 such as that shown in Figure 1 by inserting an additional focal plane electrode 25 into the space between an existing pair of ToF correction electrodes 24. Two further embodiments are now described that do not require an additional electrode to act as focal plane electrode 25. Both embodiments instead adapt the potential set on an existing electrode so that the electrode can also function as focal plane correction electrode 25.

[0065] 6 illustrates a tilted mirror mass analyzer 10 like that shown in FIG. 1, and therefore common parts will not be described to avoid redundancy. As with the mass analyzer 10 of FIG. 1, the mirror electrodes 12 are divided into a series of electrodes 121-125, each of which can be biased at a different potential. Conventionally, the innermost electrode 121 of each mirror electrode 12 is grounded to provide a stable starting surface for the next electrode 122, which is set to a relatively high potential.

[0066] However, it is recognized that the innermost electrode 121 can be biased at a small potential away from ground without affecting the operation of the mirror electrodes 12. Thus, the innermost electrode 121 of each mirror electrode 12 can be used as a focal plane correction electrode 25 by setting a small potential necessary to correct the focal plane of the ion beam 20. Alternatively, the innermost electrode 121 of one mirror electrode 12 can be used as a focal plane correction electrode 25, and the innermost electrode 121 of the other mirror electrode 12 can be grounded. If the innermost electrode 121 of both mirror electrodes 12, rather than the innermost electrode 121 of just one mirror electrode 12, is used as a focal plane correction electrode 25, a smaller potential is required on each innermost electrode 121, and symmetry is maintained for each ion beam oscillation between the mirror electrodes 12.

[0067] Figure 7 shows a tilting mirror mass analyzer 10 like those shown in Figures 1 and 6, so to avoid redundancy, common parts will not be described. In practice, the ToF correction electrodes 24 may be supported by a carrier 26, as shown in Figure 7 (the carrier 26 has been omitted from Figures 1 and 6 for clarity). In use, a potential is applied to the ToF correction electrodes 24 to provide ToF correction, such that a potential step is introduced between the ToF correction electrodes 24 and their carriers 26.

[0068] It is recognized that the small potential required to correct the focal plane of the ion beam 20 can be added to the potential applied to the ToF correction electrode 24 so that the ToF correction electrode 24 also functions as the focal plane correction electrode 25. To ensure that the ToF correction electrode 24 still provides the necessary correction of the ToF of the ions 20, a potential step is maintained between the ToF correction electrode 24 and its carrier 26. Thus, the same potential required to correct the focal plane can be applied to both the ToF correction electrode 24 and its carrier 26. As a result, in this embodiment, the combination of the ToF correction electrode 24 and its carrier 26 acts as the focal plane correction electrode 25.

[0069] Those skilled in the art will appreciate that the above-described embodiments can be modified in many different ways without departing from the scope of the invention as defined by the appended claims.

[0070] Another possible improvement using focal plane correction with focal plane correction electrodes 25 is to provide variable correction for different m / z ions. This can be achieved, for example, by applying a time-dependent voltage to focal plane correction electrodes 25 so that the average voltage seen by ions 20 with different m / z ratios changes as lower m / z ions leave the mass analyzer 10 before higher m / z ions. This can provide at least some compensation for mass-dependent variations in ion energy, as is known to be caused by extractive traps.

[0071] A special case occurs when an RF frequency is applied to the focal plane correction electrode 25, which can then bring the m / z range into resonance at a controlled frequency and phase, potentially allowing compensation for m / z regions known to be under space charge effects.

[0072] Certain proposed types of extraction traps, such as extraction from RF carpets, have the disadvantage of producing a very large m / z dependence of the focal plane position. The focal plane correction electrode 25 can be used to correct for this m / z dependence by imposing a short-time dependence on its applied voltage.

Claims

1. 1. A method of mass analysis in a multi-reflecting time-of-flight mass spectrometer having a mass analyzer with two mirror electrodes and a focal plane correction electrode, comprising: each mirror electrode is elongated generally along a drift direction (y-direction), each mirror electrode faces the other in a z-direction, the z-direction being orthogonal to the y-direction, the focal plane correction electrode extends along at least a portion of the drift direction within or adjacent to a space between the mirror electrodes, and the method comprises: injecting ions into the mirror electrode and providing a potential to the mirror electrode, the potential reflecting the ions in a resulting ion beam and causing the ions to follow a zigzag path as they drift along the mirror electrode; providing a potential to the focal plane correction electrode to set the focal plane position of the ion beam to coincide with a detector surface of an ion detector located at the end of the path of the ions through the mirror electrode; adjusting the potential provided to the focal plane correction electrode during a scan to mitigate drift of the focal plane position of the ion beam away from the detector surface of the ion detector.

2. 1. A method of mass analysis in a multi-reflecting time-of-flight mass spectrometer having a mass analyzer with two mirror electrodes and a focal plane correction electrode, comprising: each mirror electrode is elongated generally along a drift direction (y-direction), each mirror electrode faces the other in a z-direction, the z-direction being orthogonal to the y-direction, the focal plane correction electrode extends along at least a portion of the drift direction within or adjacent to a space between the mirror electrodes, and the method comprises: injecting ions into the mirror electrode and providing a potential to the mirror electrode, the potential reflecting the ions in a resulting ion beam and causing the ions to follow a zigzag path as they drift along the mirror electrode; providing a potential to the focal plane correction electrode to set the focal plane position of the ion beam to coincide with a detector surface of an ion detector located at the end of the path of the ions through the mirror electrode; adjusting the potential provided to the focal plane correction electrode between scans to mitigate drift of the focal plane position of the ion beam away from the detector surface of the ion detector.

3. 1. A method of mass analysis in a multi-reflecting time-of-flight mass spectrometer having a mass analyzer with two mirror electrodes and a focal plane correction electrode, comprising: each mirror electrode is elongated generally along a drift direction (y-direction), each mirror electrode faces the other in a z-direction, the z-direction being orthogonal to the y-direction, the focal plane correction electrode extends along at least a portion of the drift direction within or adjacent to a space between the mirror electrodes, and the method comprises: injecting ions into the mirror electrode and providing a potential to the mirror electrode, the potential reflecting the ions in a resulting ion beam and causing the ions to follow a zigzag path as they drift along the mirror electrode; providing a potential to the focal plane correction electrode to set the focal plane position of the ion beam to coincide with a detector surface of an ion detector located at the end of the path of the ions through the mirror electrode; adjusting the potential to the focal plane correction electrode between scans to mitigate drift of the focal plane position of the ion beam away from the detector surface of the ion detector as a function of the number of ions in the mass analyzer.

4. 1. A method of mass analysis in a multi-reflecting time-of-flight mass spectrometer having a mass analyzer with two mirror electrodes and a focal plane correction electrode, comprising: each mirror electrode is elongated generally along a drift direction (y-direction), each mirror electrode faces the other in a z-direction, the z-direction being orthogonal to the y-direction, the focal plane correction electrode extends along at least a portion of the drift direction within or adjacent to a space between the mirror electrodes, and the method comprises: injecting ions into the mirror electrode and providing a potential to the mirror electrode, the potential reflecting the ions in a resulting ion beam and causing the ions to follow a zigzag path as they drift along the mirror electrode; providing a potential to the focal plane correction electrode to set the focal plane position of the ion beam to coincide with a detector surface of an ion detector located at the end of the path of the ions through the mirror electrode; adjusting the potential provided to the focal plane correction electrode between scans to mitigate drift in the focal plane position of the ion beam away from the detector surface of the ion detector, or adjusting the potential to the focal plane correction electrode between scans to mitigate drift in the focal plane position of the ion beam away from the detector surface of the ion detector as a function of the number of ions in the mass analyzer; The method, wherein the scanning includes a first scan and a second scan, the first scan is not a zoom mode scan, and the second scan is a zoom mode scan.

5. 1. A method of mass analysis in a multi-reflecting time-of-flight mass spectrometer having a mass analyzer with two mirror electrodes and a focal plane correction electrode, comprising: each mirror electrode is elongated generally along a drift direction (y-direction), each mirror electrode faces the other in a z-direction, the z-direction being orthogonal to the y-direction, the focal plane correction electrode extends along at least a portion of the drift direction within or adjacent to a space between the mirror electrodes, and the method comprises: injecting ions into the mirror electrode and providing a potential to the mirror electrode, the potential reflecting the ions in a resulting ion beam and causing the ions to follow a zigzag path as they drift along the mirror electrode; providing a potential to the focal plane correction electrode to set a focal plane position of the ion beam to coincide with a detector surface of an ion detector located at an end of a path of the ions through the mirror electrode; the mirror electrodes are segmented into electrodes extending in the y-direction and separated in the z-direction; The method, wherein providing the potential to the focal plane correction electrode includes providing the potential to one or both of the mirror electrodes closest to the space between the mirror electrodes.

6. 6. The method of claim 1, comprising providing the potential to the focal plane correction electrode to set an effective length of oscillation of the ions between the mirror electrodes such that a total effective path length of the ions coincides with the focal plane position of the ion beam with the detector surface of the ion detector.

7. 2. The method of claim 1, comprising adjusting the potential to the focal plane correction electrode during a scan to mitigate drift of the focal plane position of the ion beam away from the detector surface of the ion detector as a function of the number of ions in the mass analyzer.

8. 8. The method of claim 1 or 7, wherein the scan includes a portion where the mass analyzer (10) is not operating in zoom mode and another portion where the mass analyzer (10) is operating in zoom mode.

9. 8. The method of claim 1 or 7, wherein the mass analyzer (10) is operating in a zoom mode having a first portion in which the ions (20) make a first number of passes above and below the mass analyzer (10) and a second portion in which the ions (20) make a second number of passes above and below the mass analyzer (10), and wherein the first number and the second number are not the same.

10. 5. The method of claim 4, wherein the first scan is a zoom mode scan in which the ions (20) make a first number of passes above and below the mass analyzer (10), and the second scan is a zoom mode scan in which the ions (20) make a second number of passes above and below the mass analyzer (10), and the first number and the second number are not the same.

11. A method according to any one of claims 1 to 5, comprising providing a potential to the focal plane correction electrode having a value between -150V and +150V.

12. the mirror electrodes are tilted at a tilt angle relative to one another such that the spacing between mirrors in the z direction decreases as the distance along the y direction increases; the mass analyzer further comprising a time-of-flight correction electrode; the method further comprising providing an additional potential to the time-of-flight correction electrode to correct for spread in the time-of-flight of ions along their paths through the mirror electrodes caused by the tilt angle of the mirror electrodes; A method according to any one of claims 1 to 5, wherein providing the potential to the focal plane correction electrode comprises providing the potential and the further potential to the time-of-flight correction electrode.

13. the time-of-flight correction electrode is supported by a carrier; 13. The method of claim 12, wherein providing the potential to the focal plane correction electrode comprises providing the potential and the further potential to the time-of-flight correction electrode and providing the potential to the carrier.

14. 1. A method for calibrating a mass analyzer in a multi-reflecting time-of-flight mass spectrometer, comprising: the mass analyzer comprises two mirror electrodes and a focal plane correction electrode, each mirror electrode being elongated generally along a drift direction (y-direction), each mirror electrode facing the other in a z-direction, the z-direction being orthogonal to the y-direction, the focal plane correction electrode extending along at least a portion of the drift direction within or adjacent to a space between the mirror electrodes, and the method comprising: injecting ions into the mirror electrode and providing a potential to the mirror electrode, the potential reflecting the ions in a resulting ion beam and causing the ions to follow a zigzag path as they drift along the mirror electrode; providing a range of potentials to said focal plane correction electrodes; detecting ions at a detector surface of an ion detector disposed at an end of a path of the ions through the mirror electrode; measuring the resolution of the mass analyzer at each of a plurality of potentials provided to the focal plane correction electrode.

15. 15. The method of claim 14, wherein measuring the resolution of the mass analyzer at each of a plurality of potentials provided to the focal plane correction electrode comprises measuring a width of a peak corresponding to a number of ions as a function of the m / z ratio of the ions.

16. 1. A multi-reflecting time-of-flight mass analyzer, comprising: two mirror electrodes, each elongated generally along a drift direction (y-direction) away from the ion implantation point, each mirror electrode facing the other in a z-direction, the z-direction being orthogonal to the y-direction; a focal plane correction electrode extending along at least a portion of the y-direction in or adjacent to the spaces between the mirror electrodes; A multi-reflecting time-of-flight mass analyser comprising: a controller configured to operate the mass analyser according to the method of any one of claims 1 to 5.

17. 17. The multi-reflecting time-of-flight mass analyzer of claim 16, wherein the two mirror electrodes are tilted at a tilt angle relative to each other such that the spacing between the mirrors in the z direction decreases as the distance along the y direction increases.

18. 17. A multi-reflecting time-of-flight mass analyzer as claimed in claim 16, wherein the width of the focal plane correction electrode is substantially the same in the z direction along the length of the focal plane correction electrode in the y direction.

19. 17. A multi-reflecting time-of-flight mass analyzer according to claim 16, comprising a pair of focal plane correction electrodes positioned on either side of the path of the ion beam through the mass analyzer.

Images