Imaging mass spectrometer

Abstract

A time-of-flight mass spectrometer is disclosed comprising ion optics that map an array of ions at an ion source array (71) to a corresponding array of positions on a position sensitive ion detector (79). The ion optics include at least one gridless ion mirror (76) for reflecting ions, which may compensate for various aberrations and allows the spectrometer to have relatively high mass and spatial resolutions.

Claims

1. A time-of-flight mass spectrometer comprising: an ion source array for supplying or generating ions at an array of positions; a position sensitive ion detector having an array of separate detection regions configured such that ions received at different ones of the detection regions are determined as having originated from different positions in said array of positions; and ion optics arranged and configured to guide ions from the ion source array to the position sensitive detector so as to map ions from the array of positions on the ion source array to an array of positions on the position sensitive detector; wherein the ion optics includes at least two ion mirrors for reflecting ions, at least one of which is a gridless ion mirror; wherein said two ion mirrors are spaced apart from each other in a first dimension (X-dimension) and are each elongated in a second dimension (Z-dimension) or along a longitudinal axis that is orthogonal to the first dimension; and wherein the spectrometer is configured such that the ions drift in the second dimension (Z-dimension) or along the longitudinal axis towards the detector as they are reflected between the mirrors; further comprising an ion introduction mechanism for introducing packets of ions into the space between the mirrors such that they travel along a trajectory that is arranged at an angle to the first and second dimensions such that the ions repeatedly oscillate in the first dimension (X-dimension) between the mirrors as they drift through said space in the second dimension (Z-dimension).

2. The spectrometer of claim 1, wherein the step of mapping ions from the array of positions on the ion source array to the array of positions on the position sensitive detector comprises mapping ions from a 2D array of positions on the ion source array to a corresponding 2D array of positions on the position sensitive detector.

3. The spectrometer of claim 1, wherein said ion optics, including the at least two ion mirrors, are arranged and configured such that the ions are reflected by each of the mirrors and between the mirrors a plurality of times before reaching the detector.

4. The spectrometer of claim 1, wherein the ion introduction mechanism comprises an orthogonal ion accelerator for orthogonally accelerating ions into one of the ion mirrors.

5. The spectrometer of claim 1, wherein the ion optics comprise one or more ion optical lens through which the ions pass, in use, for focusing ions in a plane defined by the first and second dimensions (X-Z plane).

6. The spectrometer of claim 1, wherein the ion source array comprises a target plate and an ionizing device for generating at least one primary ion beam, at least one laser beam, or at least one electron beam for ionizing one or more analytical samples located on the target plate at said array of positions.

7. The spectrometer of claim 6, wherein the ionizing device is configured to direct one of the primary ion beams, laser beams or electron beams at each position in said array of positions at the ion source array; or wherein said at least one primary ion beam, at least one laser beam or at least one electron beam is continuously scanned or stepped between different positions of said array of positions on the target plate; or wherein each position of the different positions of said array of positions on the target plate comprises an area, and wherein said at least one primary ion beam, at least one laser beam or at least one electron beam is continuously scanned or stepped across different portions of said area.

8. The spectrometer of claim 1, wherein the ion source array comprises a single ion source for generating ions and an ion divider for dividing or guiding the ions generated by the ion source to the array of positions on the ion source array.

9. The spectrometer of claim 1, further comprising an electrostatic sector for guiding ions from the ion source array downstream towards the ion mirrors; and/or comprising an electrostatic sector for guiding ions from the ion mirrors downstream towards the detector.

10. The spectrometer of claim 1, further comprising an array of quadrupoles, ion guides or ion traps configured so that ions generated or supplied at different positions, in said array of positions on the ion source array, are transmitted into different quadrupoles, ion guides or ion traps in said array of quadrupoles, ion guides or ion traps.

11. The spectrometer of claim 10, wherein the spectrometer is configured to apply electrical potentials at the exits of the quadrupoles, ion guides or ion traps so as to trap and release ions from the quadrupoles, ion guides or ion traps in a pulsed manner downstream towards the detector.

12. The spectrometer of claim 1, wherein the ion source array comprises an ion source and an ion guide configured to receive ions from the ion source and to guide ions received from the ion source at different times to different positions in said array of positions at the ion source.

13. The spectrometer of claim 12, wherein an ion separator is provided between the ion source and ion guide for separating ions according to a physicochemical property such that ions having different values of said physicochemical property are guided to different positions in said array of positions at the ion source.

14. The spectrometer of claim 1, further comprising a fragmentation or reaction device downstream of the ion source array for fragmenting the ions to produce fragment ions or for reacting the ions with reagent ions or molecules so as to form product ions; and wherein said detector or another detector is provided to detect the fragment or product ions.

15. The spectrometer of claim 14, wherein the spectrometer is configured to repeatedly switch the fragmentation or reaction device between a first fragmentation or reaction mode that provides a high level of fragmentation or reaction and a second fragmentation or reaction mode that provides a lower level or no fragmentation or reaction, during a single experimental run; and/or wherein the spectrometer is configured to repeatedly switch between a first mode in which ions are fragmented or reacted in the fragmentation or reaction device and a second mode in which ions bypass the fragmentation or reaction device, during a single experimental run.

16. A time-of-flight mass spectrometer comprising: an ion source array for supplying or generating ions at an array of positions; a position sensitive ion detector having an array of separate detection regions configured such that ions received at different ones of the detection regions are determined as having originated from different positions in said array of positions; and ion optics arranged and configured to guide ions from the ion source array to the position sensitive detector so as to map ions from the array of positions on the ion source array to an array of positions on the position sensitive detector; wherein the ion optics include a gridless ion mirror for reflecting ions and an electrostatic or magnetic sector for receiving ions and guiding the ions into the gridless ion mirror; wherein the gridless ion mirror and the electrostatic or magnetic sector are configured such that the ions are transmitted from the electrostatic or magnetic sector into the ion mirror a plurality of times such that the ions are reflected by said ion mirror a plurality of times.

17. A method of time-of-flight mass spectrometry comprising: providing a time-of-flight mass spectrometer as claimed in claim 16; supplying or generating ions at an array of positions on an ion source array; and using the ion optics to guide ions from the ion source array to the position sensitive detector so as to map ions from the array of positions on the ion source array to an array of positions on the position sensitive detector; and determining that ions received at different ones of the detection regions on the position sensitive detector have originated from different positions in said array of positions on the ion source array; wherein ions are reflected from the ion mirror into the electrostatic or magnetic sector and are transmitted from the electrostatic or magnetic sector into each of the ion mirrors a plurality of times such that the ions are reflected by each ion mirror a plurality of times.

18. A method of time-of-flight mass spectrometry comprising: supplying or generating ions at an array of positions on an ion source array; providing a position sensitive ion detector having an array of separate detection regions; using ion optics to guide ions from the ion source array to the position sensitive detector so as to map ions from the array of positions on the ion source array to an array of positions on the position sensitive detector; and determining that ions received at different ones of the detection regions in the position sensitive detector have originated from different positions in said array of positions; wherein the ion optics includes two ion mirrors that reflect ions, at least one of which is a gridless ion mirror; wherein said two ion mirrors are spaced apart from each other in a first dimension (X-dimension) and are each elongated in a second dimension (Z-dimension) or along a longitudinal axis that is orthogonal to the first dimension; and wherein packets of ions are introduced into the space between the ion mirrors such that they travel along a trajectory that is arranged at an angle to the first and second dimensions such that the ions repeatedly oscillate in the first dimension (X-dimension) between the mirrors as they drift in the second dimension (Z-dimension) or along the longitudinal axis towards the detector.

19. The method of claim 18, wherein the ions are reflected multiple times by each of said ion mirrors.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) Various embodiments will now be described, by way of example only, and with reference to the accompanying drawings in which:

(2) FIG. 1 shows a known mass microscope;

(3) FIGS. 2A and 2B illustrate a known multi-reflecting mass spectrometer;

(4) FIG. 3 schematically illustrates an analyzer of an embodiment of the present invention, wherein ions are transferred from pixels of an ion source array to corresponding pixels of an ion detector array;

(5) FIGS. 4A to 4C show telescopic and microscopic lens arrangements that may be used in the present invention;

(6) FIG. 5 shows a schematic of a spectrometer according to an embodiment of the present invention wherein electric sectors guide ions into and from a multi-reflecting time of flight region;

(7) FIG. 6 shows various different topologies that may be used to form electrostatic fields in the time of flight region of the embodiments of the present invention;

(8) FIGS. 7A-7C and 8A-8C show various arrays of ion sources that may be used in the embodiments of the present invention;

(9) FIGS. 9A-9C show a schematic of an instrument according to an embodiment of the present invention for mapping ions from a 1D array of ion sources to a detector;

(10) FIG. 10 shows a schematic of another instrument according to an embodiment of the present invention for mapping ions from a 1D array to a detector;

(11) FIG. 11 shows a schematic of an instrument according to an embodiment of the present invention for mapping ions from a 2D array to a 2D detector;

(12) FIG. 12A shows a 2D mapping instrument having an array of pulsed vacuum ion sources; and FIG. 12B shows an embodiment that uses a mask for separating individual secondary ion beams emitted from an ion source target plate;

(13) FIG. 13 illustrates an embodiment comprising a single source, a distributing RF guide and a 1D array of RF quadrupoles; and

(14) FIG. 14 illustrates an embodiment comprising a single ion source and a magnetic sector for converting the ion beam into an array of multiple ion beams of different mass to charge ratios.

DETAILED DESCRIPTION

(15) In order to assist the understanding of the present invention, a prior art instrument will now be described with reference to FIG. 1. FIG. 1 shows a mass microscope 10 as described in U.S. Pat. No. 5,128,543. The mass microscope comprises a target T that is illuminated by a laser pulse, a position sensitive Time of Flight (TOF) detector 16, and an analyzer that is formed by lenses L, slits S and three 90-degree spherical electrostatic sectors 13, 14 and 15 that are separated by field-free regions. Secondary ion packets originate from point 11 on the target T with an angular spread. The ions travel within the dashed curved area of trajectories and are focused onto the position sensitive detector 16 at point 17. A multiplicity of emitting spots form a magnified two dimensional image on the detector 16, while the TOF detector also measures the ion masses by their flight times. In an all-mass mode, a dual microchannel plate (MCP) detector with resistive anode is used to determine the X and Y positions of rare striking ions. Alternatively, imaging may be performed on a phosphor screen downstream of an MCP by using higher ion fluxes and selecting ions of a single mass with a time gate. The typical size of the image field is 200 microns, the spatial resolution is 3 m and the magnification from the target to the detector is x60. A moderate mass resolution of about 3,000 is achieved, although this is limited by the short flight path available in the sectors 13-15.

(16) More recent multi-sector systems provide higher mass resolutions, although at a compromised spatial resolution of 100 m for DE-MALDI sources. A small viewing field, and moderate spatial and mass resolutions are characteristic for electric sector TOF instruments since they have a limited flight path length and compensate only for first order spatial and time-of-flight aberrations.

(17) FIGS. 2A and 2B illustrate a prior art instrument according to WO 2005/001878. The instrument is a multi-reflecting mass spectrometer 20 comprising a pair of planar mirrors 21, a drift space 22, a periodic lens array 23, a pulsed ion source 24 and a detector 26. The planar ion mirrors 21 are formed by metal frames and are extended in a direction along the ion drift direction Z. The ions pulsed into the drift space 22 between the ion mirrors 21 such that they perform multiple reflections between the ion mirrors 21 as they drift in the z-direction to the detector 26. The multiple mirror reflections extend the flight path of the ions, which improves mass resolution. The periodic lens 23 confine the ion packets along the main zig-zag trajectory 25.

(18) FIG. 2B shows a view in the X-Y plane. Due to lower order lens time of flight aberrations, the analyzer has higher acceptance in the Y-direction. WO2007044696 proposes using an orthogonal accelerator oriented in vertical Y-direction.

(19) The ion mirrors employed in WO 2005/001878 are known to simultaneously provide second order time-of-flight focusing:
T|BB=T|BK=T|KK=T|YY=T|YK=T|YB=0(1)
with spatial confinement in the vertical Y-direction and with compensation of second order spatial aberrations after an even number of reflections:
Y|B=Y|K=0; Y|BB=Y|BK=Y|KK=0(2a)
B|Y=B|K=0; B|YY=B|YK=B|KK=0(2b)
combined with a third order time per energy focusing
T|K=T|KK=T|KKK=0(3)
where the aberrations are expressed with the Taylor expansion coefficients, Y is vertical coordinate, B is the angle to axis, K is ion energy and T is the flight time.

(20) In WO 2013/063587, the focusing properties of planar MRTOFs were improved by achieving third order full time-of-flight focusing, including cross terms:
T|BBK=T|YBK=T|YYK=0(4)
and by reaching up to fifth order time-per-energy focusing:
T|K=T|KK=T|KKK=T|KKKK=T|KKKKK=0(5)

(21) Both spatial and time-of-flight aberrations of mirrors appear far superior compared to sector based TOF mass spectrometers, since sectors compensate for only first order aberrations, i.e. satisfy only equation 1 above.

(22) Although ion mirrors provide advanced ion optical properties compared to sectors, the spatial focusing and image mapping properties of gridless planar ion mirrors were not appreciated and were not used for multiple practical reasons. The present invention may be embodied by the instrument described in relation to FIGS. 2A and 2B, wherein the ion mirrors are gridless ion mirrors.

(23) FIG. 3 schematically illustrates the ability of analyzer to transfer ions from pixels of the ion source array 44 to corresponding pixels of the ion detector array 45. Pixelated detectors, such as those disclosed in U.S. Pat. No. 8,884,220, may be used to record time-of-flight signals from a matrix of individual pixels in the detector by using an array channel data system 47.

(24) The spatial dimensions of the ion source array (i.e. view field) may be, for example, up to 7-10 mm and that the number of spots may form a 66 matrix, whilst retaining a mass resolution of approximately 100,000-200,000 for each individual pixel. The combination of a large field of view, and the spatial and mass resolutions provided is unprecedented and provides opportunities for high throughput mass spectrometric analysis. The analyzers may have a larger field of view and/or a larger source matrix density, such as a field of view up to 15-20 mm and/or a source matrix density of at least 1010.

(25) The mapping MRTOF described herein may be used for a number of applications. For example, the instrument may be used for crude surface imaging at a high throughput rate. Alternatively, or additionally, the instrument may be used for analyzing multiple samples deposited onto a surface as a macroscopic sample array. Such an analysis may be enhanced by sample micro-scanning within a pixel, i.e. within a sample well. The instrument may be used to analyze ions from multiple independent ionization sources, such as atmospheric or ambient sources, for high throughput analysis. For example, the instrument may analyze multiple sample spots ionized by ambient sources. A sample may be spatially separated by mass or mobility, and the instrument may be used for simultaneous parallel mass analysis of different separation fractions.

(26) The ion mapping from the ion source to the detector may be performed in one dimension or in two dimensions. For example, in one dimensional ion mapping ions may be generated from multiple sample regions that are distributed along the Y-dimension (or Z-dimension) of the ion source, and these ions may be mapped onto the detector at respective multiple regions that are distributed along the Y-dimension (or Z-dimension) of the detector. In two dimensional ion mapping ions may be generated from multiple sample regions that are distributed in the Y-Z plane of the ion source, and these ions may be mapped onto the detector at respective multiple regions that are distributed in the Y-Z plane of the detector.

(27) The field of view of an analyzer may be limited in both the Y- and Z-dimensions, before high order spatial aberrations degrade spatial resolution and cross-term aberrations degrade mass resolution. For example, the field of view may be 1 mm or less in any dimension. However, the position sensitive detector and/or the source array may occupy a relatively large area (e.g. larger than 1 mm in any dimension), or may have a relatively large (or small) pixel size. Also, the ion source and detector may be different sizes. The imaging and mapping system therefore may be subjected to a mismatch in spatial scales and/or a lack of space within the MRTOF analyzer to accommodate the source or detector. This may be accommodated for, as discussed further below.

(28) Although the spatial resolution of the described embodiment is moderate in terms of number of resolved pixels, it is very unusual for TOF analyzers to sustain imaging properties at large fields of view in comparison to prior art TOF mass microscopes, in which the imaging field is well under 1 mm.

(29) Due to the spatial resolution of the MRTOF, it can be seen that the ion packets land on separated spots of the ion detector. As a result, the analyzer transfers ions from a matrix of ion source spots to a corresponding matrix of spots on the detector. This system may allow independent acquisition of a matrix of ion beams or ion packets, with minimal ion losses and without any signal interference between individual pixels at the detector. This leads to an improvement in the analysis throughput. Although a 66 matrix of ion sources has been described, denser matrices and larger fields of view may be provided using the analyzer.

(30) Telescopic (e.g. microscopic) ion optical sets, including lenses, mirrors or sectors may be used to map the ions from the source to the detector. FIGS. 4A to 4C show telescopic and microscopic lens arrangements that may be used.

(31) FIG. 4A shows a schematic of a telescopic device 50 for interfacing a source array 51 that is relatively wide in the Y- and Z-dimensions to an analyzer having a detector 52 that is smaller in the Y- and Z-dimensions.

(32) FIG. 4B shows a schematic of a microscope lens set 53 for expanding the ion beams from a source array 54 in the Y- and Z-dimensions. For example, the microscope lens set 53 may image a small surface with a field of view of about 1 mm in each of the Y- and Z-dimensions to a wider ion packet array within the analyzer 55, e.g. optimized to an array size of about 3-5 mm in each of the Y- and Z-dimensions.

(33) FIG. 4C shows a schematic of a telescopic expander 56 for expanding the ion beams from a source array 57 that is relatively small in the Y- and Z-dimensions to an analyzer 58 having a detector that is larger in the Y- and Z-dimensions (e.g. 15-25 mm). Such a detector may be used to retain macroscopic pixels and handle larger ion fluxes.

(34) FIG. 5 shows an embodiment comprising a multi-beam ion source 71 for forming a 1D or 2D array of continuous ion beams. A static telescopic lens system 72 is provided for converting the beam array to a beam array having smaller dimensions. A beam converter 73 is provided for forming pulsed ion packets. An isochronous and imaging sector 75 is provided for transferring ion packets into the TOF region 76. The ions then separate according to time of flight in the TOF region 76. An isochronous imaging sector 77 is provided for guiding ions out of the TOF region 76 and through a magnifying lens 78 and then onto a pixelated detector 79. The use of sectors, such as electrostatic sectors, is particularly useful as it allows the ion source or detector to be moved externally from the MRTOF analyzer.

(35) Both sectors 75 and 77 may be either cylindrical, torroidal or spherical, depending on whether 1D or 2D ion mapping is desired. A cylindrical sector may be used for 1D mapping, or torroidal or spherical sectors may be used for 2D mapping. The sectors may be combined with electrostatic lenses. Both sectors may be composed of several sector sections for optimal spatial resolution and isochronicity. The sector steering angles may be optimized depending on the overall arrangement, for example, as described in WO 2006/102430.

(36) Electrostatic sectors serve multiple functions. They allow a relatively large ion source array and detector to be arranged outside of the MRTOF, whilst introducing ions into and extracting ions from the TOF region. Also, sectors are capable of removing excessive energy spread of the ions so as to optimize spatial and mass resolution with only moderate ion losses. Sectors may also be used as part of telescopic arrangements for optimal adoption of spatial scales between the ion source, the TOF analyzer and the detector.

(37) In the analyzers of the embodiments described herein, spatial resolution may be primarily limited by high order spatial aberrations, such as spherical aberration Y|YYY or view-field curvature Y|BBY, or by other high order cross-aberrations including energy terms. Thus, spatial resolution is expected to improve at smaller ion trajectory offset and smaller view field. The smaller view field may be magnified with telescopic lenses or sectors, also may incorporate diverging trajectories of the MRTOF analyzer, as has been described in relation to FIG. 4.

(38) Although only the use of planar ion mirrors for the TOF region have been described above, it is contemplated that other geometries may be employed.

(39) FIG. 6 shows various different topologies of planar and curved electrodes that may be used to form two-dimensional electrostatic fields for use as the TOF regions in the analyzers of embodiments. These topologies may be used to provide the ion mapping properties described above, whilst providing denser packaging of ion trajectories. It may be desired for the analyzers to combine both sectors and ion mirrors, since ion mirrors are capable of compensating for multiple sector aberrations. Combined (hybrid) systems may have similar ion optical properties to systems built from only ion mirrors.

(40) The topology labeled 101 schematically illustrates the electrode arrangement for the planar MRTOF that has already been described above, having two parallel, straight ion mirrors. The topology labeled 102 schematically illustrates the electrode arrangement for a hybrid folded analyzer having a sector that guides ions between two ion mirrors. The topology labeled 103 schematically illustrates the electrode arrangement for another hybrid system built using multiple sectors and an ion mirror. The topology labeled 104 schematically illustrates the electrode arrangement for another analyzer that may be used for multiplexing, e.g. as described in WO 2011/086430. The topology labeled 105 schematically illustrates the electrode arrangement for an analyzer that is similar to topology 101, except that the mirrors are cylindrically wrapped. The topology labeled 106 schematically illustrates the electrode arrangement for an analyzer that is similar to topology 102, except that the mirrors and sector are cylindrically wrapped. The topology labeled 107 schematically illustrates the electrode arrangement for an analyzer that is similar to topology 105, except that the upper mirror is replaced by a spherical sector. The illustrated instruments having mixed symmetry and employing curved ion trajectory axes provide compact analyzers and allow geometrical up-scaling at a given instrument size. Ion mapping and imaging properties, as with TOF resolution, are rapidly improved with the analyzer up-scaling due to the fast reduction of high order aberrations.

(41) As described above, the pixelated detector may provide independent mass spectral analysis for each individual pixel, or groups of pixels in the ion source. Prior art ion mapping instruments typically have a field of view with each dimension under 1 mm. In contrast, the embodiments described herein may provide instruments having lower resolution ion mapping but with a much larger field of view, such as up to 1010 mm in combination with parallel (simultaneous) acquisition of high resolution mass spectra for all mapped pixels. The mass spectral mapping of macroscopic size spots (e.g. spots having a dimension in each direction of 1-2 mm) allows the opportunity of parallel and independent analysis for multiple ion sources, either from 1D or 2D arrays.

(42) Various methods and apparatus are contemplated herein for miniaturizing ion source arrays, ion transfer arrays, ion optics arrays, and forming appropriate pulsed converters for such arrays, enabling multi-channel MRTOF with high throughput analysis.

(43) The mapping MRTOF described herein allows parallel analysis of multiple ion flows. Various arrays of ambient ion sources are known, although they are conventionally multiplexed in an atmospheric or vacuum interface for analysis in a single channel mass spectrometer. In contrast, the ion source arrays may be used in the present invention for parallel analysis and hence the instrument provides a much higher throughput than prior art instruments.

(44) FIGS. 7A-7C show various arrays of ion sources that may be used with the mapping MRTOF. The ion source may comprise an array of independent ion sources, such as ESI, APCI, APPI, CGD, DESI, DART, or MALDI ion sources. Each array may comprise multiple ion sources of the same type or of different types. The arrays of ion sources may operate at atmospheric pressure, or at lower pressures, such as 1-100 Torr gas pressure, e.g. in the case of gaseous MALDI ion sources or conditioned glow discharge (e.g. as described in WO 2012/024570). The ion sources in any given ion source array may ionize multiple different samples simultaneously and therefore may provide the instrument with a high throughput. The ion sources in any given ion source array may be connected to multiple samples, e.g. to multiple chromatographic channels or may be used for surface imaging at ambient gas pressure.

(45) Different types of ion sources may be used in any given array of ion sources. The ion sources may be used for the simultaneous analysis of the same sample, for example, for obtaining additional information due to variations in softness, charge states, selectivity, fragmentation patterns, variations in discrimination effects, or for calibrations in mass, intensity or at quantitative concentration measurements.

(46) FIG. 7A shows a schematic of an ion source array comprising an array of ESI spray micro-tips 132 connected to a multi-well sample plate 131. The sample flow to spray tips 132 may be induced by pressurizing the sample with gas. If a relatively large array dimension is used (e.g. 386 wells), the well plate 131 may be incrementally moved across the array of sampling nozzles 132.

(47) In one example of practical importance, the instrument may be used for proteomic analyses. State of the art proteomic analyses with single channel LC-MS-MS may last for several hours, as several thousand runs may be required for each study. For higher throughput the multi-channel MRTOF described herein may be used. The proteomic samples may be pre-separated, e.g. by affinity separation or salt exchange chromatography and prior to the step of enzymatic digestion. Then separated fractions may be analyzed in parallel using multiple independent LC-MS channels or LC-MS.sup.E channels (more preferable), whilst using a single mapping MRTOF mass spectrometer as described herein. Compared to the conventional single channel LC-MS-MS experiment, the MRTOF is expected to obtain more information per sample (e.g. in research programs) or obtain the same information at much faster LC gradients (e.g. for high throughput clinical analysis). Alternatively, multiple proteomic samples may be analyzed in parallel for higher throughput with a LC-MS.sup.E method. Higher throughput may also be highly desirable for other LC-MS and GC-MS analyses in clinical, environmental, and metabolomic studies.

(48) FIG. 7B shows a schematic of an ion source array for 1D array flow sampling. The ion source may be used for ambient surface imaging. A DART or DESI flux 134 of primary particles (e.g. charged droplets or metastable Penning Argon atoms) may be used to ionize a sample or samples over a relatively large sample surface 135. A linear array of nozzles 136 may be provided to sample ions from a linear array of parallel surface pixels on the target surface 135. The spatial resolution (i.e. pixel size) is defined by the size of ion collection into each nozzle, typically being about 3 times larger than the nozzle diameter. The nozzle diameter may be chosen to be 0.1-0.3 mm for a spatial resolution of 0.3-1 mm. As the 1D array of nozzles collects ions from a strip along the target surface 135, the sample plate may be scanned across the entrances to the nozzles. The resolution of the surface imaging may be somewhat improved with sample plate scans 137. The array analysis notably accelerates the surface analysis with DART and DESI, which is slow with existing single channel mass spectrometers.

(49) FIG. 7C shows a schematic of another ion source array. The spatial resolution of the ambient surface analysis may be enhanced in this embodiment by using an array of small size ionizing beams, such as focused laser beams 139. The laser beams 139 may be produced using an array of micro-lenses or using interference of coherent laser beams. The sample plate may be scanned across the laser beams, or vice versa. For example, each laser beam may be scanned across the target plate within a portion corresponding to a pixel on the target plate. This embodiment provides parallel analysis of the source array with ion mapping to the detector and high mass resolution.

(50) FIG. 8A shows a further embodiment of the source array. In this embodiment, ESI spray tips 130 are assisted with focusing electrodes in order to provide sharper focused ESI plumes. Ion flows from multiple sources 130 are sampled by electric fields and by gas flow into an array of heated capillaries 141. The heated capillaries may have sharp tips or cones with sampling apertures at their tops. The ions may then be transmitted into and confined in channels 142. The channels may be defied by apertured plates and RF potentials may be applied to these plates so as to confine the ions in the channels.

(51) A capillary diameter of about 0.5 mm nay be used for higher sensitivity, leading to approximately 1 L/s gas flux through the 36 channels. A mechanical pump (e.g. a scroll pump) may be used to evacuate a large gas flux past the capillaries, for example with a pumping speed above 30 L/s, as shown by white arrows. This brings the gas pressure down to under 30 Torr, i.e. into the range for effective RF confining within RF channels 142.

(52) FIG. 8B shows a further embodiment of the source array wherein the sampling plate 144 comprises sharp cones with relatively smaller sampling nozzles apertures, limiting the sampled gas flow. Ions are further sampled by gas flow into relatively wider channels 146 that may be machined in a heated block 145, for example by point EDM. Once gas flow is limited by apertures of sampling plate 144, the internal part of the block 145 may be constructed of split pieces, for example, from plates, cylinders, cones, or wedges, for ease of making channels 146 and for cleaning.

(53) The nozzle spacing may be spread spatially for efficient sampling from an array of multiple macroscopic ion sources, while channels 146 may converge towards the exit. Since ion collection diameter may be desired to be at least three times the nozzle aperture diameter, for imaging applications, the nozzle diameter could be reduced, for example, to 0.3 mm so as to reduce the gas load through the nozzle array, which may be about 0.4 L/s for 36 channels. A single mechanical pump pumping at 10 L/s may be provided to drop the gas pressure to under 30 Torr. Even lower gas loads may be provided by using finer nozzles for surface imaging at higher spatial resolutions.

(54) FIG. 8C shows a further embodiment of the source array that is similar to that of FIG. 8B, except that a sectioned nozzle array 149 is provided with distributed pumping, as shown by the white arrows. If a relatively large number of channels (e.g. 100) are used or larger nozzle apertures are used (e.g. for improved sensitivity), the nozzle array 149 may comprise two or more aligned stages of heated channels with differential gas evacuation in between the stages. Ion transfer between the stages may be assisted by gas dynamic focusing of ions on the axis of each heated capillary and/or by electrostatic focusing onto sharp capillary tips of the second stage. Alternatively, the nozzle array may comprise perforated apertures with alternated DC potentials and with distributed pumping between the plates. Gas jets formed on the axis of each channel will transfer ions at nearly sonic speed this way, generating the time alternated force required to provide spatial confinement of ions to the axis.

(55) It is desired to form ion beams and ion packets, e.g. for small size arrays.

(56) FIGS. 9A-9C depict a schematic of a multi-channel MRTOF having a 1D array of ambient ion sources and configured to perform 1D ion mapping onto the detector 175. As shown in FIG. 9A, the instrument comprises a 1D array of RF quadrupoles 165, a set of micro-lenses 171 for forming a low divergence beam array 172, a telescopic lens 173 (e.g. having a magnification of one, or having size compression), an orthogonal accelerator 175 with a wire mesh 176, a lens 178 terminating the field of the orthogonal accelerator 175, and a sectioned deflector 177.

(57) FIG. 9B depicts the ion focusing downstream of the quadrupole array 165 by micro-lens 171. In this example, the pitch of quadrupole array is 2 mm with inscribed diameter of each quadrupole being 1.4 mm. An RF signal of 5 MHz with an amplitude of 300-500V is used to compress the ion flow to a diameter under d=0.1 mm. The ion flow is refocused at the electrostatic extraction point by an exit skimmer (the first set of apertures downstream of the quadrupole array), and is then expanded to a diameter of approximately D=0.5 mm within the micro-lens 171. The micro-lens array 171 with 1 mm diameter apertures accelerates ions to an energy eU=50 eV and forms wider but less divergent ion beams 172. The beam expansion D/d=5 causes a proportional reduction of ion beam angular divergence. The angular divergence of thus formed ion beams may be estimated as 2*(kT/eU){circumflex over ()}0.5*D/d and is approximately =10 mrad, i.e. half a degree. Without the micro-lens, the divergence would be 2.5 degrees. The reduction of the angular divergence of the beams serves two important purposes: it reduces ion beam interference at mapping, and it proportionally reduces the turn-around time in the orthogonal accelerator 175.

(58) The array of ion beams then enters the telescopic lens 173. The telescopic lens is used for delivering narrow ion beams into the orthogonal accelerator 175, thus preserving ion beam separation. The telescopic lens also interfaces the spatial scale of the ion source to MRTOF field of view. For example, a 20 mm wide beam array may be compressed into a beam array within the accelerator 175 that is 7-10 mm wide. The icon 173 illustrates a particular example of the telescopic lens with unit magnification. The view is compressed about twice in the Z scale. The lens is 120 mm long and with a 30 mm inner diameter. The beam array is refocused by two lenses without any additional spreading of beam width, despite an initial divergence angle of 2 degrees. The telescopic lens may be tuned to provide spatial ion beam refocusing in the middle of the accelerator 175. Without the telescopic lens, the ion beams would spread for 1 mm while passing into the accelerator, which must be spaced from the quadrupole array, at least for reasons of differential pumping.

(59) The orthogonal accelerator 175 shown in FIG. 9C is designed to accept a wide (e.g. 10 mm) array of ion beams while minimizing angular ion scattering if using any mesh. The intermediate stages of the accelerator 175 may employ a mesh 176 made of wires oriented along ion beams, but may use an accelerating field of equal strength around the mesh to minimize the ion scattering on the mesh. The exit stage of the accelerator may be terminated by a wide open lens 177 to avoid angular ion scattering. Any ion beam angular focusing is accounted for and balanced with other spatially focusing elements of the MRTOF, e.g. either the ion mirror 21 or periodic lenses 23 of FIG. 2 or 5.

(60) The ion beams at the entrance of the orthogonal accelerator 175 may have a diameter under 1 mm, a mean ion energy of 50 eV, and an angular divergence of about 0.5 degrees. In order to provide a short sub-nanosecond turn-around time, the accelerator may be arranged with a large extraction field, e.g. 300-500 V/mm, thus creating an energy spread of about 300-500 eV.

(61) In order to handle ion packets having a large energy spread, the MRTOF may be operated at the highest practical acceleration voltage applied to drift region, e.g. 8 to 10 kV. The natural inclination angle of ion trajectories is =70 mrad (square root of energies 50 eV and 10 keV). In case of orienting ion beams along the Z-direction, and if no measures are taken, the ion packet advance would appear too high, i.e. 70 mm per mirror reflection, which would require an MRTOF having a large width in the Z-direction. To drop the inclination angle , the orthogonal accelerator 175 is tilted at the angle , and the packets are then steered by a deflector for the same angle . The deflector 178 may be composed of several sections for a more uniform deflection field. The ion beam energy at the accelerator entrance may be adjusted so that both the tilt and steering provide mutual compensation of the first order time aberration, as described in WO 2007/044696. In the chosen example of =70 mrad, =20 mrad, a resultant inclination angle of =30 mrad, at 5% relative energy spread, and if using ion packets under 25 mm length, the amplitude of residual second order aberration T|ZK stays under 1 ns with the peak FWHM being under 0.25 ns. With the chosen Z-pitch per ion reflection of 30 mm, the practical ion packet length is expected about 15 mm. At 50 eV ion energy, ions of 1000 amu travel with speed of 3 mm/s and traverse the useful extracted 15 mm portion of continuous packet within 5 s time.

(62) FIG. 10 shows an embodiment 180 of 1D multi-channel MR-TOF. The MRTOF instrument may comprise an array of ambient ion sources forming an array of ion flows 181, or may comprise a single ion source producing a single ion flow that is then split into multiple ion flows 182. The instrument comprises a multi-channel interface 183, oriented along the Z-axis, or a similar multi-channel interface 184 being oriented along the Y direction. The instrument comprises a 1D or 2D imaging MRTOF analyser 186, as described herein, and a pixelated detector 187 that is connected to a multi-channel data acquisition system 188.

(63) The array interfaces 183 or 184 may comprise a nozzle array 140 of type described above, an array of RF ion guide channels 163, an array of RF quadrupoles 165 having exit skimmers (optionally connected to pulse generator 185), an array of micro-lens 171, a telescopic lens 173, and an orthogonal accelerator 175.

(64) In one, continuous mode of operation, ion flows 181 may be separately transferred from individual ion sources, through individual channels of interface 183, into the orthogonal accelerator 175 as spatially separated ion beams. Each of the ions beams is then converted into spatially distinguished ion packets, elongated in the Z-direction and narrow in the Y-direction. The mapping MRTOF 186 transfers ion packets to the pixelated detector 187 without mixing the packets. The pixels of data system may be combined into strips along the Z-direction, and data system 188 may acquire multiple mass spectra in parallel, for each channel. The MRTOF 180 effectively forms an array of parallel operating mass spectrometers, while sharing a common vacuum chamber, differential pumping system, electronics and unifying analytical components, e.g. including making multiple apertures in one block rather than making multiple blocks for the nozzles, RF ion guide channels, RF quadrupoles, and ion optics.

(65) In another operational mode, extraction pulses are applied (from block 185) to the exit skimmers of the RF quadrupoles 165 in a manner that traps and releases ions in the RF quadrupoles. The pulses of the orthogonal accelerator 175 are synchronized in time with the pulses of the ions from the quadrupoles. A single pulse may be applied to the quadrupoles and the orthogonal accelerator in order to analyze ions from all channels simultaneously. This method enables an improvement in the duty cycle of the accelerator, though at the expense of a narrower mass range being admitted in each pulse. It is also contemplated that the timing of the extraction pulses 185 may vary between channels or between accelerator shots. This may be used to admit a wider overall mass range, or optimize the delay for the expected mass range of a particular quadrupole channel. The pulsed ion release may also be used to form a crude mass separation in the second direction, along the ion beams. The two dimensional pixelated detector may thus detect a narrow mass range per pixel, which reduces spectral population per pixel.

(66) FIG. 11 illustrates a MRTOF for performing two-dimensional mapping. The 2D Multi-channel MRTOF 190 comprises a 2D array of ambient sources 191, a 2D nozzle array 192, a 2D array of RF ion guide channels 193, a 2D curved interface 194; a 2D array pulsed converter 195, a 2D imaging MRTOF analyzer 197, a 2D pixelated detector 197, and a 2D array data system 198.

(67) The 2D array of ambient sources 191 may be of the type described herein above, e.g. in the form of a 2D array of spray tips 130. The 2D nozzle array 192 may be of the type described herein above, e.g. in the form of capillary array 141 and heated block 143 with machined channels (optionally a split heated block 148 of plates with channels). The curved interface 194 may be a 2D array of RF ion guide channels (194 RF), e.g. composed of mutually tilted perforated plates or PCB boards. Alternatively, the curved interface 194 may be a 2D array of electrostatic sectors (194 ES) for bypassing fringing fields of the ion mirrors, e.g. as described in U.S. Pat. No. 7,326,925 (X-inlet). The curved interface 194 allows the ion source array to be located externally to the MRTOF analyzer such that it does not interfere with the MRTOF analyzer.

(68) Compared to ambient sources, arranging an array of vacuum ion sources is the task of relatively lower complexity, since vacuum ion sources do not require multi-channel ion transfer interfaces and a powerful pumping system. The task is even simpler if using naturally pulsed ion sources, like pulsed SIMS, MALDI or DE-MALDI.

(69) FIG. 12A shows an embodiment of a 2D mapping MRTOF having an array of pulsed vacuum ion sources 210. The instrument may comprise a mapped target plate 211, which may be a mapped sample or a multi-well sample plate. An array of focused primary ion beams 212 may be directed onto the target plate 211 in order to ionize the sample thereon. Alternatively, an array of laser beams may be used to ionize the samples on the target plate 211. Different ion beams or laser beams may be directed onto different regions of the target plate 211 in order to ionize different areas/pixels on the target plate 211. Alternatively, a laser beam such as a scanning focused beam 213, may be scanned across the target plate to ionize the sample thereon. The beam may be scanned across the target plate so as to ionize different areas/pixels at different times. The instrument further comprises a mapping MRTOF analyzer 196, a pixelated detector 197, and a multi-channel data system 198 for parallel mass spectral acquisition.

(70) As described above, a variety of vacuum ion sources may be used. For example, when a plurality of laser beams are used to ionize the sample, an array 212 of fine-focused primary laser beams may be provided from a single, wide laser beam with the aid of multiple UV lenses or by an array of concave reflectors. When a single laser beam 213 is scanned across the target plate to ionize the sample, this may be performed with galvanic fast-moved mirrors. The laser beam(s) may be pulsed for MALDI, LD or DE MALDI ionization. When ion beams are directed at the target plate to ionize the sample, an array 212 of primary ion beams (e.g. for SIMS ionization) may be formed by an array of electrostatic micro-lenses. The primary ion beams 213 may be scanned across the target plate in a stepped or continuous and smooth manner. The ion beams may be scanned in at least one direction by electrostatic deflectors.

(71) When pulsed ionization is performed (e.g. SIMS, MALDI, DE MALDI, or LD), and when mapping within a wide field of view, the secondary ions (i.e. analyte ions) may be focused by an array of micro-lenses, optionally followed by a single wide aperture telescopic lens such as the type described in relation to FIG. 9. As the primary beams may be focused to a much finer spot size (e.g. 10-100 m) as compared to pixel size (e.g. 0.1-1 mm), the sample plate and/or ion beams and/or laser beam(s) may be micro-scanned (e.g. rastered) within sample pixel boundaries, as illustrated by arrows and R icon in FIG. 12. Where multiple ion or laser beams are used to ionize the sample, the ion or laser beams may aligned in a 1D array on the target plate that extends in a first direction, and the 1D array may be scanned or stepped across the target plate in a second (e.g. orthogonal) direction.

(72) FIG. 12B shows an embodiment 214 that uses a close view mask 215 for separating individual secondary ion beams emitted from the target plate, e.g. if a continuous glow discharge ionization process is used. The spatial focusing of individual ion beams may be assisted by a micro-lens array 216 that may be followed by a large aperture single lens 217. Ion packets may be formed by pulsed acceleration past the mask 215.

(73) The parallel analysis by mapping multiple spots in a vacuum highly accelerates the analysis throughput. Using relatively fine ionizing beams in a vacuum allows multiple strategies for high spatial resolution for large overall sample sizes.

(74) As described above, the primary beam 213 may be rastered across the target plate. Rastering the primary beam 213 may be of assistance where the dose of the primary beam is limited by the sample stability. Rastering of the primary beam may be performed at a faster time scale than the period of the pulsed acceleration. In this manner, a single ion beam effectively acts as multiple beams. The rastering may use stepped selection of ionization spots, rather than smooth scanning. For higher throughput at high spatial resolution, the primary beam spots may be selected with a strategy of non-redundant sampling (NRS), e.g. as described in WO 2013/192161 and depicted by icon 215. The combination of spots within a pixel/area may be varied between acceleration pulses. The signal on the detector may be acquired as a data string without losing time information. The mass spectrum for a particular fine spot may then be extracted by correlation with the position of the spot. For practical convenience, the encoding pattern may be the same for all pixels and may be performed with surface 2D stepped rastering.

(75) The resolution of MRTOF devices is limited by the initial parameters of the incoming ion beam. For pulsed acceleration of the ions, the angular divergence of a continuous ion beam introduces velocity spread V in the TOF direction, which leads to so-called turn-around time T. The time spread T could possibly be reduced by using higher strength accelerating pulsed fields E, since T=V*m/qE. However, unfortunately the field strength is limited by the energy acceptance of the analyzer X*E<K. Thus, the ion beam emittance Em=X*V limits TOF MS resolution. The problem may be solved by using finer size quadrupoles, however, this requires the use of multiple quadrupoles to avoid space-charge expansion of the ion cloud at practical ion currents of several nA to tens of nA.

(76) FIG. 13 illustrates an embodiment comprising a single source 301, a distributing RF guide 308, 1D array of small quadrupoles (RFQ) 165, a planar lens 305; and either a mapping MRTOF 180 or a mapping Re-TOF 220. In operation, a single ion flow (e.g. up to a few nano-Amperes for LC-MS instruments) from the source 301 is distributed into multiple ion beams by the distributor 308, which may be, for example, a slit RF channel. The ions then enter multiple channels of the 1D RFQ array 165. The 1D RFQ array 165 may be made by EDM for better precision and a small inscribed diameter of RFQ. Distribution of the ion current between multiple RFQ channels drops the ion current per channel, thus avoiding (or reducing) space-charge effects and the resulting beam expansion. Each of the RF-only ion guides 165 may have a small inscribed radius R1 mm and may be operated at elevated frequencies of, for example, 10 MHz and an amplitude of at least V=1 kV in order to form narrow ion beams. To keep parameter q=4V*ze/m/R.sup.2(2 pi*F).sup.2<1 at a low m/z of 100 amu, at R=1 mm and at high amplitude V=1 kV (o-p), higher frequencies of F=10 MHz are desired. The dynamic well in a RFQ is known to be W(r)=(r/R).sup.2*q*V/4. For an upper m/z of 2000 amu (q=0.05), the beam size in an RFQ may be estimated assuming W(r)=kT: d=2R*(4 kT/qVe).sup.0.5=0.1 mm.

(77) Ion beams may be extracted from the RFQ array 165 by a negative bias on skimmers, which form local crossovers near the skimmer plane. The planar optics 305 then provide ion beam spatial expansion while reducing angular divergence in the X-direction, say by 10-fold (e.g. in line with U.S. Pat. No. 8,895,920). Planar optics 365 allow mixing of multiple beams in the Y-direction, thus forming wide ion packets in the orthogonal accelerator 185, illustrated by the dark square.

(78) Strong spatial compression of ion beams in the X-direction reduces the beam emittance, thus reducing the turn-around time and increasing the resolution in the MRTOF 190 or Re-TOF 220.

(79) FIG. 14 shows an embodiment 250 that may be used, for example, for parallel tandem MS-MS. The instrument comprises: an ion source 251, an electrostatic energy filter 252, a magnetic sector 253, an RF ion guide channel array 255 forming a dimensional converter for forming a 2D array of ion flows; and a 2D mapping MRTOF analyzer 190. In operation, ions are generated by the ion source 251 and pass through the electrostatic energy filter 252 and magnetic sector 253. The energy filter 252 and sector 253 separate the ions according to mass to charge ratio (in a direction substantially perpendicular to the flight paths of the ions) so as to form a 1D array of ion beams 254. The sector instrument may be a Mattauch-Herzog instrument for separating a relatively wide mass range. The resolution of the magnet sector mass separator may be about 100 so as to accept a relatively wide mass range (say 5:1), while using a static magnet. The magnetic sector instrument may be made from rare earth material magnetic plates. These features enable a moderate size and cost, and the use of a sub-keV acceleration energy to ease ion collection in the downstream RF array 255.

(80) Multiple ion beams of different mass to charge ratios are transmitted from the magnetic sector 253 into the RF ion guide array 255. Within RF array 255, ion flows may be slowed down in gas collisions. The ions may be redistributed from a 1D array into a 2D flow array of ions by the dimensional converter. The dimensional converter is exemplified here by a series of RF arrays 256,257,258. RF array 256 has a column of slit-shaped channels. RF array 257 is configured to converge ions from the slit-shaped channels into apertures. RF array 258 converges ions from rows of apertures to a regular square pattern of apertures. RF voltages are applied to the arrays so as to repel ions from electrode walls by RF field confinement, thus converging the ions as described. The ions may therefore be transformed from a 1D array to a 2D array prior to mass analysis.

(81) At least some of the ions may be fragmented. Ion beam array 254 may be slowed, downstream of the magnetic sector to a few tens of electron volts for enabling ion fragmentation in the RF array 255. The RF array 255 may serve as a CID or SID cell for tandem MS-MS analysis. One or more electrical potential, such as DC potentials, may be travelled along the RF array 255 in order to drive the ions through the device and/or to control the above-mentioned fragmentation that may take place.

(82) The 2D array of ion beams is then mass analyzed in parallel with the 2D mapping MRTOF 190, thus providing comprehensive all-channel spectra. The 2D array of channels may have a larger number of channels than the 1D array 254. The system therefore dramatically enhances the analysis throughput by handling (e.g. fragmenting and analyzing) multiple ion beams in parallel.

(83) As described above, the ions may be fragmented, at least some of the time, so as to produce spectral data for the fragment ions. It is contemplated that the instrument may repeatedly switch the fragmentation on and off (or repeatedly bypass the fragmentation) during a single experimental run so as to provide both MS data and MS/MS data. The parent ion data may then be correlated with the respective fragment ion data.

(84) While tandem spectrometer 250 employs many standard MS components, differential pumping (shown by white arrows) appears the most challenging part for practical implementation. While the vacuum in a small size magnet sector has to be at least 1E-5 Tor, gas dampening in the RF guides requires at least 1E-2 tor. The gas load into magnet sector can be reduced by additional stage of differential pumping and/or using SID fragmentation (e.g. in cell 256) and/or using elongated RF channels in the fragmentation cell (e.g. cell 256) for reduced conductivity between gas supplied at port 259 and the magnetic sector.