Patent Publication Number: US-8115165-B2

Title: Mass selector

Description:
FIELD 
     The specification relates generally to mass spectrometers and specifically to a mass spectrometer and method for performing high resolution mass spectrometry. 
     BACKGROUND 
     In conventional mass spectrometer systems, it is challenging to achieve high mass resolution of a precursor ion for MS/MS. While electrostatic traps have been used to achieve high mass resolution, this is done at the expense of first exciting ions within the trap and then ejecting ions that are not of interest, until only ions of interest remain. The remaining ions of interest can be subsequently ejected from the electrostatic trap, fragmented and analyzed. If it is desired to analyze other ions, the electrostatic trap must be refilled and other ions of interested selected in a similar manner. While these techniques can achieve high mass resolution, they are generally very wasteful of sample, which can often be available in limited quantities. 
     SUMMARY 
     A first aspect of the present specification provides a method of operating a mass spectrometer. The mass spectrometer comprises an electrostatic trap and a mass analyzer. The electrostatic trap comprises an entrance end, an exit end, an entrance end ion mirror and an exit end ion mirror, a central field-free region, and a longitudinal axis. The mass analyzer is enabled to receive ions from the exit end. The method comprises admitting ions into the electrostatic trap via the entrance end. The method further comprises trapping ions in the electrostatic trap, the ions oscillating between the entrance end ion mirror and the exit end ion mirror along the longitudinal axis. The method further comprises waiting for the ions to separate into bunches of ions of different m/z values via the oscillating. The method further comprises exciting a given bunch of ions of a given m/z value along the longitudinal axis until at least a portion of the given bunch overcomes a barrier field at the exit end ion mirror, thereby exiting the electrostatic trap, leaving behind remaining ions in the electrostatic trap. The method further comprises analyzing at least a portion of the given bunch via the mass analyzer. 
     Exciting the subset of the ions can comprise applying an oscillating electric field along the longitudinal axis in phase with an oscillation of the given bunch along the longitudinal axis. The oscillating electric field can be applied between a pair of at least one of ring electrodes, grid electrodes and aperture containing plate electrodes, located in the central field-free region. The oscillating electric field can be applied in at least one of the entrance end ion mirror and the exit end ion mirror. 
     The method can further comprise compensating each of the entrance end ion mirror and the exit end ion mirror to maintain timing and phase of the oscillating during the exciting. 
     The method can further comprise fragmenting at least a portion of the given bunch in a fragmentation module prior to the analyzing. The method can further comprise decelerating the given bunch prior to the fragmenting. Decelerating can occur via at least one of a decelerating lens, a decelerating electric field, and an ion focussing field. 
     The method can further comprise: exciting a second given bunch of the remaining ions of a second given m/z value along the longitudinal axis until at least a portion of the second given bunch overcomes the barrier field at the exit end ion mirror, thereby exiting the electrostatic trap, leaving behind further remaining ions in the electrostatic trap; and analyzing at least a portion of the second given bunch via the mass analyzer. 
     A second aspect of the specification provides a mass spectrometer. The mass spectrometer comprises an electrostatic trap and a mass analyzer. The electrostatic trap comprises an entrance end, an exit end, an entrance end ion mirror and an exit end ion mirror, a central field-free region, and a longitudinal axis. The electrostatic trap is enabled to: admit ions therein via the entrance end; trap ions therein such that the ions oscillate between the entrance end ion mirror and the exit end ion mirror along the longitudinal axis; wait for the ions to separate into bunches of ions of different m/z values via the oscillating; and excite a given bunch of ions of a given m/z value along the longitudinal axis until at least a portion of the given bunch overcomes a barrier field at the exit end ion mirror, thereby exiting the electrostatic trap, leaving behind remaining ions in the electrostatic trap. The mass analyzer is enabled to receive ions from the exit end and analyze at least a portion of the given bunch. 
     To excite the subset of the ions, the electrostatic trap is further enabled to apply an oscillating electric field along the longitudinal axis in phase with an oscillation of the given bunch along the longitudinal axis. The electrostatic trap can further comprise a pair of at least one of ring electrodes, grid electrodes and aperture containing plate electrodes located in the central field-free region, the oscillating electric field applied there between. The electrostatic trap further can be further enabled to apply the oscillating electric field in at least one of the entrance end ion mirror and the exit end ion mirror. 
     The electrostatic trap further can be further enabled to compensate each of the entrance end ion mirror and the exit end ion mirror to maintain timing and phase of the oscillating when the given bunch of ions is excited 
     The mass spectrometer can further comprise a fragmentation module enabled to fragment at least a portion of the given bunch prior to the given bunch being analyzes at the mass analyzer. The mass spectrometer can be further enabled to decelerate the given bunch prior to fragmenting the given bunch. The mass spectrometer can further comprise at least one of a decelerating lens, a decelerating electric field apparatus, and an ion focussing field apparatus for decelerating the given bunch prior to the fragmenting the given bunch. 
     The electrostatic trap can be further enabled to: excite a second given bunch of the remaining ions of a second given m/z value along the longitudinal axis until at least a portion of the second given bunch overcomes the barrier field at the exit end ion mirror, thereby exiting the electrostatic trap, leaving behind further remaining ions in the electrostatic trap at least a portion of the second given bunch analyzed via the mass analyzer. 
    
    
     
       BRIEF DESCRIPTIONS OF THE DRAWINGS 
       Embodiments are described with reference to the following figures, in which: 
         FIG. 1  depicts a block diagram of a mass spectrometer for performing high resolution mass spectrometry, according to non-limiting embodiments; 
         FIG. 2  depicts an electrostatic trap, according to non-limiting embodiments; 
         FIG. 3  depicts the electrostatic of  FIG. 2  with bunches of ions oscillating therein, according to non-limiting embodiments; 
         FIG. 4  depicts the electrostatic of  FIG. 2  with a bunches of ions overcoming a barrier field at an exit end ion mirror, according to non-limiting embodiments; 
         FIG. 5  depicts a method for performing high resolution mass spectrometry, according to non-limiting embodiments. 
     
    
    
     DETAILED DESCRIPTION OF THE EMBODIMENTS 
       FIG. 1  depicts a block diagram of a mass spectrometer  100  for performing high resolution mass spectrometry, according to non-limiting embodiments. Mass spectrometer  100  generally comprises an ion source  120 , ion optics  130 , an electrostatic trap (EST)  140 , a fragmentation module  150  and a mass analyzer  160 , which are generally arranged such that ions produced at ion source  120  can be transferred to mass analyzer  160  for analysis. In some embodiments, mass spectrometer  100  can further comprise a processor  185  for controlling operation of mass spectrometer  100 , including but not limited to controlling ion source  120  to ionise the ionisable materials, and controlling transfer of ions between modules of mass spectrometer  100 . In particular, processor  185  controls EST  140 , as described below. 
     In operation, ionisable materials are introduced into ion source  120 . Ion source  120  generally ionises the ionisable materials to produce precursor ions which are transferred to ion optics  130  (also identified as Q 0 , indicative that ion optics  130  take no part in the mass analysis). Precursor ions are transferred from ion optics  130  to EST  140  which selectively and sequentially filters precursor ions, in a manner described below. Selected precursor ions can then be transferred to fragmentation module  150  (also identified as q 2 ) for fragmentation, to form respective product ions. Product ions are subsequently transferred to mass analyzer  160  for mass analysis, resulting in production of product ion spectra. 
     Furthermore, while not depicted, mass spectrometer  100  can comprise any suitable number of vacuum pumps to provide a suitable vacuum in ion source  120 , ion optics  130 , EST  140 , fragmentation module  150  and/or mass analyzer  160 . It is understood that in some embodiments a vacuum differential can be created between certain elements of mass spectrometer  100 : for example a vacuum differential is generally applied between ion source  120  and ion optics  130 , such that ion source  120  is at atmospheric pressure and ion optics  130  are under vacuum. While also not depicted, mass spectrometer  100  can further comprise any suitable number of connectors, power sources, RF (radio-frequency) power sources, DC (direct current) power sources, gas sources (e.g. for ion source  120  and/or fragmentation module  150 ), and any other suitable components for enabling operation of mass spectrometer  100 . 
     Ion source  120  comprises any suitable ion source for ionising ionisable materials. Ion source  120  can include, but is not limited to, an electrospray ion source, an ion spray ion source, a corona discharge device, and the like. In these embodiments, ion source  120  can be connected to a mass separation system (not depicted), such as a liquid chromatography system, enabled to dispense (e.g. elute) ionisable to ion source  120  in any suitable manner. 
     In specific non-limiting embodiments, ion source  120  can comprise a matrix-assisted laser desorption/ionisation (MALDI) ion source, and samples of ionisable materials are first dispensed onto a MALDI plate, which can generally comprise a translation stage. Correspondingly, ion source  120  is enabled to receive the ionisable materials via the MALDI plate, which can be inserted into the MALDI ion source, and ionise the samples of ionisable materials in any suitable order. In these embodiments, any suitable number of MALDI plates with any suitable number of samples dispensed there upon can be prepared prior to inserting them into the MALDI ion source. 
     Precursor ions produced at ion source  120  are transferred to ion optics  130 , for example via a vacuum differential and/or a suitable electric field(s). Ion optics  130  can generally comprise any suitable multipole including, but limited to, a quadrupole rod set. Ion optics  130  are generally enabled to cool and focus precursor ions, and can further serve as an interface between ion source  120 , at atmospheric pressure, and subsequent lower pressure vacuum modules of mass spectrometer  100 . 
     Precursor ions are then transferred to EST  140 , for example via any suitable vacuum differential and/or a suitable electric field(s), EST  140  enabled to selectively and sequentially filter ions, which are transferred to fragmentation module  150 . 
     Attention is now directed to  FIG. 2 , which depicts a block diagram of EST  140 , according to non-limiting embodiments. EST  140  comprises an entrance end  210  and an exit end  220 . Entrance end  210  is generally enabled to accept ions from ion optics  130  such that EST  140  can be filled with ions. Furthermore, exit end  220  is generally enabled to allow ions to exit from EST  140  such that ions can be transferred to fragmentation chamber  150 . In general, ions travel along and/or parallel to a longitudinal axis  225 . EST  140  further comprises an entrance end ion mirror  230 , proximate entrance end  210 , and an exit end ion mirror  240 , proximate exit end  230 . Each ion mirror  230 ,  240  is enabled to use a static electric field to reverse the direction of travel of ions entering it, and further comprises a barrier field that retains ions within EST  140 . Hence, ions admitted into EST  140  via entrance end  210  are trapped within EST  140 , the ions oscillating between entrance end ion mirror  230  and exit end ion mirror  240  along longitudinal axis  225 . 
     EST  140  further comprises electrodes  250 , which can comprise, in some non-limiting embodiments, a pair of ring electrodes, depicted in cross-section in  FIG. 2 . In other embodiments, electrodes  250  can include, but are not limited to, a pair of grids and a pair of plates containing apertures. In general, electrodes  250  can be located in a central nominally field free region of EST  140 , approximately equidistant between ion mirrors  230 ,  240 . It is understood, however, that electrodes  250  can be located at any suitable location within EST  140 . In any event, electrodes  250  are enabled to selectively excite ions of interest, for example by applying an excitation field E (depicted in  FIG. 3 ) between electrodes  250  when ions of interest are oscillating proximal electrode  250 ; in embodiments where electrodes  250  comprises a pair of ring electrodes, electrodes  250  are enabled to selectively excite ions passing between them. 
     EST  140  can further comprise any number of suitable electrodes (not depicted) for causing ions to oscillate between ion mirrors  230 ,  240  via the application of suitable static and time varying electric fields (e.g. including, but not limited to, RF (radio-frequency) and sinusoidal fields, etc.). In particular, ions of different mass-to-charge (m/z) ratios will oscillate with a unique period of oscillation (though not necessarily sinusoidally). Hence, once ions are admitted into EST  140 , after a period of time, ions separate into bunches of ions of different (m/z) values as they oscillate. This is generally depicted in  FIG. 3 , which is substantially similar to  FIG. 2 , however with bunches of ions if different m/z values: (m/z) 1 , (m/z) 2 , and (m/z) 3 , and hence each oscillating at respective different frequencies f 1 , f 2 , and f 3 . In general, over time, ions tend to separate into bunches of a single, narrow range of mass-to-charge ratios, of greater than 10,000 mass resolution. Ions introduced in to EST  140  are further understood to oscillate in the range of frequencies from 10 s to 100 s of kHz. 
     A bunch of ions of (m/z) 1  will pass a given point within EST  140 , for example a midpoint M between electrodes  250 , at times t 1   1 , t 1   2 , t 1   3 , . . . , where the difference between each successive time is constant (i.e. t 1   3 −t 1   2 =t 1   2 −t 1   1 ). Bunches of ions of (m/z) 2  will pass the same given point M at times t 2   1 , t 2   2 , t 2   3 , . . . where the difference between each successive time is also a constant (i.e. t 2   3 −t 2   2 =t 2   2 −t 2   1 ). Bunches of ions of (m/z) 3  will pass the same given point M at times t 3   1 , t 3   2 , t 3   3 , . . . where the difference between each successive time is constant (i.e. t 3   3 −t 3   2 =t 3   2 −t 3   1 ). Furthermore, t 3   3 −t 3   2 ≠t 2   2 −t 2   1 ≠t 1   2 −t 1   1  as each bunch of ions of (m/z) 1 , (m/z) 2 , and (m/z) 3 , are oscillating at different frequencies f 1 , f 2 , and f 3 . Hence, each bunch of ions of (m/z) 1 , (m/z) 2 , and (m/z) 3  will pass given point M at different times 
     A bunch of ions of a given (m/z) n  can then be selectively excited by applying excitation field E via electrodes  250 , at particular times tn 1 , tn 2 , tn 3  . . . when the bunch of ions of the given (m/z) n  are passing a given point M (e.g. ions of (m/z) 3  in  FIG. 3 ), or are generally within the region between the two electrodes  250 . Excitation field E can be at least one of generally sinusoidal, square or of any suitable shape that can be optimized for ejection efficiency. Better selection efficiency can be obtained if the spacing between electrodes  250  is relatively short, compared to the distance between ion mirrors  230  and  240 . Furthermore, the frequency f n  and time that the bunch of ions of (m/z) n  passing the given point M can be determined by measuring the frequency of electric fields caused by the oscillation of the bunch of ions of (m/z)n within EST  140 , for example as they pass through electrodes  250 ; a Fourier transform of the measured signal provides a frequency spectrum that can further be transformed into a mass spectrum. Furthermore, excitation field E can comprise an oscillating electric field along longitudinal axis  225  applied in phase with an oscillation of the given bunch of ions of (m/z) n  along longitudinal axis  225 . 
     In some embodiments, however, such an oscillating electric field can be applied in at least one of entrance end ion mirror  230  and exit end ion mirror  240 . In these embodiments, electrodes  250  are not present in EST  140 . For example, a small perturbation can be applied to the back of one or both ions mirrors  230 ,  240  in phase with a selected bunch of ions of mass (m/z) n . Such a perturbation selectively energizes the selected bunch if ions such that the barrier field at exit end ion mirror  240  can be overcome. 
     Furthermore, in some embodiments, each of entrance end ion mirror  239  and exit end ion mirror  240  can be compensated to maintain timing and phase of oscillating ions when excited. 
     In any event, a given bunch of ions of a given m/z value can be excited along longitudinal axis  225  until at least a portion of the given bunch overcomes a barrier field at exit end ion mirror  240 , the given bunch of ions thereby exiting EST  140 , leaving behind remaining ions in EST  140 . Such a situation is depicted in  FIG. 4  (substantially similar to  FIG. 3 ), where the bunch of ions of (m/z) 3  has been excited by application of excitation field E between electrodes  250  each time the bunch of ions of (m/z) 3  passes given point M. Once the bunch of ions of (m/z) 3  is excited to a given energy, the barrier field at end ion mirror  240  is overcome, and the bunch of ions (m/z) 3  exits EST  140 , leaving behind bunches of ions of (m/z) 1 , (m/z) 2 . Hence, ions of a single, narrow range of mass-to-charge ratios can be selected and analyzed, with a mass resolutions of greater than 10,000. In some embodiments, only a portion a given bunch of ions of (m/z) n  overcomes the barrier field at exit end ion mirror  240 . 
     In any event, the given bunch of ions of (m/z) n  (or portion thereof) can then be transmitted to fragmentation module  150  for fragmentation such that fragmented respective product ions are produced. In some embodiments, the given bunch of ions of (m/z) n  are decelerated prior to fragmentation in order to control and select the energy of fragmentation. In these embodiments, decelerating can occur via at least one of a decelerating lens (not depicted), a decelerating electric field (applied via a decelerating field apparatus, not depicted), and an ion focussing field (applied via an ion focussing field apparatus, not depicted), between EST  140  and fragmentation module  150 . In some embodiments, fragmentation module  150  can be operated in alternating low energy fragmentation and high energy fragmentation modes to first identify precursor (i.e. parent) ions and associated respective product (i.e. child) ions of each mass range. 
     Once fragmented, product ions are transferred to mass analyzer  160  for analysis and production of product ion spectra. Mass analyzer  160  can comprise any suitable mass spectrometer module including, but not limited to, a time of flight (TOF) mass spectrometry module, a quadrupole mass spectrometry module and the like. 
     Once the given bunch of ions of (m/z) n  has been fragmented and analyzed, successive bunches of ions of (m/z) m , can be excited in EST  140  in a similar manner, each fragmented and analyzed in turn. Thus ions in EST  140  are not discarded and sample is used efficiently. 
     Attention is now directed to  FIG. 5  which depicts a method  500  for operating a mass spectrometer comprising an electrostatic trap. In order to assist in the explanation of the method  500 , it will be assumed that the method  500  is performed using mass spectrometer  100 . Furthermore, the following discussion of the method  500  will lead to a further understanding of mass spectrometer  100  and its various components. However, it is to be understood that mass spectrometer  100  and/or method  500  can be varied, and need not work exactly as discussed herein in conjunction with each other, and that such variations are within the scope of present embodiments. 
     At step  510  ions are admitted into EST  140  via entrance end  210 . It is understood that ions are produced in ion source  120  and are transferred to EST  140  via ion optics  130 . 
     At step  520  ions are trapped in EST  140 , ions oscillating between entrance end ion mirror  230  and exit end ion mirror  249  along longitudinal axis  225  by application of suitable electric fields in ion mirrors  230 ,  240  and between ion mirrors  230 ,  240 . 
     At step  530 , ions separate into bunches of ions of different m/z values via the oscillating, as described above. In particular, a suitable period of time elapses such that ions separate into bunches of different m/z values due to the respective different oscillation frequencies. 
     At step  540 , a given bunch of ions of a given m/z value are excited along longitudinal axis  225  until at least a portion of the given bunch overcomes a barrier field at exit end ion mirror  240 , thereby exiting EST  140 , leaving behind remaining ions in EST  140 . Excitation occurs via application of excitation field E between electrodes  250  when the given bunch of ions passes given point M. Application of excitation field E can occur when the given bunch of ions is travelling in either direction between ion mirrors  230 ,  240 . Furthermore, the remaining ions in EST  140  continue to oscillate between ion mirrors  230 ,  240 . Alternatively, a perturbation can be applied at one or both of ion mirrors  230 ,  240 , as described above, to excite the given bunch of ions of the given m/z. 
     In some embodiments, at step  550 , once the given bunch of ions have excited EST  140 , the given bunch of ions can be fragmented in fragmentation module  150  prior to analysis of at least a portion of the given bunch ions via mass analyzer  160 , at step  560 . 
     At step  570  it can be determined if more ions in EST  140  are to be selected and analyzed. If not, method  500  ends at step  580 . Ions remaining in EST  140  can be flushed and ions of a new sample can be introduced into EST  140 , as desired. 
     However, if it is determined at step  570  that more ions in EST  140  are to be selected and analyzed, steps  540  through  560  are repeated such that a second given bunch of remaining ions of a second given m/z value are excited along longitudinal axis  225  until at least a portion of the second given bunch overcomes the barrier field at exit end ion mirror  240 , thereby exiting EST  140 , leaving behind further remaining ions in EST  140 . The second given bunch can then be fragmented (if desired) and analyzing said mass analyzer  160 . Steps  540  to  570  can be repeated any suitable number of times until ions no ions of interest remain in EST  140 . 
     In general, then, by operating EST  140  in a mode where a period of time elapses to allow ions to oscillate into bunches if ions of different (m/z), and then selectively excited a bunch of ions of interest until it overcomes the barrier field at exit end ion mirror  240 , very high mass resolutions can be achieved. Furthermore, as ions remaining in EST  140  are not discarded, at least a second bunch of ions can be similarly excited, transferred from EST  140  and analyzed, such that ions from samples of limited quantities are not wasted. 
     Those skilled in the art will appreciate that in some embodiments, the functionality of mass spectrometer  100  can be implemented using pre-programmed hardware or firmware elements (e.g., application specific integrated circuits (ASICs), electrically erasable programmable read-only memories (EEPROMs), etc.), or other related components. In other embodiments, the functionality of mass spectrometer  100  can be achieved using a computing apparatus that has access to a code memory (not shown) which stores computer-readable program code for operation of the computing apparatus. The computer-readable program code could be stored on a computer readable storage medium which is fixed, tangible and readable directly by these components, (e.g., removable diskette, CD-ROM, ROM, fixed disk, USB drive). Alternatively, the computer-readable program code could be stored remotely but transmittable to these components via a modem or other interface device connected to a network (including, without limitation, the Internet) over a transmission medium. The transmission medium can be either a non-wireless medium (e.g., optical and/or digital and/or analog communications lines) or a wireless medium (e.g., microwave, infrared, free-space optical or other transmission schemes) or a combination thereof. 
     Persons skilled in the art will appreciate that there are yet more alternative implementations and modifications possible for implementing the embodiments, and that the above implementations and examples are only illustrations of one or more embodiments. The scope, therefore, is only to be limited by the claims appended hereto.