Apparatus and method for pulsed-mode charge detection mass spectrometry

Abstract

A charge detection mass spectrometer comprises: an ion trap configured to receive and store ions therein and to selectively release the stored ions therefrom; and an electrostatic linear ion trap (ELIT) spaced apart from the ion trap, the ELIT comprising a first ion mirror and a second ion mirror and a charge detection cylinder positioned therebetween; and a device for selectively controlling the ion trap to release at least some of the stored ions therefrom to travel toward and into the ELIT, and for controlling the first ion mirror and the second ion mirror in a manner that traps a single ion among the ions traveling therein in the ELIT and causes the trapped ion to oscillate back and forth between the first ion mirror and the second ion mirror each time the ion passes through the charge detection cylinder and induces a corresponding charge thereon.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This patent application claims the benefit of and priority to U.S. Provisional Patent Application Serial No. 62 / 905,921, filed on September 25, 2019, the disclosure of which is expressly incorporated herein by reference in its entirety.

[0003] Government Rights

[0004] This invention was made with government support under GM 131100 awarded by the National Institutes of Health. The government has certain rights in the invention. Technical Field

[0005] The present invention relates generally to charge detection mass spectrometry instruments and, more particularly, to apparatus and methods for performing pulsed mode operation of such instruments. Background Art

[0006] Mass spectrometry provides identification of the chemical components of a substance by separating its gaseous ions according to their mass and charge. A variety of instruments and techniques have been developed for determining the mass of such separated ions, and one such technique is known as charge detection mass spectrometry (CDMS). In CDMS, the mass of an ion is determined based on a measured mass-to-charge ratio of the ion (typically referred to as "m / z") and a measured charge of the ion.

[0007] The high level of uncertainty in m / z and charge measurements using early CDMS detectors led to the development of electrostatic linear ion trap (ELIT) detectors, in which ions are oscillated back and forth through a charge detection cylinder. Multiple passes of the ions through such a charge detection cylinder provide multiple measurements for each ion, and it has been shown that the uncertainty in the charge measurement increases with n. 1 / 2 and decreases, where n is the number of charge measurements. However, such multiple charge measurements necessarily limit the speed at which ion m / z and charge measurements can be obtained using current ELIT designs. Therefore, it is desirable to seek improvements in ELIT design and / or operation that increase the rate of ion m / z and charge measurements (relative to those that can be obtained using current ELIT designs). Summary of the invention

[0008] The present invention may include one or more of the features recited in the attached claims, and / or one or more of the following features and their combinations. In one aspect, a charge detection mass spectrometer may include: an ion source configured to generate ions from a sample; an ion trap configured to receive and store the generated ions therein and selectively release the stored ions therefrom; an electrostatic linear ion trap (ELIT) spaced from the ion trap, the ELIT comprising a first ion mirror and a second ion mirror and a charge detection cylinder positioned therebetween; and a device for selectively controlling the ion trap to release at least some of the stored ions therefrom to travel toward and into the ELIT, and for controlling the first ion mirror and the second ion mirror in a manner that captures at least one of the ions traveling therein in the ELIT and causes at least one of the captured ions to oscillate back and forth between the first ion mirror and the second ion mirror each time it passes through the charge detection cylinder and induces a corresponding charge thereon.

[0009] In another aspect, a charge detection mass spectrometer may include: an ion source configured to generate ions from a sample; at least one voltage source configured to produce a plurality of output voltages; an ion trap coupled to a first set of the plurality of output voltages and configured to receive and store generated ions therein in response to its capture state, and to selectively release stored ions therefrom in response to its transmission state; an electrostatic linear ion trap (ELIT) spaced apart from the ion trap, the ELIT comprising a front ion mirror and a rear ion mirror and a charge detection cylinder positioned therebetween, the front ion mirror and the rear ion mirror each being coupled to a second set and a third set of the plurality of output voltages, respectively. group, and is configured to respond to its transmission state to cause ions to be transmitted therethrough, and is configured to respond to its reflection state to reflect ions entering therein from a charge detection cylinder back into the charge detection cylinder; and processing circuitry, which is used to control a first set of voltages to its transmission state to cause the ion trap to release at least some of the stored ions therefrom to travel toward the ELIT via a front ion mirror and into the ELIT, and thereafter to control a third set of voltages followed by a second set of voltages to its reflection state to capture at least one of the ions traveling therethrough and cause at least one trapped ion to oscillate back and forth between the front ion mirror and the rear ion mirror each time it passes through the charge detection cylinder and induces a corresponding charge thereon.

[0010] In yet another aspect, a method for operating a charge detection mass spectrometer is provided, the charge detection mass spectrometer comprising an electrostatic linear ion trap (ELIT) having a charge detection cylinder positioned between a front ion mirror and a rear ion mirror, the ion trap being spaced apart from the front ion mirror. The method may include: generating ions from a sample; storing the generated ions in an ion trap; controlling the ion trap to release at least some of the stored ions therefrom and to travel toward an ELIT via a front ion mirror and into the ELIT; after controlling the ion trap to release the stored ions, controlling a rear ion mirror to a reflective state in which the rear ion mirror reflects ions entering therein from a charge detection cylinder backward through the charge detection cylinder and toward the front ion mirror; and after controlling the rear ion mirror to its reflective state, controlling the front ion mirror to a reflective state in which the front ion mirror reflects ions entering therein from the charge detection cylinder backward through the charge detection cylinder and toward the rear ion mirror to capture at least one of the ions released from the ion trap in the ELIT, so that at least one trapped ion oscillates between the front ion mirror and the rear ion mirror each time it passes through the charge detection cylinder and induces a corresponding charge thereon. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 is a simplified diagram of an ion mass detection system including an embodiment of an electrostatic linear ion trap (ELIT) array having control and measurement components coupled thereto.

[0012] Figure 2A for Figure 1 A magnified view of an example ion mirror in an ion mirror of an ELIT array illustrated in FIG. 5 , wherein the mirror electrodes are controlled to generate an ion transport electric field within the example ion mirror.

[0013] Figure 2B for Figure 1 A magnified view of another example ion mirror in the ion mirror of the ELIT array illustrated in FIG. 5 , wherein the mirror electrodes are controlled to produce an ion reflecting electric field within the example ion mirror.

[0014] Figure 3 This is a simplified flow chart showing the control Figure 1 Example of a process for operation of an ELIT array to determine ion mass and charge information.

[0015] Figures 4A-4E show Figure 1 A simplified diagram of an ELIT array showing the Figure 3 The process illustrated in FIG. 1 is sequential control and operation of multiple ion mirrors.

[0016] Figure 5AA simplified block diagram of an embodiment of an ion separation instrument including any ELIT array illustrated and described herein and showing an example ion processing instrument which may form part of an ion source upstream of the ELIT array(s) and / or may be arranged downstream of the ELIT array(s) to further process the ions(s) leaving the ELIT array(s).

[0017] Figure 5B is a simplified block diagram of another embodiment of an ion separation instrument including any of the ELIT arrays illustrated and described herein and illustrating an example implementation combining a conventional ion processing instrument with any of the embodiments of the ion mass detection system illustrated and described herein.

[0018] Figure 6 is a simplified diagram of an ion mass detection system including another embodiment of an electrostatic linear ion trap (ELIT) array having control and measurement components coupled thereto.

[0019] Fig. 7A For the Figure 6 A simplified perspective view of an example embodiment of a single ion steering channel implemented in an ion steering channel array is shown in FIG.

[0020] Figure 7B For simplified perspective, the diagram Fig. 7A Example operating modes of the ion steering channel illustrated in FIG.

[0021] Figure 7C For simplified perspective, the diagram Fig. 7A Another example operating mode of the ion steering channel illustrated in FIG.

[0022] Figures 8A-8F for Figure 6 A simplified diagram of an ELIT array showing example control and operation of the ion steering channel array and the ELIT array.

[0023] Fig. 9 is a simplified diagram of an ion mass detection system including yet another embodiment of an electrostatic linear ion trap (ELIT) array having control and measurement components coupled thereto.

[0024] Fig.10 is a simplified diagram of an embodiment of a charge detection mass spectrometer instrument configured for operation in its pulsed mode.

[0025] Fig.11 For illustration Fig.10 A timing diagram of an example pulse mode operation of the instrument.

[0026] Fig. 12A The results for HBV T=4 capsid with sample concentrations of 10 µg / mL and 0.5 µg / mL are shown. Fig.10 CDMS mass distribution diagram measured by the instrument.

[0027] Fig. 12B is the concentration of the molecule during 10,000 capture events for the concentration range from 0.5 µg / mL to 10 µg / mL. Fig. 12A A logarithmic plot of the number of ions detected in the 3.8 MDa to 4.4 MDa mass window is shown in FIG.

[0028] Fig.13A The results for HBV T=4 capsid with 1 µg / mL protein concentration are shown. Fig.10 CDMS mass distribution plots measured by an instrument of , including distributions measured under normal (ie, non-pulsed) operation of the instrument and distributions measured under pulsed mode operation of the instrument as described herein.

[0029] Fig. 13B Shows something like Fig.13A , but with HBV T=4 capsids having protein concentrations of 0.05 µg / mL and 0.5 µg / mL.

[0030] Fig.14 The HBV capsid is shown with peaks due to T=3 capsid at about 3.0 MDa and T=4 capsid at 4.05 MDa. Fig.10 CDMS mass distribution plots measured for an instrument of , including distributions measured under normal (i.e., non-pulsed) operation of the instrument (wherein the protein concentration is 100 ug / ml) and distributions measured under pulsed mode operation of the instrument (wherein the protein concentration is 1 ug / ml).

[0031] Fig.15 A PCR product for pyruvate kinase (PK) solution is shown with peaks due to PK tetramer (230 kDa), octamer (460 kDa), dodecamer (690 kDa) and hexadecamer (920 kDa). Fig.10 CDMS mass distribution plots measured by an instrument, including distributions measured under normal (i.e., non-pulsed) operation of the instrument and including distributions measured under pulsed mode operation of the instrument, as described herein, wherein the delay time is adjusted to transmit tetramers and again to transmit octamers and dodecamers. DETAILED DESCRIPTION

[0032] For the purposes of promoting an understanding of the principles of the invention, reference will now be made to a number of illustrative embodiments shown in the drawings, and specific language will be used to describe the same.

[0033] The present disclosure relates to an electrostatic linear ion trap (ELIT) array comprising two or more ELITs or ELIT regions, and a device for controlling them so that at least two of the ELITs or ELIT regions are simultaneously operated to measure the mass-to-charge ratio and charge of at least one ion trapped therein. In this way, the rate of ion measurement is increased by a factor of two or more compared to a conventional single ELIT system, and a corresponding reduction in the total ion measurement time is achieved. In some embodiments, examples of which will be described below with respect to Figure 1-4E Described in detail, the ELIT array can be implemented in the form of two or more ELIT regions arranged in series (i.e., cascaded), and the ion mirrors at opposite ends of each of the two or more cascaded ELIT or ELIT regions are controlled to sequentially capture at least one ion in each ELIT or ELIT region, and are controlled to cause the (multiple) trapped ions in at least two of the ELIT or ELIT regions to oscillate back and forth simultaneously through corresponding charge detectors positioned therein to measure the mass-to-charge ratio and charge of the (multiple) trapped ions. In other embodiments, as will be described below with respect to Figure 6-10 As described in detail, the ELIT array can be implemented in the form of two or more ELITs arranged in parallel relative to each other. The ion steering array can be controlled to direct at least one ion sequentially or simultaneously into each of the parallel arranged ELITs, after which the two or more ELITs are controlled to cause the (multiple) trapped ions in at least two of the ELITs to oscillate back and forth simultaneously through the charge detectors in each corresponding ELIT to measure the mass-to-charge ratio and charge of the (multiple) trapped ions.

[0034] refer to Figure 1, ion mass detection system 10 is shown as including an embodiment of an electrostatic linear ion trap (ELIT) array 14 having control and measurement members connected thereto. In the illustrated embodiment, ion mass detection system 10 includes an ion source 12, which is operatively connected to the entrance of ELIT array 14. As will be described with respect to Fig. 5, ion source 12 illustratively includes any conventional device or equipment for generating ions from a sample, and may further include one or more devices and / or instruments for separating, collecting, filtering, splitting and / or standardizing ions according to one or more molecular characteristics. As an illustrative example (which should not be considered as limiting in any way), ion source 12 may include conventional electrospray ionization source, matrix-assisted laser desorption ionization (MALDI) source, etc., which are connected to the entrance of a conventional mass spectrometer. Mass spectrometer may be any conventional design, including, for example, but not limited to time-of-flight (TOF) mass spectrometer, reflectometer, Fourier transform ion cyclotron resonance (FTICR) mass spectrometer, quadrupole mass spectrometer, triple quadrupole mass spectrometer, sector magnetic mass spectrometer, etc. In any case, the ion outlet of the mass spectrometer is operatively coupled to the ion inlet of the ELIT array 14. The sample from which the ions are generated may be any biological or other material.

[0035] In the illustrated embodiment, the ELIT array 14 is illustratively provided in the form of a cascade (i.e., in series or end-to-end) arrangement of three ELITs or ELIT regions. Three separate charge detectors CD1, CD2, CD3 are each surrounded by corresponding ground cylinders GC1-GC3, and are operatively connected together by relative mirror electrodes. The first mirror electrode M1 is operatively positioned between the ion source 12 and one end of the charge detector CD1, the second mirror electrode M2 ​​is operatively positioned between the opposite end of the charge detector CD1 and one end of the charge detector CD2, the third mirror electrode M3 is operatively positioned between the opposite end of the charge detector CD2 and one end of the charge detector CD3, and the fourth mirror electrode is operatively positioned at the opposite end of the charge detector CD3. In the illustrated embodiment, each of the ion mirrors M1-M3 defines axially adjacent ion mirror regions R1, R2, and the ion mirror M4 illustratively defines a single ion mirror region R1. Illustratively, the region R2 of the first mirror electrode M1, the charge detector CD1, the region R1 and CD1 of the second mirror electrode M2, and the space between the mirror electrodes M1, M2 together define a first ELIT or ELIT region E1 of the ELIT array 14, the region R2 of the second mirror electrode M2, the charge detector CD2, the region R1 and CD2 of the third mirror electrode M3, and the space between the mirror electrodes M2, M3 together define a second ELIT or ELIT region E2 of the ELIT array 14, and the region R2 of the third mirror electrode M3, the charge detector CD3, the region R1 and CD3 of the mirror electrode M4, and the space between the mirror electrodes M3, M4 together define a third ELIT or ELIT region E3 of the ELIT array 14. It will be understood that in some alternative embodiments, the ELIT array 14 may include fewer cascaded ELITs or ELIT regions (e.g., two cascaded ELITs or ELIT regions), and in other alternative embodiments, the ELIT array 14 may include more cascaded ELITs or ELIT regions (e.g., four or more cascaded ELITs or ELIT regions). The construction and operation of any such alternative ELIT array 14 will generally follow Figure 1-4E The construction and operation of the embodiments are illustrated in and described below.

[0036] In the illustrated embodiment, four corresponding voltage sources V1-V4 are electrically connected to ion mirrors M1-M4, respectively. Each voltage source V1-V4 illustratively includes one or more switchable DC voltage sources that can be controlled or programmed to selectively generate a number N of programmable or controllable voltages, where N can be any positive integer. Figure 2A and Figure 2BIllustrative examples of such voltages are described to establish one of two different operating modes for each ion mirror M1-M4, either individually and / or together, as will be described in detail below. In any case, a longitudinal axis 24 extends centrally through the charge detectors CD1-CD3 and the ion mirrors M1-M4, and the central axis 24 defines an ideal path of travel along which ions move within the ELIT array 14 and portions thereof under the influence of the electric fields selectively established by the voltage sources V1-V4.

[0037] The voltage sources V1-V4 are illustratively shown as being electrically connected to a conventional processor 16 including a memory 18 by a number P of signal paths, the memory 18 having instructions stored therein, which, when executed by the processor 16, cause the processor 16 to control the voltage sources V1-V4 to generate a desired DC output voltage for selectively establishing an electric field in regions R1, R2 of the corresponding ion mirrors M1-M4. P may be any positive integer. In some alternative embodiments, one or more of the voltage sources V1-V4 may be programmable to selectively generate one or more constant output voltages. In other alternative embodiments, one or more of the voltage sources V1-V4 may be configured to generate one or more time-varying output voltages of any desired shape. It will be understood that in alternative embodiments, more or fewer voltage sources may be electrically connected to the mirror electrodes M1-M4.

[0038] Each charge detector CD1-CD3 is electrically connected to a signal input of a corresponding one of the three charge sensitive preamplifiers CP1-CP3, and a signal output of each charge preamplifier CP1-CP3 is electrically connected to the processor 16. Each of the charge preamplifiers CP1-CP3 can illustratively operate in a conventional manner to receive a detection signal detected by a corresponding one of the charge detectors CD1-CD3 to generate a charge detection signal corresponding thereto and supply the charge detection signal to the processor 16. The processor 16 can then illustratively operate to receive and digitize the charge detection signal generated by each of the charge preamplifiers CP1-CP3, and store the digitized charge detection signal in the memory 18. The processor 16 is further illustratively connected to one or more peripheral devices 20 (PD), which are used to provide (multiple) signal inputs to the processor 16, and / or the processor 16 provides (multiple) signal outputs to the one or more peripheral devices 20 (PD). In some embodiments, the peripheral device 20 includes at least one of a conventional display monitor, a printer, and / or other output device, and in such embodiments, the memory 18 has instructions stored therein that, when executed by the processor 16, cause the processor 16 to control one or more such output peripheral devices 20 to display and / or record an analysis of the stored, digitized charge detection signal. In some embodiments, a conventional microchannel plate (MP) detector 22 may be disposed at the ion exit of the ELIT array 14, i.e., at the ion exit of the ion mirror M4, and electrically connected to the processor 16. In such embodiments, the microchannel plate detector 22 is operable to supply a detection signal to the processor 16, the detection signal corresponding to the detected ions and / or neutrals.

[0039] As will be described in more detail below, the voltage sources V1-V4 are illustratively controlled in a manner that causes ions to be introduced from the ion source 12 into the ELIT array 14 and to selectively capture and confine at least one ion to oscillate within each of three separate ELIT or ELIT regions E1-E3, such that each (multiple) trapped ion repeatedly passes through a corresponding one of the charge detectors CD1-CD3 in a corresponding one of the three ELIT or ELIT regions E1-E3. Multiple charge and oscillation period values ​​are measured at each charge detector CD1-CD3, and the recorded results are processed to determine the mass-to-charge ratio and mass value of the (multiple) ions captured in each of the three ELIT or ELIT regions E1-E3. Depending on many factors (including but not limited to the size of the three ELIT or ELIT regions E1-E3, the ion oscillation frequency, and the residence time of the ions in each of the three ELIT or ELIT regions E1-E3), the (multiple) trapped ions oscillate simultaneously in at least two of the three ELIT or ELIT regions E1-E3, and in a typical embodiment, oscillate simultaneously in each of the three ELIT or ELIT regions E1-E3, so that ion charge and mass-to-charge ratio measurements can be collected simultaneously from at least two of the three ELIT or ELIT regions E1-E3.

[0040] Reference now Figure 2A and Figure 2B , showing Figure 1 An embodiment of one of the ion mirrors MX of the ELIT array 14, where X=1-4, illustrates an example construction and operation of the embodiment. Figure 2A and Figure 2B In each of the illustrated ion mirrors, the illustrated ion mirror MX comprises a cascade arrangement of seven spaced apart conductive mirror electrodes. For each of the ion mirrors M2-M4, the first electrode 301 is formed by a grounded cylinder GC X-1 Formation, ground cylinder GC X-1 Around the charge detector CD X-1 On the other hand, the first electrode 301 of the ion mirror M1 is formed by the ion outlet of the ion source 12 (IS), or as part of the ion focusing or conversion stage between the ion source 12 and the ELIT array 14. Figure 2B The former is shown in the figure, and Figure 2A The latter is shown. In either case, the first mirror electrode 301 defines an aperture A1 centrally therethrough, which serves as an ion inlet and / or outlet to and from the corresponding ion mirror MX. The aperture A1 is illustratively conical in shape, which is located at the GC X-1 or between the inner and outer surfaces of the IS from the limit in the GC X-1 The first diameter P1 at the inner face of the IS increases linearly to X-1Or the enlarged diameter P2 at the outer face of IS. The first mirror electrode 301 illustratively has a thickness of D1.

[0041] The second mirror electrode 302 of the ion mirror MX is spaced apart from the first mirror electrode 301 and defines a passage through it of diameter P2. The third mirror electrode 303 is spaced apart from the second mirror electrode 302 and also defines a passage through it of diameter P2. The second mirror electrode 302 and the third mirror electrode 303 illustratively have equal thicknesses of D2 (D2≥D1). The fourth mirror electrode 304 is spaced apart from the third mirror electrode 303. The fourth mirror electrode 304 defines a passage through it of diameter P2 and illustratively has a thickness D3 (D3≈3D2). The plate or grid 30A is illustratively positioned centrally within the passage of the fourth mirror electrode 304 and defines a central aperture CA through it of diameter P3. In the illustrated embodiment, P3<P1, however in other embodiments, P3 may be greater than or equal to P1. The fifth mirror electrode 305 is spaced apart from the fourth mirror electrode 304, and the sixth mirror electrode 306 is spaced apart from the fifth mirror electrode 305. Illustratively, the fifth mirror electrode 305 and the sixth mirror electrode 306 are identical to the third mirror electrode 303 and the second mirror electrode 302 , respectively.

[0042] For each of the ion mirrors M1-M3, the seventh mirror electrode 307 is formed by a grounded cylinder GC X Formation, ground cylinder GC X Around the charge detector CD X ion mirror M4 is the last in the sequence. In either case, the seventh mirror electrode 307 defines an aperture A2 passing centrally therethrough, which serves as an ion inlet and / or outlet for ions to and from the ion mirror MX. The aperture A2 is illustratively a mirror image of the aperture A1 and has a conical shape, which is located in the GC. X The outer and inner surfaces of the X The enlarged diameter P2 at the outer surface of GC decreases linearly to X The seventh mirror electrode 307 illustratively has a thickness of D1. In some embodiments, as shown by Figure 1 2, the last ion mirror in the sequence (i.e., M4 in FIG. 2) may terminate at plate or grid 30A, such that M4 includes only mirror electrodes 301-303 and only a portion of mirror electrode 304 (including plate or grid 30A). In such an embodiment, the central aperture CA of M4 defines an ion exit path from ELIT array 14.

[0043] The mirror electrodes 301-307 are illustratively equally spaced from each other by spaces S1. In some embodiments, such spaces S1 between the mirror electrodes 301-307 may be voids (i.e., vacuum gaps), and in other embodiments, such spaces S1 may be filled with one or more non-conductive materials (e.g., dielectric materials). The mirror electrodes 301-307 are axially aligned (i.e., co-linear) such that the longitudinal axis 24 passes centrally through each aligned passage and also passes centrally through the apertures A1, A2, and CA. In embodiments in which the spaces S1 include one or more non-conductive materials, such materials will also define corresponding passages therethrough that are axially aligned (i.e., co-linear) with the passages defined by the mirror electrodes 301-307 and have a diameter of P2 or greater.

[0044] In each of the ion mirrors M1-M4, region R1 is defined between aperture A1 of the mirror electrode 301 and a central aperture CA defined by the plate or grid 30A. In each of the ion mirrors M1-M3, an adjacent region R2 is defined between a central aperture CA defined by the plate or grid 30A and an aperture A2 of the mirror electrode 307.

[0045] Within each ELIT or ELIT region E1-E3, a respective charge detector CD1-CD3 (each in the form of an elongated conductive cylinder) is positioned and spaced apart by a space S2 between corresponding ones of the ion mirrors M1-M4. Illustratively, S2>S1, however in alternative embodiments, S2 may be less than or equal to S2. In any case, each charge detection cylinder CD1-CD3 illustratively defines an axial passage through it of diameter P4, and each charge detection cylinder CD1-CD3 is oriented relative to the ion mirrors M1-M4 so that the longitudinal axis 24 extends centrally through its passage. In the illustrated embodiment, P1<P4<P2, however in other embodiments, the diameter of P4 may be less than or equal to P1, or greater than or equal to P2. Each charge detection cylinder CD1-CD3 is illustratively disposed within a field-free region of a corresponding one of the ground cylinders GC1-GC3, and each ground cylinder GC1-GC3 is positioned between and forms part of a corresponding one of the ion mirrors M1-M4, as described above. In operation, the ground cylinders GC1-G3 are illustratively controlled to ground potential so that the first electrode 301 and the seventh electrode 307 are always at ground potential. In some alternative embodiments, one or both of the first electrode 301 and the seventh electrode 307 in one or more of the ion mirrors M1-M4 can be set to any desired DC reference potential, and in other alternative embodiments, one or both of the first electrode 301 and the seventh electrode 307 in one or more of the ion mirrors M1-M4 can be electrically connected to a switchable DC or other time-varying voltage source.

[0046] As briefly described above, the voltage sources V1-V4 are illustratively controlled in a manner that causes ions to be introduced from the ion source 12 into the ELIT array 14 and causes at least one ion to be selectively captured and confined to oscillate within each of three separate ELIT or ELIT regions E1-E3, so that each (multiple) captured ion repeatedly passes through a corresponding one of the charge detectors CD1-CD3 in a corresponding one of the three ELIT or ELIT regions E1-E3. At each time the corresponding (multiple) oscillating ions pass through the charge detectors CD1-CD3, the charge and oscillation period values ​​are measured at each charge detector CD1-CD3. The measured values ​​are recorded, and the recorded results are processed to determine the mass-to-charge ratio and mass value of the (multiple) ions captured in each of the three ELIT or ELIT regions E1-E3.

[0047] In each ELIT or ELIT region E1-E3 of the ELIT array 14, by controlling the voltage source V1-V4 to selectively establish ion transmission and ion reflection electric fields in the regions R1, R2 of the ion mirror M1-M4, at least one ion is captured and oscillates between the relative regions of the corresponding ion mirror M1-M4. In this regard, each voltage source VX is illustratively configured in one embodiment to generate seven DC voltages DC1-DC7, and is configured to supply each of the voltages DC1-DC7 to a corresponding one of the mirror electrodes 301-307 of the corresponding ion mirror MX. In some embodiments in which one or more of the mirror electrodes 301-307 will always be maintained at ground potential, one or more such mirror electrodes 301-307 may alternatively be electrically connected to the ground reference of the voltage supply source VX, and the corresponding one or more voltage outputs DC1-DC7 may be omitted. Alternatively or additionally, in embodiments in which any two or more of the mirror electrodes 301-307 are to be controlled to the same non-zero DC value, any such two or more mirror electrodes 301-307 may be electrically connected to a single one of the voltage outputs DC1-DC7, and redundant ones of the output voltages DC1-DC7 may be omitted.

[0048] If Figure 2A and Figure 2B As shown in the example diagram, by selective application of voltages DC1-DC7, each ion mirror MX is able to be in ion transmission mode ( Figure 2A ) and ion reflectance mode ( Figure 2B ) between the control, in this ion transmission mode ( Figure 2A ) in which the voltages DC1-DC7 generated by the voltage source VX establish an ion transmission electric field in each of the regions R1, R2 of the ion mirror MX. Figure 2B), the voltages DC1-DC7 generated by the voltage source VX establish an ion trapping or reflection electric field in each of the regions R1, R2 of the ion mirror MX. In the ion transmission mode, the voltages DC1-DC7 are selected to establish an ion transmission electric field TEF1 in the region R1 of the ion mirror MX, and are selected to establish another ion transmission electric field TEF2 in the region R2 of the ion mirror MX, as determined by Figure 2A . Illustratively, ion transport electric fields TEF1 and TEF2 are established to focus ions toward a central longitudinal axis 24 within the ion mirror MX so as to maintain a narrow ion trajectory about the axis 24 throughout the ELIT array 14, while also accelerating ions traveling in either direction through two regions R1, R2 of the ion mirror MX. In ion reflection mode, voltages DC1-DC7 are selected to establish an ion trapping or reflection electric field REF1 within region R1 of the ion mirror MX, and are selected to establish another ion trapping or reflection electric field REF2 within region R2 of the ion mirror MX, as determined by Figure 2B The example is illustrated in FIG. Illustratively, ion trapping or reflection electric fields REF2 and REF2 are established so as to cause one or more ions traveling axially toward the central aperture CA of MX to be reversed in direction and to be transmitted axially away from the central aperture CA by the reflection electric fields REF1, REF2 in the opposite direction. Each ion reflection electric field REF1, REF2 does this by first decelerating and stopping, i.e., capturing, one or more ions traveling to the corresponding regions R1, R2 of the ion mirror MX, and then accelerating such one or more ions in the opposite direction backward through the corresponding regions R1, R2, so that one or more ions travel away from the corresponding regions R1, R2 in the opposite direction, and one or more ions enter the corresponding regions R1, R2 from the opposite direction. Thus, along the central longitudinal axis 24 from the charge detection cylinder CD X-1 Ions travelling into region R1 of ion mirror MX are reflected by electric field REF1 back along central longitudinal axis 24 towards charge detection cylinder CD. X-1 ion mirrors M1-M4 are controlled to the ion transmission and reflection modes described above. It will be understood that the following values ​​of DC1-DC7 are provided by way of example only, and other values ​​of one or more of DC1-DC7 may alternatively be used.

[0049] Table I

[0050]

[0051] Reference now Figure 3 , showing a simplified flow chart of process 100, process 100 is used to control voltage sources V1-V4 to selectively and sequentially control ion mirrors M1-M4 between the transmission and reflection modes of ion mirrors M1-M4 described above, so that ions are introduced from ion source 12 into ELIT array 14, and then sequentially at least one ion is selectively captured and confined to oscillate within each of three separate ELIT or ELIT regions E1-E3, so that each (multiple) captured ion repeatedly passes through a corresponding one of charge detectors CD1-CD3 in a corresponding one of the three ELIT or ELIT regions E1-E3. Each time the corresponding (multiple) oscillating ions pass through charge detector CD1-CD3, the charge and oscillation period values ​​are measured and recorded at each charge detector CD1-CD3, and the ion mass value is then determined based on the recorded data. In the illustrated embodiment, process 100 is illustratively stored in memory 18 in the form of instructions, which, when executed by processor 16, cause processor 16 to perform the described functions. In alternative embodiments where one or more of the voltage sources V1-V4 are programmable independently of the processor 16, one or more aspects of the process 100 may be performed in whole or in part by one or more such programmable voltage sources V1-V4. However, for purposes of this disclosure, the process 100 will be described as being performed solely by the processor 16. With reference to FIGS. 4A-4E , the process 100 will be described as operating on one or more positively charged ions, however it will be understood that the process 100 may alternatively operate on one or more negatively charged particles.

[0052] Referring to FIG4A , process 100 begins at step 102, where processor 16 is operable to control voltage sources V1-V4 to set each voltage DC1-DC7 in a manner that causes all ion mirrors M1-M4 to operate in an ion transmission mode so that the transmission electric fields TEF1, TEF2 established in each respective region R1, R2 operate to accelerate ions and pass ions therethrough. In an exemplary embodiment, voltage sources V1-V4 are illustratively controlled at step 102 of process 100 to generate voltages DC1-DC7 according to a full-pass transmission mode as illustrated in Table I above. In any case, when each of voltage sources V1-V4 is set at step 102 to control ion mirrors M1-M4 to operate in an ion transmission mode, ions entering M1 from ion source 12 pass through all ion mirrors M1-M4 and all charge detectors CD1-CD3 and leave M4, as illustrated by the exemplary ion trajectory 50 depicted in FIG4A . Such control of ion mirrors M1-M4 to their respective transmission modes thus draws one or more ions from ion source 12 into and through the entire ELIT array 14, as shown in Figure 4A. The ion trajectory 50 depicted in Figure 4A may illustratively represent a single ion or a collection of ions.

[0053] After step 102, process 100 proceeds to step 104, where processor 16 is operable to pause and determine when to proceed to step 106. In one embodiment of step 102, the ELIT array 14 is illustratively controlled in a "random trapping mode" in which ion mirrors M1-M4 remain in their transmission mode for a selected period of time during which one or more ions generated by ion source 12 are expected to enter and travel through ELIT array 14. As a non-limiting example, the selected period of time that processor 16 spends at step 104 before moving to step 106 when operating in random trapping mode is approximately 1-3 milliseconds (ms), depending on the axial length of ELIT array 14 and the speed of ions entering ELIT array 14, however it will be understood that in other embodiments, such a selected period of time may be greater than 3 ms or less than 1 ms. Before the selected period of time has passed, process 100 follows the "no" branch of step 104 and loops back to the beginning of step 104. After the selected time period has elapsed, process 100 follows the "yes" branch of step 104 and proceeds to step 106. In some alternative embodiments of step 104, such as in embodiments including a microchannel plate detector 22, processor 16 may be configured to proceed to step 106 only after one or more ions are detected by detector 22, with or without an additional delay period, so as to ensure that the ions are transmitted through the ELIT array 14 before proceeding to step 106. In other alternative embodiments, the ELIT array 14 may illustratively be controlled by processor 16 in a "triggered capture mode" in which ion mirrors M1-M4 are maintained in their ion transmission mode until at least one ion is detected at charge detector CD3. Prior to such detection, process 100 follows the "no" branch of step 104 and loops back to the beginning of step 104. Detection of at least one ion at charge detector CD3 by processor 16 indicates that at least one ion has passed through charge detector CD3 toward ion mirror M4 and serves as a trigger event that causes processor 16 to follow the “yes” branch of step 104 and proceed to step 106 of process 100 .

[0054] After the "yes" branch of step 104 and referring to FIG. 4B, processor 16 can be operated at step 106 to control voltage source V4 to set its output voltage DC1-DC7 in a manner that changes or switches the operation of ion mirror M4 from an ion transmission mode of operation to an ion reflection mode of operation, in which an ion reflection electric field R41 is established within region R1 of M4. As described above, ion reflection electric field R41 operates to reflect one or more ions entering region R1 of M4 back toward ion mirror M3 (and through charge detector CD3), as described above with respect to Figure 2BDescribed. The output voltages DC1-DC7 generated by the voltage sources V1-V3, respectively, do not change at step 106, so that the ion mirrors M1-M3 are each maintained in the ion transmission mode. As a result, one or more ions traveling toward the ion mirror M4 in the ELIT array 14 are reflected back toward the ion mirror M3, and will be transmitted along the axis 24 toward the ion inlet of M1, as illustrated by the ion trajectory 50 illustrated in FIG. 4B.

[0055] After step 106, process 100 proceeds to step 108, where processor 16 is operable to pause and determine when to proceed to step 110. In an embodiment of step 108 in which the ELIT array 14 is controlled by processor 16 in a random trapping mode, at step 108, ion mirrors M1-M3 remain in their transmission mode for a selected time period during which one or more ions may enter the ELIT or ELIT region E3. As a non-limiting example, the selected time period that processor 16 spends at step 108 before moving to step 110 when operating in random trapping mode is approximately 0.1 milliseconds (ms), however it will be understood that in other embodiments, such a selected time period may be greater than 0.1 ms or less than 0.1 ms. Before the selected time period has passed, process 100 follows the "no" branch of step 108 and loops back to the beginning of step 108. After the selected time period has passed, process 100 follows the "yes" branch of step 108 and proceeds to step 110. In an alternative embodiment of step 108 in which the ELIT array 14 is controlled by the processor 16 in a triggered capture mode, the ion mirrors M1-M3 are maintained in their ion transmission modes until at least one ion is detected at the charge detector CD3. Prior to such detection, the process 100 follows the "no" branch of step 108 and loops back to the beginning of step 108. The detection of at least one ion at the charge detector CD3 by the processor 16 ensures that at least one ion has moved through the charge detector CD3 and serves as a trigger event that causes the processor 16 to follow the "yes" branch of step 108 and proceed to step 110 of the process 100.

[0056] After the "yes" branch of step 108 and referring to Figure 4C, the processor 16 can be operated at step 110 to control the voltage source V3 to set its output voltage DC1-DC7 in the following manner: this manner changes or switches the operation of the ion mirror M3 from the ion transmission operation mode to the ion reflection operation mode, in which the ion reflection electric field R31 is established in the region R1 of M3, and the ion reflection electric field R32 is established in the region R2 of M3. As a result, at least one ion is trapped in the ELIT or ELIT region E3, and due to the reflection electric fields R32 and R41 established in the region R2 of the ion mirror M3 and the region R1 of the ion mirror M4, respectively, at least one trapped ion oscillates between M3 and M4 each time it passes through the charge detection cylinder CD3 (as illustrated by the ion trajectory 503 depicted in Figure 4C). Each time at least one ion passes through the charge detection cylinder CD3, it induces a charge on the cylinder CD3, which is detected by the charge preamplifier CP3 (see Figure 1 ). At step 112, as at least one ion oscillates back and forth between ion mirrors M3, M4 and passes through charge detection cylinder CD3, processor 16 is operable to record the amplitude and timing of each such CD3 charge detection event and store it in memory 18.

[0057] As described above, the ion reflection electric field R31 operates to reflect one or more ions entering region R1 of M3 back toward ion mirror M2 (and through charge detector CD2), as described above with respect to Figure 2B The output voltages DC1-DC7 generated by the voltage sources V1-V2, respectively, are not changed at steps 110 and 112, so that the ion mirrors M1-M2 are each maintained in the ion transmission mode. As a result, one or more ions traveling toward the ion mirror M3 in the ELIT array 14 are reflected back toward the ion mirror M2 and will be transmitted along the axis 24 toward the ion inlet of M1, as shown by the ion trajectory 50 illustrated in FIG. 4C. 1,2 Pictured.

[0058] After steps 110 and 112, process 100 proceeds to step 114, where processor 16 is operable to pause and determine when to proceed to step 116. In an embodiment of step 114 in which the ELIT array 14 is controlled by processor 16 in a random trapping mode, at step 114, ion mirrors M1-M2 remain in their transmission mode for a selected time period during which one or more ions may enter the ELIT or ELIT region E2. As a non-limiting example, the selected time period that processor 16 spends at step 114 before moving to step 116 when operating in a random trapping mode is approximately 0.1 milliseconds (ms), however it will be understood that in other embodiments, such a selected time period may be greater than 0.1 ms or less than 0.1 ms. Before the selected time period has passed, process 100 follows the "no" branch of step 114 and loops back to the beginning of step 108. After the selected time period has passed, process 100 follows the "yes" branch of step 114 and proceeds to step 116. In an alternative embodiment of step 114 in which the ELIT array 14 is controlled by the processor 16 in a triggered capture mode, the ion mirrors M1-M2 are maintained in their ion transmission mode until at least one ion is detected at the charge detector CD2. Prior to such detection, the process 100 follows the "no" branch of step 114 and loops back to the beginning of step 114. The detection of at least one ion at the charge detector CD2 by the processor 16 ensures that at least one ion moves through the charge detector CD2 and serves as a trigger event that causes the processor 16 to follow the "yes" branch of step 114 and proceed to step 116 of the process 100.

[0059] As described above, the ion reflection electric field R21 operates to reflect one or more ions entering region R1 of M2 back toward ion mirror M1 (and through charge detector CD1), as described above with respect to Figure 2B The output voltage DC1-DC7 produced by the voltage source V1 does not change at steps 116 and 118, so that the ion mirror M1 remains in the ion transmission mode. As a result, one or more ions traveling toward the ion mirror M2 in the ELIT array 14 are reflected back toward the ion mirror M1 and will be transmitted along the axis 24 toward the ion inlet of M1, as illustrated by the ion trajectory 501 illustrated in Figure 4D.

[0060] After the "yes" branch of step 114 and while at least one ion in the ELIT or ELIT region E3 continues to oscillate back and forth between ion mirrors M3 and M4 as it passes through the charge detection cylinder CD3, process 100 proceeds to step 116. Referring to FIG4D, processor 16 is operable at step 116 to control voltage source V2 to set its output voltage DC1-DC7 in a manner that changes or switches the operation of ion mirror M2 from an ion transmission mode of operation to an ion reflection mode of operation, in which an ion reflection electric field R21 is established within region R1 of M2 and an ion reflection electric field R22 is established within region R2 of M2. As a result, at least one ion is trapped within the ELIT or ELIT region E2, and due to the reflection electric fields R22 and R31 established within region R2 of ion mirror M2 and region R1 of ion mirror M3, respectively, at least one trapped ion oscillates between M2 and M3 each time it passes through charge detection cylinder CD2 (as illustrated by ion trajectory 502 depicted in FIG4D). Each time at least one ion passes through the charge detection cylinder CD2, it induces a charge on the cylinder CD2 which is detected by the charge preamplifier CP2 (see Figure 1 ). At step 118, as at least one ion oscillates back and forth between ion mirrors M2, M3 and passes through charge detection cylinder CD2, processor 16 is operable to record the amplitude and timing of each such CD2 charge detection event and store it in memory 18. Thus, after step 116, at least one ion passes through charge detection cylinder CD3 of ELIT or ELIT region E3 to oscillate back and forth between ion mirrors M3 and M4, and at the same time, at least another ion passes through charge detection cylinder CD2 of ELIT or ELIT region E2 to oscillate back and forth between ion mirrors M2 and M3.

[0061] After steps 116 and 118, process 100 proceeds to step 120, where processor 16 is operable to pause and determine when to proceed to step 122. In an embodiment of step 120 in which the ELIT array 14 is controlled by processor 16 in a random trapping mode, at step 120, ion mirror M1 is maintained in its transmission mode of operation for a selected time period during which one or more ions may enter the ELIT or ELIT region E1. As a non-limiting example, the selected time period that processor 16 spends at step 120 before moving to step 122 when operating in a random trapping mode is approximately 0.1 milliseconds (ms), however it will be understood that in other embodiments, such a selected time period may be greater than 0.1 ms or less than 0.1 ms. Before the selected time period has passed, process 100 follows the "no" branch of step 120 and loops back to the beginning of step 120. After the selected time period has passed, process 100 follows the "yes" branch of step 120 and proceeds to step 122. In an alternative embodiment of step 120 in which the ELIT array 14 is controlled by the processor 16 in a triggered capture mode, the ion mirror M1 is maintained in its ion transmission mode of operation until at least one ion is detected at the charge detector CD1. Prior to such detection, the process 100 follows the "no" branch of step 120 and loops back to the beginning of step 120. The detection of at least one ion at the charge detector CD1 by the processor 16 ensures that at least one ion has moved through the charge detector CD1 and serves as a trigger event that causes the processor 16 to follow the "yes" branch of step 120 and proceed to step 122 of the process 100.

[0062] After the "yes" branch of step 120, and while at least one ion in the ELIT or ELIT region E3 continues to oscillate back and forth between ion mirrors M3 and M4 through charge detection cylinder CD3, and while at least one other ion in the ELIT or ELIT region E2 simultaneously continues to oscillate back and forth between ion mirrors M2 and M3 through charge detection cylinder CD2, process 100 proceeds to step 122. Figure 4E , the processor 16 at step 122 is operable to control the voltage source V1 to set its output voltage DC1-DC7 in a manner that changes or switches the operation of the ion mirror M1 from the ion transmission operation mode to the ion reflection operation mode, in which the ion reflection electric field R11 is established in the region R1 of M1, and the ion reflection electric field R12 is established in the region R1 of M1. As a result, at least one ion is trapped in the ELIT or ELIT region E1, and due to the reflection electric fields R12 and R21 established in the region R2 of the ion mirror M1 and the region R2 of the ion mirror M2, respectively, at least one trapped ion is removed each time it passes through the charge detection cylinder CD1 (as indicated by Figure 4EEach time at least one ion passes through the charge detection cylinder CD1, it induces a charge on the cylinder CD1, which is detected by the charge preamplifier CP1 (see Figure 1 ). At step 124, as at least one ion oscillates back and forth between ion mirrors M1, M2 and passes through charge detection cylinder CD1, processor 16 is operable to record the amplitude and timing of each such CD1 charge detection event and store it in memory 18. Thus, after step 122, at least one ion passes through charge detection cylinder CD3 of ELIT or ELIT region E3 to oscillate back and forth between ion mirrors M3 and M4, and at the same time, at least one other ion passes through charge detection cylinder CD2 of ELIT or ELIT region E2 to oscillate back and forth between ion mirrors M2 and M3, and also at the same time, at least one more ion passes through charge detection cylinder CD1 of ELIT or ELIT region E1 to oscillate back and forth between ion mirrors M1 and M2.

[0063] After steps 122 and 124, process 100 proceeds to step 126, where processor 16 is operable to pause and determine when to proceed to step 128. In one embodiment, processor 16 is configured (i.e., programmed) to allow ions to simultaneously traverse the ELIT or each of the ELIT regions E1-E3 for a selected time period (i.e., total ion cycle measurement time), during which ion detection events (i.e., by each of charge detectors CD1-CD3) are recorded by processor 16. As a non-limiting example, the selected time period that processor 16 spends at step 126 before moving to step 128 is approximately 100-300 milliseconds (ms), however, it will be understood that in other embodiments, such a selected time period may be greater than 300 ms or less than 100 ms. Before the selected time period has passed, process 100 follows the "no" branch of step 126 and loops back to the beginning of step 126. After the selected time period has elapsed, process 100 follows the “yes” branch of step 126 and proceeds to steps 128 and 140. In some alternative embodiments of process 100, at step 126, voltage sources V1-V4 may illustratively be controlled by processor 16 to allow (multiple) ions to oscillate back and forth through charge detectors CD1-CD3 for a selected number of times (i.e., a total number of measurement cycles), during which ion detection events (i.e., by each of charge detectors CD1-CD3) are recorded by processor 16. Before the processor counts the selected number of ion detection events by one or more of charge detectors CD1-CD3, process 100 follows the “no” branch of step 126 and loops back to the beginning of step 126. The detection of the selected number of ion detection events by processor 16 serves as a trigger event, which causes processor 16 to follow the “yes” branch of step 126 and proceed to steps 128 and 140 of process 100.

[0064] Following the "yes" branch of step 126, the processor 16 at step 128 is operable to control the voltage sources V1-V4 to set respective output voltages DC1-DC7 in a manner that changes or switches the operation of all ion mirrors M1-M4 from an ion reflection mode of operation to an ion transmission mode of operation in which the ion mirrors M1-M4 are each operated to allow ions to pass therethrough. Illustratively, the voltage sources V1-V4 are illustratively controlled at step 128 of process 100 to generate voltages DC1-DC7 according to an all-pass transmission mode as illustrated in Table I above, which reestablishes the ion trajectory 50 illustrated in FIG. 4A, wherein (i) all ions within the ELIT array 14 are transmitted through and out of the ELIT array 14 under the influence of the ion transmission electric fields TEF1, TEF2 established in each of the ion mirrors M1-M4, and (ii) all ions entering M1 from the ion source 12 pass through all ion mirrors M1-M4 and all charge detectors CD1-CD3.

[0065] After step 128, the processor 16 can be operated to pause for a selected time period at step 130 to allow the ions contained within the ELIT array 14 to be transmitted away from the ELIT array 14. As a non-limiting example, the selected time period spent by the processor 12 at step 130 before looping back to step 102 to restart the process 100 is approximately 1-3 milliseconds (ms), however it will be understood that in other embodiments, such a selected time period may be greater than 3 ms or less than 1 ms. Before the selected time period has passed, the process 100 follows the "no" branch of step 130 and loops back to the beginning of step 130. After the selected time period has passed, the process 100 follows the "yes" branch of step 130 and loops back to step 102 to restart the process 100.

[0066] Also, after the "yes" branch of step 126, process 100 additionally proceeds to step 140 to analyze the data collected during steps 112, 118, and 124 of process 100 just described. In the illustrated embodiment, data analysis step 140 illustratively includes step 142, wherein processor 16 is operable to calculate a Fourier transform of the recorded grouped stored charge detection signals provided by each of charge preamplifiers CP1-CP3. Processor 16 is illustratively operable to perform step 142 using any conventional digital Fourier transform (DFT) technique, such as, for example, but not limited to, a conventional fast Fourier transform (FFT) algorithm. In any case, at step 142, the processor 16 is operable to calculate three Fourier transforms FT1, FT2 and FT3, wherein FT1 is the Fourier transform of the recorded group charge detection signal provided by the first charge preamplifier CP1 and therefore corresponds to the charge detection event detected by the charge detection cylinder CD1 of the ELIT or ELIT region E1, FT2 is the Fourier transform of the recorded group charge detection signal provided by the first charge preamplifier CP2 and therefore corresponds to the charge detection event detected by the charge detection cylinder CD2 of the ELIT or ELIT region E2, and FT3 is the Fourier transform of the recorded group charge detection signal provided by the first charge preamplifier CP3 and therefore corresponds to the charge detection event detected by the charge detection cylinder CD3 of the ELIT or ELIT region E3.

[0067] After step 142, process 100 proceeds to step 144, where processor 16 is operable to calculate three sets of ion mass-to-charge ratio values ​​(m / z1, m / z2, and m / z3), ion charge values ​​(z1, z2, and z3), and ion mass values ​​(m1, m2, and m3), each of which varies with a corresponding one of the calculated Fourier transform values ​​FT1, FT2, FT3). Thereafter, at step 146, processor 16 is operable to store the calculated results in memory 18 and / or control one or more of peripheral devices 20 to display the results for viewing and / or further analysis.

[0068] It is generally understood that the mass-to-charge ratio (m / z) of the ion(s) oscillating back and forth between opposing ion mirrors in any ELIT or ELIT regions E1-E3 is inversely proportional to the square of the fundamental frequency ff of the oscillating ions(s) according to the following equation:

[0069] m / z=C / ff 2 ,

[0070] where C is a constant that varies with the ion energy and also with the size of the corresponding ELIT or ELIT region, and the fundamental frequency ff is determined directly from the corresponding calculated Fourier transform. Thus, ff1 is the fundamental frequency of FT1, ff2 is the fundamental frequency of FT2, and ff3 is the fundamental frequency of FT3. Typically, C is determined using conventional ion trajectory simulations. In any case, the value of the ion charge z is related to the magnitude of the FT FT, taking into account the number of ion oscillation periods. MAG The ion mass m is then calculated as the product of m / z and z. Therefore, with respect to the recorded set of charge detection signals provided by the first charge preamplifier CP1, the processor 16 can be operated at step 144 to calculate m / z1=C / ff1 2 、z1=F(FT MAG1 ) and m1=(m / z1)(z1). With respect to the recorded group charge detection signal provided by the second charge preamplifier CP2, the processor 16 is similarly operable at step 144 to calculate m / z2=C / ff2 2 、z2=F(FT MAG2 ) and m2=(m / z2)(z2), and with respect to the recorded group charge detection signal provided by the third charge preamplifier CP3, the processor 16 is also operable at step 144 to calculate m / z3=C / ff3 2 、z3=F(FT MAG3 ) and m3=(m / z3)(z3).

[0071] Reference now Figure 5A , a simplified block diagram of an embodiment of an ion separation instrument 60 is shown, which may include any of the ELIT arrays 14, 205, 302 illustrated and described herein, and may include any of the ion mass detection systems 10, 200, 300 illustrated and described herein, and may include any number of ion processing instruments that may form part of the ion source 12 upstream of the ELIT array(s), and / or may include any number of ion processing instruments that may be disposed downstream of the ELIT array(s) to further process the ions(s) exiting the ELIT array(s). In this regard, the ion source 12 may be provided at Figure 5A The diagram in the figure shows a number Q of ion source stages IS1-IS Q , which may be or form part of the ion source 12. Alternatively or in addition, the ion processing instrument 70 may be Figure 5A 1 and 2. The ion processing apparatus 70 is shown as an ion outlet coupled to the ELIT array 14, 205, 302, wherein the ion processing apparatus 70 may include any number of ion processing stages OS1-OS2. R , where R can be any positive integer.

[0072] Focusing on the ion source 12, it will be understood that the ion source 12 entering the ELIT 10 may be or include ion source stages IS1-IS2. Q ion source 12 may include any conventional ion source in the form of one or more of the conventional ion sources (such as described above), and may further include one or more conventional instruments for separating ions according to one or more molecular properties (e.g., according to ion mass, ion mass-to-charge ratio, ion mobility, ion retention time, etc.), and / or one or more conventional ion processing instruments for collecting and / or storing ions (e.g., one or more quadrupoles, hexapole rods, and / or other ion traps), for filtering ions (e.g., according to one or more molecular properties (such as ion mass, ion mass-to-charge ratio, ion mobility, ion retention time, etc.)), for fragmenting or otherwise dissociating ions, for normalizing ion charge states, etc. It will be understood that ion source 12 may include one or any combination (in any order) of any such conventional ion sources, ion separation instruments, and / or ion processing instruments, and some embodiments may include multiple adjacent or spaced-apart such conventional ion sources, ion separation instruments, and / or ion processing instruments of any such conventional ion sources, ion separation instruments, and / or ion processing instruments.

[0073] Turning now to the ion processing instrument 70, it will be appreciated that the instrument 70 may be or include ion processing stages OS1-OS2. R One or more conventional instruments and / or one or more conventional ion processing instruments in the form of one or more of the foregoing, the one or more conventional instruments for separating ions according to one or more molecular properties (e.g., according to ion mass, ion mass-to-charge ratio, ion mobility, ion retention time, etc.), the one or more conventional ion processing instruments for collecting and / or storing ions (e.g., one or more quadrupoles, hexapole rods, and / or other ion traps), for filtering ions (e.g., according to one or more molecular properties (such as ion mass, ion mass-to-charge ratio, ion mobility, ion retention time, etc.)), for fragmenting or otherwise dissociating ions, for normalizing ion charge states, etc. It will be understood that the ion processing instrument 70 may include one or any combination (in any order) of any such conventional ion separation instruments and / or ion processing instruments, and some embodiments may include multiple adjacent or spaced-apart such conventional ion separation instruments and / or ion processing instruments of any such conventional ion separation instruments and / or ion processing instruments. In any embodiment including one or more mass spectrometers, any one or more such mass spectrometers may be arranged in the manner described above with respect to Figure 1 Any form of implementation described.

[0074] As Figure 5AIn one specific embodiment of the ion separation instrument 60 illustrated in FIG. 1 (which should not be considered limiting in any way), the ion source 12 illustratively includes 3 stages, and the ion processing instrument 70 is omitted. In this example embodiment, the ion source stage IS1 is a conventional ion source (e.g., electrospray, MALDI, etc.), the ion source stage IS2 is a conventional mass filter (e.g., a quadrupole or hexapole ion guide operated as a high-pass or bandpass filter), and the ion source stage IS3 is any type of mass spectrometer described above. In this embodiment, the ion source stage IS2 is controlled in a conventional manner to preselect ions with desired molecular characteristics for analysis by a downstream mass spectrometer, and only such preselected ions are passed to the mass spectrometer, where the ions analyzed by the ELIT array 14, 205, 302 will be the preselected ions separated by the mass spectrometer according to mass-to-charge ratio. The preselected ions leaving the ion filter may be, for example, ions having a specified ion mass or mass-to-charge ratio, ions having an ion mass or ion mass-to-charge ratio above and / or below a specified ion mass or ion mass-to-charge ratio, ions having an ion mass or ion mass-to-charge ratio within a specified ion mass or ion mass-to-charge ratio range, etc. In some alternative embodiments of this example, the ion source stage IS2 may be a mass spectrometer, and the ion source stage IS3 may be an ion filter, and the ion filter may be capable of operating in other ways as just described to preselect ions leaving the mass spectrometer that have desired molecular characteristics for analysis by the downstream ELIT array 14, 205, 302. In other alternative embodiments of this example, the ion source stage IS2 may be an ion filter, and the ion source stage IS3 may include a mass spectrometer followed by another ion filter, wherein the ion filters each operate as just described.

[0075] As Figure 5A In another specific embodiment of the ion separation instrument 60 illustrated in FIG. 1 (which should not be considered limiting in any way), the ion source 12 illustratively includes two stages, and the ion processing instrument 70 is omitted. In this example embodiment, the ion source stage IS1 is a conventional ion source (e.g., electrospray, MALDI, etc.), and the ion source stage IS2 is a conventional mass spectrometer of any type described above. This is in addition to the above description of Figure 1 An embodiment is described in which the ELIT array 14, 205, 302 is operable to analyze ions leaving a mass spectrometer.

[0076] As Figure 5AIn yet another specific embodiment of the ion separation instrument 60 illustrated in FIG. 1 (which should not be considered limiting in any way), the ion source 12 illustratively includes 2 stages, and the ion processing instrument 70 is omitted. In this example embodiment, the ion source stage IS1 is a conventional ion source (e.g., electrospray, MALDI, etc.), and the ion processing stage OS2 is a conventional single-stage or multi-stage ion mobility spectrometer. In this embodiment, the ion mobility spectrometer is operable to separate ions generated by the ion source stage IS1 over time according to one or more functions of ion mobility, and the ELIT array 14, 205, 302 is operable to analyze ions leaving the ion mobility spectrometer. In an alternative embodiment of this example, the ion source 12 may include only a single stage IS1 in the form of a conventional ion source, and the ion processing instrument 70 may include a conventional single-stage or multi-stage ion mobility spectrometer as a single stage OS1 (or as stage OS1 of a multi-stage instrument 70). In this alternative embodiment, the ELIT array 14, 205, 302 is operable to analyze ions generated by the ion source stage IS1, and the ion mobility spectrometer OS1 is operable to separate ions leaving the ELIT array 14, 205, 302 over time according to one or more functions of ion mobility. As another alternative embodiment of this example, a single-stage or multi-stage ion mobility spectrometer may be after both the ion source stage IS1 and the ELIT array 14, 205, 302. In this alternative embodiment, the ion mobility spectrometer after the ion source stage IS1 is operable to separate ions generated by the ion source stage IS1 over time according to one or more functions of ion mobility, the ELIT array 14, 205, 302 is operable to analyze ions leaving the ion source stage ion mobility spectrometer, and the ion mobility spectrometer of the ion processing stage OS1 after the ELIT array 14, 205, 302 is operable to separate ions leaving the ELIT array 14, 205, 302 over time according to one or more functions of ion mobility. In any implementation of the embodiments described in this paragraph, additional variations may include a mass spectrometer operatively positioned upstream and / or downstream of a single-stage or multi-stage ion mobility spectrometer in the ion source 12 and / or ion manipulation instrument 210 .

[0077] As Figure 5AIn another specific embodiment of the ion separation instrument 60 illustrated in FIG. 1 (which should not be considered as limiting in any way), the ion source 12 illustratively includes 2 stages, and the ion processing instrument 70 is omitted. In this example embodiment, the ion source stage IS1 is a conventional liquid chromatograph (e.g., HPLC, etc.), which is configured to separate molecules in a solution according to molecular retention time, and the ion source stage IS2 is a conventional ion source (e.g., electrospray, etc.). In this embodiment, the liquid chromatograph is operable to separate molecular components in a solution, the ion source stage IS2 is operable to generate ions from a solution flow leaving the liquid chromatograph, and the ELIT array 14, 205, 302 is operable to analyze the ions generated by the ion source stage IS2. In an alternative embodiment of this example, the ion source stage IS1 may alternatively be a conventional size exclusion chromatograph (SEC), which is operable to separate molecules in a solution by size. In another alternative embodiment, the ion source stage IS1 may include a conventional liquid chromatograph followed by a conventional SEC (or vice versa). In this embodiment, ions are generated by ion source stage IS2 from a twice separated solution: a first separation based on molecular retention time followed by a second separation based on molecular size (or vice versa). In any of the embodiments described in this paragraph, additional variations may include a mass spectrometer operatively positioned between ion source stage IS2 and ELIT 14, 205, 302.

[0078] Reference now Figure 5B, showing a simplified block diagram of another embodiment of an ion separation instrument 80, which illustratively includes a multi-stage mass spectrometer instrument 82 and also includes any ion mass detection system 10, 200, 300 (i.e., CDMS) illustrated and described herein, which is implemented as a high ion mass analysis component. In the illustrated embodiment, the multi-stage mass spectrometer instrument 82 includes an ion source (IS) 12 (as illustrated and described herein), followed by and coupled to a first conventional mass spectrometer (MS1) 84, followed by and coupled to a conventional ion dissociation stage (ID) 86 (which is operable to dissociate ions leaving the mass spectrometer 84, for example, by one or more of collision induced dissociation (CID), surface induced dissociation (SID), electron capture dissociation (ECD) and / or photo induced dissociation (PID), etc.), followed by and coupled to a second conventional mass spectrometer (MS2) 88, followed by a conventional ion detector (D) 90 (for example, such as a microchannel plate detector or other conventional ion detector). The ion mass detection system 10 , 200 , 300 (ie, CDMS) is coupled in parallel with and to the ion dissociation stage 86 such that it can selectively receive ions from the mass spectrometer 84 and / or from the ion dissociation stage 86 .

[0079] MS / MS (e.g., using only ion separation instrument 82) is a well-established method, in which precursor ions of specific molecular weight are selected by a first mass spectrometer 84 (MS1) based on their m / z values. The mass-selected precursor ions are fragmented in the ion dissociation stage 86, for example, by collision-induced dissociation, surface-induced dissociation, electron capture dissociation, or light-induced dissociation. The fragmented ions are then analyzed by a second mass spectrometer 86 (MS2). Only the m / z values ​​of the precursor ions and the fragmented ions are measured in both MS1 and MS2. For high-quality ions, the charge state is not resolved, and therefore, it is impossible to select precursor ions with specific molecular weights based only on m / z values. However, by connecting the instrument 82 to the CDMS 10, 200, 300 illustrated and described herein, it is possible to select a narrow range of m / z values ​​and then use CDMS 10, 200, 300 to determine the mass of the m / z-selected precursor ions. Mass spectrometers 84, 88 can be, for example, one or any combination of a sector magnetic mass spectrometer, a time-of-flight mass spectrometer, or a quadrupole mass spectrometer, but in alternative embodiments, other mass spectrometer types can be used. In any case, the precursor ions of the m / z selection with known mass leaving MS1 can be split in the ion dissociation stage 86, and the resulting fragmented ions can then be analyzed by MS2 (wherein only the m / z ratio is measured) and / or by CDMS instruments 10, 200, 300 (wherein the m / z ratio and charge are measured simultaneously). Therefore, low-quality fragments can be analyzed by conventional MS, while high-quality fragments (wherein the charge state is not resolved) are analyzed by CDMS.

[0080] Reference now Figure 6 , shows an ion mass detection system 200, which includes another embodiment of an electrostatic linear ion trap (ELIT) array 205 having control and measurement components coupled thereto. In the illustrated embodiment, the ELIT array 205 includes three individual ELITs 202, 204, 206, each of which is connected to a Figure 1 For example, the ELIT 202 includes a charge detection cylinder CD1 surrounded by a ground chamber GC1, wherein one end of the ground chamber GC1 defines one of the mirror electrodes of an ion mirror M1, and the opposite end of the ground chamber GC1 defines one of the mirror electrodes of another ion mirror M2, and wherein the ion mirrors M1, M2 are arranged at opposite ends of the charge detection cylinder 202. The ion mirror M1 is illustratively structurally and functionally similar to the ion mirror M2. Figure 1-2B Each of the ion mirrors M1-M3 illustrated in FIG. 1 is identical to each other, and ion mirror M2 is illustratively structurally and functionally identical to Figure 1-2B The voltage source V1 (illustratively structurally and functionally identical to the ion mirror M4 shown in FIG. Figure 1-2B) is operatively coupled to ion mirror M1, and another voltage source V2 (illustratively structurally and functionally identical to ion mirror M1) is operatively coupled to ion mirror M1. Figure 1-2B 1 and 2) is operatively coupled to ion mirror M2. Ion mirror M1 defines an ion inlet aperture AI1, which is illustratively structurally and functionally similar to Figure 2A The aperture A1 of the ion mirror MX illustrated in FIG. 1 is identical, and the ion mirror M2 defines an exit aperture AO1 which is illustratively similar in structure and operation to that described above with respect to FIG. Figure 1 and Figure 2B The aperture CA of the ion mirror M4 is the same as that described. The longitudinal axis 241 extends centrally through the ELIT 202 and illustratively bisects the apertures AI1 and AO1. The charge preamplifier CP1 is electrically coupled to the charge detection cylinder CD1 and is illustratively structurally and functionally identical to the charge detection cylinder CD1. Figure 1 The charge preamplifier CP1 shown in FIG. 2 and described above is the same.

[0081] ELIT 204 is illustratively the same as ELIT 202 just described, wherein ion mirrors M3, M4 correspond to ion mirrors M1, M2 of ELIT 202, wherein voltage sources V3, V4 correspond to voltage sources V1, V2 of ELIT 202, and wherein inlet / exit apertures AI2 / AO2 define a longitudinal axis 242 that extends through ELIT 204 and illustratively bisects apertures AI2, AO2. Charge amplifier CP2 is electrically coupled to charge detection cylinder CD2 of ELIT 204 and is illustratively structurally and functionally identical to ELIT 204. Figure 1 The same as the charge preamplifier CP2 shown in FIG. 1 and described above.

[0082] ELIT 206 is also illustratively identical to ELIT 202 just described, wherein ion mirrors M5, M6 correspond to ion mirrors M1, M2 of ELIT 202, wherein voltage sources V5, V6 correspond to voltage sources V1, V2 of ELIT 202, and wherein inlet / exit apertures AI3 / AO3 define a longitudinal axis 243 extending through ELIT 206 and illustratively bisecting apertures AI3, AO3. Charge amplifier CP3 is electrically coupled to charge detection cylinder CD3 of ELIT 206 and is illustratively structurally and functionally identical to ELIT 202. Figure 1 The same as the charge preamplifier CP3 shown in FIG. 1 and described above.

[0083] Voltage sources V1-V6 and charge preamplifiers CP1-CP3 are operatively coupled to a processor 210, which includes a processor 210 as described above. Figure 1The memory 212 described herein, wherein the memory 212 illustratively has instructions stored therein, which, when executed by the processor 210, cause the processor 210 to control the operation of the voltage sources V1-V6 to control the ion mirrors M1-M6 between an ion transmission mode of operation and an ion reflection mode of operation, as described above. Alternatively, one or more of the voltage sources V1-V6 may be programmable to operate as described. In any case, the instructions stored in the memory 212 further illustratively include instructions that, when executed by the processor 210, cause the processor to receive, process and record (store) charge signals detected by the charge preamplifiers CP1-CP3, and process the recorded charge signal information to calculate the mass of ions captured within each of the ELITs 202, 204, 206, as described above. Illustratively, the processor 210 is connected to one or more peripheral devices 214, which may be connected to the peripheral devices 214 described above. Figure 1 The one or more peripheral devices 20 described are identical.

[0084] exist Figure 6 In the embodiment illustrated in FIG. 1 , an embodiment of an ion steering array 208 is shown, which is operatively coupled between the ion source 12 and the ion inlet apertures AI1-AI3 of each ELIT 202, 204, 206 in the ELIT array 205. The ion source 12 is illustratively as described with respect to Figure 1 5, and is configured to generate ions through the ion aperture IA and supply the ions to the ion steering array 208. The ion steering voltage source V ST operatively coupled to and between processor 210 and ion steering array 208. As will be described in detail below, processor 210 is illustratively configured (ie, programmed) to control ion steering voltage source V ST, so that the ion steering array 208 selectively steers and directs ions exiting the ion orifice IA of the ion source 12 into the ELITs 202, 204, and 206 via the respective entrance orifices AI1-AI3 of the ELITs 202, 204, and 206. The processor 210 is further configured (i.e., programmed) to control the voltage sources V1-V6 so that the ion mirrors M1-M6 of the ELITs 202, 204, 206 selectively switch between the ion transmission mode and the ion reflection mode to thereby capture at least one ion in each of the ELITs 202, 204, 206, and then cause such ions to oscillate back and forth between the respective ion mirrors M1 / M2, M3 / M4, and M5 / M6, and pass through the respective charge detection cylinders CD1-CD3 of the ELITs 202, 204, 206, so as to measure and record ion charge detection events detected by the respective charge preamplifiers CP1-CP3, as described above.

[0085] Ion steering array 208 illustratively includes three sets of four conductive pads P1-P4, P5-P8, and P9-P12 arranged on each of two spaced apart planar substrates such that each of the conductive pads P1-P12 on one of the planar substrates is aligned with and faces a corresponding one of the conductive pads on the other substrate. Figure 6 In the embodiment illustrated in FIG. 2 , only one of the substrates 220 is shown.

[0086] Reference now Figures 7A-7C , showing a portion of the ion steering array 208, which illustrates the control and operation of the ion steering array 208 to selectively steer ions to a desired location. Figure 7B and Figure 7C , the voltage sources DC1-DC4 of the illustrated portion of the ion steering array 208 are controlled to cause ions exiting the ion aperture IA of the ion source 12 in the direction indicated by arrow A to be redirected by approximately 90 degrees so as to be directed along a path aligned with (i.e., co-linear with) the ion inlet aperture AI1 of the ELIT 202. Although not illustrated in the accompanying drawings, any number of conventional planar ion blankets and / or other conventional ion focusing structures may be used to focus the ion trajectories exiting the ion aperture IA of the ion source, and / or to align the ion trajectories selectively altered by the ion steering array 208 with the ion inlet apertures AI1-AI3 of the respective ELITs 202, 204, 206.

[0087] Specifically refer to Fig. 7A, a pattern of four substantially identical and spaced apart conductive pads P11-P41 is formed on an inner major surface 220A of one substrate 220 having an opposite outer major surface 220B, and an identical pattern of four substantially identical and spaced apart conductive pads P12-P42 is formed on an inner major surface 222A of another substrate 222 having an opposite outer surface 222B. The inner surfaces 220A, 222A of the substrates 220, 222 are spaced apart in a generally parallel relationship, and the conductive pads P11-P41 are juxtaposed above corresponding ones of the conductive pads P12-P42. The spaced apart inner major surfaces 220A and 222A of the substrates 220, 222 illustratively define a distance D of width therebetween. P In one embodiment, the width D of the channel 225 is P is approximately 5 cm, however in other embodiments, the distance D P It may be larger or smaller than 5 cm. In any case, substrates 220 , 222 together form the illustrated portion of ion steering array 208 .

[0088] The opposing pad pairs P31, P32 and P41, P42 are upstream of the opposing pad pairs P11, P12 and P21, P22, and the opposing pad pairs P11, P12 and P21, P22 are conversely downstream of the opposing pad pairs P41, P42 and P31, P32. In this regard, the "unchanged ion travel direction" (as that term is used herein) through the channel 225 is "upstream" and is generally parallel to the direction A of ions leaving the ion source 12. The lateral edges 220C, 222C of the substrates 220, 222 are aligned (as are the opposite lateral edges 220D, 222D), and the "changed direction of ion travel" (as that term is used herein) through the channel 225 is from the aligned edges 220C, 222C toward the aligned edges 220D, 222D, and is substantially perpendicular to both such aligned edges 220C, 222C and 220D, 222D.

[0089] exist Figure 6 In the embodiment shown in the figure, the ion steering voltage source V ST Illustratively, the device is configured to generate at least 12 switchable DC voltages, each of which is operatively connected to a corresponding opposing pair of conductive pads P1-P12. Four of the 12 DC voltages DC1-D4 are switched at Fig. 7AThe first DC voltage DC1 is electrically connected to each of the juxtaposed conductive pads P11 and P12, the second DC voltage DC2 is electrically connected to each of the juxtaposed conductive pads P21 and P22, the third DC voltage DC3 is electrically connected to each of the juxtaposed conductive pads P31 and P32, and the fourth DC voltage DC4 is electrically connected to each of the juxtaposed conductive pads P41 and P42. In the illustrated embodiment, for example, via the processor 210 and / or via the voltage source V ST Each of the DC voltages DC1-DC12 is independently controlled by programming, however in alternative embodiments, two or more of the DC voltages DC1-DC12 may be controlled together as a group. In any case, it will be understood that although the voltages DC1-DC12 are illustrated and disclosed as DC voltages, the present disclosure contemplates other embodiments in which the voltage source V ST Alternatively or additionally configured to generate any number of AC voltages (such as, for example, one or more RF voltages), and configured to supply any one or more such AC voltages to corresponding ones of the conductive pads or pairs of conductive pads, and / or to one or more ion blankets or other ion focusing structures in embodiments including the same.

[0090] Reference now Figure 7B and Figure 7C , Figure 6 The operation of the ion steering channel array 208 illustrated in FIG. Fig. 7A and Figure 7B The four opposing pairs of conductive pads P11 / P12, P21 / P22, P31 / P32 and P41 / P42 are described as illustrative examples. It will be understood that Figure 6 The four conductive pads P5-P8 and the four conductive pads P9-P12 shown on the substrate 220 in FIG. 1 also each include pairs of conductive pads arranged on the inner surfaces 220A and 222A of the corresponding substrates 220 and 222, which are opposite, aligned and juxtaposed, and each set of four pairs of conductive pads can be powered by a voltage source V ST In any case, for the sake of clarity, in Figure 7B and Figure 7C The DC voltages DC1-DC4 are omitted and, instead, a voltage source V ST The DC voltages DC1-DC4 generated and applied to the connected pairs of conductive pads P11 / P12, P21 / P22, P31 / P32 and P41 / P42 are graphically represented. Figure 7B , the illustrated portion of the ion steering array 208 is shown in the following state: In this state, the reference potential V REF applied to each of the conductive pad pairs P11 / P12, P21 / P22 and is less than VREF A potential of -XV is applied to each of the conductive pad pairs P31 / P32 and P41 / P42. Illustratively, V REF can be any positive or negative voltage, or can be zero volts (e.g., ground potential), and -XV can be less than V REF Any voltage, positive voltage, negative voltage or zero voltage, is applied to the substrate 220, 222 so as to establish an electric field E1 that is parallel to the sides 220C / 222C and 220D / 222D of the substrates 220, 222 and extends in the unchanged ion travel direction, i.e., from the downstream conductive pad pair P11 / P12, P21 / P22 toward the upstream conductive pad pair P31 / P32 and P41 / P42, as shown in FIG. Figure 7B As depicted in . Figure 7B , ions A leaving the ion source 12 via the ion aperture IA enter the channel 225 between the downstream conductive pad pairs P11 / P12, P21 / P22, and are diverted or directed (or guided) by the electric field E1 along an unchanged ion travel direction 230, which is in the same direction as the electric field E1 and is aligned (i.e., co-linear) with the ion aperture IA of the ion source 12. Such ions A are illustratively directed through the channel 225 along an unchanged travel direction, as shown in FIG. Figure 7B As shown in the figure.

[0091] Now specifically refer to Figure 7C , when the direction of ion A is changed from Figure 7B When the unchanged ion traveling direction shown in the figure is changed to the desired changed ion traveling direction, the voltage source V ST The generated DC voltages DC1 and DC3 are switched so that the reference potential V REF applied to each of the conductive pad pairs P21 / P22, P31 / P32 and is less than V REF A potential of -XV is applied to each of the conductive pad pairs P11 / P12, P41 / P42 to establish an electric field E2 that is perpendicular to the sides 220C / 222C and 220D / 222D of the substrates 220, 222 and extends in the unchanged ion travel direction, i.e., from the sides 220C / 222C of the substrates 220, 222 toward the sides 220D / 222D of the substrates 220, 222, as shown in FIG. Figure 7C As depicted in . Figure 7C2 , ions A leaving the ion source 12 through the ion aperture IA and entering the channel 225 are diverted or directed (or guided) by the electric field E2 along a changed ion travel direction 240, which is in the same direction as the electric field E2 and is aligned (i.e., co-linear) with the ion aperture IA of the ion source 12. Such ions A are illustratively directed through the channel 225 along an unchanged travel direction between the conductive pad pairs P11 / P12, P41 / P42, as shown in FIG. Figure 7C In some embodiments, one or more conventional ion blankets and / or other conventional ion focusing structures may be used to Figure 7C The ion trajectory 240 illustrated in FIG. 2 confines the ions.

[0092] Reference again Figure 6 The instructions stored in the memory 212 illustratively include the following instructions: When executed by the processor 210, the instructions cause the processor 210 to control the ion steering voltage source V ST , to selectively generate and switch voltages DC1-DC12 in a manner that guides ions along the ion steering array 208 and sequentially guides at least one ion into each ion entrance orifice AI1-AI3 of each corresponding ELIT 202, 204, 206, and also controls voltage sources V1-V6 to selectively generate and switch DC voltages generated thereby in a manner that controls corresponding ion mirrors M1-M6 between their ion transmission mode and ion reflection mode to capture at least one ion guided by the ion steering array 208 into each ELIT 202, 204, 206, and then, when the processor 210 records the corresponding ion charge detection information in the memory 214, causes each (multiple) trapped ions to oscillate back and forth between the corresponding ion mirrors M1-M6 of each ELIT 202, 204, 206, as described above with respect to Figure 1 -4B described. With the help of Figures 8A-8F , one example of such a process will be described as operating on one or more positively charged ions, however it will be understood that process 100 may alternatively operate on one or more negatively charged particles. In the following description, reference to any specific one or more of the conductive pads P1-P12 will be understood to refer to the opposing, juxtaposed, spaced-apart pairs of conductive pads disposed on the inner surfaces 220A, 222A of the substrates 220, 222, respectively, as described with reference to Fig. 7A , and references to voltages applied to any specific one or more of the conductive pads P1-P12 will be understood to be applied to both of such opposing, juxtaposed, spaced-apart pairs of conductive pads, as described with respect to Figure 7B and Figure 7C It will be further understood that Figures 8A-8F The DC voltage V REF can be any positive or negative voltage, or can be zero volts (e.g., ground potential), and also Figures 8A-8F The DC voltage -XV shown in the figure can be less than V REF any voltage, positive voltage, negative voltage or zero voltage, so as to establish a corresponding electric field in channel 225, which is controlled by V REF The conductive pad extends in the direction toward the conductive pad controlled by -XV, as shown by Figure 7B and Figure 7C The example in the figure is shown.

[0093] refer to Fig. 8A , the processor 210 is operable to control the voltage source V ST , to apply -XV to each of pads P5-P7, and V REF Applied to each of pads P1-P4. In some embodiments, V ST V REF Applied to each of pads P9-P12 (eg Fig. 8A ), however in other embodiments, V ST Can be controlled to apply -XV to each of pads P9-P12. In any case, the electric field generated by such voltage application within channel 225 of ion steering array 208 pulls ions exiting ion aperture IA of ion source 12 through channel 225 in an unchanged ion travel direction along the illustrated ion trajectory 250.

[0094] refer to Figure 8B , the processor 210 can then operate to control the voltage source V ST , to switch the voltage applied to pads P2 and P4 to -XV, and otherwise maintain the previously applied voltages at P1, P3, and P5-P12. The electric field established in channel 225 of ion steering array 208 resulting from such switched voltage application diverts ions that were previously traveling along ion trajectory 250 toward ion inlet aperture AI1 of M1 of ELIT 202 along the altered ion travel direction. Fig. 8A The ion trajectory 250 illustrated in FIG. 1 travels from the ion source 12 in an unchanged ion travel direction. Simultaneously with, before, or after this switching, the processor 210 can be operated to control the voltage sources V1 and V2 to generate voltages that cause both ion mirrors M1 and M2 to operate in their ion transmission modes, for example, as described with respect to FIG. Figure 1-2BAs a result, ions traveling along ion trajectory 252 through channel 225 of ion steering array 208 are directed through M1 into entrance aperture AI1 of ELIT 202 and are transported through M1, through charge detection cylinder CD1, and through M2 by the ion transport fields established in each of ion mirrors M1 and M2, as also described by Figure 8B 252 is illustrated in FIG. 25. In some embodiments, one or more conventional ion blankets and / or other conventional ion focusing structures may be operably positioned between the ion steering array 208 and the ion mirror M1 of the ELIT 202 to direct ions traveling along the ion trajectory 252 into the ion inlet orifice AI1 of the ELIT 202. In any case, the processor 210 is operable at some point thereafter to control V2 to generate a voltage that causes the ion mirror M2 to switch from an ion transmission mode of operation to an ion reflection mode of operation (e.g., as also described with respect to FIG. 25). Figure 1-2B The timing of this switching of M2 illustratively depends on whether the operation of ELIT 202 is controlled by processor 210 in a random trapping mode or in a triggered trapping mode, as described with respect to Figure 3 Described.

[0095] refer to Figure 8C , the processor 210 can then be operated to control the voltage source V1 to generate a voltage that causes the ion mirror M1 to switch from the ion transmission mode to the ion reflection mode of operation. The timing of this switching of M1 illustratively depends on whether the operation of the ELIT 202 is controlled by the processor 210 in the random capture mode or the triggered capture mode (as described with respect to Figure 3 ), but in any case, switching of M1 to its ion reflectron mode traps at least one ion within ELIT 202, as indicated by Figure 8C 252. In the case where at least one such ion is trapped within the ELIT 202, and where both M1 and M2 are controlled by voltage sources V1 and V2, respectively, to operate in their ion reflectron modes, the ion(s) trapped within the ELIT 202 oscillate back and forth between the ion mirrors M1 and M2 each time they pass through the charge detection cylinder CD1 and induce a corresponding charge thereon, which is detected by the charge preamplifier CP1 and recorded by the processor 210 in the memory 212, as described above with respect to Figure 3 Described.

[0096] While or after controlling the ELIT 202 (as just described), and with the ion(s) oscillating back and forth within the ELIT 202 between the ion mirrors M1, M2, the processor 210 can be operable to control V ST, to switch the voltage applied to pads P2 and P4 back to V REF , switch the voltage applied to pads P5-P8 from -XV to V REF , and the voltage applied to pads P9-P12 is from V REF Switch to -XV, also like Figure 8C The electric field generated by such voltage application in the channel 225 of the ion steering array 208 again pulls ions exiting the ion aperture IA of the ion source 12 through the channel 225 in an unchanged ion travel direction along the illustrated ion trajectory 250 .

[0097] Reference now Fig.8D , the processor 210 can then operate to control the voltage source V ST , to switch the voltage applied to pads P6 and P8 to -XV, and otherwise maintain the previously applied voltages at P1-P4, P5, P7, and P9-P12. The electric field established within channel 225 of ion steering array 208 resulting from such switched voltage application diverts ions that were previously traveling along ion trajectory 254 toward ion inlet aperture AI2 of M2 of ELIT 204 along the altered ion travel direction. Figure 8C The ion trajectory 250 illustrated in FIG. 2 travels from the ion source 12 in an unchanged ion travel direction. Simultaneously with, before, or after this switching, the processor 210 is operable to control voltage sources V3 and V4 to generate voltages that cause both ion mirrors M3 and M4 to operate in their ion transmission modes. As a result, ions traveling along the ion trajectory 254 through the channel 225 of the ion steering array 208 are directed through M3 into the entrance orifice AI2 of the ELIT 204 and are transmitted by the ion transmission field established in each of the ion mirrors M3 and M4 through M3, through the charge detection cylinder CD2, and through M4, as also shown by Fig.8D 254 is illustrated in FIG. 25. In some embodiments, one or more conventional ion blankets and / or other conventional ion focusing structures may be operably positioned between the ion steering array 208 and the ion mirror M3 of the ELIT 204 to direct ions traveling along the ion trajectory 254 into the ion inlet orifice AI2 of the ELIT 204. In any case, the processor 210 is operable at some point thereafter to control V4 to generate a voltage that causes the ion mirror M4 to switch from an ion transmission mode of operation to an ion reflection mode of operation so as to reflect the ions backward toward M3. The timing of this switching of M4 illustratively depends on whether the operation of the ELIT 204 is controlled by the processor 210 in a random capture mode or in a triggered capture mode, as described with respect to FIG. Figure 3 Described.

[0098] exist Fig.8DAfter the operating state illustrated in FIG. , the processor 210 is able to operate (similarly as described with respect to Figure 8C 2) to control voltage source V3 to generate a voltage that switches ion mirror M3 from the ion transmission mode to the ion reflection mode of operation. The timing of this switching of M3 illustratively depends on whether the operation of ELIT 204 is controlled by processor 210 in the random capture mode or the triggered capture mode (as described with respect to FIG. Figure 3 ), but in any case, switching of M3 to its ion reflectron mode traps at least one ion within ELIT 204, as indicated by Fig. 8E 254. In the case where at least one such ion is trapped within the ELIT 204, and where both M3 and M4 are controlled by voltage sources V3 and V4, respectively, to operate in their ion reflection modes, the ion(s) trapped within the ELIT 204 oscillate back and forth between the ion mirrors M3 and M4 each time they pass through the charge detection cylinder CD2 and induce a corresponding charge thereon, which is detected by the charge preamplifier CP2 and recorded by the processor 210 in the memory 212, as described above with respect to Figure 3 Described. Fig. 8E In the operating state illustrated in , ions oscillate back and forth simultaneously within each of ELITs 202 and 204 , and ion charge / timing measurements taken from each of charge preamplifiers CP1 and CP2 are therefore collected and stored by processor 210 simultaneously.

[0099] In controlling ELIT 204 (as just mentioned Fig. 8E 202 and 204, and in the case where (a plurality of) ions are simultaneously oscillating within each of the ELITs 202 and 204, the processor 210 is operable to control V ST , to switch the voltage applied to pads P6 and P8 back to V REF , so that pads P1-P12 are controlled to Figure 8C The electric field generated by such voltage application in the channel 225 of the ion steering array 208 again pulls the ions passing through the channel 225 and out of the ion aperture IA of the ion source 12 along the illustrated ion trajectory 250 in an unchanged ion travel direction, as shown in FIG. Figure 8C Thereafter, the processor 210 can be operated to control the voltage source V ST , to switch the voltage applied to pads P9 and P11 to V REF, and in addition maintain the previously applied voltages at P1-P8, P5, and P11-P12. The electric field established within the channel 225 of the ion steering array 208 resulting from such switched voltage application diverts the ions that were previously traveling along the altered ion travel direction along the ion trajectory 256 toward the ion entrance aperture AI3 of the ion mirror M5 of the ELIT 206. Figure 8C The ion trajectory 250 illustrated in FIG. 2 travels from the ion source 12 in an unchanged ion travel direction. Simultaneously with, before, or after this switching, the processor 210 can be operated to control voltage sources V5 and V6 to generate voltages that cause both ion mirrors M5 and M6 to operate in their ion transmission modes. As a result, ions traveling along the ion trajectory 253 through the channel 225 of the ion steering array 208 are directed through M5 into the entrance orifice AI3 of the ELIT 206 and are transmitted by the ion transmission field established in each of the ion mirrors M5 and M6 through M5, through the charge detection cylinder CD3, and through M6, as indicated by Fig. 8E In some embodiments, one or more conventional ion blankets and / or other conventional ion focusing structures may be operably positioned between the ion steering array 208 and the ion mirror M5 of the ELIT 206 to direct ions traveling along the ion trajectory 256 into the ion entrance aperture AI3 of the ELIT 206.

[0100] In any case, processor 210 can be operated at some point thereafter to control V6 to generate a voltage that causes ion mirror M6 to switch from an ion transmission mode of operation to an ion reflection mode of operation so as to reflect ions back toward M5. The timing of this switching of M6 illustratively depends on whether the operation of ELIT 206 is controlled by processor 210 in a random capture mode or in a triggered capture mode, as described with respect to FIG. Figure 3 Thereafter, the processor 210 can operate (similarly as described with respect to Figure 8C 206 is controlled by the processor 210 (as described above) to generate a voltage that switches the ion mirror M5 from the ion transmission mode to the ion reflection mode of operation. The timing of this switching of M5 illustratively depends on whether the operation of the ELIT 206 is controlled by the processor 210 in the random capture mode or the triggered capture mode (as described above). Figure 3 ), but in any case, switching of M5 to its ion reflectron mode traps at least one ion within ELIT 206, as indicated by Figure 8F256. In the case where at least one such ion is trapped within the ELIT 206, and where both M5 and M6 are controlled by voltage sources V5 and V6, respectively, to operate in their ion reflectron modes, the ion(s) trapped within the ELIT 206 oscillate back and forth between the ion mirrors M5 and M6 each time they pass through the charge detection cylinder CD3 and induce a corresponding charge thereon, which is detected by the charge preamplifier CP3 and recorded by the processor 210 in the memory 212, as described above with respect to Figure 3 Described. Figure 8F In the operating state illustrated in , ions oscillate back and forth simultaneously within each of ELITs 202 , 204 , and 206 , and ion charge / timing measurements taken from each of charge preamplifiers CP1 , CP2 , and CP3 are therefore simultaneously collected and stored by processor 210 .

[0101] Also like Figure 8F As illustrated in FIG. 1 , while or after controlling ELIT 206 (as just described), and with ion(s) oscillating simultaneously within each of ELITs 202, 204, and 206, processor 210 can be operable to control V ST , to switch the voltage applied to pads P5-P8 to -XV, and to switch the voltage applied to P10 and P12 to V REF (or switch the voltage applied to P9 and P11 to -XV) so that pads P1-P12 are controlled to Fig. 8A The electric field generated by such voltage application in the channel 225 of the ion steering array 208 again pulls the ions passing through the channel 225 and out of the ion aperture IA of the ion source 12 along the illustrated ion trajectory 250 in an unchanged ion travel direction, as shown in FIG. Fig. 8A As shown in the figure.

[0102] After the ions have oscillated back and forth within each of the ELITs 202, 204, and 206 for the total ion cycle measurement time or the total number of measurement cycles, for example, as described above with respect to Figure 3 As described in step 126 of the process 100 illustrated in FIG. 1 , the processor 210 is operable to control the voltage sources V1-V6 to switch each of the ion mirrors M1-M6 to their ion transmission operating modes, thereby causing the ions trapped therein to exit the ELITs 202, 204, 206 via the ion exit orifices AO1-AO3, respectively. The operation of the ion mass detection system 200 then illustratively returns to the above description of Figure 8B Simultaneously or at another convenient time, the set of recorded ion charge / timing measurements is processed by processor 210 (e.g., as described with respect to Figure 3), to determine the mass of ions processed by each respective one of the ELITs 202, 204, 206.

[0103] Depending on a number of factors (including, but not limited to, the size of the ELITs 202, 204, 206, the oscillation frequency or frequencies of the ions passing through each ELIT 202, 204, 206, and the total number of measurement cycles / total ion cycle measurement time in each ELIT 202, 204, 206), the ions may oscillate back and forth within at least two of the ELITs 202, 204, and 206 simultaneously, and the ion charge / timing measurements obtained from the respective ones of the charge preamplifiers CP1, CP2, and CP3 may therefore be collected and stored simultaneously by the processor 210. For example, in Figure 8F In the embodiment illustrated in , ions oscillate back and forth in at least two of the ELITs 202, 204, and 206 simultaneously, and the ion charge / timing measurements obtained from each of the charge preamplifiers CP1, CP2, and CP3 are therefore collected and stored simultaneously by the processor 210. In other embodiments, the total number of measurement cycles of the ELIT 202 or the total ion cycle measurement time may expire before at least one ion is trapped in the ELIT 206, as described above. In such a case, the processor 210 may control the voltage sources V1 and V2 to switch the ion mirrors M1 and M2 to their transmission operating modes, thereby causing the oscillating (multiple) ions therein to leave through the ion mirror M2 before causing at least one ion to oscillate in the ELIT 206. In such an embodiment, the ions may not oscillate back and forth in all of the ELITs 202, 204, and 206 simultaneously, but may oscillate back and forth in at least two of the ELITs 202, 204, and 206 at any one time.

[0104] Reference now Fig. 9 , shows an ion mass detection system 300, which includes another embodiment of an electrostatic linear ion trap (ELIT) array 302 having control and measurement components coupled thereto. In the illustrated embodiment, the ELIT array 302 includes three individual ELITs E1-E3, each of which is connected to Figure 6 The ELITs 202, 204, 206 shown in FIG. are configured identically. Fig. 9 In the embodiment shown in FIG. 1 , the structure and function of the Figure 1-2B A voltage source V1, which is identical to the voltage source V1 illustrated in FIG. 1 , is operatively coupled to the ion mirror M1 of each ELIT E1 - E3 and is illustratively structurally and functionally identical to the ion mirror M1 of each ELIT E1 - E3. Figure 1-2BAnother voltage source V2, which is identical to the voltage source V4 illustrated in FIG, is operatively connected to the ion mirror M2 of each ELIT E1-E3. In an alternative embodiment, two or more ion mirrors M1 in the ELIT E1-E3 may be combined into a single ion mirror, and / or two or more ion mirrors M2 in the ELIT E1-E3 may be combined into a single ion mirror. In any case, the voltage sources V1, V2 are electrically connected to the processor 304, and the three charge preamplifiers CP1-CP3 are electrically connected between the processor 304 and the corresponding charge detection cylinders CD1-CD3 of a corresponding one of the ELITs E1-E3. The memory 306 illustratively includes instructions that, when executed by the processor 304, cause the processor 304 to control the voltage sources V1 and V2 to control the operation of the ELITs E1-E3, as described below. Illustratively, the processor 304 is operatively connected to one or more peripheral devices 308, which may be connected to the above description of the peripheral devices 308. Figure 1 The one or more peripheral devices 20 described are identical.

[0105] The ion mass detection system 300 is similar to the ion mass detection system 200 in some respects, in that the ion mass detection system 300 includes the ion source 12 operatively coupled to the ion steering array 208, the structure and operation of which are described above. The instructions stored in the memory 306 further illustratively include the following instructions: when executed by the processor 304, the instructions cause the processor 304 to control the ion steering array voltage source V ST , as described below.

[0106] exist Fig. 9 In the embodiment illustrated in FIG. 3 , the ion mass detection system 300 further illustratively includes three conventional ion traps IT1-IT3, each having a respective ion inlet TI1-TI3 and an opposite ion outlet TO1-TO3. The ion trap IT1 is illustratively positioned between the set of conductive pads P1-P4 and the ion mirror M1 of the ELITE E1, such that a longitudinal axis 241 extending centrally through the ELITE 1 bisects the ion inlet TI1 and the ion outlet TO1 of IT1, and also passes centrally between the pad pairs P1 / P2 and P3 / P4, as shown in FIG. Fig. 9. The ion trap IT2 is similarly positioned between the group of conductive pads P5-P8 and the ion mirror M1 of the ELIT E2, so that the longitudinal axis 242 extending centrally through the ELIT E2 bisects the ion inlet TI2 and the ion outlet TO2 of IT2 and also passes centrally between the pad pairs P5 / P6 and P7 / P8, and the ion trap IT3 is likewise positioned between the group of conductive pads P9-P12 and the ion mirror M1 of the ELIT E3, so that the longitudinal axis 243 extending centrally through the ELIT E3 bisects the ion inlet TI3 and the ion outlet TO3 of IT3 and also passes centrally between the pad pairs P9 / P10 and P11 / P12. The ion traps IT1-IT3 may each be any conventional ion trap, examples of which may include, but are not limited to, conventional quadrupole ion traps, conventional hexapole ion traps, and the like.

[0107] Ion trap voltage source V IT is operatively coupled between processor 304 and each of ion traps IT1-IT3. Voltage source V IT Illustratively configured to generate appropriate DC and AC (eg, RF) voltages for individually and independently controlling the operation of each of the ion traps IT1 - IT3 in a conventional manner.

[0108] Processor 304 is illustratively configured (eg, programmed) to control the ion steering array voltage source V ST , so as to remove one or more ions (such as those related to Figures 8A-8F ion traps IT1-IT3). In some embodiments, one or more conventional ion blankets and / or other ion focusing structures may be positioned between ion steering array 208 and one or more of ion traps IT1-IT3 to direct ions from ion steering array 208 to ion entrances TI1-TI3 of corresponding ion traps IT1-IT3. Processor 304 is further configured (e.g., programmed) to control ion trap voltage source V IT , to generate corresponding control voltages for controlling the ion inlets TI1-TI3 of the ion traps IT1-IT3 to accept ions therein, and for controlling the conventional ion traps IT1-IT3 to capture or confine such ions therein.

[0109] When the ion traps IT1-IT3 are filled with ions, the processor 304 is configured (i.e., programmed) to control V1 and V2 to generate a suitable DC voltage, which controls the ion mirrors M1 and M2 of the ELIT E1-E2 to operate in their ion transmission operating mode, so that any ions contained therein leave through the ion exit orifices AO1-AO3, respectively. When at least one ion is trapped in each of the ion traps IT1-IT3 via the control of the ion steering array 208 and the ion traps IT1-IT3 (as just described), the processor 304 is configured (i.e., programmed) to control V2 to generate a suitable DC voltage, which controls the ion mirrors M2 of the ELIT E1-E3 to operate in their ion reflection operating mode. Thereafter, the processor 304 is configured to control the ion trap voltage source V IT , to generate a suitable voltage, which causes the ion outlets TO1-TO3 of the corresponding ion traps IT1-IT3 to be opened simultaneously to guide at least one ion trapped therein to a corresponding one of the ELIT E1-E3 via the corresponding ion entrance orifices AI1-AI3 of the corresponding ion mirrors M1. When the processor 304 determines that at least one ion enters each of the ELIT E1-E3, for example, after a certain period of time has elapsed after the simultaneous opening of the ion traps IT1-IT3 or after charge detection by each of the charge preamplifiers CP1-CP3, the processor 304 is operable to control the voltage source V1 to generate a suitable DC voltage, which controls the ion mirrors M1 of the ELIT E1-E3 to operate in their ion reflection operation mode, thereby trapping at least one ion in each of the ELIT E1-E3.

[0110] With the ion mirrors M1 and M2 of each ELIT E1-E3 operating in the ion reflection mode of operation, at least one ion in each ELIT E1-E3 simultaneously oscillates back and forth between M1 and M2 each time it passes through a corresponding one of the charge detection cylinders CD1-CD3. The corresponding charges induced on the charge detection cylinders CD1-CD3 are detected by the corresponding charge preamplifiers CP1-CP3, and the charge detection signals generated by the charge preamplifiers CP1-CP3 are stored in the memory 306 by the processor 304 and subsequently processed by the processor 304 (e.g., as described with respect to Figure 3 ) as described in step 140 of process 100 illustrated in FIG. 1 to determine the mass of ions processed by each respective one of ELITs E1-E3.

[0111] Although the embodiments of ion mass detection systems 200 and 300 are respectively Figure 6-8F and Fig. 9, each including three ELITs, but it will be understood that either or both of such systems 200, 300 may alternatively include fewer (e.g., 2) or more (e.g., 4 or more) ELITs. The control and operation of the various components in any such alternative embodiments will generally follow the concepts described above, and those skilled in the art will recognize that any modifications to system 200 and / or system 300 required to implement any such alternative (multiple) embodiments will involve only mechanical steps. In addition, although the embodiments of ion mass detection systems 200 and 300 are respectively described in Figure 6-8F and Fig. 9 200, 300 are each illustrated as including an example ion steering array 208, but it will be understood that one or more other ion guide structures may alternatively or additionally be used to steer or guide ions (as described above), and any such alternative (multiple) ion guide structures are intended to fall within the scope of the present disclosure. As a non-limiting example, a DC quadrupole beam deflector array may be used with either or both of systems 200, 300 to steer or guide ions as described. In such embodiments, one or more focusing lenses and / or ion blankets may also be used to focus ions into a variety of ion traps, as described above.

[0112] Reference now Fig.10 , showing an embodiment of a charge detection mass spectrometer instrument 400, which indicates Fig. 9 A variation of the apparatus 300 shown in FIG. Fig.10 In the instrument 400 illustrated in FIG. 4 , ions generated in the ion source region 402 are captured by and stored in the ion trap 418, and the ion trap 418 is then controlled in a pulsed mode to selectively supply the ions stored therein to an ion mass and charge detector 434. The instrument 400 can thus be configured and operated to capture and store the generated ions in the ion trap 418, and then control the ion trap 418 in a pulsed manner to controllably supply time-compressed ion packets to the ion mass and charge detector 434 (e.g., in the form of a single-stage electrostatic linear ion trap (ELIT) 434). In some embodiments, the ion outlet of the ion trap 418 can be spaced apart from the ion inlet of the detector 434 by a distance that allows the ions traveling therebetween to be separated in time according to their mass-to-charge ratio values. By varying the delay time between releasing the ions from the ion trap 418 and capturing the ions in the detector 434 in such an embodiment, ions having different mass-to-charge ratio windows or ranges can thus be captured. In some embodiments, the ion filter 424 is positioned between the ion trap 418 and the detector 434, and in such embodiments, the ion filter 424 can be controlled to filter ions leaving the ion trap 418 based on their mass-to-charge ratio to alternatively or additionally select or limit the mass-to-charge ratio or mass-to-charge ratio range of ions supplied by the ion trap 418 to the detector 434.

[0113] As briefly described above, Fig.10 The instrument 400 illustrated in FIG. 4 includes an ion source region 402 configured to generate ions and supply the generated ions to an ion inlet of an ion trap 418. In the illustrated embodiment, the ion source region 402 includes an ion source 404, which is connected to a source region 408 via a capillary 406. In some embodiments, the capillary 406 may be temperature controlled, for example, heated and / or cooled. In any case, the source region 408 is operatively connected to a pump P1, and the pump P1 is operable to control the region 408 to a vacuum so that the region 408 defines a first differential pumping region. The ion source 404 is illustratively positioned outside the source region 404, for example, at atmospheric pressure or other pressures, and is configured to supply ions from a sample to the source region 408 via the capillary 406. In some such embodiments, the ion source 404 is a conventional electrospray ion source (ESI). In such embodiments, ESI source 404 is operatively coupled to output V1 of voltage source 450, and voltage source 450 is configured to generate a suitable DC or time-varying signal at V1 for controlling operation of ESI source 404. In any case, the sample from which ion source 404 generates ions is illustratively a biological material, although in other embodiments, the sample may be or include a non-biological material.

[0114] In some embodiments in which the ion source 404 is positioned outside of the differentially pumped source region 408 and is operable to generate and supply ions to the source region 408 (as described above), the source region 408 may illustratively include an ion processing dock 410 configured to efficiently transmit ions having a broad mass distribution to an ion inlet of an ion trap 418. In some such embodiments, the dock 410 may illustratively include a drift tube 412 having an open end positioned adjacent to or spaced apart from an ion outlet end of the capillary 406 and having an opposite end coupled to one end of a funnel region 414 that tapers from the end of the drift tube 412 to an ion outlet of reduced cross-section. An ion blanket 416 may be operably coupled to the ion outlet of the funnel region 414 and may define an ion passage therethrough that is coupled to an ion inlet of the ion trap 418. At least one output V2 of the voltage source 450 is electrically coupled to the docking portion 410 and supplies a number K of DC and / or time-varying voltage signals to the docking portion 401 to control its operation, where K may be any positive integer. The central longitudinal axis A of the instrument 400 illustratively passes centrally through the various ion inlets and outlets just described and further described below. In embodiments including the same, the docking portion 410 illustratively defines a virtual jet disruptor therein, which is configured to disrupt a gas jet generated by a gas flow through the capillary 406 and into the differential pumping region 408 to thermalize the ions and focus the ions into the ion trap 418. Additional details regarding the structure and operation of embodiments of the docking portion 410 are illustrated and described in co-pending International Patent Applications Nos. PCT / US2019 / 013274 (filed on January 11, 2019) and PCT / US2019 / 035379 (filed on June 4, 2019), both entitled HYBRID ION FUNNEL-ION CARPET (FUNPET) ATMOSPHERIC PRESSURE INTERFACE FOR CHARGE DETECTION MASS SPECTROMETRY, the disclosures of which are expressly incorporated herein by reference in their entireties.

[0115] In some alternative embodiments, source region 408 may not include docking portion 410. In other alternative embodiments, ion source 404 may be provided in the form of one or more other conventional ion sources, one or more of which may be positioned outside of source region 408, and / or one or more of which may be positioned inside source region 408. In some such embodiments, source region 408 may include docking portion 410, and in other such embodiments, docking portion 410 may be omitted.

[0116] The ion inlet of the ion trap 418 is illustratively defined by a central aperture formed through a conductive plate, grid, etc. 420 electrically connected to an output V3 of the voltage source 450. The ion outlet of the ion trap 418 is spaced apart from the ion inlet along a central axis A and is also illustratively defined by a central aperture formed through a conductive plate, grid, etc. 422 electrically connected to another output V5 of the voltage source 450. Another pump P2 is operatively coupled to the ion trap 418 and is illustratively operable to pump the ion trap 418 to a pressure lower than the pressure of the source region 408 (e.g., a higher vacuum) such that the ion trap 418 defines a second differential pumping region. In some embodiments, P2 is configured and operable to control the ion trap 418 to a pressure of 10-100 millibars, however in other embodiments, P2 may control the ion trap 418 to a pressure outside of this range. In some embodiments, the gas source GS is operably coupled to the ion trap 418, and in such embodiments, may be operable to supply a buffer or other gas to the interior of the ion trap 418. In some such embodiments, the gas is selected so that ion collisions therewith cause a reduction in ion energy. In one embodiment, the ion trap 418 is configured as a conventional hexapole ion trap, however, in alternative embodiments, the ion trap 418 may have other conventional configurations (e.g., quadrupole, octopole, etc.). In any case, the ion trap 418 will typically include a number of elongated conductive rods surrounding the axis A, to which the output V4 of the voltage source 450 is operably coupled. Illustratively, the output V4 is coupled to the rods in such a manner that each relative group or pair of rods is out of phase with the other relative pairs of rods, and the output voltage V4 is illustratively a time-varying (e.g., radio frequency) voltage. In some embodiments, V4 may further include one or more DC voltages.

[0117] The operation of ion trap 418 is conventional, because voltage V3 and V5 are controllable DC voltages, which are controlled to allow ions to enter trap 418 via ion inlet, so that ions are trapped therein, and ions are released from ion outlet. For example, voltage V3 is illustratively controlled to a DC potential, which sets the ion energy. In an embodiment including it, gas source GS supplies background gas, and ions entering ion trap 418 collide with the background gas to thermalize excess kinetic energy, which is picked up by ions from the gas flow from source region 408 to ion trap 418. Time-varying voltage V4 is operated to limit ions in the radial direction, and voltage V5 is controlled to trap ions in ion trap 418 and eject ions from ion trap 418. For example, in order to transmit ions through ion trap 418, V5 is typically controlled to a potential less than the potential of V4, and in order to collect and store (i.e., trap) ions, potential B5 is illustratively increased to a potential at which ions no longer pass through the ion outlet transmission of ion trap 418.

[0118] In some embodiments, as briefly described above, the instrument 400 may include a mass-to-charge ratio filter 424 having an ion inlet, which is illustratively coupled to or integrated with the ion outlet of the ion trap 418. The ion outlet is spaced apart from the ion inlet of the filter 424 along the central axis A and is illustratively defined by a central orifice formed through a conductive plate, grid, etc. 426 electrically connected to another output V7 of the voltage source 450. Another pump P3 is operably coupled to the filter 424 and is illustratively operable to pump the filter 424 to a pressure lower than the pressure of the ion trap 418 (e.g., a higher vacuum) so that the filter 424 defines a third differential pumping region. In some embodiments, a gas source GS is operably coupled to the filter 424.

[0119] The mass-to-charge ratio filter 424 is illustratively provided in the form of a conventional quadrupole mass-to-charge filter, however in alternative embodiments, the filter 424 may be provided in the form of a hexapolar, octapolar or other conventional configuration. In any case, the mass-to-charge ratio filter 424 will typically include a plurality of elongated conductive rods surrounding the axis A, to which the output V6 of the voltage source 450 is operatively coupled. Illustratively, the output V6 is coupled to the rods in such a manner that each set or pair of rods that are opposite is out of phase with the other pairs of opposite rods, and the output voltage V6 is illustratively a time-varying (e.g., radio frequency) voltage. In some embodiments, V6 may further include one or more DC voltages.

[0120] In some embodiments, voltage V7 is set to a voltage sufficiently lower than voltage V5 to allow ions to be transmitted through filter 424. In other embodiments, voltage V7 may be switched similarly to the voltage of V5 so as to operate filter 424 as a second ion trap. In any case, in embodiments in which voltage V6 is only time-varying (e.g., RF only), mass-to-charge ratio filter 424 illustratively operates as a high-pass filter, thereby only allowing ions above a selected mass-to-charge ratio value to pass through filter 424. The selected mass-to-charge ratio value illustratively varies with the magnitude of the time-varying voltage V6. In such embodiments, mass-to-charge ratio filter 424 thus operates as a high mass-to-charge ratio filter to preselect only ions (i.e., pass ions) having a mass-to-charge ratio above a selectable mass-to-charge ratio threshold. In some alternative embodiments, voltage V6 includes a time-varying and DC component, and mass-to-charge ratio filter 424 illustratively operates as a bandpass filter, thereby only allowing ions within a selected mass-to-charge ratio range to pass through filter 424. The selected mass-to-charge ratio range illustratively varies with the magnitude of the time-varying and DC components. In such an embodiment, the mass-to-charge ratio filter 424 thus operates as a mass-to-charge ratio band filter to preselect (ie, pass ions through) only ions having a mass-to-charge ratio within a selectable ion mass-to-charge ratio range.

[0121] In some alternative embodiments, the mass-to-charge ratio filter 424 may be positioned upstream of the ion trap 418. In such embodiments, the filter 424 may be controlled in any of the modes just described to allow only ions to enter the ion trap 418 that have a mass-to-charge ratio within a specified mass-to-charge ratio range. In some such embodiments, the mass-to-charge ratio filter 424 may be positioned upstream and downstream of the ion trap 418. In such embodiments, the mass-to-charge ratio filter 424 upstream of the ion trap 418 may be illustratively controlled to allow only ions having a mass-to-charge ratio within a selected mass-to-charge ratio range to pass through, and the mass-to-charge ratio filter 424 downstream of the ion trap 418 may be controlled to allow only ions having a mass-to-charge ratio within a subset of the selected mass-to-charge ratio range to pass through. Alternatively, both mass-to-charge ratio filters 424 may be controlled to allow only ions having a mass-to-charge ratio within the same mass-to-charge ratio range to pass through. In this latter embodiment, the upstream mass-to-charge ratio filter 424 can be controlled to allow only ions having a mass-to-charge ratio within a selected mass-to-charge ratio range to enter the ion trap 418, and the mass-to-charge ratio filter 424 downstream of the ion trap 418 can be used to allow ions leaving the ion trap 418 to be separated in a timely manner as they pass through the mass-to-charge ratio filter 424 on their way to the detector 434.

[0122] In some alternative embodiments, a conventional drift tube may replace (i.e., substitute for) the mass-to-charge ratio filter 424. In some such embodiments, the axial passage defined by the drift tube may have a constant cross-sectional area. In some such embodiments, the drift tube may be configured and controlled using one or more voltages generated by the voltage source 450 to radially focus ions traveling axially therethrough. In other embodiments, at least a portion of the drift tube adjacent to its ion outlet end may be funnel-shaped, i.e., wherein the cross-sectional area of ​​the axial passage decreases in the direction of the ion outlet. In some such embodiments, at least the funnel section may be configured and controlled using one or more voltages generated by the voltage source 450 to radially focus ions traveling axially therethrough, and in other embodiments, the entire drift tube may be configured and controlled using one or more voltages generated by the voltage source 450 to radially focus ions traveling axially therethrough. In some such embodiments, the plate or grid 426 may be replaced with a conventional ion blanket defining a central orifice therethrough, wherein the ion blanket is configured and controlled utilizing one or more voltages generated by the voltage source 450 to further focus the ions into the orifice and through the orifice to the next stage of the instrument 400.

[0123] The instrument 400 further includes a fourth differential pumping region 428 having an ion inlet that is coupled to or integrated with the ion outlet of the mass-to-charge ratio filter 424. A fourth pump P4 is operatively coupled to the region 428 and configured to pump the region 428 to a pressure less than the pressure of the filter 424. In the illustrated embodiment, the fourth differential pumping region 428 includes an ion lens and a deflector 430 followed by a conventional energy analyzer 432 electrically connected to a voltage output V8 of the voltage source 450. In one embodiment, the energy analyzer 432 is a dual hemispherical deflection energy analyzer (HDA) configured to transmit a narrow band of ion energies centered around a nominal ion energy of 130 eV / z. In alternative embodiments, the energy analyzer 432 may be implemented in other conventional forms and / or configured to transmit ion energies centered around other ion energy values.

[0124] The instrument 400 further includes an ion mass and charge detector 434, which in the illustrated embodiment is provided in the form of a single-stage electrostatic linear ion trap (ELIT). The ELIT configuration is generally a single-stage ELIT14, which Figure 1-2B For example, ELIT 434 includes spaced apart end caps 436, 438, each of which illustratively represents Figure 2A and Figure 2B 4 and 5. The ELIT 434 is operatively coupled to a pump P5 configured and controlled to establish a pressure (e.g., a vacuum) within a fifth differential pumping region defined by the ELIT chamber. In one embodiment, the pump P5 is controlled to provide a pressure of approximately 10 -9 A pressure of 1000 mbar is established within the ELIT 434, however in other embodiments pump P5 may be controlled to establish a higher or lower pressure within the ELIT chamber.

[0125] The input of a conventional charge sensitive preamplifier 442 is electrically connected to the charge detection cylinder 440, and the output of the preamplifier 442 is electrically connected to the input of a conventional processor 444. The processor 444 illustratively includes or is connected to a memory 446, in which instructions that can be executed by the processor 444 to control the operation of the instrument 444 as will be described below are stored. In some embodiments, the processor 444 is operatively connected to one or more peripheral devices PD 448 via a number P of signal paths, where P can be any positive integer. In some embodiments, the processor 444 can also be electrically connected to a voltage source 450 via a number M of signal paths, where M can be any positive integer. In such an embodiment, the processor 444 can be programmed to control the operation of the voltage source 450. In an alternative embodiment, the voltage source 450 itself can be programmable and / or manually controllable. In any case, the charge sensitive preamplifier 442, the processor 444, the memory 446, and the (multiple) peripheral devices 448 are all illustratively as described above with respect to Figure 1 Just as described.

[0126] A voltage output V9 of the voltage source 450 is electrically connected to the ion mirror 436, and another voltage output V10 of the voltage source 450 is electrically connected to the ion mirror 438. It will be understood that the voltages V9 and V10 each illustratively include a number of different switchable voltages for controlling the operation of the respective ion mirrors 436, 438, as described by Figure 2A and Figure 2B and described in detail above, and the operation of ELIT 434 under the control of such voltages V9 and V10 is also as described above with respect to Figure 1-4E As described in each level depicted in.

[0127] Reference now Fig.10 and Fig.11, pulsed operation of the CDMS instrument 400 includes selective control of at least voltages V5, V9, and V10. It will be appreciated that high states of voltages V5, V9, and V10 corresponding to an ion storage or trapped state in the case of V5 (i.e., the V5 voltage at which the ions are trapped and stored within the ion trap 418) or an ion trapping or reflection state in the case of ion mirrors 436, 438 (i.e., the V9 and V10 voltages which cause the ion mirrors 436, 438 to operate in their reflection mode to receive ions therein from the charge detection cylinder 440) reverse the direction of travel of the ions and accelerate the ions backward through the charge detection cylinder 440 and toward the other ion mirror, such that the ions are trapped within the ELIT 434 and oscillate back and forth between the ion mirrors 436, 438 each time they pass through the detection cylinder 440, as described above. The low state of voltages V5, V9 and V10 corresponds to a transmission state, ie, a voltage at which ions are released and ejected from ion trap 418 and cause ion mirrors 436, 438 to operate in their transmission mode to transmit ions therethrough, as described above.

[0128] The ion source 404 is responsive to a voltage V1 generated by a voltage source 450 to generate ions. In some embodiments, the processor 444 is operable to execute instructions stored in the memory 446 to control the voltage V1 to cause the ion source 404 to generate ions. In alternative embodiments, the voltage source 450 itself may be programmed in this manner, or the voltage source 450 may be manually controlled to generate V1. In any case, the generated ions pass through the source region 408 and enter the ion trap 418. In embodiments in which the source region 408 includes a docking portion 410, the voltage source 450 is operable to generate one or more voltages V2 for controlling the docking portion 410 to cause the ions to pass through the docking portion 410, as briefly described above. In any case, the voltage V3 generated by the voltage source 450 controls the ion entrance of the ion trap 418 to set the energy of the ions entering from the source region 408 to a target energy, for example, approximately 130 eV / z. Initially, as Fig.11 As indicated in , voltage(s) V5 are set to a trapping state to capture, trap and accumulate generated ions in ion trap 418, and voltages V9 and V10 are set to a transmission state to clear ELIT 434 by allowing any ions traveling toward ELIT 434 to pass therethrough.

[0129] The pulse operation of the apparatus 400 begins when the voltage(s) V5 are switched to the transmission state for a period of time t W The pulse width duration t is t, after which the voltage (s) V5 is switched back to the trapped state again. W434 , and ions stored in the ion trap 418 are released or ejected therefrom and into the region 424, and travel toward the ELIT 434 in response to the electric field established by the voltages V5 and V7. In an embodiment in which the region 424 includes a mass-to-charge ratio filter, only ions pass through the region 424 and enter the region 428, which have a mass-to-charge ratio value selected for passing through the (multiple) voltages V6. Ions pass through the region 428 and enter the ion mirror 436 of the ELIT 434, which have energies in a narrow band of energies with respect to the transmission energy of the energy analyzer 432, and ions with energies outside the narrow band are deflected away from the ion entrance of the ELIT 434.

[0130] The delay time t after the voltage(s) V5 transitions to the ion transmission state to release ions from the ion trap 418 is D1 At the expiration, the voltage V10 on the rear ion mirror or end cap 438 switches from the transmission state to the trapping or reflection state. Ions that enter the rear ion mirror or end cap 438 from the charge detection cylinder 440 are then reversed in direction by the ion reflection electric field established therein and are accelerated by the ion reflection electric field back through the charge detection cylinder 440 toward the front ion mirror or end cap 436, as described above with respect to Figure 2A and Figure 2B Another delay time t after the voltage (s) V5 is switched to the ion transmission state to release ions from the ion trap 418 is D2 At the expiration, the voltage V9 on the front ion mirror or end cap 436 switches from the transmission state to the capture or reflection state. Upon such a switch of the voltage V9 to the capture or reflection state, ions in the charge detection cylinder 440 or in the rear ion mirror or end cap 438 will thereby be trapped within the ELIT 434, and with both ion mirrors 436, 438 in their reflection modes, the trapped ion(s) will oscillate back and forth between the ion mirrors 436, 438 each time they pass through the charge detection cylinder 440 and induce corresponding charges thereon, as described above. Fig.11 As depicted in FIG. 4 , the ion(s) will remain trapped within the ELIT 434 for a trapping time period t trap , and in the capture time period t trapAt the end, voltages V9 and V10 are returned to their transmission states to clear ELIT 434 before starting the sequence again. The resulting charge detection signal generated by charge preamplifier 442 in response to the detection of the charge induced on the charge detection cylinder by the ions passing therethrough will be processed by processor 444 (as described above) to determine the mass and charge of the trapped ion(s). In some embodiments, the voltages are controlled as just described so as to trap a single ion in ELIT 434, and in other embodiments, the voltages may be controlled so as to trap more than one ion in ELIT 434.

[0131] The pulsed mode operation of the CDMS instrument 400 provides improved detection efficiency by accumulating and storing ions in the ion trap 418 and then controllably releasing the ions from the trap 418 so that their arrival at the ELIT 434 is synchronized with the opening and closing of the ion mirrors 436, 438 (i.e., transmission mode and reflection mode, respectively).

[0132] There is a considerable distance D1 (eg, 0.86 m) between the ion exit of the ion trap 418 and the front end of the charge detection cylinder 440. Fig.10 In one embodiment, D1 is approximately 0.86 meters, however in alternative embodiments, D1 may be greater or less than 0.86 meters. In any case, the time it takes for an ion to travel D1 depends on its kinetic energy and its mass-to-charge ratio (m / z). Since the energy analyzer 432 transmits only ions within a narrow kinetic energy distribution, this transition or travel time depends primarily on the ion m / z. If the pulse width duration t W is short, then the range of m / z values ​​will be captured for a given total delay time t D , where t D is the transition of voltage(s) V5 to the ion transport state (i.e., t W The falling edge of V5 at t, which corresponds to the opening of the ion exit of ion trap 418 and the release or ejection of ions therefrom) and the transition of voltage V9 to an ion trapping or reflectron state (i.e., t W The rising edge of V9 after the subsequent rising edge of V5 at , which corresponds to the time between the closing of the ion mirror 436 of the ELIT 434 (i.e., reflectron mode) and the corresponding trapping of the (multiple) ions in the ELIT 434), i.e., t D =t D1 +t D2 Under these conditions, when the front end cap is switched to reflectron mode, the maximum mass-to-charge ratio m / z that can be captured is MAX The (i.e., slowest) ions are those that have just entered the detection cylinder:

[0133] m / z MAX =2eE[tD 2 / d1 2 ] (1).

[0134] In Equation 1, e is the elementary charge, E is the ion energy, and d1 is as described above and in Fig.10 As shown in . The minimum mass-to-charge ratio that can be captured is m / z MIN The (i.e., fastest) ions are those that travel through the charge detection cylinder 440, are reflected by the rear ion mirror or end cap 438, travel back through the charge detection cylinder 440, and are about to leave the front ion mirror or end cap 436 when the voltage V9 is switched to the reflective state:

[0135] m / z MIN =2eE[t D 2 / (d1+2d2+d3) 2 ] (2).

[0136] In equation 2, d2 is the length of the charge detection cylinder 440, and d3 is the distance between the ion entrance / exit of the corresponding ion mirror 436, 438 and the corresponding end of the charge detection cylinder 440. The 2d2 in equation (2) is generated because the ions travel back and forth through the charge detection cylinder 440, and d3 is generated by the time spent in the end caps. In some embodiments of the ELIT 434, d2=d3, so that the time it takes for the ions to travel through the charge detection cylinder 440 is equal to the time it takes to travel through each end cap 436, 438. In such an embodiment, equation (2) is summarized as follows:

[0137] m / z MIN =2eE[t D 2 / (d1+3d2) 2 ] (3).

[0138] The ratio of the maximum m / z to the minimum m / z that can be trapped is therefore given by:

[0139] m / z MAX / m / z MIN =(d1+3d2) 2 / d1 2 (4).

[0140] Therefore, the range of m / z values ​​that can be captured is a function of the ion energy and the delay time t DLonger delay times shift the m / z window to larger m / z values, but the relative width of the m / z window remains unchanged. As described above, the ratio of the maximum m / z value to the minimum m / z value of the CDMS instrument 400 where d2=d3 is 1.38, so a single delay time t D The width of the captured m / z window is m / z MIN to 1.38×m / z MIN For example, if the delay time t D Setting this so that 25 kDa is the minimum m / z value that can be trapped, ions with m / z values ​​up to 34.5 kDa can be trapped simultaneously.

[0141] Example

[0142] Truncated hepatitis B virus (HBV) capsid protein (Cp149) was assembled in 300 mM sodium chloride for 24 hours, dialyzed into 100 mM ammonium acetate (Sigma Aldrich, 99.999% trace metal base), and stored for at least one week before use (to give assembly errors time to correct themselves). The initial concentration of the capsid protein was 1 mg / mL. The assembly mainly produced an icosahedral T=4 capsid (in terms of diameter, about 32 nm) composed of 120 capsid protein dimers, together with a smaller amount (in this case, about 5%) of an icosahedral T=3 capsid with 90 protein dimers. The pseudo-critical concentration of HBV assembly in 300 mM NaCl is 3.7 μM, and therefore the final capsid concentration is about 0.22 μM. The stock solution sample was purified by a size exclusion chromatography (SEC) with a 6 kDa cutoff value. Aliquots of the purified solution were then diluted with 100 mM ammonium acetate to the desired concentrations ranging from 0.05 µg / mL to 100 µg / mL.

[0143] Pyruvate kinase (PK) was prepared at 10 mg / ml in ammonium acetate. An aliquot of the stock solution was purified by SEC with a 6 kDa cutoff. The purified solution was then diluted to 2 mg / mL using 100 mM ammonium acetate.

[0144] Fig. 12A Show use Fig.10 Portions of two representative mass distributions of HBV samples measured by the CDMS instrument 400 illustrated in FIG. 4 and described above. Results are shown for two concentrations: Fig. 12A 10 µg / mL (100-fold dilution of HBV stock solution) indicated as 500 in Fig. 12A 0.5 µg / mL (2000-fold dilution) of 502. Fig. 12AThe CDMS profile shown in was recorded for 16.6 minutes (10,000 capture events) and is plotted with a 25 kDa bin. At a concentration of 10 µg / mL (labeled 500), there is a major peak at a mass of approximately 4.05 MDa, close to the expected mass for the T=4 capsid of HBV Cp149. At a concentration of 0.5 µg / mL (labeled 502), the peak almost disappears. Note that the spurious signal rate in CDMS is very small because the ions are measured for a relatively long time (100 ms). The HBV T=4 capsid ions carry approximately 140 elementary charges, and the likelihood that a random noise signal could masquerade as an ion signal of this magnitude over a period of 100 ms is very small. Therefore, the background noise in the region of interest is also very small.

[0145] It should be noted that the number of analytes contained in the electrospray droplets can affect the detection efficiency. An estimate of the average number of capsids present in the droplets can be obtained illustratively from the concentration and droplet size. The average size of the primary electrospray droplets can then be estimated from the electrospray conditions. For an estimated droplet size of 70 nm, at the concentration of the HBV stock solution (1 mg / mL), the average number of capsids per droplet is about 0.025 (i.e., 1 in 40 droplets contains a capsid).

[0146] Fig. 12B A logarithmic plot 504 of integrated counts in the range of 3.8 MDa to 4.4 MDa versus HBV concentration from 0.5 μg / mL to 10 μg / mL is shown. The points are measured values, and the line is illustratively a least squares fit. For a logarithmic plot of response versus concentration, a slope of 1.0 is expected, and a slope close to 1.0 is observed. For example, in Fig. 12B In the graph 504 of , the slope is 1.031. Based on these results, the detection limit of HBV T=4 capsid can be taken as about 0.5 µg / mL. This corresponds to 1.1×10 −10 mol / L or 6.6×10 10 particles / mL. During the 16.6-minute collection period, approximately 1.3 µL of solution was electrosprayed. Taking this into account, the detection limit is therefore approximately 0.14 femtomoles or 8.6 × 10 7 During the 16.6-min data acquisition time, 19 ions were detected. Therefore, the detection efficiency of HBV T=4 capsid was about 2.2×10 -7 .

[0147] Fig.13A The normal mode (ie, non-pulsed) is shown (at Fig.13A 602) and a pulse mode as described herein (in Fig.13A600 in FIG. 4 ) for HBV capsids at a concentration of 1 µg / mL as measured by CDMS instrument 400. Clearly, the intensity in distribution 600 measured using pulsed mode is much greater than the intensity in distribution 602 measured in normal (non-pulsed) mode; the normal mode distribution contains 15 ions and the pulsed mode distribution contains 3695 ions, so the intensity gain in this example is 246.

[0148] Fig. 13B Another comparison of mass distributions is shown between normal (non-pulsed) mode 606 and pulsed mode 604. In this case, the normal mode distribution 606 was measured using a concentration of 0.5 μg / mL and the pulsed mode distribution 604 was measured using a concentration of 0.05 μg / mL. The normal mode distribution 606 contains 8 ions and the pulsed mode distribution 604 contains 145 ions, so the intensity gain is 181 (accounting for the concentration difference).

[0149] The intensity gain depends on the capture efficiency, pulse width t W and the delay time t D1 and t D2 (All in Fig.11 418). It was found that the signal from the ions trapped in the ion trap 418 persisted for more than 20 seconds after the electrospray source 404 was turned off, indicating that the ions were efficiently trapped in the ion trap 418. W If the pulse width t is too short, there is not enough time for the ions to leave the ion trap 418. On the other hand, if the pulse width t W Too long, and the benefit of accumulating ions in the ion trap 418 is lost and the signal approaches the value of the non-pulsed mode. The intensity gain from the pulsed mode of operation is found to be about 200 on average, with a pulse width t W and the delay time t D1 and t D2 Optimization. For an m / z of 2800 Da, it should be noted that only about 1 ion in 620 can be captured in the non-pulsed operating mode of the CDMS instrument 400. By operating in pulsed mode (as described above), most of the signal lost in non-pulsed mode can be recovered. With the pulsed operating mode illustrated and described herein, the detection limit for HBV T=4 capsid is about 200 times lower: 5.5×10 -13 mol / L or 3.3×10 8 particles / mL. This corresponds to approximately 0.7 attomoles or 4.3×10 5 The detection efficiency of HBV T=4 capsid using the pulse operation mode was about 4.4×10 -5 (ie, 200 times the detection efficiency using non-pulsed mode).

[0150] It is relatively easy to inject many ions into ELIT at the same time using the high sensitivity provided by pulse mode CDMS. However, although it is feasible to analyze multiple ion capture events and determine the m / z values ​​and charges of several simultaneously captured ions, the ion-ion interactions in ELIT 434 can cause trajectory and energy fluctuations, which reduce the m / z resolution capability. Because the capture of multiple ions with similar m / z values ​​can lead to errors in data analysis, the measurements depicted in the accompanying drawings are limited to samples, in which (on average) each capture event captures one ion. The distribution of captured ions is a Poisson distribution, and when the average capture efficiency is about 1.0, about one-third of the capture events are empty, another one-third contain a single ion, and the remaining one-third contain two or more ions. For a sample concentration of 10 μg / mL, the number of ions captured in pulse mode is much larger than one in an average of each event, and the sample must be diluted to perform the measurements depicted in the accompanying drawings.

[0151] As described above, the assembly of HBV capsid proteins results in a small number of smaller T=3 capsids in addition to T=4. The average m / z of T=4 ions is 28700 Da, and the average m / z of T=3 ions is 25500 Da. The ratio of these m / z values ​​is 1.13, which falls within the range that can be captured simultaneously. At this point, Fig.14 CDMS mass distributions 700, 702 of HBV measured using the CDMS instrument 400 are shown, showing a T=3 peak at approximately 3.0 MDa and a T=4 peak at 4.05 MDa. Distribution 702 was measured using the CDMS instrument 400 under normal operating conditions (i.e., non-pulsing), and distribution 700 was measured using the CDMS instrument 400 operating in pulsed mode (as described above). The HBV protein concentration was 100 µg / mL for non-pulsing (distribution 702) and 1 µg / mL for pulsing (distribution 700). The fraction of T=3 capsids (from integrated counts) was 0.0435 in the normal mode distribution 702 and 0.0470 in the pulsed mode distribution 700. However, the detection efficiency in the normal mode distribution 702 is different from the (m / z) 1 / 2 The ratio of the intensity of the CDMS instrument 400 is proportional to the m / z ratio because the larger m / z (i.e., slower) ions spend longer in the trappable region of the ELIT 434. In the pulsed mode operation of the CDMS instrument 400, all ions in the trappable region of the ELIT 434 are trapped, and the detection efficiency of these ions does not depend on the m / z ratio. After correcting the normal mode ratio for detection efficiency, the ratio increases to 0.0461 (compared to 0.0470 for the pulsed mode). Therefore, the intensity ratio is not significantly affected by the pulsed mode of operation.

[0152] If the m / z distribution is different from the m / z described above MIN to 1.38×m / z MIN The wider the window, the more you can adjust the total delay time t D , to capture different parts of the distribution. For example, Fig.15 The CDMS mass distribution of a pyruvate kinase (PK) sample measured using CDMS instrument 400 is shown. Mass distribution 804 is measured under normal (i.e., non-pulsed) conditions, where peaks due to PK tetramers (230 kDa), octamers (460 kDa), dodecamers (690 kDa), and hexadecamers (920 kDa) are apparent. It is not possible to transmit all oligomers simultaneously in pulse mode. However, by adjusting the delay time t D , it is possible to transmit different m / z bands. The mass distribution 800 is measured in pulse mode with a delay time t D is optimized to transmit m / z values ​​including the tetramer (transmitting m / z values ​​ranging from about 6600 Da to 9150 Da), and mass distribution 802 is measured in pulse mode with a delay time t D Optimized to transmit octamers and dodecamers. In both cases, the ratio of the minimum and maximum mass-to-charge ratios transmitted is close to the value predicted above (1.38). The ability to select parts of the m / z distribution is valuable in many applications. For example, because individual ions are processed in CDMS, it is beneficial not to spend time processing ions that do not contain useful information. Therefore, as just described, it is valuable to distinguish parts of the m / z distribution that do not contain useful information. Many samples contain a considerable amount of low-quality ions that can be distinguished using this method.

[0153] In the illustrated embodiment of the instrument 400 just described, the ion mass and charge detector 434 is provided in the form of a single-stage electrostatic linear ion trap (ELIT), however it will be appreciated that in other embodiments, the ion mass and charge detector 434 may alternatively be provided in the form of a multi-stage ELIT (e.g., as described herein with respect to Figure 1-4E 14) or multiple single-stage ELITs (e.g., as described herein with respect to Figure 6-8F ), or in some embodiments, in the form of one or more orbital traps (e.g., as disclosed in co-pending International Patent Application No. PCT / US2019 / 013278 described below). In the first two cases, the operation of the instrument 400 can be modified consistently with the description of the systems 10, 200 set forth above to sequentially supply ions to each of the multiple ELITs or ELIT stages. Figure 1-4EIn the case of a multi-stage ELIT of the type illustrated in FIG. 4 and described above, it will be noted that each ELIT region (e.g., E1, E2, and E3) will be spaced a progressively greater distance away from the ion trap 418, so that the minimum and maximum mass-to-charge ratio values ​​will be somewhat different for each. It will be further noted that, as given by equation (4) above, the range of mass-to-charge ratios that can be trapped within each of the ELIT regions will progressively decrease in value as the distance of the ELIT region from the ion trap 418 increases.

[0154] It will be appreciated that the dimensions of the various components of any ELIT and / or array 14, 205, 302, 434 illustrated in the accompanying drawings and described above may be illustratively selected to establish a desired ion oscillation duty cycle therein and / or within each ELIT or ELIT region E1-E3, corresponding to the ratio of the time spent by the (multiple) ions in the corresponding (multiple) charge detection cylinder CD1-CD3 to the total time spent by the (multiple) ions traversing the combination of the corresponding ion mirror and the corresponding (multiple) charge detection cylinder CD1-CD3 during one complete oscillation cycle. For example, for the purpose of reducing noise in the determination of the fundamental frequency magnitude caused by harmonic frequency components of the measurement signal, a duty cycle of approximately 50% may be desirable in one or more of the ELIT or ELIT regions. Details concerning such sizing considerations for achieving a desired duty cycle (e.g., such as 50%) are illustrated and described in co-pending International Patent Application No. PCT / US2019 / 013251, filed on January 11, 2019, and entitled ELECTROSTATIC LINEAR ION TRAP DESIGNFOR CHARGE DETECTION MASS SPECTROSCOPY, the disclosure of which is expressly incorporated herein by reference in its entirety.

[0155] It will be further understood that one or more charge calibration or reset devices may be used with the charge detection cylinder(s) of any one or more of the ELIT and / or arrays 14, 205, 302, 434, and / or in any one or more of the regions E1-E3 of the ELIT or ELIT array. An example of such a charge calibration or reset device is illustrated and described in co-pending International Patent Application Nos. PCT / US2019 / 013284 (filed on January 11, 2019) and PCT / US2019 / 035381 (filed on June 4, 2019), both entitled APPARATUS AND METHOD FOR CALIBRATING OR RESETTING A CHARGE DETECTOR, the disclosures of which are expressly incorporated herein by reference in their entirety.

[0156] It will be further understood that one or more charge detection optimization techniques may be used with any one or more of the ELITs and / or arrays 14, 205, 302, 434, and / or with one or more (multiple) regions E1-E3 of such ELITs and / or ELIT arrays, for example, for triggering a capture or other charge detection event. Examples of some such charge detection optimization devices and techniques are illustrated and described in co-pending International Patent Application No. PCT / US2019 / 013280, filed on January 11, 2019, and entitled APPARATUS AND METHOD FOR CAPTURING IONS IN AN ELECTROSTATIC LINEAR ION TRAP, the disclosure of which is expressly incorporated herein by reference in its entirety.

[0157] It will be further understood that one or more ion source optimization devices and / or techniques may be used with one or more embodiments of the ion source 12 illustrated and described herein, some examples of which are illustrated and described in co-pending international patent applications No. PCT / US2019 / 013274 (filed on January 11, 2019) and PCT / US2019 / 035379 (filed on June 4, 2019), both entitled HYBRID ION FUNNEL-ION CARPET (FUNPET) ATMOSPHERIC PRESSURE INTERFACE FOR CHARGEDETECTION MASS SPECTROMETRY, the disclosures of which are expressly incorporated herein by reference in their entirety.

[0158] It will be further understood that any ion mass detection system 10, 60, 80, 200, 300, 400 illustrated and described herein may be implemented according to real-time analysis and / or real-time control techniques, some examples of which are illustrated and described in co-pending International Patent Application No. PCT / US2019 / 013277, filed on January 11, 2019, and entitled CHARGE DETECTION MASS SPECTROMETRY WITH REAL TIME ANALYSIS AND SIGNAL OPTIMIZATION, the disclosure of which is expressly incorporated herein by reference in its entirety.

[0159] It will be further understood that any ion mass detection system 10, 60, 80, 200, 300, 400 illustrated and described herein may be configured to supply multiple ions to any one or more of the ELITs and / or arrays 14, 205, 302, 434 illustrated and described herein, such that one or more of such ELITs and / or ELIT arrays can be operated to measure the mass and charge of multiple ions at a time, some examples of which are illustrated and described in co-pending International Patent Application No. PCT / US2019 / 013285 filed on January 11, 2019 and entitled APPARATUS AND METHOD FOR SIMULTANEOUSLY ANALYZING MULTIPLE IONS WITH AN ELECTROSTATICLINEAR ION TRAP, the disclosure of which is expressly incorporated herein by reference in its entirety.

[0160] It will be further understood that in one or more of the ion mass detection systems 10, 60, 80, 200, 300, 400 illustrated and described herein, at least one ELIT may alternatively be provided in the form of an orbital trap, some examples of which are illustrated and described in co-pending international patent application No. PCT / US2019 / 013278, filed on January 11, 2019 and entitled ORBITRAP FOR SINGLE PARTICLE MASS SPECTROMETRY, the disclosure of which is expressly incorporated herein by reference in its entirety.

[0161] It will be further understood that the CDMS instrument 400 may additionally include Figure 5A 1 and 10. The CDMS instrument 400 is an embodiment of an ion mass detection system illustrated in FIG. 1 and described above (ie, including alternatives to the ion mass detection systems 10, 200, 300). Likewise, it will be understood that the CDMS instrument 400 may additionally include an ion mass detection system. Figure 5B Embodiments of the ion mass detection system illustrated in and described above (ie, including alternatives to the ion mass detection systems 10 , 200 , 300 ).

[0162] Although the present invention is illustrated and described in detail in the foregoing drawings and description, the present invention is to be regarded as illustrative rather than restrictive in nature, understanding that only illustrative embodiments of the present invention are shown and described and that all changes and modifications within the spirit of the present invention are desired to be protected.

Claims

1. A charge detection mass spectrometer, comprising: an ion source configured to generate ions from the sample, at least one voltage source configured to generate a plurality of output voltages, an ion trap coupled to a first set of the plurality of output voltages and configured to receive and store generated ions therein in response to a trapping state thereof and to selectively release stored ions therefrom in response to a transport state thereof, an electrostatic linear ion trap (ELIT) spaced from the ion trap, the ELIT comprising front and rear ion mirrors and a charge detection cylinder positioned therebetween, the front and rear ion mirrors each being coupled to a second and third set of the plurality of output voltages, respectively, and configured to respond to a transmission state thereof to cause ions to be transmitted therethrough and to respond to a reflection state thereof to reflect ions entering therethrough from the charge detection cylinder back into the charge detection cylinder, and processing circuitry for controlling said first set of voltages to said transmission state thereof so as to cause said ion trap to release at least some of said stored ions therefrom to travel toward and into said ELIT via said front ion mirror, and thereafter to control a third set of voltages followed by a second set of voltages to said reflection state thereof so as to trap at least one of said ions travelling therein and cause said at least one trapped ion to oscillate back and forth between said front ion mirror and said rear ion mirror each time it passes through said charge detection cylinder and induces a corresponding charge thereon, wherein the processing circuit is configured to control the first set of voltages from the captured state thereof to the transmitted state for a pulse width duration, and is configured to control the first set of voltages from the transmitted state thereof to the captured state in response to expiration of the pulse width duration, wherein the processing circuit is configured to: control the third group of voltages from the transmission state thereof to the reflection state upon expiration of a first delay time from control of the first group of voltages from the capture state thereof to the transmission state, and control the second group of voltages from the transmission state thereof to the reflection state upon expiration of a second delay time from control of the third group of the plurality of output voltages from the transmission state to the reflection state, Wherein, the minimum and maximum mass-to-charge ratio values ​​of the at least one ion trapped in the ELIT are proportional to the sum of the first delay time and the second delay time, and the sum of the first delay time and the second delay time is controlled by the processing circuit to select the corresponding minimum mass-to-charge ratio value and maximum mass-to-charge ratio value of the ions trapped in the ELIT.

2. The charge detection mass spectrometer of claim 1 , further comprising a charge sensitive amplifier having an output and an input coupled to the charge detection cylinder, the amplifier responsive to detection of charge induced on the charge detection cylinder by the at least one ion passing through the charge detection cylinder to produce a charge detection signal at the output of the amplifier, in, The processing circuit is configured to process a plurality of the charge detection signals to determine therefrom a mass and a charge of the at least one trapped ion.

3. The charge detection mass spectrometer of claim 1 , further comprising a mass-to-charge ratio filter positioned between the ion trap and the ELIT, the mass-to-charge ratio filter being configured to allow only ions to pass therethrough, The ions have a mass-to-charge ratio above a mass-to-charge ratio threshold, below a mass-to-charge ratio threshold, or within a selected mass-to-charge ratio range.

4. A method of operating a charge detection mass spectrometer, the charge detection mass spectrometer comprising an electrostatic linear ion trap (ELIT) and an ion trap, the electrostatic linear ion trap (ELIT) having a charge detection cylinder positioned between a front ion mirror and a rear ion mirror, the ion trap being spaced apart from the front ion mirror, the method comprising: Generate ions from the sample, storing the generated ions in the ion trap, controlling the ion trap to release at least some of the stored ions therefrom and travel toward and into the ELIT via the front ion mirror, upon expiration of a first delay time from controlling the ion trap to release stored ions, controlling the rear ion mirror to a reflective state in which the rear ion mirror reflects ions entering therein from the charge detection cylinder back through the charge detection cylinder and toward the front ion mirror, and upon expiration of a second delay time from controlling the rear ion mirror to its said reflective state, controlling the front ion mirror to a reflective state in which the front ion mirror reflects ions entering therein from the charge detection cylinder backwards through the charge detection cylinder and toward the rear ion mirror to capture in the ELIT at least one of the ions released from the ion trap such that the at least one trapped ion oscillates between the front ion mirror and the rear ion mirror each time it passes through the charge detection cylinder and induces a corresponding charge thereon, Wherein, the minimum and maximum mass-to-charge ratio values ​​of the at least one ion trapped in the ELIT are proportional to the sum of the first delay time and the second delay time, and the sum of the first delay time and the second delay time is controlled to select the corresponding minimum mass-to-charge ratio value and maximum mass-to-charge ratio value of the ions trapped in the ELIT.

5. The method of claim 4, further comprising processing, with a processor, a plurality of induced detections of the charges to determine therefrom a mass and a charge of the at least one trapped ion.

6. The method according to claim 4 further comprises filtering the ions released from the ion trap before at least some of the stored ions travel into the ELIT via the front ion mirror so as to allow only ions having a mass-to-charge ratio above or below a mass-to-charge ratio threshold or having a mass-to-charge ratio within a selected mass-to-charge ratio range to enter the ELIT.

7. The method according to claim 4, wherein: The mass-to-charge ratio range of ions that can be trapped within the ELIT varies with the distance between the ion trap and the ELIT and the internal axial dimension of the ELIT.

8. The method of claim 7, further comprising configuring the spectrometer for trapping a selected range of ion mass-to-charge ratios within the ELIT by establishing corresponding distances between the ion trap and the ELIT.

9. The charge detection mass spectrometer according to claim 1, wherein: The ion outlet of the ion trap is spaced apart from a first end of the charge detection cylinder facing the front ion mirror by a first distance, and the length of the charge detection cylinder between the first end thereof and a second end of the charge detection cylinder facing the rear ion mirror defines a second distance, and the first distance and the second distance are selected to limit the mass-to-charge ratio range of ions that can be trapped within the ELIT.

10. The charge detection mass spectrometer of claim 9, further comprising a charge sensitive amplifier having an output and an input coupled to the charge detection cylinder, the amplifier responsive to detection of charge induced on the charge detection cylinder by the at least one ion passing through the charge detection cylinder to produce a charge detection signal at the output of the amplifier, in, The processing circuit is configured to process a plurality of the charge detection signals to determine therefrom a mass and a charge of the at least one trapped ion.

11. The charge detection mass spectrometer of claim 9, further comprising a mass-to-charge ratio filter positioned between the ion trap and the ELIT, the mass-to-charge ratio filter being configured to allow only ions to pass therethrough, The ions have a mass-to-charge ratio above a mass-to-charge ratio threshold, below a mass-to-charge ratio threshold, or within a selected mass-to-charge ratio range.

12. The method according to claim 4, further comprising: spacing the ion outlet of the ion trap a first distance from the end of the charge detection cylinder facing the front ion mirror of the ELIT, and forming the charge detection cylinder to define a second distance between opposite ends of the charge detection cylinder, The first distance and the second distance define a mass-to-charge ratio range of ions that can be captured within the ELIT.

13. The method of claim 12, further comprising processing, with a processor, a plurality of induced detections of the charges to determine therefrom a mass and a charge of the at least one trapped ion.

14. The method of claim 12, further comprising filtering the ions released from the ion trap to allow only ions having a mass-to-charge ratio above or below a mass-to-charge ratio threshold or having a mass-to-charge ratio within a selected mass-to-charge ratio range to enter the ELIT.

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