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WO2007140401A2 - Procédé pour faire fonctionner un instrument de séparation de substances à analyser - Google Patents

Procédé pour faire fonctionner un instrument de séparation de substances à analyser Download PDF

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Publication number
WO2007140401A2
WO2007140401A2 PCT/US2007/069963 US2007069963W WO2007140401A2 WO 2007140401 A2 WO2007140401 A2 WO 2007140401A2 US 2007069963 W US2007069963 W US 2007069963W WO 2007140401 A2 WO2007140401 A2 WO 2007140401A2
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WO
WIPO (PCT)
Prior art keywords
analyte
gate
ion
instrument
analytes
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.)
Ceased
Application number
PCT/US2007/069963
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English (en)
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WO2007140401A3 (fr
Inventor
David E. Clemmer
Stormy L. Koeniger
Samuel I. Merenbloom
Stephen J. Valentine
Stephen Naylor
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
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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Filing date
Publication date
Application filed by Indiana University Research and Technology Corp, PREDICTIVE PHYSIOLOGY AND MEDICINE Inc filed Critical Indiana University Research and Technology Corp
Publication of WO2007140401A2 publication Critical patent/WO2007140401A2/fr
Anticipated expiration legal-status Critical
Publication of WO2007140401A3 publication Critical patent/WO2007140401A3/fr
Ceased legal-status Critical Current

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Classifications

    • 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 analytes as a function of at least one analyte characteristic, and more specifically to methods for operating such instruments.
  • Analytical instruments are known that are configured to separate analytes as a function of one or more analyte characteristics. It is desirable with such instruments to investigate properties of analytes 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 of operating an analyte separation instrument is provided.
  • the analyte separation instrument may have an inlet with a first gate that is controllable to allow or inhibit entrance of analytes into the instrument from an analyte 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 analytes therethrough.
  • the method may comprise activating the first gate to allow entrance of a packet of a mixture of analytes from the analyte source into the instrument, allowing the packet of analytes to separate between the first and second gates as a function of a first analyte characteristic, 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 a corresponding plurality of discrete analyte groups separated from each of other according to the function of the first analyte characteristic.
  • the method may further comprise repeatedly activating the first gate, allowing the packet of analytes 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.
  • 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 further 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 analytes 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 analyte separation instrument may be a liquid chromatograph, and the first analyte characteristic may be analyte retention time.
  • the analyte separation instrument may be a gas chromatograph, and the first analyte characteristic may be analyte retention time.
  • the analyte separation instrument may be a capillary electrophoresis instrument, and the first analyte characteristic may be analyte charge-to-size ratio or electrophoretic mobility.
  • the analyte separation instrument may be a mobility spectrometer, and the first analyte characteristic may be analyte mobility.
  • the analyte source may include another analyte separation instrument configured to separate analytes as a function of a second analyte characteristic.
  • Activating the first gate may comprise activating the first gate for a predefined time period to allow entrance into the inlet of the analyte separation instrument of at least a portion of the analytes separated as a function of the second analyte characteristic.
  • the analyte separation instrument may further comprise an analyte detector configured to detect analytes that pass through the second gate.
  • the method may further comprise processing the analyte detection signals produced by the analyte detector to determine analyte separation information.
  • the analyte separation instrument may comprise a plurality of cascaded stages each configured to separate analytes as a function of the first analyte characteristic. Allowing the packet of analytes to separate may comprise allowing the packet of analytes to separate as a function of the first analyte characteristic in one or more of the cascaded stages.
  • the method may further comprise activating at least some of the analytes within the analyte separation instrument. Activating at least some of the analytes in the analyte separation instrument may comprise fragmenting at least some of the analytes in the analyte separation instrument. Alternatively or additionally, activating at least some of the analytes in the analyte separation instrument may comprise inducing conformational changes in at least some of the analytes without fragmenting the at least some of the analytes.
  • the analyte separation instrument may be an ion mobility spectrometer, the packet of a mixture of analytes may be a packet of a mixture of ions, and the first analyte characteristic may be ion mobility. Each of the plurality of discrete ion groups may have a different range of ion mobilities.
  • the analyte separation instrument may further comprise a liquid chromatograph having an inlet configured to receive analytes exiting the ion mobility spectrometer. The liquid chromatograph may be configured to separate analytes as a function of analyte retention time. An analyte detector may be positioned to detect analytes exiting the liquid chromatograph.
  • the method may further comprise processing the analyte detection signals produced by the analyte detector to determine multi-dimensional analyte separation information.
  • the liquid chromatograph may include a first gate that is controllable to allow or inhibit entrance of analytes into the inlet of the liquid chromatograph, and a second gate that is separated by a distance from the first gate and that is controllable to allow or inhibit passage of analytes therethrough.
  • the method may further comprise activating the first gate of the liquid chromatograph to allow entrance of selected analytes from the ion mobility spectrometer therein, allowing the selected analytes to separate between the first and second gates of the liquid chromatograph as a function of the analyte retention time, and activating the second gate of the liquid chromatograph at a plurality of successive discrete time periods after activating the first gate of the liquid chromatograph and before reactivating the first gate of the liquid chromatograph to allow passage therethrough - A -
  • the method may further comprise repeatedly activating the first gate of the liquid chromatograph, allowing the selected analytes to separate between the first and second gates of the liquid chromatograph and activating the second gate of the liquid chromatograph 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 liquid chromatograph, to each of the times at which the second gate of the liquid chromatograph is activated.
  • the analyte separation instrument may further comprise a gas chromatograph having an inlet configured to receive analytes exiting the ion mobility spectrometer.
  • the gas chromatograph may be configured to separate analytes as a function of analyte retention time.
  • An analyte detector may be positioned to detect analytes exiting the gas chromatograph.
  • the method may further comprise processing the analyte detection signals produced by the analyte detector to determine multi-dimensional analyte separation information.
  • the gas chromatograph may includes a first gate that is controllable to allow or inhibit entrance of analytes into the inlet of the gas chromatograph, and a second gate that is separated by a distance from the first gate and that is controllable to allow or inhibit passage of analytes therethrough.
  • the method may further comprise activating the first gate of the gas chromatograph to allow entrance of selected analytes from the ion mobility spectrometer therein, allowing the selected analytes to separate between the first and second gates of the gas chromatograph as a function of the analyte retention time, and activating the second gate of the gas chromatograph at a plurality of successive discrete time periods after activating the first gate of the gas chromatograph and before reactivating the first gate of the gas chromatograph to allow passage therethrough of a corresponding plurality of discrete groups of analytes separated from each of other according to the analyte retention time.
  • the method may further comprise repeatedly activating the first gate of the gas chromatograph, allowing the selected analytes to separate between the first and second gates of the gas chromatograph and activating the second gate of the gas chromatograph 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 gas chromatograph, to each of the times at which the second gate of the gas chromatograph is activated.
  • the analyte separation instrument may further comprise a capillary electrophoresis instrument having an inlet configured to receive ions exiting the ion mobility spectrometer.
  • the capillary electrophoresis instrument may be configured to separate ions as a function of ion charge-to-size ratio or electrophoretic mobility.
  • An ion detector may be positioned to detect ions exiting the capillary electrophoresis instrument.
  • the method may further comprise processing the ion detection signals produced by the ion detector to determine multi-dimensional ion separation information.
  • the capillary electrophoresis instrument may include a first gate that is controllable to allow or inhibit entrance of ions into the inlet of the capillary electrophoresis instrument, 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.
  • the method may further comprise activating the first gate of the capillary electrophoresis instrument to allow entrance of one of the plurality of discrete ion groups exiting the ion mobility spectrometer therein, allowing the one of the plurality of discrete ions groups to separate between the first and second gates of the capillary electrophoresis instrument as a function of the charge-to-size ratio or electrophoretic mobility, and activating the second gate of the capillary electrophoresis instrument at a plurality of successive discrete time periods after activating the first gate of the capillary electrophoresis instrument and before reactivating the first gate of the capillary electrophoresis instrument to allow passage therethrough of a corresponding plurality of discrete groups of ions separated from each of other according to the charge-to-size ratio or electrophoretic mobility.
  • the method may further comprise repeatedly activating the first gate of the capillary electrophoresis instrument, allowing the one of the plurality of discrete ion groups to separate between the first and second gates of the capillary electrophoresis instrument and activating the second gate of the capillary electrophoresis instrument 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 capillary electrophoresis instrument, to each of the times at which the second gate of the capillary electrophoresis instrument is activated.
  • the analyte separation instrument may further comprise another ion mobility spectrometer having an inlet configured to receive ions exiting the ion mobility spectrometer.
  • the another ion mobility spectrometer may be configured to separate ions as another function of ion mobility.
  • An ion detector may be positioned to detect ions exiting the another ion mobility spectrometer.
  • the method may further comprise processing the ion detection signals produced by the ion detector to determine multi-dimensional ion separation information.
  • the another ion mobility spectrometer may include a first gate that is controllable to allow or inhibit entrance of ions into the inlet of the another ion mobility spectrometer, 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.
  • the method may further comprise activating the first gate of the another ion mobility spectrometer to allow entrance of one of the plurality of discrete ion groups exiting the ion mobility spectrometer therein, allowing the one of the plurality of discrete ions groups to separate between the first and second gates of the another ion mobility spectrometer according to the another function of ion mobility, and activating the second gate of the another ion mobility spectrometer at a plurality of successive discrete time periods after activating the first gate of the another ion mobility spectrometer and before reactivating the first gate of the another ion mobility spectrometer to allow passage therethrough of a corresponding plurality of discrete groups of ions separated from each of other according to the another function of ion mobility.
  • the method may further comprise repeatedly activating the first gate of the another ion mobility spectrometer, allowing the one of the plurality of discrete ion groups to separate between the first and second gates of the another ion mobility spectrometer and activating the second gate of the another ion mobility spectrometer 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 another ion mobility spectrometer, to each of the times at which the second gate of the another ion mobility spectrometer is activated.
  • the analyte separation instrument may be an ion separation instrument configured to separate ions as a function of ion mass-to-charge ratio
  • the packet of a mixture of analytes may be a packet of a mixture of ions
  • the first analyte characteristic may be ion mass-to-charge ratio.
  • Each of the plurality of discrete ion groups may have a different range of ion mass-to-charge ratios.
  • the analyte separation instrument may further comprise a liquid chromatograph having an inlet configured to receive analytes exiting the ion separation instrument. The liquid chromatograph may be configured to separate analytes as a function of analyte retention time.
  • An analyte detector may be positioned to detect analytes exiting the liquid chromatograph.
  • the method may further comprise processing the analyte detection signals produced by the analyte detector to determine multi-dimensional analyte separation information.
  • the analyte separation instrument may further comprise a gas chromatograph having an inlet configured to receive analytes exiting the ion separation instrument.
  • the gas chromatograph may be configured to separate analytes as a function of analyte retention time.
  • An analyte detector may be positioned to detect analytes exiting the gas chromatograph.
  • the method may further comprise processing the analyte detection signals produced by the analyte detector to determine multi-dimensional analyte separation information.
  • the analyte separation instrument may further comprise a capillary electrophoresis instrument having an inlet configured to receive ions exiting the ion separation instrument.
  • the capillary electrophoresis instrument may be configured to separate ions as a function of ion charge-to-size ratio or electrophoretic mobility.
  • An ion detector may be positioned to detect ions exiting the capillary electrophoresis instrument.
  • the method may further comprise processing the ion detection signals produced by the ion detector to determine multi-dimensional ion separation information.
  • the analyte separation instrument may further comprise another ion separation instrument having an inlet configured to receive ions exiting the ion separation instrument.
  • the another ion separation instrument may be configured to separate ions as another function of ion mass-to-charge ratio.
  • An ion detector may be positioned to detect ions exiting the another ion separation instrument.
  • the method may further comprise processing the ion detection signals produced by the ion detector to determine multi-dimensional ion separation information.
  • the analyte separation instrument may further comprise another analyte separation instrument having an inlet with a first gate that is controllable to allow or inhibit analytes into the another analyte separation instrument from the ion separation instrument, and a second gate that is separated by a distance from the first gate of the another analyte separation instrument and that is controllable to allow or inhibit passage of analytes therethrough.
  • the method may further comprise activating the first gate of the another analyte separation instrument to allow entrance of one of the plurality of discrete analyte groups exiting the ion separation instrument therein, allowing the one of the plurality of discrete analyte groups to separate between the first and second gates of the another analyte separation instrument according to a second analyte characteristic, and activating the second gate of the another analyte separation instrument at a plurality of successive discrete time periods after activating the first gate of the another analyte separation instrument and before reactivating the first gate of the another analyte separation instrument to allow passage therethrough of a corresponding plurality of discrete groups of analytes separated from each of other according to the second analyte characteristic.
  • the method may further comprise repeatedly activating the first gate of the another analyte separation instrument, allowing the one of the plurality of discrete analyte groups to separate between the first and second gates of the another analyte separation instrument and activating the second gate of the another analyte separation instrument 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 another analyte separation instrument, to each of the times at which the second gate of the another analyte separation instrument is activated.
  • the another analyte separation instrument may be one of a liquid chromatograph configured to separate analytes as a first function of analyte retention time, a gas chromatograph configured to separate analytes as a second function of analyte retention time, a capillary electrophoresis instrument configured to separate ions as a function of ion charge-to-size ratio or electrophoretic mobility, another ion separation instrument configured to separate ions as another function of ion mass-to-charge ratio and an ion mobility spectrometer configured to separate ions as a function of ion mobility.
  • the analyte separation instrument may be a liquid chromatograph configured to separate analytes as a function of analyte retention time, and the first analyte characteristic may be analyte retention time.
  • the analyte separation instrument may further comprise another liquid chromatograph having an inlet configured to receive analytes exiting the liquid chromatograph.
  • the another liquid chromatograph may be configured to separate analytes as another function of analyte retention time.
  • Ann analyte detector may be positioned to detect analytes exiting the another liquid chromatograph.
  • the method may further comprise processing the analyte detection signals produced by the analyte detector to determine multi-dimensional analyte separation information.
  • the analyte separation instrument may further comprise a gas chromatograph having an inlet configured to receive analytes exiting the liquid chromatograph.
  • the gas chromatograph may be configured to separate analytes as a function of analyte retention time.
  • An analyte detector may be positioned to detect analytes exiting the gas chromatograph.
  • the method may further comprise processing the analyte detection signals produced by the analyte detector to determine multi-dimensional analyte separation information.
  • the analyte separation instrument may further comprise a capillary electrophoresis instrument having an inlet configured to receive analytes exiting the liquid chromatograph.
  • the capillary electrophoresis instrument may be configured to separate ions as a function of ion charge-to-size ratio or electrophoretic mobility.
  • An ion detector may be positioned to detect ions exiting the capillary electrophoresis instrument.
  • the method may further comprise processing the ion detection signals produced by the ion detector to determine multi-dimensional ion separation information.
  • the analyte separation instrument may further comprise an ion mobility spectrometer having an inlet configured to receive analytes exiting the liquid chromatograph.
  • the ion mobility spectrometer may be configured to separate ions as a function of ion mobility.
  • An ion detector may be positioned to detect ions exiting the ion mobility spectrometer.
  • the method may further comprise processing the ion detection signals produced by the ion detector to determine multi-dimensional ion separation information.
  • the analyte separation instrument may further comprise an ion separation instrument having an inlet configured to receive analytes exiting the liquid chromatograph.
  • the ion separation instrument may be configured to separate ions as a function of ion mass-to-charge ratio.
  • An ion detector may be positioned to detect ions exiting the ion separation instrument.
  • the method may further comprise processing the ion detection signals produced by the ion detector to determine multi-dimensional ion separation information.
  • the analyte separation instrument may further comprise another analyte separation instrument having an inlet with a first gate that is controllable to allow or inhibit analytes into the another analyte separation instrument from the liquid chromatograph, and a second gate that is separated by a distance from the first gate of the another analyte separation instrument and that is controllable to allow or inhibit passage of analytes therethrough.
  • the method may further comprise activating the first gate of the another analyte separation instrument to allow entrance of one of the plurality of discrete analyte groups exiting the liquid chromatograph therein, allowing the one of the plurality of discrete analyte groups to separate between the first and second gates of the another analyte separation instrument according to a second analyte characteristic, and activating the second gate of the another analyte separation instrument at a plurality of successive discrete time periods after activating the first gate of the another analyte separation instrument and before reactivating the first gate of the another analyte separation instrument to allow passage therethrough of a corresponding plurality of discrete groups of analytes separated from each of other according to the second analyte characteristic.
  • the method may further comprise repeatedly activating the first gate of the another analyte separation instrument, allowing the one of the plurality of discrete analyte groups to separate between the first and second gates of the another analyte separation instrument and activating the second gate of the another analyte separation instrument 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 another analyte separation instrument, to each of the times at which the second gate of the another analyte separation instrument is activated.
  • the another analyte separation instrument may be one of another liquid chromatograph configured to separate analytes as another function of analyte retention time, a gas chromatograph configured to separate analytes as yet another function of analyte retention time, a capillary electrophoresis instrument configured to separate ions as a function of ion charge-to-size ratio or electrophoretic mobility, an ion separation instrument configured to separate ions as a function of ion mass-to- charge ratio and an ion mobility spectrometer configured to separate ions as a function of ion mobility.
  • the analyte separation instrument may be a gas chromatograph configured to separate analytes as a function of analyte retention time, and the first analyte characteristic may be analyte retention time.
  • the analyte separation instrument may further comprise a liquid chromatograph having an inlet configured to receive analytes exiting the gas chromatograph.
  • the liquid chromatograph may be configured to separate analytes as another function of analyte retention time.
  • An analyte detector may be positioned to detect analytes exiting the liquid chromatograph.
  • the method may further comprise processing the analyte detection signals produced by the analyte detector to determine multi-dimensional analyte separation information.
  • the analyte separation instrument may further comprise another gas chromatograph having an inlet configured to receive analytes exiting the gas chromatograph.
  • the another gas chromatograph may be configured to separate analytes as another function of analyte retention time.
  • An analyte detector may be positioned to detect analytes exiting the another gas chromatograph.
  • the method may further comprise processing the analyte detection signals produced by the analyte detector to determine multi-dimensional analyte separation information.
  • the analyte separation instrument may further comprise a capillary electrophoresis instrument having an inlet configured to receive analytes exiting the gas chromatograph.
  • the capillary electrophoresis instrument may be configured to separate ions as a function of ion charge-to-size ratio or electrophoretic mobility.
  • An ion detector may be positioned to detect ions exiting the capillary electrophoresis instrument.
  • the method may further comprise processing the ion detection signals produced by the ion detector to determine multidimensional ion separation information.
  • the analyte separation instrument may further comprise an ion mobility spectrometer having an inlet configured to receive analytes exiting the gas chromatograph.
  • the ion mobility spectrometer may be configured to separate ions as a function of ion mobility.
  • An ion detector may be positioned to detect ions exiting the ion mobility spectrometer.
  • the method may further comprise processing the ion detection signals produced by the ion detector to determine multi-dimensional ion separation information.
  • the analyte separation instrument may further comprise an ion separation instrument having an inlet configured to receive analytes exiting the gas chromatograph.
  • the ion separation instrument may be configured to separate ions as a function of ion mass-to-charge ratio.
  • An ion detector may be positioned to detect ions exiting the ion separation instrument.
  • the method may further comprise processing the ion detection signals produced by the ion detector to determine multidimensional ion separation information.
  • the analyte separation instrument may further comprise another analyte separation instrument having an inlet with a first gate that is controllable to allow or inhibit analytes into the another analyte separation instrument from the gas chromatograph, and a second gate that is separated by a distance from the first gate of the another analyte separation instrument and that is controllable to allow or inhibit passage of analytes therethrough.
  • the method may further comprise activating the first gate of the another analyte separation instrument to allow entrance of one of the plurality of discrete analyte groups exiting the gas chromatograph therein, allowing the one of the plurality of discrete analyte groups to separate between the first and second gates of the another analyte separation instrument according to a second analyte characteristic, and activating the second gate of the another analyte separation instrument at a plurality of successive discrete time periods after activating the first gate of the another analyte separation instrument and before reactivating the first gate of the another analyte separation instrument to allow passage therethrough of a corresponding plurality of discrete groups of analytes separated from each of other according to the second analyte characteristic.
  • the method may further comprise repeatedly activating the first gate of the another analyte separation instrument, allowing the one of the plurality of discrete analyte groups to separate between the first and second gates of the another analyte separation instrument and activating the second gate of the another analyte separation instrument 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 another analyte separation instrument, to each of the times at which the second gate of the another analyte separation instrument is activated.
  • the another analyte separation instrument may be one of a liquid chromatograph configured to separate analytes as another function of analyte retention time, another gas chromatograph configured to separate analytes as yet another function of analyte retention time, a capillary electrophoresis instrument configured to separate ions as a function of ion charge-to- size ratio or electrophoretic mobility, an ion separation instrument configured to separate ions as a function of ion mass-to-charge ratio and an ion mobility spectrometer configured to separate ions as a function of ion mobility.
  • the analyte separation instrument may be a capillary electrophoresis instrument configured to separate ions as a function of ion charge-to- size ratio or electrophoretic mobility
  • the packet of a mixture of analytes may be a packet of a mixture of ions
  • the first analyte characteristic may be ion charge-to- size ratio or electrophoretic mobility.
  • Each of the plurality of discrete ion groups may have a different range of ion charge-to-size ratios or electrophoretic mobilities.
  • the analyte separation instrument may further comprise a liquid chromatograph having an inlet configured to receive analytes exiting the capillary electrophoresis instrument.
  • the liquid chromatograph may be configured to separate analytes as a function of analyte retention time.
  • An analyte detector may be positioned to detect analytes exiting the liquid chromatograph.
  • the method may further comprise processing the analyte detection signals produced by the analyte detector to determine multidimensional analyte separation information.
  • the analyte separation instrument may further comprise a gas chromatograph having an inlet configured to receive analytes exiting the capillary electrophoresis instrument.
  • the gas chromatograph may be configured to separate analytes as a function of analyte retention time.
  • An analyte detector may be positioned to detect analytes exiting the gas chromatograph.
  • the method may further comprise processing the analyte detection signals produced by the analyte detector to determine multi-dimensional analyte separation information.
  • the analyte separation instrument may further comprise another capillary electrophoresis instrument having an inlet configured to receive ions exiting the capillary electrophoresis instrument.
  • the another capillary electrophoresis instrument may be configured to separate ions as another function of ion charge-to-size ratio or electrophoretic mobility.
  • An ion detector may be positioned to detect ions exiting the capillary electrophoresis instrument.
  • the method may further comprise processing the ion detection signals produced by the ion detector to determine multi-dimensional ion separation information.
  • the analyte separation instrument may further comprise an ion mobility spectrometer having an inlet configured to receive ions exiting the capillary electrophoresis instrument.
  • the ion mobility spectrometer may be configured to separate ions as a function of ion mobility.
  • An ion detector may be positioned to detect ions exiting the ion mobility spectrometer.
  • the method may further comprise processing the ion detection signals produced by the ion detector to determine multi-dimensional ion separation information.
  • the analyte separation instrument may further comprise an ion separation instrument having an inlet configured to receive ions exiting the capillary electrophoresis instrument.
  • the ion separation instrument may be configured to separate ions as a function of ion mass-to-charge ratio.
  • An ion detector may be positioned to detect ions exiting the ion separation instrument.
  • the method may further comprise processing the ion detection signals produced by the ion detector to determine multi-dimensional ion separation information.
  • the analyte separation instrument may further comprise another analyte separation instrument having an inlet with a first gate that is controllable to allow or inhibit analytes into the another analyte separation instrument from the capillary electrophoresis instrument, and a second gate that is separated by a distance from the first gate of the another analyte separation instrument and that is controllable to allow or inhibit passage of analytes therethrough.
  • the method may further comprise activating the first gate of the another analyte separation instrument to allow entrance of one of the plurality of discrete analyte groups exiting the capillary electrophoresis instrument therein, allowing the one of the plurality of discrete analyte groups to separate between the first and second gates of the another analyte separation instrument according to a second analyte characteristic, and activating the second gate of the another analyte separation instrument at a plurality of successive discrete time periods after activating the first gate of the another analyte separation instrument and before reactivating the first gate of the another analyte separation instrument to allow passage therethrough of a corresponding plurality of discrete groups of analytes separated from each of other according to the second analyte characteristic.
  • the method may further comprise repeatedly activating the first gate of the another analyte separation instrument, allowing the one of the plurality of discrete analyte groups to separate between the first and second gates of the another analyte separation instrument and activating the second gate of the another analyte separation instrument 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 another analyte separation instrument, to each of the times at which the second gate of the another analyte separation instrument is activated.
  • the another analyte separation instrument may be one of a liquid chromatograph configured to separate analytes as a first function of analyte retention time, a gas chromatograph configured to separate analytes as a second function of analyte retention time, another capillary electrophoresis instrument configured to separate ions as another function of ion charge-to-size ratio or electrophoretic mobility, an ion separation instrument configured to separate ions as a function of ion mass-to-charge ratio and an ion mobility spectrometer configured to separate ions as a function of ion mobility.
  • FIG. 1 is a diagram illustrating an example analyte separation instrument.
  • FIG. 2 is a timing diagram illustrating operation of the analyte 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 intensity vs. ion drift time for a human hemoglobin tryptic digest sample illustrating operation of the analyte separation instrument of FIG. 1 in the form of a two-stage ion mobility spectrometer.
  • FIG. 1 a generalized analyte separation instrument 10 is illustrated.
  • the instrument 10 may take any of myriad forms.
  • the instrument 10 includes an analyte source 12 coupled to an inlet of an analyte separation instrument 14 (ASI) having an analyte outlet.
  • ASI an analyte separation instrument 14
  • the analyte separation instrument 14 is generally configured to separate analytes in time, in space or in time and space, as a function of at least one analyte characteristic.
  • the analyte source 12 may be conventional in construction, and may be configured to produce analytes in any known form including, but not limited to, neutrals, e.g., uncharged particles, and ions, e.g., charged particles. Examples of analyte sources that produce uncharged analytes include, but are not limited to, one or a combination of solutions, one or two-dimensional gels, and the like.
  • analyte sources 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 analyte source 12 may be integral with the analyte separation instrument 14.
  • the analyte source 12 may be or include one or more analysis instruments configured to separate analytes in time, space or both, as a function of one or more corresponding analyte characteristics.
  • the analyte separation instrument 14 has an analyte inlet gate, G 1 , which may be controlled to allow analytes from the analyte source 12 to enter the instrument 14 via its analyte inlet.
  • the analyte inlet gate, G 1 may be or include, for example, a grid, screen or other suitable structure that may be activated to allow charged analytes to pass therethrough, and that may be deactivated to inhibit passage therethrough of charged analytes.
  • the analyte inlet gate, G may be or include, for example, a flow valve or other suitable structure that may be activated to allow uncharged analytes to pass therethrough, and that may be deactivated to inhibit passage therethrough of uncharged analytes.
  • the analyte inlet gate, Gi may be located at, or integral with, the analyte inlet of the instrument 14, downstream of the analyte inlet of the instrument 14 (i.e., within the instrument 14) or in the analyte source 12.
  • the instrument 14 may have any number, F, of gates, wherein F may be any positive integer greater than 2.
  • the instrument 14 has an analyte outlet gate, Gp, which may be controlled to allow analytes to exit the active region of the instrument 14 via its analyte outlet.
  • Gp an analyte outlet gate
  • the analyte outlet gate, GF may be or include, for example, a grid, screen or other suitable structure that may be activated to allow charged analytes to pass therethrough, and that may be deactivated to inhibit passage of charged analytes therethrough.
  • the analyte outlet gate, GF may be or include, for example, a flow valve or other suitable structure that may be activated to allow uncharged analytes to pass therethrough, and that may be deactivated to inhibit passage of uncharged analytes therethrough.
  • the analyte outlet gate, GF may be located at, or integral with, the analyte outlet of the instrument 14, upstream of the analyte outlet of the instrument 14, (i.e., within the instrument 14) or downstream of the analyte outlet of the instrument 14 (i.e., outside of the instrument 14).
  • the analyte separation instrument is configured to separate analytes in time as a function of an analyte characteristic.
  • the analyte separation instrument 14 may be formed by cascading any number, F-I, of stages (Si - SF-O of equal or varying length each configured to separate analytes in time, space or both, as a function of an analyte characteristic, wherein F may be any positive integer greater than 1.
  • a total number of "F" analyte gates are included so that each stage of the instrument 14 has an analyte inlet gate and an analyte outlet gate.
  • Any one or more of the "F" stages may further include one or more additional analyte processing structures.
  • additional analyte processing structures include, but are not limited to, analyte focusing structures such as one or more conventional analyte focusing funnels, one or more analyte 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.
  • analyte activation refers to a process of inducing structural changes in analytes resulting from collisions of the analytes with a buffer gas or buffer gas mixture in the presence of a high AC and/or DC electric field. In the presence of sufficiently high electric fields, high energy collisions of analytes with the buffer gas or gas mixture result in fragmentation of at least some of the analytes. Analyte activation under sufficiently high electric fields thus corresponds to analyte fragmentation.
  • examples of implementations of the analyte separation instrument 14 include, but are not limited to, a conventional reverse phase chromatograph, such as a liquid chromatograph that includes all partition, absorption, ion exchange and affinity selections, configured to separate analytes as a function of analyte retention time, a conventional gas chromatograph configured to separate analytes as a function of analyte retention time, a conventional capillary electrophoresis instrument capable of all capillary electrophoresis separations including capillary electrochromatography and configured to separate analytes as a function of analyte charge-to-size ratio or electrophoretic mobility, a conventional mobility spectrometer, configured to separate analytes as a function of analyte mobility and a conventional mass analyzer configured to separate analytes in time as a function of analyte mass-to-charge ratio.
  • a conventional reverse phase chromatograph such as a liquid chromatograph that includes all partition, absorption, ion
  • Examples of conventional mobility spectrometers include, but are not limited to, single and multiple-stage ion mobility spectrometers, high-field asymmetric waveform ion mobility spectrometers (FAIMS) employing a constant compensation voltage, high-field asymmetric waveform ion mobility spectrometers (FAIMS) employing a differential compensation voltage, and the like.
  • Examples of conventional mass analyzers 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.
  • the instrument 10 may, in some embodiments, further include any number, G, of analyte processing instruments, APIi - APIQ, indicated by dashed-line representation generally in FIG. 1 at 16, that are located downstream of the analyte separation instrument 14 (i.e., after the analyte outlet of the instrument 14), where G may be any positive integer.
  • the number of analyte processing instruments 16 may be or include, for example, a conventional reverse phase chromatograph, such as a liquid chromatograph that includes all partition, absorption, ion exchange and affinity selections, configured to separate analytes as a function of analyte retention time, a conventional gas chromatograph configured to separate analytes as a function of analyte retention time, a conventional capillary electrophoresis instrument capable of all capillary electrophoresis separations including capillary electrochromatography and configured to separate analytes as a function of analyte charge-to-size ratio or electrophoretic mobility, a conventional mobility spectrometer configured to separate analytes as a function of analyte mobility and a conventional mass analyzer configured to separate analytes as a function of an
  • the number of analyte processing instruments 16 may be or include one or more conventional instruments configured to process analytes in a manner differently than separating analytes as a function of an analyte characteristic.
  • analyte processing instruments include, but are not limited to, a conventional analyte filter configured to collect and/or allow passage therethrough only of analytes within a predefined range of analyte mass-to-charge ratios, a conventional analyte trap configured to collect and selectively eject analytes, a conventional collision cell configured to fragment analytes, a conventional charge neutralization device configured to normalize various analyte charge states to a target charge state (e.g., to a +1 charge state).
  • Other conventional analyte processing instruments will occur to those skilled in the art, and any one or more such other conventional analyte processing instruments may be included in the analyte processing instrument 16.
  • the number of analyte processing instruments 16 may be or include a conventional reverse phase chromatograph, such as a liquid chromatograph that includes all partition, absorption, ion exchange and affinity selections, configured to separate analytes as a function of analyte retention time, a conventional gas chromatograph configured to separate analytes as a function of analyte retention time, a conventional capillary electrophoresis instrument capable of all capillary electrophoresis separations including capillary electrochromatography and configured to separate analytes as a function of analyte charge-to-size ratio or electrophoretic mobility and a conventional mobility spectrometer configured to separate analytes as a function of analyte mobility.
  • a conventional reverse phase chromatograph such as a liquid chromatograph that includes all partition, absorption, ion exchange and affinity selections, configured to separate analytes as a function of analyte retention time
  • a conventional gas chromatograph configured to separate analy
  • the instrument 10 further includes an analyte detector 18 that is positioned to receive analytes exiting the analyte separation instrument 14 in embodiments that do not include any of the analyte processing instruments 16, and that is positioned to receive analytes exiting the last of the one or more analyte processing instruments 16 in embodiments that include one or more such analyte processing instruments 16.
  • the analyte detector 18 may be a conventional analyte detector configured to produce analyte detection signals corresponding to arrival of analytes at the detector 18. Such signals are provided to a conventional processor 20 that is configured to process these signals and determine analyte separation information therefrom to determine single or multi-dimensional analyte separation information.
  • the analyte separation information will be one-dimensional analyte separation information, and in all other embodiments the analyte separation information will be multi-dimensional analyte separation information.
  • 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 gating sources 22 may alternatively or additionally include a number of conventional flow control mechanisms configured to control the flow of liquid and/or gas into and/or out of the various sections of the instrument 10 in a conventional manner.
  • the gating source 22 provides a number, H, of gating signals to the analyte source 12, where H may be any positive integer.
  • the voltage source 22 provides a number, J, of gating signals to the analyte separation instrument 14, where J may be any positive integer, and provides a number, K, of gating signals to the analyte processing instrument 16, where K may be any positive integer.
  • the gating signals may include AC, DC and/or pulsed voltages, and in the case of flow control mechanisms the gating signals may include conventional control signals for controlling operation of the flow control mechanisms.
  • the instrument 10 may, in some embodiments, 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 analyte separation instrument 14 and to the analyte processing instrument 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 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 analyte separation instrument 10 of FIG. 1 is shown. In one simplified implementation of the instrument 10, the analyte processing instrument 16 of FIG.
  • F an analyte inlet gate
  • Gi an analyte gate separated by a distance from Gi
  • G 2 an analyte gate separated by a distance from Gi
  • 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 24.
  • 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 analytes from the analyte source 12 are initially "gated" into the analyte separation instrument 14 by activating the gate Gj for a gate activation time period, TG IA> 34. Thereafter, the gate Gi is deactivated for a time period P GID - During the time period TG IA> analytes from the analyte source 12 enter the analyte separation instrument 14 through the gate Gi and the inlet of the analyte separation instrument 14, and into the first stage, S 1 , of the instrument 14. After entering the inlet of the analyte separation instrument 14, the analytes travel through Si toward the gate G 2 while separating as a function of an analyte characteristic.
  • the second gate, G 2 Upon the passage of a delay time, Tp, following activation of the first gate, Gi, 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 analyte groups to pass through the second gate, G 2, and into the second stage, S 2 , of the analyte separation instrument 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 analytes will thus be transmitted through the gate G 2 and into the second stage, S 2 , of the analyte separation instrument 14 where they will further separate as a function of the analyte characteristic.
  • 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 analytes through the second gate, G 2 .
  • the activation times, T A , 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.”
  • Analyte 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 P c where the gate G 2 is inactive have been spanned.
  • the plurality of successive discrete G 2 activation times i.e., the "teeth" of the comb
  • an offset time period, ⁇ is added to value of the most recent time delay value, TD, 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 + ⁇ .
  • an offset time period, ⁇ is again added to the value of the most recent time delay value, TD, 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 + 2 ⁇ .
  • This again shifts all of the "teeth" on the G 2 comb forward in time from their previous positions by an amount equal to the value of ⁇ or PR.
  • This process continues until the time period Pc is spanned by a sufficient number of successive additions to the delay time, TD, of the offset value ⁇ .
  • a flowchart is shown of one illustrative process 50 for operating the analyte separation instrument 14 as just described with respect to FIGS. 2 and 3.
  • 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 analytes 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 analytes in the subset of the entire range of analytes traveling through the instrument 14 that have the shortest travel time between the gates Gi and G 2 .
  • the delay time, T D 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 analytes traveling through the instrument 14 and/or the analytes are densely populated, e.g., tightly packed, in one or more analyte ranges or throughout the entire analyte range, it is desirable to select larger values of Pc so that manageable amounts of analyte separation information may be captured with each set of the plurality of successive discrete G 2 activation times.
  • the total amount of data captures will increase with increasing values of Pc as large values of Pc will generally necessitate a large number of subsequent, time-shifted sets of the plurality of successive discrete G 2 activation times.
  • the value of Pc will therefore generally be chosen based on a tradeoff between at least these concerns.
  • step 56 the gate G 2 activation time, T A , is determined.
  • T A the gate G 2 activation time
  • Selection of T A 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 T A will depend upon the desired peak resolution of the analyte separation information. Generally, T A will be selected to be a suitable value between these two limits.
  • the activation times, T A of the second gate, G 2 , are illustrated as being a constant, predefined value. It will be understood, however, that the activation times, T A , may alternatively change, e.g., increase or decrease, linearly between adjacent activations of the first gate, G ⁇ . Alternatively still, the activation times, T A , may change, e.g., increase or decrease, non-linearly between adjacent activations of the first gate, Gj. The extent to which such activation times, T A , change linearly or non-linearly will depend upon the type of analyte separation instrument(s) implemented in the instrument 10 and the underlying physics governing movement of analytes therethrough.
  • step 58 the resolution period, PR, or equivalently the offset time, ⁇ , is determined.
  • P R (or ⁇ ) 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 analyte separation range is captured with no overlap and no gaps between the information.
  • step 58 the process 50 advances to step 60 where 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.
  • REPS repetition value
  • 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, P c , between activations of the gate G 2 is periodic between T D + ⁇ and the next activation of the gate G 1 , 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.
  • the instrument 10 was essentially as described with respect to FIGS. 2 and 3. Specifically, the analyte processing instrument 16 was omitted, and the analyte separation instrument 14 was provided in the form of a two-stage ion mobility spectrometer. 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 analyte source 12. The first gate, G 1 , was positioned at the ion inlet of the ion mobility spectrometer 14 as illustrated in FIG.
  • the second gate, G 2 was separated by a first distance from the first gate, G 1
  • the final gate, G F was positioned at the ion outlet of the ion mobility spectrometer 14 and 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 detector 18 was positioned to receive ions exiting the final gate, G F , of the ion mobility spectrometer 14. 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 100 microseconds, and a period, Pc, between G 2 activations of approximately 1.0 millisecond, and with a total number of eight G 2 activations per comb.
  • the G2 comb teeth were then advanced in time by an offset value, ⁇ , of 100 microseconds, and a total of 11 combs were used to span Pc-
  • FIG. 5 shows a plot 80 of ion intensity (detected by the detector 18 of FIG. 1) 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 22-55 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 also shows a plot 82 of ion intensity vs. ion drift time with the second gate, G 2 , operated as a comb having eight teeth following the delay period, T D , as described above. As ions from this comb are allowed to diffuse through the rest of the instrument 14, the illustrated pulses diffuse into peaks, the shapes of which are defined by the total diffusion of each packet of ions.
  • FIG. 5 further shows a plot 84 of ion intensity vs. ion drift time with the second gate, G 2 , operated as second eight-tooth comb in which an offset time of approximately 100 microseconds is added to the delay time, T D .
  • each of the observed peaks corresponds to a slightly different distribution of ions, differing slightly in mobilities, as compared with the first comb.
  • ions from the second comb diffuse through the rest of the instrument 14, and the illustrated pulses diffuse into peaks having shapes defined by the total diffusion of each packet of ions.
  • the entire distribution of ions spanning each Pc is sampled. As shown in the last plot 86 of FIG. 5, the entire distribution of ions is sampled using 11 consecutive 8-tooth combs. It will be noted that the summation 86 of the 11 consecutive 8-tooth combs has a shape that is substantially similar to the original ion distribution 80.
  • operating the ion separation instrument 14 according to the combing technique described herein sends fewer ions out of the ion mobility instrument 14 at any one time than by operating the instrument 14 using conventional techniques. This technique provides for the ability to enhance peak detection by providing more space in each of the successive analyte groups to further separate in one or more downstream separation stages and/or instruments.
  • analyte separation instrument is disclosed with reference to the analyte separation instrument 14 of FIG. 1, it will be understood that this method may alternatively or additionally be implemented with any one or more analyte separation instrument included in the analyte source 12 and/or analyte processing instrument 16, and within one or multiple stages of the analyte separation instrument 14.
  • the combing technique described herein in the context of analyte separation in one dimension may thus extend to a "brush" technique where analytes may be separated using the combing technique in two or more dimensions.
  • another embodiment of the instrument 10 may comprise the analyte separation instrument 14 as just described, and also a single or multiple-stage analyte processing instrument 16 provided in the form of another analyte separation instrument.
  • the analyte separation instrument 14 may be operated using the combing technique just described, and the analyte separation instrument 16 may also be operated as a comb, i.e., using the combing technique described herein, to produce multi-dimensional ion separation information.
  • the analyte separation instrument 16 will have an inlet with a first gate that is controllable to allow or inhibit analytes into the analyte separation instrument 16 from the analyte separation instrument 14.
  • a second gate will be separated by a distance from the first gate of the analyte separation instrument 16, and this gate will be controllable as described above to allow or inhibit the passage of analytes therethrough.
  • the detector 18 will be positioned to detect analytes exiting the analyte separation instrument 16.
  • the first gate of the analyte separation instrument 16 is activated to allow entrance therein of consecutive ones of the plurality of discrete analyte groups exiting the analyte separation instrument 14.
  • the discrete analyte groups will then separate between the first and second gates of the analyte separation instrument 16 according to a second analyte characteristic.
  • the second gate of the analyte separation instrument 16 is activated at a plurality of successive discrete time periods after activating the first gate of the analyte separation instrument 16 and before reactivating the first gate of the analyte separation instrument 16 to allow passage therethrough of a corresponding plurality of discrete groups of analytes separated from each of other according to the second analyte characteristic.
  • the first gate of the analyte separation instrument 16 is repeatedly activated which allow the various discrete analyte groups to separate between the first and second gates of the analyte separation instrument 16, and between repeated activations of the first gate the second gate of the analyte separation instrument 16 is activated a plurality of times.
  • an offset time relative to activating the first gate of the analyte separation instrument 16 is consecutively added to each of the times at which the second gate of the analyte separation instrument 16 is activated.
  • the analyte separation instrument 16 may take the form of a liquid chromatograph configured to separate analytes as another function of analyte retention time, a gas chromatograph configured to separate analytes as yet another function of analyte retention time, a capillary electrophoresis instrument configured to separate ions as a function of ion charge-to-size ratio or electrophoretic mobility, an ion separation instrument configured to separate ions as a function of ion mass-to-charge ratio and an ion mobility spectrometer configured to separate ions as a function of ion mobility, in embodiments in which the analyte separation instrument 14 is any of a gas chromatograph, a liquid chromatograph, a capillary electrophoresis instrument and a mass
  • the analyte separation instrument 16 may take the form of a liquid chromatograph configured to separate analytes as another function of analyte retention time, a gas chromatograph configured to separate analytes as yet another function of analyte retention time, a capillary electrophoresis instrument configured to separate ions as a function of ion charge-to- size ratio or electrophoretic mobility and another ion mobility spectrometer configured to separate ions as another function of ion mobility.
  • analyte separation instrument 14 and analyte processing instruments 16 have been described herein as including at least first and second gates, it will be understood that such gates may in some embodiments be implanted in the form of actual gates as described above, or may instead be implemented in the form of two or more cascaded analysis instruments.
  • the instrument 10 may comprise a two-stage ion mobility spectrometer 14, followed by two cascaded capillary electrophoresis instruments.
  • the "gates" of the two- stage ion mobility spectrometer 14 may be provided in the form of actual gates, as described herein.
  • the first gate of the capillary electrophoresis instrument may correspond to an inlet gate of a first one of the cascaded capillary electrophoresis instruments
  • the second gate of the capillary electrophoresis instrument may correspond to the outlet gate of the first one of the cascaded capillary electrophoresis instruments, and/or the inlet gate of the second one of the cascaded capillary electrophoresis instruments.

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Abstract

L'invention concerne un procédé pour faire fonctionner un instrument de séparation de substances à analyser (10, 14). Cet instrument (10, 14) possède une première porte (G1) et une seconde porte (G2-GF) situées à une certaine distance l'une de l'autre. La première porte (G1) est activée pour permettre à un ensemble constitué d'un mélange de substances à analyser, provenant d'une source de substances à analyser (12), d'entrer dans ledit instrument. L'ensemble de substances à analyser peut être séparé entre la première et la seconde porte (G1, G2-GF) en fonction d'une première caractéristique des substances à analyser. La seconde porte (G2-GF) est activée à plusieurs périodes discrètes successives après l'activation de la première porte (G1) et avant la réactivation de cette première porte (G1) afin de permettre le passage d'une pluralité correspondante de groupes de substances à analyser discrets séparés les uns des autres en fonction de la première caractéristique des substances à analyser.
PCT/US2007/069963 2006-05-30 2007-05-30 Procédé pour faire fonctionner un instrument de séparation de substances à analyser Ceased WO2007140401A2 (fr)

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CN110687565A (zh) * 2019-09-20 2020-01-14 天津大学 一种用于x射线探测器的光生电荷的快速计算方法
CN110687565B (zh) * 2019-09-20 2023-01-20 天津大学 一种用于x射线探测器的光生电荷的快速计算方法

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