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WO2007140400A2 - Procédé pour faire fonctionner un instrument de séparation d'ions - Google Patents

Procédé pour faire fonctionner un instrument de séparation d'ions Download PDF

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Publication number
WO2007140400A2
WO2007140400A2 PCT/US2007/069960 US2007069960W WO2007140400A2 WO 2007140400 A2 WO2007140400 A2 WO 2007140400A2 US 2007069960 W US2007069960 W US 2007069960W WO 2007140400 A2 WO2007140400 A2 WO 2007140400A2
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WIPO (PCT)
Prior art keywords
ion
gate
activating
ions
discrete
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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PCT/US2007/069960
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English (en)
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WO2007140400A3 (fr
Inventor
David E. Clemmer
Stormy L. Koeniger
Samuel I. Merenbloom
Stephen J. Valentine
Stephen Naylor
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Indiana University Research and Technology Corp
PREDICTIVE PHYSIOLOGY AND MEDICINE Inc
Original Assignee
Indiana University Research and Technology Corp
PREDICTIVE PHYSIOLOGY AND MEDICINE Inc
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Publication of WO2007140400A2 publication Critical patent/WO2007140400A2/fr
Publication of WO2007140400A3 publication Critical patent/WO2007140400A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing

Definitions

  • This disclosure relates generally to analytical instruments operable to separate ions as a function of at least one ion characteristic, and more specifically to methods for operating such instruments.
  • Analytical instruments are known that are configured to separate ions as a function of one or more ion characteristics.
  • One such instrument is a tandem combination of an ion mobility spectrometer followed by a mass spectrometer. It is desirable with such instruments to investigate properties of ions produced from a variety of sources including, for example, but not limited to, complex biological samples.
  • the present invention may comprise one or more of the features recited in the attached claims and the following features and combinations thereof.
  • a method is provided for operating an ion separation instrument.
  • the ion separation instrument may comprise an ion mobility spectrometer and a mass analyzer.
  • the ion separation instrument may have an inlet with a first gate that is controllable to allow or inhibit entrance of ions therein from an ion source, a second gate that is separated by a distance from the first gate and that is controllable to allow or inhibit passage of ions therethrough and an ion outlet.
  • the mass analyzer may have an ion inlet configured to receive ions from the ion outlet of the ion mobility spectrometer and an ion outlet.
  • An ion detector is configured to detect ions at the ion outlet of the mass analyzer.
  • the method may comprise activating the first gate to allow entrance of a packet of a mixture of ions from the ion source into the ion mobility spectrometer, allowing the packet of ions to separate between the first and second gates as a function of ion mobility, activating the second gate at a plurality of successive discrete time periods after activating the first gate and before reactivating the first gate to allow passage therethrough of a corresponding plurality of discrete ion groups separated from each of other according to ion mobility, and separating one or more of the discrete ion groups separated from each other according to ion mobility in the mass analyzer as a function of mass-to-charge ratio.
  • the method may further comprise repeatedly activating the first gate, allowing the packet of ions to separate and activating the second gate a number of times, and for each of the number of times, consecutively adding an offset time, relative to activating the first gate, to each of the times at which the second gate is activated.
  • the time periods between activating the second gate may define inactive time periods. The number of times may be selected to span the inactive time periods.
  • Activating the second gate may comprise activating the second gate for an activation time period at each of the plurality of successive discrete time periods.
  • the activation time of the second gate may be a predefined activation time period.
  • the activation time of the second gate may change linearly with time relative to activation of the first gate. Alternatively, the activation time of the second gate may change non-linearly with time relative to activation of the first gate.
  • Activating the second gate may comprise periodically activating the second gate.
  • Activating the second gate may comprise maintaining the second gate active for an activation time at each of the plurality of successive discrete time periods.
  • a first one of the plurality of successive discrete time periods may occur after a predefined delay time following activation of the first gate.
  • the method may further comprise repeatedly activating the first gate, allowing the packet of ions to separate and activating the second gate a number of times, and adding an offset time period to the predefined delay time for each of the number of times.
  • the time periods between the periodic activations of the second gate may define inactive time periods.
  • the number of times may be selected to span the inactive time periods.
  • the ion source may comprise another ion separation instrument configured to separate ions as a function of an ion characteristic.
  • Activating the first gate may comprise activating the first gate for a predefined time period to allow entrance into the inlet of the ion mobility spectrometer of at least a portion of the ions separated as a function of the ion characteristic.
  • the ion mobility spectrometer may comprise a plurality of cascaded stages each configured to separate ions as a function of ion mobility. Allowing the packet of ions to separate may comprise allowing the packet of ions to separate as a function of ion mobility in one or more of the cascaded stages.
  • the method may further comprise activating at least some of the ions within the ion mobility spectrometer.
  • Activating at least some of the ions in the ion mobility spectrometer may comprise fragmenting at least some of the ions in the ion mobility spectrometer.
  • activating at least some of the ions in the ion mobility spectrometer may comprise inducing conformational changes in at least some of the ions without fragmenting the at least some of the ions.
  • the mass analyzer may have a first gate at the inlet thereof that is controllable to allow or inhibit ions into the mass analyzer from the ion mobility spectrometer, and a second gate that is separated by a distance from the first gate of the mass analyzer and that is controllable to allow or inhibit passage of ions therethrough.
  • the method further may comprise activating the first gate of the mass analyzer to allow entrance of one of the plurality of discrete ion groups exiting the ion mobility spectrometer therein, allowing at least one of the plurality of discrete ion groups to separate between the first and second gates of the mass analyzer according to ion mass-to-charge ratio, and activating the second gate of the mass analyzer at a plurality of successive discrete time periods after activating the first gate of the mass analyzer and before reactivating the first gate of the mass analyzer to allow passage therethrough of a corresponding plurality of discrete groups of ions separated from each of other according to ion mass-to-charge ratio.
  • the method may further comprise repeatedly activating the first gate of the mass analyzer, allowing the one of the plurality of discrete ion groups to separate between the first and second gates of the mass analyzer and activating the second gate of the mass analyzer a plurality of times, and for each of the plurality of times, consecutively adding an offset time, relative to activating the first gate of the mass analyzer, to each of the times at which the second gate of the mass analyzer is activated.
  • the mass analyzer may be a time-of-flight mass spectrometer.
  • a method of correlating ion separation information to a biomarker may comprise operating a tandem combination ion mobility spectrometer followed by a - A -
  • mass analyzer to produce a plurality of discrete ion groups from a packet of a mixture of ions, determining ion intensities of each of the plurality of discrete ion groups, creating a matrix of the ion intensities of each of the plurality of discrete ion groups, identifying entries of the matrix that define the biomarker, and creating a map correlating the biomarker to the identified entries of the matrix.
  • the ion mobility spectrometer may have an inlet with a first gate that is controllable to allow or inhibit entrance of ions therein from an ion source, and a second gate that is separated by a distance from the first gate and that is controllable to allow or inhibit passage of ions therethrough.
  • Operating the tandem combination may comprise activating the first gate to allow entrance of the packet of the mixture of ions from the ion source into the ion mobility spectrometer, allowing the packet of ions to separate between the first and second gates as a function of ion mobility, and activating the second gate at a plurality of successive discrete time periods after activating the first gate and before reactivating the first gate to allow passage therethrough of the plurality of discrete ion groups separated from each other according to ion mobility.
  • Creating a matrix of the ion intensities may comprise entering an ion intensity value of each of the plurality of discrete ion groups into a separate row or column of a common column or row of the matrix.
  • the method may further comprise repeatedly activating the first gate, allowing the packet of ions to separate and activating the second gate a number of times, and for each of the number of times, consecutively adding an offset time, relative to activating the first gate, to each of the times at which the second gate is activated.
  • Creating a matrix of ion intensity values may comprise creating another common column or row each of the number of times that activating the first gate, allowing the packet of ions to separate and activating the second gate are repeated.
  • the method may further comprise processing one of the plurality of discrete ion groups to produce an additional ion intensity value.
  • Creating a matrix of the ion intensities may comprise entering the additional ion intensity value into a row or column of the matrix that is within the common column or row and that is adjacent to the row or column in which the ion intensity value of the one of the plurality of discrete ion groups was entered such that the ion intensity value of the one of the plurality of discrete ion groups and the additional ion intensity value appear sequentially in the common column or row.
  • the method may further comprise processing each of the plurality of discrete ion groups to produce one or more additional ion intensity values.
  • Creating a matrix of the ion intensities may comprise entering the one or more additional ion intensity values for each of the plurality of discrete ion groups into the matrix such that the ion intensity value of each of the plurality of discrete ion groups and the one or more corresponding additional ion intensity values appear sequentially in the common column or row.
  • the method may further comprise repeatedly activating the first gate, allowing the packet of ions to separate and activating the second gate a number of times, and for each of the number of times, consecutively adding an offset time, relative to activating the first gate, to each of the times at which the second gate is activated.
  • Creating a matrix of ion intensity values may comprise creating another common column or row each of the number of times that activating the first gate, allowing the packet of ions to separate and activating the second gate are repeated.
  • Processing one of the plurality of discrete ion groups to produce an additional ion intensity value may comprise processing the one of the plurality of discrete ion groups within the ion mobility spectrometer in a manner that produces the additional ion intensity value.
  • Processing the one of the plurality of discrete ion groups within the ion separation instrument may comprise activating the one of the plurality discrete ion groups within the ion mobility spectrometer.
  • the ion mobility spectrometer may have a third gate that is separated by another distance from the second gate and that is controllable to allow or inhibit passage of ions therethrough.
  • Processing the one of the plurality of discrete ion groups within the ion mobility spectrometer may comprise allowing the one of the plurality of discrete ion groups to separate between the second and third gates as a function of ion mobility.
  • the method may further comprise operating the mass analyzer to produce another plurality of discrete ion groups from the plurality of discrete ion groups, determining ion intensities of each of the another plurality of discrete ion groups, and creating another matrix of the ion intensities of each of the another plurality of discrete ion groups.
  • Identifying entries of the matrix that define the biomarker may comprise identifying entries of either of the matrix and the another matrix that define the biomarker.
  • Creating a map correlating the biomarker to the identified entries of the matrix may comprise creating a map correlating the biomarker to the identified entries of either of the matrix and the anther matrix.
  • FIG. 1 is a diagram illustrating an example ion separation instrument in the form of a tandem combination of an ion mobility spectrometer followed by a mass analyzer.
  • FIG. 2 is a timing diagram illustrating operation of the ion separation instrument of FIG. 1.
  • FIG. 3 is a timing diagram further illustrating operation of the second gate of the instrument of FIG. 1.
  • FIG. 4 is a flowchart of one illustrative process for operating the instrument of FIG. 1.
  • FIG. 5 is a plot of ion mass-to-charge ratio vs. ion drift time for a human hemoglobin tryptic digest sample illustrating conventional operation of the instrument of FIG. 1.
  • FIG. 6 is a plot of mass-to-charge ratio vs. ion drift time for the human hemoglobin tryptic digest sample of FIG. 5 illustrating operation of the ion mobility spectrometer via successive activation of the ion outlet gate.
  • FIG. 7 is a plot of mass-to-charge ratio vs. ion drift time for the human hemoglobin tryptic digest sample of FIG. 5 illustrating operation of the ion mobility spectrometer via successive activation of the ion outlet gate wherein the successive ion outlet gate activation times are advanced over those of FIG. 6 by an offset value.
  • FIG. 8 is a plot of mass-to-charge ratio vs. ion drift time for the human hemoglobin tryptic digest sample of FIG. 5 illustrating operation of the ion mobility spectrometer via successive activation of the ion outlet gate wherein the successive ion outlet gate activation times are advanced over those of FIG. 7 by the offset value.
  • FIG. 9 is a plot of mass-to-charge ratio vs. ion drift time for the human hemoglobin tryptic digest sample of FIG. 5 illustrating operation of the ion mobility spectrometer via successive activation of the ion outlet gate wherein the successive ion outlet gate activation times are advanced over those of FIG. 8 by the offset value.
  • FIG. 10 is a plot of mass-to-charge ratio vs. ion drift time for the human hemoglobin tryptic digest sample of FIG. 5 illustrating operation of the ion mobility spectrometer via successive activation of the ion outlet gate wherein the successive ion outlet gate activation times are advanced over those of FIG. 9 by the offset value.
  • FIG. 11 is a flowchart of one illustrative process for mapping one or more biomarkers to corresponding ion intensity information resulting from the process of FIG. 4 using the ion separation instrument of FIG. 1.
  • FIG. 12 is a chart illustrating one illustrative technique for creating a matrix of ion intensity values according to the process of FIG. 11.
  • FIG. 13 is a diagram illustrating identification of entries in a matrix of the type illustrated in FIG. 12 that define one or more biomarkers according to the process of FIG. 11.
  • FIG. 14 is a map illustrating one illustrative technique for creating a map correlating two biomarkers to corresponding matrix locations according to the process of FIG. 11.
  • the instrument 10 includes an ion source 12 coupled to an inlet of an ion mobility spectrometer 14 (IMS) having an ion outlet.
  • IMS ion mobility spectrometer
  • the ion mobility spectrometer 14 is generally configured and operable to separate ions in time as a function of ion mobility.
  • the ion source 12 may be conventional in construction, and may be configured to produce ions, e.g., charged particles.
  • ion sources 12 that produce charged particles include, but are not limited to, electrospray ion sources, laser desorption ionization structures and techniques, such as a matrix- assisted laser desorption ionization (MALDI), irradiation of samples via other radiations sources, and the like.
  • the ion source 12 may be integral with the ion mobility spectrometer 14.
  • the ion source 12 may be or include one or more instruments configured to separate ions in time, space or both, as a function of one or more corresponding ion characteristics.
  • the ion mobility spectrometer 14 has an ion inlet gate, G 1 , which may be controlled to allow ions from the ion source 12 to enter the ion mobility spectrometer 14 via its ion inlet.
  • the ion inlet gate, G 1 may be or include, for example, a grid, screen or other suitable structure that may be activated to allow ions to pass therethrough, and that may be deactivated to inhibit passage of ions therethrough.
  • the ion inlet gate, G 1 may be located at, or integral with, the ion inlet of the ion mobility spectrometer 14, downstream of the ion inlet of the instrument 14 (i.e., within the instrument 14) or in the ion source 12.
  • the ion mobility spectrometer 14 may have any number, F, of ion gates, wherein F may be any positive integer greater than 2.
  • the ion mobility spectrometer 14 has an ion outlet gate, Gp, which may be controlled to allow ions to exit the active region of the instrument 14 via its ion outlet.
  • the ion outlet gate, G F may be or include, for example, a grid, screen or other suitable structure that may be activated to allow ions to pass therethrough, and that may be deactivated to inhibit passage of ions therethrough.
  • the ion outlet gate, GF may be located at, or integral with, the ion outlet of the ion mobility spectrometer 14, upstream of the ion outlet of the instrument 14, (i.e., within the instrument 14) or downstream of the ion outlet of the instrument 14 (i.e., outside of the instrument 14).
  • the ion mobility spectrometer is configured to separate ions in time as a function of ion mobility.
  • the ion mobility spectrometer 14 may be formed by cascading any number, F-I, of stages (Si - SF -1 ) of equal or varying length each configured to separate ions in time, space or both, as a function of ion mobility, wherein F may be any positive integer greater than 2.
  • F may be any positive integer greater than 2.
  • a total number of "F" ion gates are included so that each stage of the instrument 14 has an ion inlet gate and an ion outlet gate. Any one or more of the "F" stages may further include one or more additional ion processing structures.
  • Examples of such one or more other additional ion processing structures include, but are not limited to, ion focusing structures such as one or more conventional ion focusing funnels, one or more ion activation regions, and the like. Examples of one such class of instruments, provided in the form of an ion mobility spectrometer, are illustrated and described in U.S. Patent Application Pub. No. US 2007/0114382 Al, entitled ION MOBILITY SPECTROMETER, the disclosure of which is incorporated by reference. As used herein, the term "ion activation" refers to a process of inducing structural changes in ions resulting from collisions of the ions with a buffer gas or buffer gas mixture in the presence of a high AC and/or DC electric field.
  • examples of implementations of the ion mobility spectrometer 14 include, but are not limited to, a conventional ion mobility spectrometer, configured to separate ions as a function of ion mobility, provided in the form of a single or multiple-stage ion mobility spectrometer, a high- field asymmetric waveform ion mobility spectrometer (FAIMS) employing a constant compensation voltage, a high-field asymmetric waveform ion mobility spectrometer (FAIMS) employing a differential compensation voltage, and the like.
  • a conventional ion mobility spectrometer configured to separate ions as a function of ion mobility
  • FIMS high- field asymmetric waveform ion mobility spectrometer
  • FIMS high-field asymmetric waveform ion mobility spectrometer
  • the ion separation instrument 10 further includes a mass analyzer 16 having an ion inlet coupled to the ion outlet of the ion mobility spectrometer 14 and an ion outlet coupled to a conventional ion detector 18.
  • the mass analyzer 16 is generally configured and operable to separate ions in time as a function of ion mass- to-charge ratio. Examples of the mass analyzer 16 include, but are not limited to, a quadrupole or ion trap mass analyzer, a linear quadrupole mass analyzer, a time-of- flight mass spectrometer (TOFMS), a Fourier Transform mass spectrometer (FTMS) and a cyclotron-based mass spectrometer.
  • TOFMS time-of- flight mass spectrometer
  • FTMS Fourier Transform mass spectrometer
  • the mass analyzer 16 may comprise any number, G, of cascaded mass analyzers, MAi - MA G , i.e., arranged in tandem with respect to each other, between the ion outlet of the ion mobility spectrometer 14 and the ion detector 18, as illustrated in phantom in FIG. 1.
  • G may be any positive integer.
  • the mass analyzer 16 may include any number, G-I, of gates (and stages) similarly as described hereinabove with respect to the ion mobility spectrometer 14.
  • the instrument 10 may include one or more conventional instruments configured to process ions in a manner differently than separating ions as a function of an ion characteristic.
  • Examples of such one or more ion processing instruments include, but are not limited to, a conventional ion filter configured to collect and/or allow passage therethrough only of ions within a predefined range of ion mass-to-charge ratios, a conventional ion trap configured to collect and selectively eject ions, a conventional collision cell configured to fragment ions, and a conventional charge neutralization device configured to normalize various ion charge states to a target charge state (e.g., to a +1 charge state).
  • Other conventional ion processing instruments will occur to those skilled in the art, and any one or more such other conventional ion processing instruments may be included in the ion separation instrument 10.
  • one or more such ion processing instruments may be positioned prior to the ion mobility spectrometer 14, between one or more stages of a multi-stage ion mobility spectrometer, between the ion mobility spectrometer 14 and the mass analyzer 16, between one or more mass analyzer stages or instruments, and/or between the mass analyzer 16 and the ion detector 18.
  • the ion detector 18 is positioned to receive ions exiting the last of the one or more mass analyzers 16.
  • the ion detector 18 may be a conventional ion detector configured to produce ion detection signals corresponding to arrival of ions at the detector 18. Such signals are provided to a conventional processor 20 that is configured to process these signals and determine multi-dimensional ion separation information therefrom.
  • the instrument 10 further includes a number of gating sources, indicated generally at 22.
  • the gating sources 22 include a number of voltage sources that are configured to provide AC and/or DC operating voltages and pulsed voltages to the various sections of the instrument 10 in a conventional manner. The manner in which the gating sources are controlled to operate the instrument 10 in accordance with this disclosure will be described hereinafter.
  • the gating source 22 provides a number, H, of gating signals to the ion source 12, where H may be any positive integer.
  • the gating source 22 provides a number, J, of gating signals to the ion mobility spectrometer 14, where J may be any positive integer, and provides a number, K, of gating signals to the mass analyzer 16, where K may be any positive integer.
  • the gating signals may include AC, DC and/or pulsed voltages.
  • the instrument 10 further includes a gas source 24 that includes a number, L, of different sources of buffer or other gas, Gl - GL, where L may be any positive integer.
  • the gas source 24 is illustrated as being fluidly coupled to the ion mobility spectrometer 14 and to the mass analyzer 16, and the gas source 24 is configured to supply any one or combination of gases to each of the instruments 14 and 16.
  • the gating sources 22 may comprise one or more programmable gating sources such that the gating sources 22 are self-operating and self-controlled.
  • the processor 20 may be configured in a conventional manner to control operation of one or more of the gating sources 22.
  • the gas source 24, in one embodiment, includes one or more manually activated and/or programmable flow control mechanisms that provide for control over the supply of gas to the ion mobility spectrometer 14 and/or mass analyzer 16.
  • the processor 20 may be configured in a conventional manner to control operation of the gas source 24. Referring now to FIG. 2, a timing diagram illustrating operation of the ion separation instrument 10 of FIG. 1 is shown.
  • F ion inlet gate
  • G 2 ion gate separated by a distance from G 1 , e.g., G 2
  • an outlet gate e.g., GF.
  • the actual activation and deactivation of these gates may be carried out by supplying one or more appropriate gating signals to the gates Gi and/or G 2 via the gating sources 22, either under manual and/or programmable control of one or more of the gating sources 22 or under at least partial control of the processor 20.
  • the activation state of the gate Gi is represented by the gating signal 30, and the activation state of the gate G 2 is represented by the gating signal 32.
  • a packet of a mixture of ions from the ion source 12 are initially "gated" into the ion mobility spectrometer 14 by activating the gate Gi for a gate activation time period, T GIA , 34. Thereafter, the gate Gi is deactivated for a time period P GID - During the time period T GIA , ions from the ion source 12 enter the ion mobility spectrometer 14 through the gate Gi and the inlet of the ion mobility spectrometer 14, and into the first stage, S 1 , of the ion mobility spectrometer 14. After entering the inlet of the ion mobility spectrometer 14, the ions travel through Si toward the gate G 2 while separating as a function of ion mobility.
  • the second gate, G 2 Upon the passage of a delay time, T D , following activation of the first gate, G 1 , and before the next activation of the first gate, G 1 , the second gate, G 2 , is activated at a plurality of successive discrete time periods to allow a corresponding plurality of discrete ion groups to pass through the second gate, G 2; and into the second stage, S 2 , of the ion mobility spectrometer 14.
  • the plurality of successive time periods, Pc are illustrated as being periodic up to the next activation of the gate G 1 .
  • corresponding periodic groups of ions will thus be transmitted through the gate G 2 and into the second stage, S 2 , of the ion mobility spectrometer 14 where they will further separate as a function of the ion mobility.
  • the plurality of successive time periods, Pc need not be periodic from TD until the next activation of the gate G 1 .
  • one or more gaps in the G 2 activation times that are greater than Pc may be implemented to inhibit transmission of one or more corresponding groups of ions through the second gate, G 2 .
  • the activation times, TA, of the second gate, G 2 , at each of the successive time periods Pc resemble the "teeth" of a comb, and the process of successively activating the gate G 2 may accordingly be referred to herein as a "comb", as “combing” or as a “combing technique.”
  • a comb as "combing” or as a “combing technique.”
  • Ion separation information corresponding to these gaps is captured by incrementally shifting the plurality of successive discrete G 2 activation times, i.e., the "teeth" of the comb, forward in time following each subsequent activation of the gate Gi until the time periods Pc where the gate G 2 is inactive have been spanned.
  • an offset time period, ⁇ is added to value of the most recent time delay value, T D , resulting in a delay between activation of the gate Gi and the first one of the plurality of successive discrete G 2 activation times of TD + ⁇ .
  • the process 50 may be implemented in the form of one or more sets of programming instructions in embodiments of the instrument 10 wherein appropriate ones of the gating sources 22 are themselves programmable, or in the form of one or more software algorithms that are stored in a memory associated with the processor 20 and are executable by the processor 20 to control operation of one or more of the gating sources 22 in embodiments of the instrument 10 wherein operation of appropriate ones of the gating sources 22 are under the control of the processor 20.
  • the process 50 begins at step 52 where the delay time, TD, is determined.
  • TD is generally selected to correspond to the arrival at the gate G 2 of ions having the shortest travel time between the gates Gi and G 2 .
  • TD may be selected to correspond to the arrival at the gate G 2 of ions in the subset of the entire range of ions traveling through the instrument 14 that have the shortest travel time between the gates Gi and G 2 .
  • the delay time, TD may have a positive or zero value.
  • step 54 the period, Pc, between the comb "teeth" is determined.
  • Pc will be selected based on a number of competing concerns. For example, in cases where there exists a large number of ions traveling through the ion mobility spectrometer 14 and/or the ions are densely populated, e.g., tightly packed, in one or more ion ranges or throughout the entire ion range, it is desirable to select larger values of Pc so that manageable amounts of ion separation information may be captured with each set of the plurality of successive discrete G 2 activation times.
  • step 54 the process 50 advances to step 56 where the gate
  • G 2 activation time TA is determined. Selection of TA will generally be limited at the lower end by the reaction time of the gate G 2 and on the amount of time required to allow a useful amount of ions to travel through the gate G 2 .
  • the upper limit of TA will depend upon the desired peak resolution of the ion separation information. Generally, TA will be selected to be a suitable value between these two limits.
  • the activation times, TA, of the second gate, G 2 are illustrated as being a constant, predefined value. It will be understood, however, that the activation times, TA, may alternatively change, e.g., increase or decrease, linearly between adjacent activations of the first gate, G 1 . Alternatively still, the activation times, T A , may change, e.g., increase or decrease, non-linearly between adjacent activations of the first gate, G 1 . The extent to which such activation times, TA, change linearly or non-linearly will depend upon the type of ion mobility spectrometer(s) 14 implemented in the instrument 10 and the underlying physics governing movement of ions therethrough.
  • step 58 the resolution period, P R , or equivalently the offset time, ⁇ , is determined.
  • PR or ⁇
  • PR may be greater or less than T A , or may be identical to T A .
  • P R ( ⁇ ) is selected to be equal to T A SO that data over the entire ion separation range is captured with no overlap and no gaps between the information.
  • step 60 a repetition value, REPS, is calculated as the ratio P C /P R .
  • REPS corresponds to the number of time-shifted sets of the plurality of successive discrete G 2 activation times required to span Pc.
  • the offset time value, ⁇ is set to zero and a counter value, CNT, is set to 1.
  • step 64 it is determined whether the gate Gi has been activated. If not, the process 50 loops back to step 64.
  • step 64 the process 50 advances to step 66 where the gate G 2 is activated for an activation time T A every time period Pc beginning at a delay time T D + ⁇ from the most recent activation of the gate G 1 .
  • step 66 represents an embodiment wherein the time period, Pc, between activations of the gate G 2 is periodic between T D + ⁇ and the next activation of the gate Gi, although it will be understood that this need not be the case as described hereinabove. Modifications to the process 50 to implement an embodiment wherein the time period, Pc, between activations of the gate G 2 is not periodic would be a mechanical step for a skilled artisan.
  • step 68 the offset value ⁇ is incremented by the resolution period, P R , and the count value, CNT, is incremented by 1.
  • step 68 it is determined whether the count value, CNT, is equal to REPS. If so, the entire time period, Pc, between successive activations of the gate G 2 has been spanned and the process stops. If, however, it is determined at step 70 that the count value, CNT, is not equal to REPS, the process 50 loops back to step 64 to await the next activation of the gate Gl . When that occurs, the loop comprising step 64-70 is again executed.
  • ions in the form of a mixture of tryptic peptides were generated from a sample of human hemoglobin tryptic digest using an electrospray ion source as the ion source 12.
  • the first gate, G 1 of the ion mobility spectrometer 14 was positioned at the ion inlet of the ion mobility spectrometer 14 as illustrated in FIG. 1, the second gate, G 2 , was separated by a first distance from the first gate, G 1 , and the final gate, G F , was positioned at the ion outlet of the ion mobility spectrometer 14.
  • the final gate, GF was separated by a second distance from the second gate, G 2 .
  • the first and second distances were selected such that the second distance was twice that of the first distance.
  • the mass analyzer 16 was provided in the form of a time-of- fiight (TOF) mass spectrometer having an ion inlet coupled to the ion outlet of the ion mobility spectrometer 14.
  • the detector 18 was positioned to receive ions exiting the TOP mass spectrometer 16.
  • Ions from the electrospray ion source 12 were gated via Gi into the first stage of the ion mobility spectrometer 14 with a 100 microsecond gate pulse, and the ions then separated in time through the first stage, S 1 .
  • Ion groups were then gated out of the first stage, S 1 , and into the second stage, S 2 , via G 2 as illustrated in FIGS. 2 and 3 with a time delay, T D , of zero, an activation time, T A , of 200 microseconds, and a period, Pc, between G 2 activations of approximately 1.0 millisecond, and with a total number of seven G 2 activations per comb.
  • the G2 comb teeth were then advanced in time by an offset value, ⁇ , of 200 microseconds, and a total of 5 combs were used to span Pc-
  • the groups of ions exiting the first stage, S 1 , of the ion mobility spectrometer 14 were activated by fragmentation, and the ion fragments then separated in time through the second stage, S 2 , of the ion mobility spectrometer 14.
  • the TOF mass spectrometer 16 was pulsed at 2 microseconds with 50 microseconds between each 2 microsecond pulse.
  • FIG. 5 shows a plot 80 of ion mass-to-charge ratio (m/z) vs. ion drift time (through the ion mobility spectrometer 14) when operating the ion mobility spectrometer 14 in a conventional operating mode with the gate G 2 continuously activated or open to allow passage of ions therethrough.
  • the plot 80 illustrates a broad distribution of unresolved features that span drift times from approximately 17-40 milliseconds. This is effectively the time required for these ions to travel through all of the drift regions of the ion mobility spectrometer 14, and therefore represents a one-dimensional ion mobility spectrometer experiment.
  • FIG. 5 shows a plot 80 of ion mass-to-charge ratio (m/z) vs. ion drift time (through the ion mobility spectrometer 14) when operating the ion mobility spectrometer 14 in a conventional operating mode with the gate G 2 continuously activated or open to allow passage of ions therethrough.
  • the plot 80 illustrates a broad
  • FIG. 6 is a plot 82 of ion mass-to-charge ratio vs. ion drift time with the gate, G 2 , periodically activated as a comb having seven teeth following the delay period, TD, as described above.
  • FIG. 7 is a plot 84 of ion mass-to-charge ratio vs. ion drift time with the gate G 2 again periodically activated according to the combing technique, with the first activation beginning after a delay time of TD + ⁇ following the next activation of the gate G 1 .
  • FIG. 8 is a plot 86 of ion mass-to-charge ratio vs.
  • FIG. 9 is a plot 88 of ion mass-to-charge ratio vs. ion drift time with the gate G 2 again periodically activated according to the combing technique, with the first activation beginning after a delay time of TD + 3 ⁇ following the next activation of the gate G 1 .
  • FIG. 10 is a plot 86 of ion mass-to-charge ratio vs.
  • ion drift time with the gate G 2 again periodically activated according to the combing technique, with the first activation beginning after a delay time of TD + 4 ⁇ following the next activation of the gate G 1 .
  • operating the ion separation instrument 14 sends fewer ions out of the ion mobility instrument 14 at any one time than by operating the instrument 14 using conventional techniques, e.g., of the type illustrated in FIG. 5.
  • This technique provides for the ability to enhance peak detection by providing more space in each of the successive ion groups to further separate in one or more downstream separation stages and/or instruments. It should be noted that while the method described herein of operating a ion separation instrument 10 is disclosed with reference to the ion mobility spectrometer 14 of FIG.
  • this method may alternatively or additionally be implemented with any one or more ion separation instruments included in the ion source 12 and/or mass analyzer 16, and within one or multiple stages of the ion mobility spectrometer 14.
  • the combing technique described herein in the context of ion separation in one dimension may thus extend to a "brush" technique where ions may be separated using the combing technique in two or more dimensions.
  • the combing technique just described may be implemented in a single stage, multiple stage or cascaded arrangement of the mass analyzer 16.
  • the ion mobility spectrometer 14 may thus be operated using the combing technique just described, and the mass analyzer 16 may also be operated as a comb, i.e., using the combing technique described herein, to produce multi-dimensional ion separation information.
  • the mass analyzer 16 will have an inlet with a first gate that is controllable to allow or inhibit ions into the mass analyzer 16 from the ion mobility spectrometer 14.
  • a second gate will be separated by a distance from the first gate of the mass analyzer 16, and this gate will be controllable as described above to allow or inhibit the passage of ions therethrough.
  • the detector 18 will be positioned to detect ions exiting the mass analyzer 16.
  • the first gate of the mass analyzer 16 is activated to allow entrance therein of consecutive ones of the plurality of discrete ion groups exiting the ion mobility spectrometer 14.
  • the discrete ion groups will then separate between the first and second gates of the mass analyzer 16 according to a ion mass-to-charge ratio.
  • the second gate of the mass analyzer 16 is activated at a plurality of successive discrete time periods after activating the first gate of the mass analyzer 16 and before reactivating the first gate of the mass analyzer 16 to allow passage therethrough of a corresponding plurality of discrete groups of ions separated from each of other according to ion mass-to-charge ratio.
  • the first gate of the mass analyzer 16 is repeatedly activated which allow the various discrete ion groups to separate between the first and second gates of the mass analyzer 16, and between repeated activations of the first gate the second gate of the mass analyzer 16 is activated a plurality of times. For each of the plurality of times, an offset time, relative to activating the first gate of the mass analyzer 16, is consecutively added to each of the times at which the second gate of the mass analyzer 16 is activated.
  • the first gate, G 1 may correspond to a gate in or at an ion acceleration region of a first one of the mass analyzers
  • the second gate, G 2 may correspond to a gate in or at an ion acceleration region of a second one of the m mass analyzers.
  • FIG. 11 a flowchart is shown of one illustrative process 100 for mapping one or more biomarkers to corresponding ion intensity information resulting from the ion separation process of FIG. 4.
  • At least some of the process 100 may be provided in the form of one or more software algorithms that may be stored in a memory associated with the processor 20 and that may be executed by the processor 20.
  • one or more such algorithms may be stored in a memory associated with a remote processor, such as a conventional personal computer, laptop computer or the like, and may be executed by such a remote processor.
  • the process 100 begins at step 102 where the ion intensity data that was generated according to the ion separation process of FIG. 4 is used to create a matrix of ion intensity values.
  • the matrix 120 generally has a number, M, of rows, wherein M may be any positive integer.
  • Each row represents a comb number, corresponding to a single set of ion intensity values resulting from a corresponding set of the plurality of successive discrete activation times of the second gate, G 2 , of the ion mobility spectrometer 14.
  • row 1 represents the ion intensity values resulting from comb number 1, corresponding to the ion intensity values resulting from the plurality of successive discrete gate G 2 activation times that begin after the delay time T D from the first activation of the gate G 1 .
  • Row 2 represents the ion intensity values resulting from comb number 2, corresponding to the ion intensity values resulting from the plurality of successive discrete gate G 2 activation times that begin after the delay time T D + ⁇ from the second activation of the gate Gi and so forth.
  • the value of M corresponds to the total number of sets of gate G 2 activation times required to span the complete range of ions traveling through the ion mobility spectrometer 14.
  • the ion intensity values resulting from the various different comb numbers could be entered in consecutive columns.
  • the matrix 120 generally has N "coarse" columns, wherein N may be any positive integer.
  • N may be any positive integer.
  • Each of the N coarse columns corresponds to a tooth of the comb, i.e., to one of the plurality of successive activation times of the gate G 2 in each set of activation times.
  • the coarse column 1 holds ion intensity values resulting from the first activation of the gate G 2 following each activation of the gate Gi
  • column 2 holds ion intensity values resulting from the second activation of the gate G 2 following each activation of the gate Gi ; and so forth.
  • the value of N thus corresponds to the total number of gate G 2 activation times following each activation of the gate G 1 .
  • the ion intensity values resulting from the various different comb numbers are entered in consecutive columns
  • the ion intensity values corresponding to the various teeth of any comb number could be entered in "coarse" rows.
  • the matrix 120 would be an M x N matrix populated with ion intensity values as just described.
  • other forms of the ion mobility spectrometer 14 may include two or more ion separation stages, one or more ion activation regions, and/or the like. Ion separation, ion activation and/or other ion processing may occur before, during and/or after the combing process 50 described herein.
  • ions may continue to resolve, i.e., further separate, change in conformation, fragment or undergo one or more additional ion processing, e.g., ion mass filtering, ion trapping, charge normalization, etc., that results in additional ion intensity information.
  • additional ion processing e.g., ion mass filtering, ion trapping, charge normalization, etc.
  • the matrix 120 of FIG. 12 includes a number, P, of additional "fine” columns following each "coarse” column where the additional ion intensity information resulting from such further ion separation, ion activation and/or other ion processing of each "coarse" group of ions is stored.
  • P may be any positive integer, and the value of P corresponds to the total number of additional ion intensity data values that result from further ion separation, ion activation and/or other ion processing of each "coarse" group of ions. In the general case, this then results in a total number of PP +N columns of the matrix 120.
  • the additional ion intensity values could be entered in "fine" rows next to the "coarse" rows.
  • Step 102 of the process 100 presupposes that an ion mobility spectrometer has been operated in a manner that produces a plurality of discrete ion groups from a packet of a mixture of ions, as described herein, and that ion intensities of each of the plurality of discrete ion groups have been determined.
  • the matrix of the ion intensities can be created by entering an ion intensity value of each of the plurality of discrete ion groups into a separate row or column of a common, i.e., the same, column or row of the matrix. Thus, if the ion intensity values are entered in separate columns, they must appear in the same, or common, row of the matrix, as illustrated in FIG. 12.
  • the ion intensity values are entered in separate rows of the matrix, they must then appear in the same, or common, column of the matrix. For each new comb, another common column or row is created in the matrix to accommodate the ion intensity values associated with the new comb. If an additional ion intensity value is generated from one of the discrete ion groups, the additional ion intensity value is entered into a row (or column) of the matrix that is within the common column (or row), and that is adjacent to the row (or column) in which the ion intensity value of the discrete ion group was entered such that the ion intensity value of the discrete ion group and the additional ion intensity value appear sequentially in the common column (or row). Multiple ion intensity values generated by any discrete ion group likewise appear sequentially in the matrix as illustrated in FIG. 7.
  • biomarker may be any substance that is used as an indicator of a biological state.
  • one type of biomarker may be any kind of substance indicating the existence (past or present) of living organisms.
  • Another type of biomarker may be any substance that is introduced in an organism for the purpose of examining organ function or other aspects of health.
  • biomarker may be any substance whose detection indicates a particular disease state or exposure to any environmental substance such as a toxin.
  • Another type of biomarker may be a fragment of DNA sequence that is associated with a disease, that changes susceptibility to disease or that causes disease.
  • Still another type of biomarker may be one of a number of components of a biological sample.
  • biomarkers of a sample of human tissue or fluid may include, but are not limited to, all proteins, proteins remaining after abundant protein removal, low analyte weight proteins, glycans, lipids, peptides without glycans, phosphorylated peptides and metabolites.
  • Other types and/or examples of biomarkers will occur to those skilled in the art, and any such other types and/or examples are contemplated by this disclosure.
  • any substance that defines a biomarker of interest relating to the sample being analyzed may be identified as being defined by a combination of ion intensity values from the matrix generated at step 102 of the process 100.
  • the biomarker Bl is identified as being defined by the ion intensity values stored in the matrix at row 5, column 4, at row 8, column 8 and at row 3, column 17.
  • the biomarker B2 is identified as being defined by the ion intensity values stored in the matrix at row 2, column 6, at row 4, column 9, at row 3, column 11 and at row 10, column 16.
  • This identification process may be done manually, or may instead be automated.
  • the identification process may be assisted by consulting one or more databases of biomarkers and/or substances.
  • step 104 may be carried out by identifying entries in any one or more of the matrices that define the biomarker.
  • the process 100 advances from step 104 to step 106 where a map is created that correlates one or more biomarkers to corresponding locations in the matrix created at step 102 of the process 100.
  • a map 140 is shown illustrating one illustrative technique for creating a map correlating the two biomarkers Bl and B2 of FIG. 13 to corresponding locations in the matrix 130.
  • the first two digits of the biomarker map values contained in the map 140 indicate the number of matrix locations that define the biomarker.
  • the biomarker B 1 is defined by three locations in the matrix 130 and the biomarker B2 is defined by four locations in the matrix 130.
  • each biomarker map value identify the number of digits used to identify the row and column of the first matrix location.
  • the second two digits in each of the biomarker map values indicate that the row and column values of the first matrix location are each single digits.
  • the next two digits of each biomarker map value are the actual row and column of the first location of the matrix 130 that defines the corresponding biomarker.
  • the first matrix location that defines the biomarker Bl is row 5, column 4, and the first matrix location that defines the biomarker B2 is row 2, column 6.
  • the remaining digits of each of the biomarker map values are processed in like manner to determine all of the matrix locations that define each of the biomarkers of interest.
  • step 106 may be carried out by creating a map that correlates the biomarker to the identified entries in any one or more of the matrices.
  • the process 100 may advance to step 108 where the map 140 is used to identify specific ion separation data to analyze when investigating one or more biomarkers of other samples.
  • the ion intensity values identified by the map created at step 106 may represent baseline values to which corresponding ion intensity values of other samples may be compared.
  • the ion intensity values identified by the map created at step 106 may be averaged with corresponding ion intensity values of multiple maps to create baseline values to which corresponding ion intensity values of other samples may be compared.
  • the process 100 may advance from step 106 to step 110 where the map 140 is used to identify specific comb and teeth numbers to monitor when investigating biomarkers of future samples of the same type used to generate the matrix created at step 102.
  • the matrix locations of the ion intensity information that define a biomarker correspond, and may be mapped back to, specific comb and tooth numbers from which the matrix was generated.
  • the comb and tooth numbers may then be used to identify specific ion intensity values to monitor for such analyses.

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Abstract

L'invention concerne un procédé pour faire fonctionner un instrument de séparation d'ions (10) comprenant un spectromètre de mobilité ionique (14) pourvu d'une entrée reliée à une source d'ions (12) et d'une sortie reliée à une entrée d'un analyseur de masse (16). Ledit procédé peut consister à activer une première porte du spectromètre de mobilité ionique (14) pour permettre à un ensemble constitué d'un mélange d'ions, provenant de la source d'ions (12), d'entrer dans ledit spectromètre, à permettre à l'ensemble d'ions de se séparer entre la première porte et une seconde porte en fonction de la mobilité ionique, à activer la seconde porte à plusieurs périodes discrètes successives après l'activation de la première porte, afin de permettre le passage d'une pluralité correspondante de groupes d'ions discrets séparés les uns des autres en fonction de la mobilité ionique, et à séparer un ou plusieurs des groupes d'ions discrets dans l'analyseur de masse (16) en fonction d'un rapport masse/charge.
PCT/US2007/069960 2006-05-30 2007-05-30 Procédé pour faire fonctionner un instrument de séparation d'ions Ceased WO2007140400A2 (fr)

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US10139369B2 (en) * 2014-12-24 2018-11-27 Hitachi High-Technologies Corporation Mass spectrometer

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