Apparatus and method for pulsed mode charge detection mass spectrometry

Abstract

To provide a charge detection mass spectrometer and a detection method.SOLUTION: A charge detection mass spectrometer includes an ion trap configured to receive and store ions therein and to selectively release stored ions therefrom, and an electrostatic linear ion trap (ELIT) spaced apart from the ion trap. The ELIT includes: first and second ion mirrors; a charge detection cylinder positioned therebetween; and means for selectively controlling the ion trap to release at least some of the stored ions therefrom to allow them to travel into the ELIT, and for controlling the first and second ion mirrors in a manner which traps in the ELIT a single one of the ions traveling therein and causes the trapped ion to oscillate back and forth between the first and second ion mirrors each time passing through and inducing a corresponding charge on the charge detection cylinder.SELECTED DRAWING: Figure 10

Description

Technical Field

[0001] Cross - reference to related applications

[0001] This patent application claims the benefit and priority of U.S. Provisional Patent Application Serial No. 62 / 905,921, filed on September 25, 2019, and the entire disclosure of which is hereby expressly incorporated herein by reference. The entire disclosure is hereby expressly incorporated herein.

[0002] Rights of the government

[0002] This invention was made with government support under Grant No. GM131100 awarded by the National Institutes of Health.

[0003] Field of the invention

[0003] The present invention generally relates to charge detection mass spectrometry (CDMS) instruments, and more specifically, to apparatus and methods for performing pulsed - mode operation of such instruments.

Background Art

[0004]

[0004] Mass spectrometry provides the identification of the chemical composition of a substance by separating the gaseous ions of the substance according to the mass and charge of the ions. Various 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 typically determined as a function of the measured ion mass - to - charge ratio, typically referred to as "m / z", and the measured charge of the ion.

[0005]

[0005] In early CDMS detectors, due to the high level of uncertainty in the measurement of m / z and charge, electrostatic linear ion traps (EL (IT) A detector will be developed, in which ions are made to oscillate back and forth through a charge detection cylinder. Multiple paths of ions through such a charge detection cylinder provide multiple measurements for each ion, and the uncertainty in charge measurement is shown to be reduced by n 1 / 2 where n here is the number of charge measurements. However, such multiple charge measurements necessarily limit the rate at which the m / z and charge of ions can be measured using the current ELIT design. Therefore, it is desirable to strive for improvements in the design and / or operation of ELIT to increase the rate of measurement of the m / z and charge of ions beyond what can be achieved using the current ELIT design.

Summary of the Invention

[0006]

[0006] The present invention can include one or more of the features recited in the appended claims, and / or one or more of the following features and combinations thereof. In one configuration, a charge detection mass spectrometer includes 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 apart from the ion trap and including a first ion mirror and a second ion mirror and a charge detection cylinder disposed therebetween, means for selectively controlling the ion trap to release at least some of the ions stored therein and move them towards the ELIT, and means for controlling the first ion mirror and the second ion mirror to trap at least one ion passing through the ELIT therein and oscillate the at least one trapped ion back and forth between the first ion mirror and the second ion mirror, passing through the charge detection cylinder each time and inducing the corresponding charge there. It can include means for causing the corresponding charge to be induced.

[0007]

[0007] In another configuration, the charge detection mass spectrometer includes an ion source configured to generate ions from a sample, at least one voltage source configured to generate a plurality of output voltages, and an ion trap coupled to a first set of the plurality of output voltages, the ion trap configured to receive and store the generated ions therein in response to its trapping state and selectively release the stored ions therefrom in response to its transmission state; an electrostatic linear ion trap (ELIT) remote from the ion trap, the ELIT including a front ion mirror, a rear ion mirror, and a charge detection cylinder disposed therebetween, the front ion mirror and the rear ion mirror being coupled to a second set of the plurality of output voltages and a third set of the plurality of output voltages, respectively, and configured to allow ions to pass therethrough in response to its transmission state and reflect ions entering therein from the charge detection cylinder back to the charge detection cylinder in response to its reflection state; and a processing circuit configured to control the first set of voltages to its transmission state to release at least some of the ions stored in the ion trap and move them through the front ion mirror into the ELIT, and then control the second set of voltages followed by the third set of voltages to its reflection state to trap at least one of the ions passing therethrough and vibrate at least one trapped ion back and forth between the front ion mirror and the rear ion mirror, inducing a corresponding charge in the charge detection cylinder each time the ion passes therethrough may include.

[0008]

[0008] In yet another configuration, a method is provided for operating a charge detection mass spectrometer that includes an electrostatic linear ion trap (ELIT) having a charge detection cylinder disposed between a front ion mirror and a rear ion mirror, and an ion trap remote from the front ion mirror. The method includes generating ions from a sample, storing the generated ions in the ion trap, controlling the ion trap to release at least some of the stored ions from the ion trap and move them through the front ion mirror into the ELIT, after controlling the ion trap to release the stored ions, controlling the rear ion mirror to a reflective state such that the rear ion mirror reflects ions entering it from the charge detection cylinder back through the charge detection cylinder toward the front ion mirror, after controlling the rear ion mirror to its reflective state, controlling the front ion mirror to a reflective state such that the front ion mirror reflects ions entering it from the charge detection cylinder back through the charge detection cylinder toward the rear ion mirror to trap at least one of the ions released from the ion trap in the ELIT such that at least one trapped ion oscillates back and forth between the front ion mirror and the rear ion mirror and passes through the charge detection cylinder each time to induce a corresponding charge therein.

Brief Description of the Drawings

[0009]

Figure 1

Figure 2A

Figure 2B

Figure 3

Figure 4

Figure 5A

Figure 5B

Figure 6

Figure 7A

Figure 7B

Figure 7C

Figure 8A

Figure 8B

Figure 8C

Figure 8D

Figure 8E

Figure 8F

Figure 9

Figure 10

Figure 11

Figure 12A

Figure 12B

Figure 13A

Figure 13B

Figure 14

Figure 15

DETAILED DESCRIPTION OF THE INVENTION

[0010]

[0030] To facilitate understanding of the principles of the invention, reference is now made to a plurality of example embodiments shown in the accompanying drawings, and specific language is used to describe them.

[0011]

[0031] This disclosure relates to an electrostatic linear ion trap (ELIT) array, which includes two or more ELITs or ELIT regions and means for controlling them, and this control enables at least two or more ELITs or ELIT regions to operate simultaneously 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 more than two times compared to a conventional single ELIT system, and correspondingly, the total ion measurement time is reduced. In some embodiments, as will be described in detail below with respect to FIGS. 1-4E, the ELIT array can be implemented in the form of two or more ELIT regions arranged in series, i.e., in cascade, and the ion mirrors at the opposing ends in each of the two or more cascade-type ELITs or ELIT regions sequentially capture at least one ion in each ELIT or each ELIT region, and cause the trapped ion(s) in at least two ELITs or ELIT regions to vibrate back and forth simultaneously through the individual charge detectors arranged therein, so that the mass-to-charge ratio and charge of the trapped ion(s) are measured, and it is controlled. In another embodiment, as will be described in detail below with respect to FIGS. 6-10, the ELIT array can be implemented in the form of two or more ELITs arranged in parallel with respect to each other. The ion steering array can be controlled to send at least one ion into each of the ELITs arranged in parallel in sequence or simultaneously, and then the two or more ELITs cause the trapped ion(s) in at least two ELITs to vibrate back and forth simultaneously through the charge detectors in each ELIT, so that the mass-to-charge ratio and charge of the trapped ion(s) are measured, and it is controlled.

[0012]

[0032] Referring to FIG. 1, an ion mass detection system 10 is shown, which includes an embodiment of an electrostatic linear ion trap (ELIT) array 14 to which control and measurement components are coupled. In an exemplary embodiment, the ion mass detection system 10 includes an ion source 12 operably coupled to the inlet of the ELIT array 14. As will be described with respect to FIG. 5, the ion source 12 can include, by way of example, any conventional device or apparatus for generating ions from a sample, and can further include one or more devices and / or apparatuses for separating, collecting, filtering, dissociating, and / or normalizing the ions. As one example, without any limitation being considered, the ion source 12 can include a conventional electrospray ionization source, a matrix-assisted laser desorption ionization (MALDI) source, or other similar ones coupled to the inlet of a conventional mass spectrometer. The mass spectrometer can be of any conventional design, and by way of example and not limitation, can include a time-of-flight (TOF) mass spectrometer, a reflectron mass spectrometer, a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer, a quadrupole mass spectrometer, a triple quadrupole mass spectrometer, a magnetic sector mass spectrometer, or other similar ones. In any case, the ion exit of the mass spectrometer is operably coupled to the ion inlet of the ELIT array 14. The sample serving as the ion generation source can be any biological material or other material.

[0013]

[0033] In an exemplary embodiment, the ELIT array 14 is provided, by way of example, with three ELITs or ELIT regions arranged in a cascade, i.e., in series or end-to-end fashion. Each of the three individual charge detectors CD1, CD2, CD3 is surrounded by its respective ground cylinder GC1-GC3 and operatively coupled together by opposing mirror electrodes. The first mirror electrode M1 is operatively disposed between the ion source 12 and one end of the charge detector CD1, the second mirror electrode M2 is operatively disposed between the opposite end of the charge detector CD1 and one end of the charge detector CD2, the third mirror electrode M3 is operatively disposed between the opposite end of the charge detector CD2 and one end of the charge detector CD3, and the fourth mirror electrode is operatively disposed at the opposite end of the charge detector CD3. In the exemplary embodiment, each of the ion mirrors M1-M3 defines axially adjacent ion mirror regions R1, R2, and the ion mirror M4 defines, by way of example, one ion mirror region R1. By way of example, the region R2 of the first mirror electrode M1, the charge detector CD1, the region R1 of the second mirror electrode M2, and the space between the CD1 and the mirror electrodes M1, M2 together define the 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 of the third mirror electrode M3, and the space between the CD2 and the mirror electrodes M2, M3 together define the 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 of the mirror electrode M4, and the space between the CD3 and the mirror electrodes M3, M4 together define the 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 a smaller number of cascaded ELITs or ELIT regions, e.g., two cascaded ELITs or ELIT regions, and in another alternative embodiment, the ELIT array 14 may include a greater number of cascaded ELITs or ELIT regions, e.g., four or more cascaded ELITs or ELIT regions.The configuration and operation of any such alternative ELIT array 14 will generally conform to the configuration and operation of the embodiments illustrated in FIGS. 1-4E and described below.

[0014]

[0034] In the exemplary embodiment, four corresponding voltage sources V1-V4 are electrically connected to ion mirrors M1-M4, respectively. Each voltage source V1-V4 includes, by way of example, one or more switchable DC voltage sources, which can be controlled or programmed to selectively produce a plurality N of programmable or controllable voltages, where N can be any positive integer. Examples of such voltages are described below with respect to FIGS. 2A and 2B to individually and / or collectively establish one of two different operating modes of each of the ion mirrors M1-M4, as will be described in detail below. In any case, the longitudinal axis 24 extends through the center of the charge detectors CD1-CD3 and the ion mirrors M1-M4, and the longitudinal axis 24 defines the ideal path of travel and its plurality of portions along which ions move within the ELIT array 14 under the influence of the electric field selectively established by the voltage sources V1-V4.

[0015]

[0035] Voltage sources V1-V4 are illustrated as being electrically connected to a conventional processor 16 by a plurality P of signal paths, where the processor 16 includes a memory 18 storing instructions which, when executed by the processor 16, cause the processor 16 to control the voltage sources V1-V4 to produce the desired DC output voltages to selectively establish electric fields within regions R1, R2 of respective ion mirrors M1-M4. P can be any positive integer. In some alternative embodiments, one or more of the voltage sources V1-V4 can be made programmable to selectively produce one or more constant output voltages. In another alternative embodiment, one or more of the voltage sources V1-V4 can be configured to produce one or more output voltages that vary in time with any desired shape. It will be understood that in alternative embodiments, more or fewer voltage sources can be electrically connected to the mirror electrodes M1-M4.

[0016]

[0036] Each charge detector CD1-CD3 is electrically connected to one input of a corresponding one of three charge sensitive preamplifiers CP1-CP3 and are electrically connected to the processor 16. Each of the charge preamplifiers CP1 - CP3 is operable in a conventional manner to receive a detection signal detected by each of the charge detectors CD1 - CD3, respectively, and create a corresponding charge detection signal and supply the charge detection signal to the processor 16. Next, the processor 16 is operable to receive and digitize the charge detection signals created by each of the charge preamplifiers CP1 - CP3, respectively, and store the digitized charge detection signals in the memory 18. The processor 16 is further coupled to one or more peripheral devices 20 (PD) for providing signal input(s) to the processor 16 and / or for providing signal input(s) from the processor 16. In some embodiments, the peripheral device 20 includes at least one of a conventional display monitor, printer, and / or other output device, and in such embodiments, the memory 18 stores instructions that, when executed by the processor 16, cause the processor 16 to control one or more such output peripheral devices 20, thereby causing the analysis of the stored and digitized charge detection signals to be displayed and / or recorded. In some embodiments, a conventional microchannel plate (MP) detector 22 can be placed at the ion exit of the ELIT array 14, i.e., at the ion exit of the ion mirror M4, and can be electrically connected to the processor 16. In such embodiments, the microchannel plate detector 22 operates to supply a detection signal to the processor 16, which corresponds to the detected ions and / or neutral substances.

[0017]

[0037] As will be described in more detail below, the voltage sources V1-V4 are, by way of example, controlled to send ions from the ion source 12 into the ELIT array 14, which selectively captures and confines at least one ion to oscillate within each of three separate ELITs or ELIT regions E1-E3, such that each captured ion (one or more) repeatedly passes through each of the respective charge detectors CD1-CD3 of the three ELITs or ELIT regions E1-E3. A plurality of charge and oscillation period values are measured at each of the charge detectors CD1-CD3, and the recorded results are processed to determine the values of mass-to-charge ratio and mass for the ion(s) captured in each of the three ELITs or ELIT regions E1-E3. Without limitation, depending on a plurality of factors including the dimensions of the three ELITs or ELIT regions E1-E3, the ion oscillation frequency and residence time of the ions within each of the three ELITs or ELIT regions E1-E3, the captured ion(s) oscillate simultaneously in at least two of the three ELITs or ELIT regions E1-E3, and in a typical implementation within each of the three ELITs or ELIT regions E1-E3, the measurement of the charge and mass-to-charge ratio of the ions is enabled to be controlled simultaneously from at least two of the three ELITs or ELIT regions E1-E3.

[0018]

[0038] Referring now to FIGS. 2A and 2B, an embodiment of one of the ion mirrors MX of the ELIT array 14 of FIG. 1 is shown, where X = 1-4, and its configuration and operation are illustrated. In each of FIGS. 2A and 2B, the exemplary ion mirror MX includes seven spaced conductive mirrors electrodes arranged in a cascade configuration. For each of the ion mirrors M2-M4, the first electrode 301 is the ground cylinder GC arranged around the individual ones of the charge detectors CD X-1 of the individual ones X-1It is formed by. On the other hand, the first electrode 301 of the ion mirror M1 is formed by the ion emission port of the ion source 12 (IS), or as part of the ion focusing or transition stage between the ion source 12 and the ELIT array 14. FIG. 2B illustrates the former, and FIG. 2A illustrates the latter. In any case, the first mirror electrode 301 defines an opening A1 passing through its center, which serves as an ion intake port to the corresponding ion mirror MX and / or an ion emission port from the corresponding ion mirror MX. The opening A1 is, for example, conical in shape, which is GC X-1 or between the inner and outer surfaces of the GC or IS, GC X-1 or from the first diameter P1 defined by the inner surface of the IS to GC X-1 or to the extended second diameter P2 on the outer surface of the IS, increasing linearly. The first mirror electrode 301 has a thickness of D1, for example.

[0019]

[0039] The second mirror electrode 302 of the ion mirror MX is spaced from the first mirror electrode 301 and defines a passage through it with a diameter P2. The third mirror electrode 303 is spaced from the second mirror electrode 302 and similarly defines a passage through it with a diameter P2. The second and third mirror electrodes 302 and 303 have equal thicknesses of D2≧D1, for example. The fourth mirror electrode 304 is spaced from the third mirror electrode 303. The fourth mirror electrode 304 defines a passage through it with a diameter P2 and has a thickness of D3≒3D2, for example. The plate or grid 30A is disposed centrally within the passage of the fourth mirror electrode 304 and defines a central opening CA with a diameter P3 passing through it. In the exemplary embodiment, P3<P1, but in other embodiments, P3 can be made greater than or equal to P1. The fifth mirror electrode 305 is spaced from the fourth mirror electrode 304, and the sixth mirror electrode 306 is spaced from the fifth mirror electrode 305. For example, the fifth and sixth mirror electrodes 305 and 306 are the same as the third and second mirror electrodes 303 and 302, respectively.

[0020]

[0040] For each of the ion mirrors M1 - M3, the seventh mirror electrode 307 is formed by a ground cylinder GC disposed around each of the individual charge detectors CD X On the other hand, since the seventh mirror electrode 307 of the ion mirror M4 is the last in order, it can be an independent electrode. In any case, the seventh mirror electrode 307 defines an opening A2 passing through its center, which serves as an inlet and / or an outlet for ions to / from the ion mirror MX. The opening A2 is, for example, a mirror image of the opening A1 and is conical, which linearly decreases from an extended diameter P2 defined by the outer surface of the GC X to a reduced diameter P1 on the inner surface of the GC X between the outer and inner surfaces of the GC X The seventh mirror electrode 307 has, for example, a thickness of D1. In some embodiments X as shown in the example of FIG. 1, the last ion mirror in order, i.e., M4 in FIG. 2, can end with a plate or grid 30A, and M4 can include only the mirror electrodes 301 - 303 and only a part of the mirror electrode 304 including the plate or grid 30A. In such an embodiment, the central opening CA of M4 defines an ion exit passage from the ELIT array 14.

[0021]

[0041] ​The mirror electrodes 301-307 are, by way of example, equally spaced from each other by only the space S1. Such a space S1 between the mirror electrodes 301-307 can, in some embodiments, be a void, i.e., a vacuum gap, and in other embodiments, such a space S1 can be filled with one or more non-conductive, i.e., insulating, materials. The mirror electrodes 301-307 are axially aligned and are thus made to be collinear, with the longitudinal axis 24 passing through the center of each of the aligned passages and also through the centers of the openings A1, A2, and CA. In embodiments where the space S1 includes one or more non-conductive materials, such materials likewise define respective passages therethrough, and those passages are axially aligned with, and thus made to be collinear with, the passages defined through the mirror electrodes 301-307 and have a diameter of P2 or more.

[0022]

[0042] In each of the ion mirrors M1-M4, the region R1 is defined between the opening A1 of the mirror electrode 301 and the central opening CA defined through the plate or grid 30A. In each of the ion mirrors M1-M3, the adjacent region R2 is defined between the central opening CA defined through the plate or grid 30A and the opening A2 of the mirror electrode 307.

[0023]

[0043] Within ELIT or each of ELIT regions E1 - E3, each of charge detectors CD1 - CD3, each in the form of a long conductive cylinder, is disposed between corresponding ones of ion mirrors M1 - M4, spaced only by space S2. As an example, S2 > S1, but in an alternative embodiment, S2 can be made less than or equal to S1. In any case, each of charge detection cylinders CD1 - CD3, for example, defines a passage of diameter P4 through it axially, and each of charge detection cylinders CD1 - CD3 is oriented with respect to ion mirrors M1 - M4 such that longitudinal axis 24 extends through the center of that passage. In an exemplary embodiment, P1 < P4 < P2, but in an alternative embodiment, the diameter of P4 can be less than or equal to P1, or greater than or equal to P2. Each of charge detection cylinders CD1 - CD3 is, for example, disposed within the field - free region of respective ones of ground cylinders GC1 - GC3, and each of ground cylinders GC1 - GC3 is disposed between and forms part of respective ones of ion mirrors M1 - M4 as described above. In operation, ground cylinders GC1 - GC3 are controlled, for example, to ground the potential such that first and seventh electrodes 301 and 307 are always at ground potential. In some alternative embodiments, either or both of first and seventh electrodes 301 and 307 in one or more of ion mirrors M1 - M4 can be set to any desired DC reference potential, and in another alternative embodiment, either or both of first and seventh electrodes 301 and 307 in one or more of ion mirrors M1 - M4 can be electrically connected to a switchable DC or other time - varying voltage source.

[0024]

[0044] As briefly described previously, the voltage sources V1-V4 are, by way of example, arranged such that ions are sent from the ion source 12 into the ELIT array 14 and at least one ion is selectively trapped, confined, and caused to oscillate within each of the three individual ELITs or ELIT regions E1-E3, and each trapped ion (one or more) is controlled to repeatedly pass through each of the charge detectors CD1-CD3 in each of the three ELITs or ELIT regions E1-E3. The values of the charge and the oscillation period are measured at each of the charge detectors CD1-CD3 each time the respective oscillating ion (one or more) passes through. The measured values are recorded and the recorded results are processed to determine the mass-to-charge ratio and mass values for the ion(s) (one or more) trapped in each of the three ELITs or ELIT regions E1-E3.

[0025]

[0045] In each of the ELITs or ELIT regions E1-E3 of the ELIT array 14, at least one ion is trapped and caused to oscillate between the opposing regions of the individual ion mirrors M1-M4 by controlling the voltage sources V1-V4 to selectively establish an ion transmission electric field and an ion reflection electric field in the regions R1, R2 of the ion mirrors M1-M4. In this regard, each voltage source VX is, by way of example, configured in one embodiment to create seven DC voltages DC1-DC7 and to supply each of the DC voltages DC1-DC7 to the respective individual mirror electrodes 301-307 of the respective ion mirror MX. In some embodiments where one or more of the mirror electrodes 301-307 are always held at ground potential, one or more such mirror electrodes 301-307 can instead be electrically connected to the ground reference of the voltage source VX and the corresponding one or more voltage outputs DC1-DC7 can be omitted. Alternatively or additionally, in embodiments where any two or more of the mirror electrodes 301-307 are controlled to the same non-zero DC value, any such two or more mirror electrodes 301-307 can be electrically connected to one of the voltage outputs DC1-DC7 and the extra output voltages DC1-DC7 can be omitted.

[0026]

[0046] As shown by the examples of FIGS. 2A and 2B, each ion mirror MX can be controlled between an ion transmission mode (FIG. 2A) in which voltages DC1 - DC7 generated by a voltage source VX establish ion transmission electric fields in respective regions R1, R2 of the ion mirror MX by selectively applying the voltages DC1 - DC7, and an ion reflection mode (FIGS. 2A and 2B) in which voltages DC1 - DC7 generated by the voltage source VX establish ion trapping or reflection electric fields in respective regions R1, R2 of the ion mirror MX. In the ion transmission mode, as shown by the example of FIG. 2A, voltages DC1 - DC7 are selected to establish an ion transmission electric field TEF1 within region R1 of the ion mirror MX and another ion transmission electric field TEF2 within region R2 of the ion mirror MX. The ion transmission electric fields TEF1 and TEF2 are established, for example, to focus ions towards the central longitudinal axis 24 within the ion mirror MX, while also accelerating ions moving in any direction through both regions R1, R2 of the ion mirror MX, and to maintain a narrow ion trajectory along axis 24 through the ELIT array 14. In the ion reflection mode, as shown by the example of FIG. 2B, voltages DC1 - DC7 are selected to establish an ion trapping or reflection electric field REF1 within region R1 of the ion mirror MX and another ion trapping or reflection electric field REF2 within region R2 of the ion mirror MX. The ion trapping or reflection electric fields REF1 and REF2 are established, for example, such that one or more ions moving axially into respective regions R1, R2 towards the central aperture CA of MX are turned around and transmitted by the reflection electric fields REF1, REF2 in the opposite direction axially away from the central aperture CA. Each of the ion reflection electric fields REF1, REF2 does this, but to do so, first, one or more ions are decelerated and stopped, i.e., trapped, and moved into the respective regions R1, R2 of the ion mirror MX, and then such one or more ions are accelerated to move back in the opposite direction through the respective regions R1, R2 so that one or more ions move away from the respective regions R1, R2 in the opposite direction to that in which they entered the respective regions R1, R2.That is, a charge detection cylinder CD along the central longitudinal axis 24. X-1 Ions moving from X-1 into the region R1 of the ion mirror MX are reflected in the opposite direction toward the inside of the charge detection cylinder CD along the central longitudinal axis 24 by the reflection electric field REF1. Also, other ions moving from the charge detection cylinder CDX along the central longitudinal axis 24 into the region R2 of the ion mirror MX are reflected in the opposite direction toward the inside of the charge detection cylinder CDX along the central longitudinal axis 24 by the reflection electric field REF2. For each of the voltage sources V1 - V4, an example of a set of output voltages DC1 - DC7 created to control the corresponding ones of the ion mirrors M1 - M4 into the above-described ion transmission mode and ion reflection mode is shown in Table 1 below. It will be understood that the following values of DC1 - DC7 are provided as merely examples, and that other values can alternatively be used for one or more of DC1 - DC7. X-1 An example of a set of output voltages DC1 - DC7 created to control the corresponding ones of the ion mirrors M1 - M4 into the above-described ion transmission mode and ion reflection mode by each of the voltage sources V1 - V4 is shown in Table 1 below. It is understood that the following values of DC1 - DC7 are provided as merely examples, and that other values can alternatively be used for one or more of DC1 - DC7.

[0027] [Table 1]

[0028]

[0047] Referring now to FIG. 3, a simplified flowchart of process 100 for controlling voltage sources V1-V4 so as to selectively and sequentially control ion mirrors M1-M4 between their aforementioned transmission and reflection modes is shown, which allows ions to be sent from ion source 12 into the ELIT array 14, and then, in turn, at least one ion is selectively captured, confined, and oscillated within each of three individual ELITs or ELIT regions E1-E3, and each captured ion (one or more) is made to repeatedly pass through each of the charge detectors CD1-CD3 of each of the three ELITs or ELIT regions E1-E3. The values of the charge and the oscillation period are measured and recorded at each of the charge detectors CD1-CD3 each time the respective oscillating ion (one or more) passes through, and then, based on the recorded data, the ion mass value is determined. In an exemplary embodiment, process 100 is stored in memory 18, for example, in the form of instructions that, when executed by processor 16, cause processor 16 to perform the functions described above. In an alternative embodiment where one or more of the voltage sources V1-V4 are independently programmable from processor 16, one or more features of process 100 may be performed, in part or in whole, by one or more such programmable voltage sources V1-V4. However, for the purposes of this disclosure, process 100 is described as being performed by processor 16 only. With reference additionally to FIGS. 4A-4E, process 100 is described as acting on ions of one or more positive charges, although alternatively it will be understood that process 100 may act on ions of one or more negative charges.

[0029]

[0048] Referring to FIG. 4A, process 100 begins at step 102, where processor 16 is operable to control voltage sources V1-V4 so as to set each of voltages DC1-DC7, and all of the ion mirrors M1-M4 are operated in the ion transmission mode. Cause the transmission electric fields TEF1 and TEF2 established in the respective individual regions R1 and R2 to operate so as to accelerate and pass ions therethrough. In one exemplary embodiment, the voltage sources V1 - V4 are controlled, for example, in step 102 of process 100, to produce the voltages DC1 - DC7 according to the all-pass transmission mode as shown in Table 1 above. In any case, using each of the voltage sources V1 - V4 set in step 102 to control the ion mirrors M1 - M4 to operate in the ion transmission mode, as shown by the exemplary ion trajectory 50 depicted in FIG. 4A, the ions entering from the ion source 12 into M1 pass through all of the ion mirrors M1 - M4 and all of the charge detectors CD1 - CD3 and exit from M4. Such control of the ion mirrors M1 - M4 to their respective transmission modes thus draws one or more ions from the ion source 12 into the entire ELIT array 14, as shown in FIG. 4A. The ion trajectory 50 depicted in FIG. 4A can represent, for example, one ion or a group of ions.

[0030]

[0049] Following step 102, process 100 proceeds to step 104, where the 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 controlled, for example, in a "random trapping mode", in which the ion mirrors M1 - M4 are maintained in their transmission modes for a selected time period during which one or more ions generated by the ion source 12 are expected to enter and move through the ELIT array 14. As one non - limiting example, the selected time period consumed at step 104 before the processor 16 proceeds to step 106 when operating in the random trapping mode is on the order of 1 - 3 milliseconds (ms), depending on the axial length of the ELIT array 14 and the speed of the ions entering the ELIT array 14, although it will be understood that in other embodiments such a selected time period may be longer than 3 ms or shorter than 1 ms. Until the selected time period has elapsed, process 100 follows the NO branch of step 104, looping back to the start 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 embodiments that include the microchannel plate detector 22, the processor 16 can be configured to proceed to step 106, with or without an additional delay period, only after one or more ions have been detected by the detector 22, to ensure that the ions have passed through the ELIT array 14 before proceeding to step 106. In other alternative embodiments, the ELIT array 14 can be controlled, for example, by the processor 16 in a "trigger trapping mode", in which the ion mirrors M1 - M4 are held in their transmission modes until at least one ion is detected by the charge detector CD3. Until such detection, process 100 follows the NO branch of step 104, looping back to the start of step 104.The detection of at least one ion by the charge detector CD3 by the processor 16 indicates at least one ion passing through the charge detector CD3 towards the ion mirror M4, and serves as a trigger event that causes the processor 16 to follow the YES branch of step 104 and proceed to step 106 of process 100.

[0031]

[0050] Following the YES branch of step 104 and referring to FIG. 4B, the processor 16 is operable in step 106 to control the voltage source V4 to set its output voltages DC1 - DC7, and to change or switch the operation of the 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 the region R1 of M4. The ion reflection electric field R41, as described above, operates to reflect one or more ions entering the region R1 of M4 back towards the ion mirror M3 (and through the charge detector CD3) as previously described with respect to FIG. 2B. The output voltages DC1 - DC7 created by the voltage sources V1 - V3 do not change in step 106 respectively, and thus each of the ion mirrors M1 - M3 remains in the ion transmission mode. As a result, one or more ions moving towards the ion mirror M4 within the ELIT array 14 are reflected back towards the ion mirror M3 and are made to pass along the axis 24 towards the ion intake of M1 as shown by the ion trajectory 50 illustrated in FIG. 4B.

[0032]

[0051] Following 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 where the ELIT array 14 is controlled by processor 16 in a random trapping mode, in step 108, the ion mirrors M1 - M3 are held in their transmission modes for a selected time period during which one or more ions can enter the ELIT or the ELIT region E3. As one non - limiting example, the selected time period consumed at step 108 before processor 16 proceeds to step 110 when operating in the random trapping mode is on the order of 0.1 milliseconds (ms), although it will be understood that in other embodiments such selected time periods may be longer or shorter than 0.1 ms. Until the selected time period elapses, process 100 follows the NO branch of step 108, looping back to the start of step 108. After the selected time period has elapsed, process 100 follows the YES branch of step 108 and proceeds to step 110. In an alternative embodiment of step 108 where the ELIT array 14 is controlled by processor 16 in a trigger trapping mode, the ion mirrors M1 - M3 are held in their ion transmission modes until at least one ion is detected by the charge detector CD3. Until such detection, process 100 follows the NO branch of step 108, looping back to the start of step 108. The detection of at least one ion by charge detector CD3 by processor 16 serves as a trigger event that ensures that at least one ion is moving through the charge detector CD3 and causes processor 16 to follow the YES branch of step 108 and proceed process 100 to step 110.

[0033]

[0052] Following the YES branch of step 108 and referring to FIG. 4C, the processor 16 is operable in step 110 to control the voltage source V3 to set its output voltages DC1 - DC7, and to change or switch the operation of the ion mirror M3 from the ion transmission mode of operation to the ion reflection mode of operation in which an ion reflection electric field R31 is established in region R1 of M3 and an ion reflection electric field R32 is established in 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 region R2 of mirror M3 and region R1 of mirror M4 respectively, at least one trapped ion oscillates between M3 and M4 and passes through the charge detection cylinder CD3 as shown by the ion trajectory 503 illustrated in FIG. 4C each time. Each time at least one ion passes through the charge detection cylinder CD3, this induces a charge in the cylinder CD3, which is detected by the charge preamplifier CP3 (see FIG. 1). In step 112, when at least one ion oscillates back and forth between the ion mirrors M3, M4 and through the charge detection cylinder CD3, the processor 16 is operable to record the amplitude and timing of each such CD3 charge detection event and store it in the memory 18.

[0034]

[0053] As described above, the ion reflection electric field R31 operates to reflect one or more ions entering region R1 of M3 back towards the ion mirror M2 (and through the charge detector CD2) as previously described with respect to FIG. 2B. The output voltages DC1 - DC7 created by each of the voltage sources V1 - V2 do not change in steps 110 and 112, and thus each of the ion mirrors M1 - M2 remains in the ion transmission mode. As a result, one or more ions moving within the ELIT array 14 towards the ion mirror M3 are reflected back towards the ion mirror M2 as shown by the ion trajectory 50 1,2 shown, and transmitted along axis 24 towards the ion intake of M1.

[0035]

[0054] Following 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 are held in their transmission modes for a selected time period during which one or more ions can enter the ELIT or the ELIT region E2. As one non - limiting example, the selected time period consumed at step 114 before processor 16 proceeds to step 116 when operating in a random trapping mode is on the order of 0.1 milliseconds (ms), although it will be understood that in other embodiments such a selected time period may be longer or shorter than 0.1 ms. Until the selected time period has elapsed, process 100 follows the NO branch of step 114, loops back to the start of step 108. After the selected time period has elapsed, 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 processor 16 in a trigger trapping mode, ion mirrors M1 - M2 are held in their ion transmission modes until at least one ion is detected by charge detector CD2. Until such detection, process 100 follows the NO branch of step 114, loops back to the start of step 114. The detection of at least one ion by charge detector CD2 by processor 16 serves as a trigger event that ensures that at least one ion is moving through charge detector CD2 and causes processor 16 to follow the YES branch of step 114 and proceed process 100 to step 116.

[0036]

[0055] As described above, the ion reflection electric field R21 operates to reflect one or more ions entering the region R1 of M2, as previously described with respect to FIG. 2B, in the opposite direction towards the ion mirror M1 (and through the charge detector CD1). The output voltages DC1-DC7 created by the voltage source V1 do not change in steps 116 and 118, and thus the ion mirror M1 remains in the ion transmission mode. As a result, one or more ions moving within the ELIT array 14 towards the ion mirror M2 are reflected back towards the ion mirror M1 as shown by the ion trajectory 501 illustrated in FIG. 4D and transmitted along the axis 24 towards the ion intake opening of M1.

[0037]

[0056] Following the YES branch of step 114, and when at least one ion within the ELIT or ELIT region E3 continues to oscillate back and forth through the charge detection cylinder CD3 between the ion mirrors M3 and M4, the process 100 proceeds to step 116. Referring to FIG. 4D, at step 116, the processor 16 is operable to control the voltage source V2 to set its output voltages DC1-DC7 and to change or switch the operation of the 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 the region R1 of M2 and an ion reflection electric field R22 is established within the region R2 of M2. As a result, at least one ion is trapped in the ELIT or ELIT region E2 and, due to the reflection electric fields R22 and R31 established within the region R2 of the mirror M2 and the region R1 of the mirror M3, respectively, at least one trapped ion oscillates between M2 and M3 and passes through the charge detection cylinder CD2 as illustrated by the ion trajectory 502 depicted in FIG. 4D each time. Each time at least one ion passes through the charge detection cylinder CD2, this induces a charge in the cylinder CD2 which is detected by the charge preamplifier CP2 (see FIG. 1). At step 118, when at least one ion oscillates back and forth between the ion mirrors M2 and M3 and through the charge detection cylinder CD2, the processor 16 for each such CD2 charge detection event It is operable to record the amplitude and timing thereof and store it in the memory 18. That is, following step 116, at least one ion oscillates back and forth between the ion mirrors M3 and M4 through the charge detection cylinder CD3 of the ELIT or the ELIT region E3, and at the same time, at least one other ion oscillates back and forth between the ion mirrors M2 and M3 through the charge detection cylinder CD2 of the ELIT or the ELIT region E2.

[0038]

[0057] Following 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 where ELIT array 14 is controlled by processor 16 in a random trapping mode, at step 120, ion mirror M1 is held in its transmission mode for a selected time period during which one or more ions can enter ELIT or ELIT region E1. As one non-limiting example, the selected time period consumed at step 120 before processor 16 proceeds to step 122 when operating in a random trapping mode is on the order of 0.1 milliseconds (ms), although it will be understood that in other embodiments such a selected time period may be longer or shorter than 0.1 ms. Until the selected time period has elapsed, process 100 follows the NO branch of step 120, looping back to the start of step 120. After the selected time period has elapsed, process 100 follows the YES branch of step 120 and proceeds to step 122. In an alternative embodiment of step 120 where ELIT array 14 is controlled by processor 16 in a trigger trapping mode, ion mirror M1 is held in its ion transmission mode until at least one ion is detected by charge detector CD1. Until such detection, process 100 follows the NO branch of step 120, looping back to the start of step 120. Detection of at least one ion by charge detector CD1 by processor 16 serves as a trigger event that ensures that at least one ion is moving through charge detector CD1 and causes processor 16 to follow the YES branch of step 120 and proceed process 100 to step 122.

[0039]

[0058] Following the YES branch of step 120, when at least one ion within ELIT or ELIT region E3 continues to oscillate back and forth through charge detection cylinder CD3 between ion mirrors M3 and M4, and at the same time at least one other ion within ELIT or ELIT region E2 continues to oscillate back and forth through charge detection cylinder CD2 between ion mirrors M2 and M3, process 100 proceeds to step 122. Referring to FIG. 4E, at step 122, processor 16 is operable to control voltage source V1 to set its output voltages DC1-DC7, and to change or switch the operation of ion mirror M1 from an ion transmission mode of operation to an ion reflection mode of operation in which an ion reflection electric field R11 is established within region R1 of M1 and an ion reflection electric field R12 is established within region R1 of M1. As a result, at least one ion is trapped in ELIT or ELIT region E1, and due to reflection electric fields R12 and R21 established within region R2 of mirror M1 and region R2 of mirror M2, respectively, at least one trapped ion oscillates between M1 and M2 and passes through charge detection cylinder CD1 as exemplified by ion trajectory 501 depicted in FIG. 4E each time. Each time at least one ion passes through charge detection cylinder CD1, this induces a charge in cylinder CD1, which is detected by charge preamplifier CP1 (see FIG. 1). At step 124, when at least one ion oscillates back and forth between ion mirrors M1, M2 and 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. That is, following step 122, at least one ion oscillates back and forth between ion mirrors M3 and M4 through charge detection cylinder CD3 of ELIT or ELIT region E3, and at the same time at least one other ion oscillates back and forth between ion mirrors M2 and M3 through charge detection cylinder CD2 of ELIT or ELIT region E2, and at the same time at least one other ion oscillates back and forth between ion mirrors M1 and M2 through charge detection cylinder CD1 of ELIT or ELIT region E1.

[0040]

[0059] Following 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, such that for a selected time period in which ion detection events by each of charge detectors CD1 - CD3 are recorded by processor 16, i.e., the total ion cycle measurement time, ions can oscillate back and forth simultaneously through each of ELIT or ELIT regions E1 - E3. As one non - limiting example, the selected time period that processor 16 consumes at step 126 before proceeding to step 128 is on the order of 100 - 300 milliseconds (ms), although it will be understood that in other embodiments such a selected time period may be longer than 300 ms or shorter than 100 ms. Until the selected time period elapses, process 100 follows the NO branch of step 126, loops back to the start 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, voltage sources V1 - V4 are, for example, controlled by processor 16 at step 126 such that ions (one or more) can oscillate back and forth through charge detectors CD1 - CD3 for a selected number of measurement cycles in which ion detection events by each of charge detectors CD1 - CD3 are recorded by processor 16, i.e., the total number. Until the processor counts a selected number of ion detection events for one or more of charge detectors CD1 - CD3, process 100 follows the NO branch of step 126, loops back to the start of step 126. The detection by processor 16 of the selected number of ion detection events serves as a trigger event that causes processor 16 to follow the YES branch of step 126 and proceed process 100 to steps 128 and 140.

[0041]

[0060] Following the YES branch of step 126, at step 128, the processor 16 is operable to control the voltage sources V1 - V4 to set their respective output voltages DC1 - DC7, and to change or switch all operations of the ion mirrors M1 - M4 from the ion reflection mode of operation to the ion transmission mode of operation in which each of the ion mirrors M1 - M4 allows ions to pass through it. As an example, at step 128 of process 100, the voltage sources V1 - V4 are controlled, for example, to create the voltages DC1 - DC7 according to the all - pass transmission mode illustrated in Table 1 above, which re - establishes the ion trajectory 50 illustrated in FIG. 4A, where (i) all ions within the ELIT array 14 pass through the ELIT array 14 and outside it under the influence of the ion transmission electric fields TEF1, TEF2 established for each of the ion mirrors M1 - M4, and (ii) all ions entering from the ion source 12 into M1 pass through all of the ion mirrors M1 - M4 and all of the charge detectors CD1 - CD3.

[0042]

[0061] Following step 128, at step 130, it is operable to pause for a selected time period to allow the ions contained within the ELIT array 14 to transmit out of the ELIT array 14. As one non - limiting example, the selected time period consumed at step 130 before the processor 16 loops back to step 102 to restart process 100 is on the order of 1 - 3 milliseconds (ms), although it will be understood that in other embodiments such a selected time period may be longer than 3 ms or shorter than 1 ms. Until the selected time period has elapsed, process 100 follows the NO branch of step 130 and loops back to the start of step 130. After the selected time period has elapsed, process 100 follows the YES branch of step 130, loops back to step 102, and restarts process 100.

[0043]

[0062] Also, following the YES branch of step 126, process 100 further proceeds to step 140 and analyzes the data collected during steps 112, 118, and 124 of process 100 described above. In an exemplary embodiment, data analysis step 140 includes, by way of example, step 142, where processor 16 is operable to compute the Fourier transform of the recorded set of charge detection signals provided to and stored in each of charge preamplifiers CP1 - CP3. By way of example, processor 16 operates to perform step 142 using any conventional digital Fourier transform (DTF) technique such as, but not limited to, a conventional fast Fourier transform (FFT) algorithm. In any case, processor 16 is operable to compute, at step 142, three Fourier transforms, FT1, FT2, and FT3, where FT1 is the Fourier transform of the set of charge detection signals provided and recorded by the first charge preamplifier CP1, and thus corresponds to the charge detection events detected by charge detection cylinder CD1 of ELIT or ELIT region E1, FT2 is the Fourier transform of the set of charge detection signals provided and recorded by the first charge preamplifier CP2, and thus corresponds to the charge detection events detected by charge detection cylinder CD2 of ELIT or ELIT region E2, and FT3 is the Fourier transform of the set of charge detection signals provided and recorded by the first charge preamplifier CP3, and thus corresponds to the charge detection events detected by charge detection cylinder CD3 of ELIT or ELIT region E3.

[0044]

[0063] Following step 142, process 100 proceeds to step 144 where processor 16 is operable to calculate three sets of the value of the mass-to-charge ratio of the ions (m / z1, m / z2, m / z3), the value of the charge of the ions (z1, z2, z3), and the value of the mass of the ions (m1, m2, m3), respectively, as a function of the respective 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 to control one or more of the peripheral devices 20 to display the results for observation and / or further analysis.

[0045]

[0064] The mass-to-charge ratio (m / z) of the ion(s) oscillating back and forth between the opposing ion mirrors in either ELIT or any of the ELIT regions E1 - E3 is given by the following equation m / z = C / ff 2 and is generally understood to be inversely proportional to the square of the fundamental frequency ff of the oscillating ion(s), where C is a constant that is a function of the ion energy and also a function of the dimensions of the individual ELIT or ELIT region, and the fundamental frequency ff is determined directly from the respective calculated Fourier transform. That is, 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 proportional to the magnitude FT of the FT taking into account the number of ion oscillation cycles. Next, the ion mass m is calculated as the product of m / z and z. That is, for the set of charge detection signals provided and recorded by the first charge preamplifier CP1, processor 16 is operable at step 144 to calculate m / z1 = C / ff1 MAG and z1 = F(FT 2 ) and m1 = (m / z1)(z1). For the set of charge detection signals provided and recorded by the second charge preamplifier CP2, processor 16 is similarly operable at step 144 to calculate m / z2 = C / ff2 MAG1 2and z2 = F(FT MAG2 ) and m2 = (m / z2)(z2) are operable to be calculated, and for a set of charge detection signals provided and recorded by a third charge preamplifier CP3, the processor 16 is similarly, in step 144, m / z3 = C / ff3 2 and z3 = F(FT MAG3 ) and m3 = (m / z3)(z3) are operable to be calculated.

[0046]

[0065] Referring now to FIG. 5A, a simplified block diagram of an embodiment of an ion separation device 60 is shown, which can include any of the ELIT arrays 14, 205, 302 illustrated and described herein, which can include any of the ion mass detection systems 10, 200, 300 illustrated and described herein, which can include any number of ion processing devices that can form part of an ion source 12 upstream of the ELIT array(s), and / or which can include any number of ion processing devices arranged downstream of the ELIT array(s) to further process the ion(s) (s) exiting the ELIT array(s). In this regard, in FIG. 5A, the ion source 12 is illustrated as including a number Q of ion source stages IS1 - IS that can be the ion source 12 or can form part of the ion source 12 Q are illustrated as being included. Alternatively or additionally, in FIG. 5A, the ion processing device 70 is illustrated as being coupled to the ion exit ports of the ELIT arrays 14, 205, 302, and the ion processing device 70 can include any number of ion processing stages OS1 - OS R and R can be any positive integer.

[0047]

[0066] Focusing on ion source 12, 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 decomposing or separating ions, for standardizing the ion charge state, and for such purposes, the source 12 of the ions entering ELIT10 is an ion source segment IS1-IS Q in the form of one or more of, can be a conventional source of ions or can include a conventional source of ions, and one or more conventional devices 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 devices for collecting and / or storing ions (e.g., one or more quadrupole ion traps, hexapole ion traps, and / or other ion traps) may further be included. It will be understood that ion source 12 can include one or any combination in any order of any such conventional ion source, ion separation device, and / or ion processing device, and that in some embodiments, a plurality of any such conventional ion source, ion separation device, and / or ion processing device may be included adjacent to or spaced apart from each other.

[0048]

[0067] Looking now at ion processing device 70, 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 decomposing or separating ions, for standardizing the ion charge state, and for such purposes, device 70 is an ion processing segment OS1-OS ROne or more conventional devices for separating ions in the form of one or more things, according to one or more molecular properties (e.g., according to ion mass, ion mass-to-charge ratio, ion mobility, ion retention time, etc.), or may include one or more conventional devices, and / or one or more conventional ion processing devices for collecting and / or storing ions (e.g., one or more quadrupole ion traps, hexapole ion traps, and / or other ion traps), or may include one or more conventional ion processing devices, will be understood. It will be understood that the ion processing device 70 may include one or any combination in any order of any of such conventional ion separation devices and / or ion processing devices, and that in some embodiments, a plurality of any of such conventional ion separation devices and / or ion processing devices may be included adjacent to or spaced apart from each other. In any implementation including one or more mass spectrometers, any one or more of such mass spectrometers can be implemented in any of the forms previously described with respect to FIG. 1.

[0049]

[0068] Without considering any limitations, the ion separation device 60 illustrated in FIG. 5A As one particular implementation, the ion source 12 includes, by way of example, three stages, and the ion processing device 70 is omitted. In this exemplary implementation, the ion source stage IS1 is a conventional source of ions, for example, electrospray, MALDI, etc., the ion source stage IS2 is a conventional mass filter of ions, for example, a quadrupole or hexapole ion guide operable as a high-pass or band-pass filter, and the ion source stage IS3 is any of the mass analyzers of the type described previously. In this embodiment, the ion source stage IS2 is controlled in a conventional manner to preselect ions having desired molecular characteristics for analysis by the downstream mass analyzer and to pass only such preselected ions to the mass analyzer, where the ions analyzed by the ELIT arrays 14, 205, 302 are the preselected ions separated by the mass analyzer according to mass-to-charge ratio. The preselected ions exiting the ion filter can be, for example, ions having the mass or mass-to-charge ratio of a particular ion, ions having the mass or mass-to-charge ratio greater than and / or less than the mass or mass-to-charge ratio of a particular ion, ions having the mass or mass-to-charge ratio within a particular range of the mass or mass-to-charge ratio of the ions, etc. In some alternative embodiments of this example, the ion source stage IS2 can be a mass analyzer, the ion source stage IS3 can be an ion filter, and the ion filter can be made operable as previously described to preselect ions having desired molecular characteristics exiting the mass analyzer for analysis by the downstream ELIT arrays 14, 205, 302. In other alternative embodiments of this example, the ion source stage IS2 can be an ion filter, and the ion source stage IS3 can include a mass analyzer followed by another ion filter, where each of these ion filters operates as described previously.

[0050]

[0069] As another specific implementation of the ion separation device 60 illustrated in FIG. 5A, which should not be considered with any limitation, the ion source 12 includes, by way of example, two stages, and the ion processing device 70 is omitted. In this exemplary implementation, the ion source stage IS1 is a conventional source of ions, such as, for example, electrospray, MALDI, etc., and the ion source stage IS2 is any of the conventional mass spectrometers of the type described previously. This is the implementation previously described with respect to FIG. 1, where the ELIT arrays 14, 205, 302 are operable to analyze the ions exiting the mass spectrometer.

[0051]

[0070] As yet another specific implementation of the ion separation device 60 illustrated in FIG. 5A, which should not be considered any limitation, the ion source 12 includes, by way of example, two stages, and the ion processing device 70 is omitted. In this exemplary implementation, the ion source stage IS1 is a conventional source of ions, such as electrospray, MALDI, etc., and the ion source stage IS2 is a conventional single or multi-stage ion mobility spectrometer. In this embodiment, the ion mobility spectrometer is operable to separate the ions generated at the ion source stage IS1 over time according to one or more functions of ion mobility, and the ELIT arrays 14, 205, 302 are operable to analyze the ions exiting the ion mobility spectrometer. In an alternative embodiment of this example, the ion source 12 can include only one stage IS1 in the form of a conventional source of ions, and the ion processing device 70 can include a conventional single or multi-stage ion mobility spectrometer as one stage OS1 (or stage OS1 of the multi-stage device 70). In this alternative embodiment, the ELIT arrays 14, 205, 302 are operable to analyze the ions generated at the ion source stage IS1, and the ion mobility spectrometer OS1 is operable to separate the ions exiting the ELIT arrays 14, 205, 302 over time according to one or more functions of ion mobility. As yet another alternative embodiment of this example, a single or multi-stage ion mobility spectrometer can be made to follow both the ion source stage IS1 and the ELIT arrays 14, 205, 302. In this alternative embodiment, the ion mobility spectrometer following the ion source stage IS1 separates the ions generated at the ion source stage IS1 according to one or more functions of ion mobility operable to separate over time, and the ELIT arrays 14, 205, 302 are operable to analyze ions exiting the ion mobility spectrometer of the ion source stage, and the ion mobility spectrometer of the ion processing stage OS1 following the ELIT arrays 14, 205, 302 is operable to separate over time the ions exiting the ELIT arrays 14, 205, 302 according to a function of one or more of the ion mobilities. In any implementation of the embodiments described in this paragraph, further variations can include a mass spectrometer operably arranged upstream and / or downstream of the single or multiple stages of ion mobility spectrometers in the ion source 12 and / or the ion processing device 210.

[0052]

[0071] As yet another specific implementation of the ion separation device 60 illustrated in FIG. 5A, which should not be considered any limitation, the ion source 12, by way of example, includes two stages and the ion processing device 70 is omitted. In this exemplary implementation, the ion source stage IS1 can be, for example, a conventional liquid chromatograph such as HPLC configured to separate molecules in a liquid according to molecular retention time, and the ion source stage IS2 can be a conventional source of ions, for example, electrospray, etc. In this implementation, the liquid chromatograph is operable to separate the molecular components in the liquid, the ion source stage IS2 is operable to generate ions from the liquid stream exiting the liquid chromatograph, and the ELIT arrays 14, 205, 302 are operable to analyze the ions generated by the ion source stage IS2. In an alternative embodiment of this example, the ion source stage IS1 can instead be a conventional size exclusion chromatograph (SEC) operable to separate molecules in a liquid by size. In another alternative embodiment, the ion source stage IS1 can include a conventional liquid chromatograph followed by a conventional SEC, or vice versa. In this implementation, the ions are generated by the ion source stage IS2 from the liquid separated twice, first according to molecular retention time and then subsequently according to molecular size, or vice versa. In any implementation of the embodiments described in this paragraph, further variations can include a mass spectrometer operably arranged between the ion source stage IS2 and the ELIT arrays 14, 205, 302.

[0053]

[0072] Referring to FIG. 5B, a simplified block diagram of another embodiment of the ion separation device 80 is shown, which includes, by way of example, a multi-stage mass spectrometer device 82, which also includes the ion mass detection systems 10, 200, 300 illustrated and described herein as being implemented as high ion mass analysis components, i.e., any of the CDMS. In the illustrated embodiment, the multi-stage mass spectrometer device 82 includes the ion source (IS) 12 illustrated and described herein, followed by a first conventional mass spectrometer (MS1) 84 coupled thereto, followed by a conventional ion dissociation stage (ID) 86 coupled thereto and operative to dissociate ions exiting the mass spectrometer by, for example, one or more of collision-induced dissociation (CID), surface-induced dissociation (SID), electron-capture dissociation (ECD), and / or photo-induced dissociation (PID), followed by a second conventional mass spectrometer (MS2) 88 coupled thereto, and followed by a conventional ion detector (D) 90, such as a microchannel plate detector or other conventional ion detector. The ion mass detection systems 10, 200, 300, i.e., the CDMS, are coupled in parallel with the ion dissociation stage 86 such that the ion mass detection systems 10, 200, 300, i.e., the CDMS, are adapted to selectively receive ions from the mass spectrometer 84 and / or the ion dissociation stage 86.

[0054]

[0073] MS / MS, for example, using only the ion separation device 82, is an established technique, in which case precursor ions of a specific molecular weight are selected by the 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 photo-induced dissociation. The fragmented ions are then analyzed by the second mass spectrometer 86 (MS2). Only the m / z values of the fragmented precursor ions are measured in both MS1 and MS2 This is the case. For high-quality ions, the charge state is not elucidated, and thus it is impossible to select precursor ions having a specific molecular weight based only on the m / z value. However, by coupling the device 82 to the CDMS 10, 200, 300 exemplified and described herein, it is possible to select a narrow range of m / z values and then determine the mass of the precursor ions selected by m / z using the CDMS 10, 200, 300. The mass analyzers 84, 88 can be, for example, one or any combination of a magnetic sector type mass spectrometer, a time-of-flight type mass spectrometer, and a quadrupole mass spectrometer, but in alternative embodiments, other types of mass analyzers can also be used. In any case, the precursor ions selected by m / z having a known mass coming out of MS1 can be fragmented in the ion dissociation stage 86, and the resulting fragmented ions can then be analyzed by MS2 (where only the m / z ratio is measured) and / or the CDMS devices 10, 200, 300 (where the m / z ratio and the charge are measured simultaneously). Therefore, low-mass fragments can be analyzed by conventional MS, and high-mass fragments (whose charge state is not elucidated) are analyzed by CDMS.

[0055]

[0074] Referring now to FIG. 6, there is shown an ion mass detection system 200 including another embodiment of an electrostatic linear ion trap (ELIT) array 205 to which control and measurement components are connected. In the illustrated embodiment, the ELIT array 205 includes three individual ELITs 202, 204, 206, each of which is configured in the same manner as the ELIT or ELIT region E3 of the ELIT array 14 illustrated in FIG. 1. For example, ELIT 202 includes a charge detection cylinder CD1 surrounded by a ground chamber GC1, one end of the ground chamber GC1 defining one of the mirror electrodes of an ion mirror M1, and the opposite end of the ground chamber GC1 defining one of the mirror electrodes of another ion mirror M2, the ion mirrors M1, M2 being disposed at opposite ends of the charge detection cylinder 202. The ion mirror M1, by way of example, has a structure and function that are the same as each of the ion mirrors M1 - M3 illustrated in FIGS. 1 - 2B, and the ion mirror M2, by way of example, has a structure and function that are the same as the ion mirror M4 illustrated in FIGS. 1 - 2B. A voltage source V1, by way of example having a structure and function that are the same as the voltage source V1 illustrated in FIGS. 1 - 2B, is operably coupled to the ion mirror M1, and another voltage source V2, by way of example having a structure and function that are the same as the voltage source V4 illustrated in FIGS. 1 - 2B, is operably coupled to the ion mirror M2. The ion mirror M1 defines an ion capture opening AI1, by way of example having a structure and function that are the same as the opening A1 of the ion mirror MX illustrated in FIG. 2A, and the ion mirror M2 defines an emission opening AO1, by way of example having a structure and operation that are the same as the opening CA of the ion mirror M4 previously described with respect to FIGS. 1 and 2B. The longitudinal axis 241 extends through the center of the ELIT 202 and, by way of example, bisects the openings AI1 and AO1. A charge preamplifier CP1 is electrically coupled to the charge detection cylinder CD1 and, by way of example, has a structure and function that are the same as the charge preamplifier CP1 illustrated in FIG. 1 and previously described.

[0056]

[0075] ELIT204 is, by way of example, the same as ELIT202 described herein. The ion mirrors M3, M4 correspond to the ion mirrors M1, M2 of ELIT202. The voltage sources V3, V4 correspond to the voltage sources V1, V2 of ELIT202. The capture / discharge apertures AI2 / AO2 define the longitudinal axis 242, which extends through ELIT204 and, by way of example, bisects the apertures AI2, AO2. The charge amplifier CP2 is electrically coupled to the charge detection cylinder CD2 of ELIT204 and, by way of example, has the same structure and function as the charge preamplifier CP2 illustrated in and previously described with reference to FIG. 1.

[0057]

[0076] Similarly, ELIT206 is, by way of example, the same as ELIT202 described herein. The ion mirrors M5, M6 correspond to the ion mirrors M1, M2 of ELIT202. The voltage sources V5, V6 correspond to the voltage sources V1, V2 of ELIT202. The capture / discharge apertures AI3 / AO3 define the longitudinal axis 243, which extends through ELIT206 and, by way of example, bisects the apertures AI3, AO3. The charge amplifier CP3 is electrically coupled to the charge detection cylinder CD3 of ELIT206 and, by way of example, has the same structure and function as the charge preamplifier CP3 illustrated in and previously described with reference to FIG. 1. and, by way of example, has the same structure and function as the charge preamplifier CP3 illustrated in and previously described with reference to FIG. 1.

[0058]

[0077] Voltage sources V1 - V6 and charge preamplifiers CP1 - CP3 are operably coupled to a processor 210 including a memory 212 described with respect to FIG. 1. The memory 212 stores, by way of example, instructions which, when executed by the processor 210, cause the processor 210 to control the operation of the voltage sources V1 - V6 so as to control the ion mirrors M1 - M6 between the ion transmission mode and the ion reflection mode described previously. Alternatively, one or more of the voltage sources V1 - V6 can be made programmable to operate as described above. In any case, the instructions stored in the memory 212 include, by way of example, further instructions which, when executed by the processor 210, cause the processor 210 to receive, process, and record (store) the charge signals detected by the charge preamplifiers CP1 - CP3, and to process the recorded charge signal information to calculate the mass of the ions captured in each of the ELITs 202, 204, 206. By way of example, the processor 210 is coupled to one or more peripheral devices 214 which can be the same as one or more of the peripheral devices 20 described previously with respect to FIG. 1.

[0059]

[0078] In the embodiment illustrated in FIG. 6, an embodiment of an ion steering array 208 is shown that is operably coupled between an ion source 12 and the ion capture apertures AI1 - AI3 of each of the ELITs 202, 204, 206 of the ELIT array 205. The ion source 12 is, by way of example, as described with respect to FIGS. 1 and / or 5, configured to generate ions and supply them to the ion steering array 208 via an ion aperture IA. The ion steering voltage source V ST is operably coupled between the processor 210 and the ion steering array 208. As will be described in detail later, the processor 210 is, by way of example, the ion steering voltage source V STIt is configured, i.e., programmed, to control so as to selectively steer and guide the ions going out from the ion opening IA of the ion source 12 to the ELITs 202, 204, 206 through the respective intake openings AI1 - AI3 to the ion - steering array 208. 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 are selectively switched between the ion - transmission mode and the ion - reflection mode, thereby causing at least one ion to be trapped in each of the ELITs 202, 204, 206. Next, such ions are vibrated back and forth through the respective charge - detection cylinders CD1 - CD3 between the respective ion mirrors M1 / M2, M3 / M4, and M5 / M6 of the ELITs 202, 204, 206 to measure and record the ion - charge - detection events detected by the respective charge pre - amplifiers CP1 - CP3 as previously described.

[0060]

[0079] The ion - steering array 208 includes, by way of example, three sets P1 - P4, P5 - P8, and P9 - P12 of four conductive pads respectively disposed on each of two separate planar substrates. Each of the conductive pads P1 - P12 on one of the planar substrates is aligned and opposed to each of the conductive pads on the other substrate. In the embodiment illustrated in FIG. 6, only one of the substrates 220 is shown.

[0061]

[0080] Referring now to FIGS. 7A - 7C, a part of the ion - steering array 208 is shown, and its control and operation for selectively steering ions to a desired position are illustrated. As shown in the examples of FIGS. 7B and 7C, the voltages DC1 - DC4 of the illustrated part of the ion - steering 208 are controlled so that the ions going out from the ion opening IA of the ion source 12 in the direction indicated by the arrow A are turned by about 90 degrees and aligned with, i.e., collinear with, the ion intake opening AI1 of the ELIT 202. It is arranged to be sent along a certain path. Although not illustrated in the figures, the ion trajectories emerging from the ion aperture IA of the ion source can be focused using any number of conventional planar ion carpets and / or other conventional ion focusing structures, and / or the ion trajectories selectively modified by the ion steering array 208 can be aligned with the respective ion capture apertures AI1 - AI3 of the ELITs 202, 204, 206.

[0062]

[0081] Referring particularly to FIG. 7A, a pattern of four substantially identical and spaced conductive pads P11 - P41 is formed on the inner major surface 220A of a substrate 220, which also has an opposite outer major surface 220B. Also, a substantially identical pattern of four substantially identical and spaced conductive pads P12 - P42 is formed on the inner major surface 222A of another substrate 222, which also has an opposite outer surface 222B. The inner surfaces 220A, 222A of the substrates 220, 222 are generally parallel and spaced apart, and the conductive pads P11 - P41 are juxtaposed over the respective ones of the conductive pads P12 - P42. The spaced inner major surfaces 220A, 222A of the substrates 220, 222 define, by way of example, a channel or space 225 of width D P therebetween. In one embodiment, the width D P of the channel 225 is about 5 cm, although in other embodiments the distance D P can be longer or shorter than 5 cm. In any case, the substrates 220, 222 together constitute an exemplary portion of the ion steering array 208.

[0063]

[0082] The pairs of opposing pads P31, P32 and P41, P42 are upstream of the pairs of opposing pads P11, P12 and P21, P22, and conversely, the pairs of opposing pads P11, P12 and P21, P22 are downstream of the pairs of opposing pads P41, P42 and P31, P32. In this regard, the “direction of unchanged ion movement” through channel 225 is, as the term is used herein, “upstream” and is generally parallel to the direction A of the ions exiting ion source 12. The lateral edges 220C, 222C of substrates 220, 222 are aligned, as are the opposite lateral edges 220D, 222D, and the “direction of changed ion movement” is, as the term is used herein, from the aligned edges 220C, 222C to the aligned edges 220D, 222D and is generally perpendicular to such aligned edges 220C, 222C and 220D, 222D.

[0064]

[0083] In the embodiment illustrated in FIG. 6, the ion steering voltage source V ST is configured to produce, by way of example, at least 12 switchable DC voltages, each of which is operatively connected to a respective pair of opposing conductive pads P1 - P12. Four of the 12 DC voltages, DC1 - DC4, are illustrated in FIG. 7A. The first DC voltage DC1 is electrically connected to each of the juxtaposed conductive pads P11, P12, the second DC voltage DC2 is electrically connected to each of the juxtaposed conductive pads P21, P22, the third DC voltage DC3 is electrically connected to each of the juxtaposed conductive pads P31, P32, and the fourth DC voltage DC4 is electrically connected to each of the juxtaposed conductive pads P41, P42. In the exemplary embodiment, each of the DC voltages DC1 - DC12 is, for example, via processor 210 and / or voltage source V STThrough programming, they are independently controlled. However, in another embodiment, two or more of the DC voltages DC1 - DC12 can be controlled as a group. In any case, the voltages DC1 - DC12 are exemplified and disclosed as DC voltages, but this disclosure also contemplates other embodiments, in which the voltage source V ST alternatively or additionally, creates any number of AC voltages, such as, for example, one or more RF voltages, and configures any one or more of such AC voltages to be supplied to corresponding ones or pairs of conductive pads and / or to one or more ion carpets or other ion focusing structures, in embodiments that include them.

[0065]

[0084] Referring now to FIGS. 7B and 7C, and by way of example using the four pairs of opposing conductive pads P11 / P12, P21 / P22, P31 / P32, and P41 / P42 of FIGS. 7A and 7B, the operation of the ion steering channel array 208 illustrated in FIG. 6 will be described. It will be understood that the four conductive pads P5 - P8 and the four conductive pads P9 - P12 illustrated on the substrate 220 of FIG. 6 also each constitute a pair of opposing, aligned and juxtaposed conductive pads disposed on the respective inner surfaces 220A, 222A of the substrates 220, 222, and that each such set of four pairs of opposing conductive pads is controllable by respective switchable DC (and / or AC) voltages DC5 - DC12 created by the voltage source V ST In any case, for clarity of illustration, DC voltages DC1 - DC4 are omitted in FIGS. 7B and 7C, and instead, the DC voltages DC1 - DC4 created by the voltage source V ST and applied to the pairs of conductive pads P11 / P12, P21 / P22, P31 / P32, and P41 / P42 to which they are connected are graphically represented. Referring particularly to FIG. 7B, the exemplary portion of the ion steering array 208 has a reference voltage V REF applied to each of the pairs of conductive pads P11 / P12, P21 / P22, and V REFA state is shown in which a smaller potential - XV is applied to each of the conductive pad pairs P31 / P32 and P41 / P42. As an example, V REF can be a positive, negative, or zero voltage, for example, a ground potential, and - XV can be any voltage of a positive, negative, or zero voltage smaller than V REF such that an electric field E1 is established as shown in FIG. 7B. This electric field E1 is parallel to the side portions 220C / 222C and 220D / 222D of the substrates 220, 222 and extends in the direction of invariant ion movement, that is, from the downstream conductive pad pairs P11 / P12, P21 / P22 to the upstream conductive pad pairs P31 / P32 and P41 / P42. When there is an electric field E1 established as illustrated in FIG. 7B, ions A exiting from the ion source 12 through the ion aperture IA enter the channel 225 between the downstream conductive pad pairs P11 / P12, P21 / P22 and are steered or guided (or directed) by the electric field E1 along the direction of invariant ion movement 230. The direction of invariant ion movement 230 is the same as the direction of the electric field E1 and is aligned, that is, collinear, with the ion aperture IA of the ion source 12. Such ions A are guided through the channel 225 along the direction of invariant movement as shown in FIG. 7B, for example.

[0066]

[0085] Now referring particularly to FIG. 7C, if it is desired to change the direction of ions A to a direction of ion movement changed from the direction of invariant ion movement shown in FIG. 7B, the DC voltages DC1, DC3 created by the voltage source V ST are switched so that the reference voltage V REF is applied to each of the conductive pad pairs P21 / P22, P31 / P32, and V REFA smaller potential - XV is applied to each of the conductive pad pairs P11 / P12 and P41 / P42, thereby establishing an electric field E2 as shown in FIG. 7C. The electric field E2 is perpendicular to the sides 220C / 222C and 220D / 222D of the substrates 220, 222 and extends in the direction of invariant ion movement, i.e., from the sides 220C / 222C of the substrates 220, 222 towards the sides 220D / 222D of the substrates 220, 22. When there is an established electric field E2 as illustrated in FIG. 7C, ions A exiting from the ion source 12 through the ion aperture IA are steered or guided (or directed) by the electric field E2 along the changed ion movement direction 240. The changed ion movement direction 240 is in the same direction as the electric field E2 and is aligned, i.e., collinear, with the ion aperture IA of the ion source 12. Such ions A are guided, for example, as shown in FIG. 7C, through the channel 225 along the direction of invariant movement between the conductive pad pairs P11 / P12, P41 / P42. In some embodiments, one or more conventional ion carpets and / or other conventional ion - focusing structures can be used to restrict the ions to follow the ion trajectory 240 illustrated in FIG. 7C.

[0067]

[0086] Referring again to FIG. 6, the instructions stored in the memory 212, when executed by the processor 210 as previously described with respect to FIGS. 1 - 4B when the processor 210 records the respective ion charge detection information in the memory 212, cause the processor 210 to selectively generate and switch the voltages DC1 - DC12 such that the ion - steering voltage source V STto control to guide ions along the ion steering array 208 and subsequently send at least one ion to each of the ion capture apertures AI1 - AI3 of each of the ELITs 202, 204, 206, and also to control the voltage sources V1 - V6 to selectively generate and switch the DC voltages created thereby, whereby each of the ion mirrors M1 - M6 is controlled between its ion transmission mode and ion reflection mode to trap at least one ion guided to each of the ELITs 202, 204, 206 by the ion steering array 208, and then to cause each trapped ion (one or more) to oscillate back and forth between the respective ion mirrors M1 - M6 of each of the ELITs 202, 204, 206. With the aid of FIGS. 8A - 8F, an example of such a process will be described as acting on ions of one or more positive charges, although it will be understood that alternatively the process 100 can act on ions of one or more negative charges. In the following description, references to particular ones of the conductive pads P1 - P12 are understood to refer to pairs of opposed, juxtaposed, and spaced conductive pads disposed on the inner surfaces 220A, 222A of the respective substrates 220, 222 as shown in the example with respect to FIG. 7A, and references to the voltages applied to particular ones of the conductive pads P1 - P12 are understood to be those applied to each of such pairs of opposed, juxtaposed, and spaced conductive pads as shown in the examples with respect to FIGS. 7B and 7C. Further, the DC voltage V REF can be any positive or negative voltage, or zero voltage, e.g., ground potential, and -XV illustrated in FIGS. 8A - 8F can be any voltage of positive, negative, or zero voltage smaller than V REF and is made to establish a corresponding electric field within the channel 225 as shown in FIGS. 7B and 7C, and this electric field is understood to extend in the direction from the conductive pad controlled by V REF to the conductive pad controlled by -XV.

[0068]

[0087] Referring to FIG. 8A, the processor 210 controls a voltage source V ST By controlling the voltage V REF to each of the pads P1-P4. ST is connected to each of the pads P9-P12 as shown in Figure 8A. REF In another implementation, V ST can be controlled to apply -XV to each of pads P9-P12. In either case, the resulting electric field within channels 225 of ion steering array 208 as a result of applying such voltages pulls ions through channels 225 and out ion aperture IA of ion source 12 in a direction of unaltered ion movement along illustrated ion trajectory 250.

[0069]

[0088] Referring to FIG. 8B, the processor 210 then controls the voltage source V ST to switch the voltages applied to pads P2 and P4 to -XV, while otherwise maintaining the voltages previously applied at P1, P3, and P5-P12. The electric field established in channels 225 of ion steering array 208 as a result of application of such switched voltages steers ions that were previously traveling from ion source 12 in an unaltered direction of ion travel along ion trajectory 250 illustrated in FIG. 8A toward ion intake aperture AI1 of M1 of ELIT 202 in an altered direction of ion travel along ion trajectory 252. Simultaneously with, or prior to, or after this switching, processor 210 is operable to control voltage sources V1 and V2 to produce voltages that cause both ion mirrors M1 and M2 to operate in their ion transmission modes, e.g., as described with respect to FIGS. 1-2B. As a result, ions traveling through the channels 225 of the ion steering array 208 along ion trajectories 252 undergo an intake opening of the ELIT 202 through M1, as illustrated by the ion trajectory 252 shown in FIG. 8B. Directed into the ion intake aperture AI1, it is transmitted through M1, through the charge detection cylinder CD1, and through M2 by the ion transmission fields established for each of the ion mirrors M1 and M2. In some embodiments, one or more conventional ion carpets and / or other conventional ion focusing structures are operably disposed between the ion steering array 208 and the ion mirror M1 of the ELIT 202 to direct ions moving along the ion trajectory 252 into the ion intake aperture AI1 of the ELIT 202. In any case, the processor 210 is operable at some later point to control V2 to create a voltage that causes, for example, as described with respect to FIGS. 1-2B, the ion mirror M2 to be switched from operating in the ion transmission mode to operating in the ion reflection mode, reflecting the ions back toward M1. The timing of this switching of M2 depends, by way of example, on whether the operation of the ELIT 202 is controlled by the processor 210 in the random trapping mode or the trigger trapping mode as described with respect to FIG. 3.

[0070]

[0089] Referring to FIG. 8C, the processor 210 is then operable to control the voltage source V1 to create a voltage that causes the ion mirror M1 to switch from ion transmission mode to ion reflection mode operation. The timing of this switch of M1 depends, by way of example, on whether the operation of ELIT202 is being controlled in the random trapping mode or the trigger trapping mode as described with respect to FIG. 3 by the processor 210, but in either case, the switch of M1 to ion reflection mode traps at least one ion within ELIT202 as illustrated by the ion trajectory 252 shown in FIG. 8C. When at least one such ion is trapped within ELIT202 and the voltage sources V1 and V2 are respectively controlled such that both M1 and M2 operate in their ion reflection modes, the ion(s) trapped within ELIT202 oscillate back and forth between the ion mirrors M1 and M2 and each time they pass through the charge detection cylinder CD1 and induce a corresponding charge thereon, this is detected by the charge preamplifier CP1 and recorded by the processor 210 in the memory 212.

[0071]

[0090] Simultaneously with or subsequent to the aforementioned control of ELIT202, and while the ion(s) are oscillating back and forth between the ion mirrors M1, M2 within ELIT202, the processor 210 is 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 switch the voltage applied to pads P9 - P12 from V REF to -XV. As a result of applying such voltages, the electric field created in the channels 225 of the ion steering array 208 draws out the ions exiting the ion aperture IA of the ion source 12 that pass through the channels 225 in the direction of invariant ion movement along the exemplary ion trajectory 250.

[0072]

[0091] Referring now to FIG. 8D, the processor 210 is then operable to control voltage source V ST to switch the voltages applied to pads P6 and P8 to -XV, and otherwise maintain the voltages previously applied at P1 - P4, P5, P7, and P9 - P12. As a result of applying such switched voltages, the electric field established within channel 225 of ion steering array 208 steers ions that were previously moving in an unchanged direction of ion movement along ion trajectory 250 illustrated in FIG. 8C from ion source 12 towards ion capture aperture AI2 of M2 of ELIT204 along a changed direction of ion movement along ion trajectory 254. Simultaneously with, prior to, or subsequent to this switching, the processor 210 is operable to control voltage sources V3 and V4 to create voltages that cause both ion mirrors M3 and M4 to operate in their ion transmission modes. As a result, ions move along ion trajectory 254 towards ion steering a Ions moving through channel 225 of ray 208 are directed into capture aperture AI2 of ELIT 204 through M3, as illustrated by ion trajectory 254 shown in FIG. 8D, and are transmitted through M3, through charge detection cylinder CD2, and through M4 by ion transmission fields established in respective ones of ion mirrors M3 and M4. In some embodiments, one or more conventional ion carpets and / or other conventional ion focusing structures are operably disposed between ion steering array 208 and ion mirror M3 of ELIT 204 to direct ions moving along ion trajectory 254 into ion capture aperture AI2 of ELIT 204. In any case, processor 210 is operable to control V4 at some later point to create a voltage that causes ion mirror M4 to be switched from operation in an ion transmission mode to operation in an ion reflection mode, reflecting the ions back toward M3. The timing of this switching of M4 depends, by way of example, on whether the operation of ELIT 204 is controlled by processor 210 in the random trapping mode described with respect to FIG. 3 or in the trigger trapping mode.

[0073]

[0092] Following the operating state illustrated in FIG. 8D, the processor 210 is operable to control the voltage source V3 to produce a voltage that causes the ion mirror M3 to switch from the ion transmission mode to the ion reflection mode of operation, in the same manner as described with respect to FIG. 8C. The timing of this switching of M3 depends, by way of example, on whether the operation of ELIT204 is being controlled by the processor 210 in the random trapping mode or the trigger trapping mode as described with respect to FIG. 3, but in either case, the switching of M3 to the ion reflection mode traps at least one ion within ELIT204, as illustrated by the ion trajectory 254 shown in FIG. 8E. When at least one such ion is trapped within ELIT204 and both M3 and M4 are controlled by the voltage sources V3 and V4, respectively, to operate in their ion reflection modes, the ion(s) trapped within ELIT204 oscillate back and forth between the ion mirrors M3 and M4 and induce a corresponding charge each time they pass through the charge detection cylinder CD2, which is detected by the charge preamplifier CP2 and recorded by the processor 210 in the memory 212. In the operating state illustrated in FIG. 8E, the ions move back and forth simultaneously within each of ELIT202 and 204, and the ion charge / timing measurements taken from each of the charge preamplifiers CP1 and CP2 are thus collected and stored simultaneously by the processor 210.

[0074]

[0093] Simultaneously with or subsequent to the aforementioned control of ELIT204 with respect to FIG. 8E, and with the ion(s) oscillating back and forth simultaneously within each of ELIT202 and 204, the processor 210 controls V ST to control the voltage applied to pads P6 and P8 to V REFSwitch to return, so that the pads P1 - P12 are controlled to the voltages illustrated in FIG. 8C. As a result of applying such voltages, the electric field generated in the channel 225 of the ion steering array 208 draws out the ions exiting the ion aperture IA of the ion source 12, which pass through the channel 225 in the direction of unchanged ion movement along the exemplary ion trajectory 250 as illustrated in FIG. 8C again. Thereafter, the processor 210 controls the voltage source V ST to switch the voltages applied to pads P9 and P11 to V REF and is operable to otherwise maintain the voltages previously applied at P1 - P8, P5, and P11 - P12. As a result of applying such switched voltages, the electric field established within the channel 225 of the ion steering array 208 steers the ions that were previously moving in the direction of unchanged ion movement along the ion trajectory 250 illustrated in FIG. 8C from the ion source 12 towards the ion capture aperture AI3 of M5 of the ELIT 206 along the changed ion movement direction along the ion trajectory 256. Simultaneously with, before, or after this switching, the processor 210 is operable to control the voltage sources V5 and V6 to create voltages that operate both the ion mirrors M5 and M6 in their ion transmission modes . As a result, the ions moving through the channel 225 of the ion steering array 208 along the ion trajectory 253 are directed into the capture aperture AI3 of the ELIT 206 through M5 as illustrated by the ion trajectory 256 shown in FIG. 8E and are transmitted through M5, through the charge detection cylinder CD3, and through M6 by the ion transmission fields established in each of the ion mirrors M5 and M6. In some embodiments, one or more conventional ion carpets and / or other conventional ion focusing structures can be operably arranged between the ion steering array 208 and the ion mirror M5 of the ELIT 206 to direct the ions moving along the ion trajectory 256 into the ion capture aperture AI3 of the ELIT 206.

[0075]

[0094] In any case, the processor 210 is operable to control V6 at some point later to create a voltage that causes the ion mirror M6 to switch from operating in the ion transmission mode to operating in the ion reflection mode, reflecting and returning the ions back towards M5. The timing of this switching of M6 depends, for example, on whether the operation of ELIT 206 is being controlled by the processor 210 in the random trapping mode or the trigger trapping mode as described with respect to FIG. 3. Thereafter, the processor 210 is operable to control the voltage source V5 to create a voltage that causes the ion mirror M5 to switch from the ion transmission mode to operating in the ion reflection mode, in a similar manner as described with respect to FIG. 8C. The timing of this switching of M5 depends, for example, on whether the operation of ELIT 206 is being controlled by the processor 210 in the random trapping mode or the trigger trapping mode as described with respect to FIG. 3, but in any case, the switching of M5 to the ion reflection mode traps at least one ion within ELIT 206, as illustrated by the ion trajectory 256 shown in FIG. 8F. When at least one such ion is trapped within ELIT 206 and the voltage sources V5 and V6 are controlled accordingly such that both M5 and M6 operate in their ion reflection modes, the ion(s) trapped within ELIT 206 oscillate back and forth between the ion mirrors M5 and M6 and each time they pass through the charge detection cylinder CD3 inducing a corresponding charge thereon, which is detected by the charge preamplifier CP3 and recorded by the processor 210 in the memory 212. In the operating state illustrated in FIG. 8F, the ions move back and forth simultaneously within each of ELITs 202, 204, and 206, and the ion charge / timing measurements taken from each of the charge preamplifiers CP1, CP2, and CP3 are thus collected and stored simultaneously by the processor 210.

[0076]

[0095] Also, as illustrated in FIG. 8F, simultaneously with or subsequent to the control of the aforementioned ELIT206, and if ions (one or more) are simultaneously oscillating within each of ELIT202, 204, and 206, the processor 210 controls V ST to switch the voltage applied to pads P5 - P8 to -XV, and the voltage applied to pads P10 and P12 to V REF (or switch the voltage applied to pads P9 and P11 to -XV), thereby controlling pads P1 - P12 to the voltages illustrated in FIG. 8A (or described with respect to FIG. 8A). As a result of applying such voltages, the electric field generated in channel 225 of ion steering array 208 again draws out ions exiting from ion aperture IA of ion source 12, through channel 225, in the direction of invariant ion movement along exemplary ion trajectory 250, as illustrated in FIG. 8A.

[0077]

[0096] For example, as previously described with respect to step 126 of process 100 illustrated in FIG. 3, after ions have oscillated back and forth in each of ELIT202, 204, and 206 for a total ion cycle measurement time or a total number of measurement cycles, the processor 210 controls voltage sources V1 - V6 to switch each of ion mirrors M1 - M6 to the ion transmission mode such that the ions trapped therein are operable to exit each of ELIT202, 204, and 206 through ion emission apertures AO1 - AO2. Next, the operation of ion mass detection system 200 returns, by way of example, to that previously described with respect to FIG. 8B. Simultaneously, or at another convenient time, the collected recorded ion charge / timing measurements are processed by the processor 210, as described with respect to step 140 of process 100 illustrated in FIG. 3, to determine the mass of the ions processed by each of ELIT202, 204, 206.

[0078]

[0097] Although not limited, depending on many factors including the dimensions of ELIT202, 204, 206, one or more frequencies of the oscillation of ions passing through each of ELIT202, 204, 206, and the total number of measurement cycles / total ion-cycle measurement time in each of ELIT202, 204, 206, the ions can oscillate back and forth simultaneously in at least two of ELIT202, 204, and 206, and the ion charge / timing measurement values taken from each of the charge preamplifiers CP1, CP2, and CP3 can thus be collected and stored simultaneously by the processor 210. In the embodiment illustrated in FIG. 8F, for example, the ions oscillate back and forth simultaneously in at least two of ELIT202, 204, and 206, and the ion charge / timing measurement values taken from each of the charge preamplifiers CP1, CP2, and CP3 are thus collected and stored simultaneously by the processor 210. In another embodiment, the total number of measurement cycles or total ion-cycle measurement time of ELIT202 can end before at least one ion is trapped within ELIT206 as described above. In such a case, the processor 210 can control the voltage sources V1 and V2 to switch the ion mirrors M1 and M2 to their transmission operating modes, whereby the ion(s) oscillating therein can exit through the mirror M2 before at least one ion is made to oscillate within ELIT206. In such an embodiment, the ions can be prevented from oscillating back and forth simultaneously in all of ELIT202, 204, and 206 and can be made to oscillate back and forth simultaneously in at least two of ELIT202, 204, and 206 at any one time.

[0079]

[0098] Referring now to FIG. 9, an ion mass detection system 300 is shown that includes yet another embodiment of an electrostatic linear ion trap (ELIT) array 302 to which control and measurement components are connected. In the illustrated embodiment, the ELIT array 302 includes three individual ELITs E1 - E3, each of which is configured in the same manner as the ELITs 202, 204, 206 illustrated in FIG. 6. In the embodiment illustrated in FIG. 9, voltage source V1 is, by way of example, the same in structure and function as voltage source V1 illustrated in FIGS. 1 - 2B and is operably coupled to the respective ion mirror M1 of ELITs E1 - E3, and another voltage source V2 is, by way of example, the same in structure and function as voltage source V4 illustrated in FIGS. 1 - 2B and is operably coupled to the respective ion mirror M2 of ELITs E1 - E3. In an alternative embodiment, the ion mirrors M1 of two or more of ELITs E1 - E3 can be merged into one ion mirror, and / or the ion mirrors M2 of two or more of ELITs E1 - E3 can be merged into one ion mirror. In any case, voltage sources V1, V2 are electrically coupled to a processor 304, and three charge preamplifiers CP1 - CP3 are electrically coupled between the processor 304 and the respective charge detection cylinders CD1 - CD3 of each of ELITs E1 - E3. Memory 306 includes, by way of example, instructions that, when executed by the processor 304, cause the processor 304 to control voltage sources V1 and V2 to control the operation of ELITs E1 - E3 as described below. By way of example, the processor 304 is operably coupled to one or more peripheral devices 308 that can be the same as one or more of the peripheral devices 20 described above with respect to FIG. 1.

[0080]

[0099] The ion mass detection system 300 is an ion... In that it includes an ion source 12 operably coupled to a steering array 208, the ion mass detection system 300 is the same as the ion mass detection system 200 in several respects. The instructions stored in the memory 306 further include, by way of example, instructions which, when executed by the processor 304, cause the processor 304 to control the ion steering array voltage source V ST as described above.

[0081]

[0100] In the embodiment illustrated in FIG. 9, the ion mass detection system 300 further includes, by way of example three conventional ion traps IT1-IT3, each having an individual ion inlet TI1-TI3 and an opposite ion outlet TO1-TO3. The ion trap IT1 is located, by way of example, as shown in FIG. 9, between a set of conductive pads P1-P4 and the ion mirror M1 of the ELIT E1, and the longitudinal axis 241 extending through the center of the ELIT E1 bisects the ion inlet TI1 and the ion outlet TO1 of the IT1 and passes through the center of the pad pairs P1 / P2 and P3 / P4. Similarly, the ion trap IT2 is located between a set of conductive pads P5-P8 and the ion mirror M1 of the ELIT E2, and the longitudinal axis 242 extending through the center of the ELIT E2 bisects the ion inlet TI2 and the ion outlet TO2 of the IT2 and passes through the center of the pad pairs P5 / P6 and P7 / P8. Likewise, the ion trap IT3 is located between a set of conductive pads P9-P12 and the ion mirror M1 of the ELIT E3, and the longitudinal axis 243 extending through the center of the ELIT E3 bisects the ion inlet TI3 and the ion outlet TO3 of the IT3 and passes through the center of the pad pairs P9 / P10 and P11 / P12. Each of the ion traps IT1-IT3 can be any conventional ion trap, examples of which can include, but are not limited to, a conventional quadrupole ion trap, a conventional hexapole ion trap, and the like.

[0082]

[0101] The ion trap voltage source V ITis operably coupled between the processor 304 and each of the ion traps IT1-IT3. The voltage source V is configured, for example, to produce appropriate DC and AC, e.g., RF, voltages to separately control the operation of each of the ion traps IT1-IT3 in a conventional manner. IT

[0083]

[0102] The processor 304 is configured, for example, programmed, to control the ion steering array voltage source V S T such that, as described with respect to FIGS. 8A-8F, one or more ions exiting the ion aperture IA of the ion source 12 are sequentially steered into the respective ion inlets TI1-TI3 of the individual ion traps IT1-IT3. In some embodiments, one or more conventional ion carpets and / or other ion focusing structures can be disposed between the ion steering array 208 and one or more of the ion traps IT1-IT3 to direct ions from the ion steering array 208 into the ion inlets TI1-TI3 of the individual ion traps IT1-IT3. The processor 304 further controls the ion trap voltage source V IT such that it produces corresponding control voltages to control the ion inlets TI1-TI3 of the ion traps IT1-IT3 to receive ions therein, and to control the ion traps IT1-IT3, as is conventional, to trap or confine ions therein, e.g., programmed.

[0084]

[0103] When the ion traps IT1-IT3 are filled with ions, the process ​The processor 304 is configured, for example programmed, to control V1 and V2 so as to create an appropriate DC voltage to control the ELITE E1-E2 ion mirrors M1 and M2 to operate in their ion transmission operation modes, whereby any ions contained therein are caused to exit through each of the ion exit ports AO1-AO3. The ion steering array 208 and ion trap I described herein Via the control of T1-IT3, when at least one ion is trapped in each of the ion traps IT1-IT3, the processor 304 is configured, for example programmed, to control V2 so as to create an appropriate DC voltage to control the ELITE E1-E3 ion mirror M2 to operate in its ion reflection operation mode. Thereafter, the processor 304 is configured to control the ion trap voltage source V IT to create an appropriate voltage to simultaneously open the ion exit ports TO1-TO3 of the individual ion traps IT1-IT3, whereby at least one ion trapped therein is directed to each of the ELITE E1-E3 via the respective ion capture apertures AI1-AI3 of the respective ion mirrors M1. When the processor 304 determines that at least one ion has entered each of the ELITE E1-E3 after a period of time following the simultaneous opening of the ion traps IT1-IT3 or following the detection of charge by each of the charge preamplifiers CP1-CP3, the processor 304 is operable to control the voltage source V1 to create an appropriate DC voltage to control the ELT E1-E3 ion mirrors M1 to operate in their ion reflection operation modes, thereby trapping at least one ion in each of the ELITE E1-E3.

[0085]

[0104] Each of the ion mirrors M1 and M2 of the ELITE E1-E3 is an ion When operating in the reflection operation mode, at least one ion in each of ELIT E1 - E3 vibrates back and forth simultaneously between M1 and M2, and in each cycle passes through each of the charge detection cylinders CD1 - CD3. The corresponding charges induced in the charge detection cylinders CD1 - CD3 are detected by the respective charge pre - amplifiers CP1 - CP3, and the charge detection signals generated by the charge pre - amplifiers CP1 - CP3 are stored in the memory 306 by the processor 304. Next, as described with respect to step 140 of process 100 illustrated in FIG. 3, for example, it is processed by the processor 304 to determine the mass of the ions processed by the individual ones of ELIT E1 - E3.

[0086]

[0105] Embodiments of the ion mass detection systems 200 and 300 are shown in FIGS. 6 - 8F and also In each of FIGS. 6-8F and 9, although each was illustrated as including three ELITs, it will be understood that one or both of such systems 200, 300 can alternatively include a lesser number, e.g., 2, or a greater number, e.g., 4 or more, of ELITs. The control and operation of the various components in any such alternative embodiments generally follow the concepts described above, and one of ordinary skill in the art will recognize that any modifications to systems 200 and / or 300 necessary to implement any such embodiment(s) relate only to mechanical steps. Further, in the embodiments of ion mass detection systems 200 and 300, in each of FIGS. 6-8F and 9, although each was illustrated as including the exemplary ion steering array 208, it will be understood that one or more other ion guiding structures can be alternatively or additionally used to steer or guide ions as described above, and that any such alternative ion guiding structure(s) are intended to be within the scope of the present disclosure. As a non-limiting example, an array of DC quadrupole beam deflectors can be used with one or both of systems 200, 300 to steer or guide ions as described above. In such embodiments, also, one or more focusing lenses and / or ion carpets can be used to focus ions into the various ion traps as described above.

[0087]

[0106] Referring now to FIG. 10, an embodiment of a charge detection mass analyzer device 400 representing a variation of the apparatus 300 illustrated in FIG. 9 is shown. In the apparatus 400 illustrated in FIG. 10, ions generated in the ion source region 402 are trapped and stored by the ion trap 418, and then the ion trap 418 is controlled in pulse mode to release them therein The stored ions are selectively supplied to an ion mass and charge detector 434. Accordingly, the apparatus 400 is configurable and operable to capture and store the generated ions in the ion trap 418 and then to control the ion trap 418 in a pulsed manner to controllably supply a time-compressed packet of ions to an ion mass and charge detector 434, such as one in the form of a single-stage electrostatic linear ion trap (ELIT) 434. In some embodiments, the ion exit port of the ion trap 418 can be spaced from the ion inlet port of the detector 434 by a distance that allows ions traveling therebetween to be temporally separated according to their mass-to-charge values. In such embodiments, by varying the delay time between the release of ions from the ion trap 418 and the capture of ions at the detector 434, ions having different mass-to-charge ratio windows or ranges can be trapped. In some embodiments, an ion filter 424 is disposed between the ion trap 418 and the detector 434, and in such embodiments, the ion filter 424 is controllable to filter ions exiting the ion trap 418 according to the mass-to-charge ratio, alternatively or additionally selecting or restricting the mass-to-charge ratio or range of mass-to-charge ratios of the ions supplied from the ion trap 418 to the detector 434.

[0088]

[0107] As briefly described above, the apparatus 400 illustrated in FIG. 10 generates ions It includes an ion source region 402 configured to form and supply the generated ions to the ion capture inlet of the ion trap 418. In an exemplary embodiment, the ion source region 402 includes an ion source 404 coupled to a source region 408 via a capillary 406. In some embodiments, the capillary 406 can be temperature controlled, e.g., heated and / or cooled. In any case, the source region 408 is operably coupled to a pump P1, and the pump P1 is operable to control the region 408 to vacuum, whereby the region 408 defines a first differently pumped region. The ion source 404 is, for example, located outside the source region 404, e.g., at atmospheric pressure or other pressures, and is configured to supply ions from the sample through the capillary 406 to the ion source region 408. In some such embodiments, the ion source 404 is a conventional electrospray ion source (EIS). In such an embodiment, the ESI source 404 is operably coupled to the output V1 of a voltage source 450, and the voltage source 150 is configured to create an appropriate DC or time-varying signal at V1 to control the operation of the ESI source 404. In any case, the sample from which the ion source 404 generates ions is, for example, a biological material, but in other embodiments, the sample can be a non-biological material or include non-biological materials.

[0089]

[0108] As described above, the ion source 404 is a first differently pumped In some embodiments located outside region 408 and operable to generate ions and supply them to source region 408, source region 408 can include, for example, an ion processing interface 410 configured to efficiently send ions having a wide mass distribution to the ion intake of ion trap 418. In some such embodiments, interface 410 can include, for example, a drift tube 412, which has an open end located near or spaced from the ion exit end of capillary 406, and an opposite end coupled to one end of a funnel region 414 that tapers to an ion exit with a reduced cross-section from the end of drift tube 412. An ion carpet 416 can be operably coupled to the ion exit of funnel region 414 and define an ion passage through which it is coupled to the ion intake of ion trap 418. At least one output V2 of voltage source 450 is electrically coupled to interface 410 and supplies a number K of DC and / or time-varying voltage signals to interface 401 to control its operation, where K can be any positive integer. The central longitudinal axis A of apparatus 400 passes through the center of the various ion intakes and exits described herein and further described later. In embodiments including this, interface 410 can define, for example, a virtual jet disrupter therein, which pumps different regions 408 through capillary 406 configured to disrupt the gas-jet generated by the incoming gas flow, thereby thermally equilibrating the ions and concentrating the ions into the ion trap 418. Further details related to the structure and operation of embodiments of the interface 410 are illustrated and described in International Patent Application No. PCT / US2019 / 013274, filed on January 11, 2019, and International Patent Application No. PCT / US2019 / 035379, filed on June 4, 2019, both of which are co-pending and both of which have the title "HYBRID ION FUNNEL-ION CARPET (FUNPET) ATMOSPHERIC PRESSURE INTERFACE FOR CHARGE DETECTION MASS SPECTROMETRY", the entire disclosures of these applications are hereby expressly incorporated herein by reference.

[0090]

[0109] In some alternative embodiments, the source region 408 can also be made to exclude the interface 410. In another alternative embodiment, the ion source 404 can be provided in the form of one or more other conventional ion sources, one or more of which can be disposed outside the source region 408 and / or one or more of which can be disposed inside the source region 408. In some such embodiments, the source region 408 can include the interface 410, and in other such embodiments, the interface 410 can be omitted.

[0091]

[0091]

[0110] The ion inlet of the ion trap 418 is, by way of example, the output of the voltage source 450 It is defined by a central opening formed through a conductive plate, grid, or the like 420 that is electrically connected to V3. The ion exit of the ion trap 418 is spaced from the ion inlet along the central axis A and is similarly defined by a central opening formed through a conductive plate, grid, or the like 422 that is electrically connected to another output V5 of the voltage source 450, by way of example. Another pump P2 is operably coupled to the ion trap 418 and is operable, by way of example, to pump at a lower pressure than that of the source region 408, for example, to a high vacuum, such that the ion trap 418 defines a second differently pumped region. In some embodiments, P2 can be configured or operable to control the ion trap 418 to a pressure of 10 - 100 mbar, although in another alternative embodiment, P2 can be one that controls the ion trap 418 to a pressure outside of this range. In some embodiments, the gas source GS can be operably coupled to the ion trap 418, and in such embodiments, it can be operable to supply a buffer or other gas into the interior of the ion trap 418. In some such embodiments, the gas is selected such that the ion energy is reduced by collisions therewith. In one embodiment, the ion trap 418 is configured as a conventional quadrupole ion trap, although in an alternative embodiment, the ion trap 418 can have another conventional configuration, for example, a quadrupole, octupole, etc. In any case, the ion trap 418 typically includes a plurality of elongated conductive rods surrounding the axis A to which the output V4 of the voltage source 450 is operably coupled. By way of example, the output V4 is coupled to the rods such that pairs or sets of the respective opposing rods are out of phase with another opposing pair, and the output voltage V4 is, by way of example, a time-varying, for example, radio frequency voltage. In some embodiments, V4 can further include one or more DC voltages.

[0092]

[0111] The voltage sources V3 and V5 are controllable DC voltages, and this voltage is such that the ions It is controlled to be able to enter the trap 418 through the ion inlet so that ions are trapped therein and also to release the ions from the ion outlet. In this regard, the operation of the ion trap 418 is conventional. For example, the voltage V3 is controlled to a DC potential that sets the ion energy, for example. Gas source GS In an embodiment including, the gas source GS supplies background gas, and this collides with the ions entering the ion trap 418 to thermalize the excess kinetic energy taken by the ions from the gas flow from the source region 408 to the ion trap 418. The time-varying voltage V4 operates to confine the ions radially, and the voltage V5 is controlled to trap the ions within the ion trap 418 and to release the ions from the ion trap 418. For example, for ions to penetrate the ion trap 418, V5 is typically controlled to a potential lower than the potential of V4, and for collecting and storing, i.e., trapping, the ions, the potential B5 is raised to a potential at which the ions cannot penetrate the ion outlet of the ion trap 418, for example.

[0093]

[0112] In some embodiments, as briefly described above, the apparatus 400 can include, for example a mass-to-charge ratio filter 424 having an ion inlet coupled to or integrated with the ion outlet of the ion trap 418. The ion outlet is spaced from the ion inlet of the filter 424 along the central axis A and is defined by a central opening formed through a conductive plate, grid, or the like 426 that is electrically connected to yet another output V7 of the voltage source 450, for example. Another pump P3 is operatively coupled to the filter 424 and is operable to pump at the filter 424 to a lower pressure than that of the ion trap 418, for example, a high vacuum, so that the filter 424 defines a third differently pumped region. In some embodiments, the gas source GS can be operatively coupled to the filter 424.

[0094]

[0113] The mass-to-charge ratio filter 424 is provided, by way of example, in the form of a conventional quadrupole mass-to-charge filter but, in alternative embodiments, the filter 424 can be provided in the form of a hexapole, octapole, or other conventional configuration. In any case, the mass-to-charge ratio filter 424 typically includes a plurality of elongated conductive rods surrounding an axis A to which the output V6 of the voltage source 450 is operatively coupled. By way of example, the output V6 is coupled to the rods such that pairs or sets of opposite rods are out of phase with another pair of opposites, and the output voltage V6 is, by way of example, a time-varying, e.g., radio frequency, voltage. In some embodiments, V6 can further include one or more DC voltages.

[0095]

[0114] In some embodiments, a voltage V is applied such that ions pass through the filter 424 7 is set to be sufficiently lower than that of voltage V5. In another embodiment, voltage V7 can be similarly switched to that of V5 so that filter 424 operates as a second ion trap. In any case in an embodiment where voltage V6 is time-varying only, e.g., RF only, mass-to-charge ratio filter 424 operates, by way of example, as a high-pass filter to allow only ions above the selected mass-to-charge ratio value to pass through filter 424. The selected mass-to-charge ratio value is, by way of example, a function of the magnitude of the time-varying voltage V6. In such an embodiment, mass-to-charge ratio filter 424 thus operates as a high mass-to-charge ratio filter to preselect, i.e., pass, only ions having a mass-to-charge ratio above the threshold of the selected mass-to-charge ratio. In some alternative embodiments, voltage V6 includes time-varying and DC components, and mass-to-charge ratio filter 424 operates, by way of example, as a band-pass filter to allow only ions within the selected range of mass-to-charge ratio to pass through filter 424. The selected range of mass-to-charge ratio is, by way of example, a function of the magnitudes of the time-varying and DC components. In such an embodiment, mass-to-charge ratio filter 424 thus operates as a mass-to-charge ratio band-pass filter to preselect, i.e., pass, only ions having a mass-to-charge ratio within the selectable range of the ion mass-to-charge ratio.

[0096]

[0115] In some alternative embodiments, mass-to-charge ratio filter 424 is an ion trap It can be arranged upstream of the wrap 418. In such an embodiment, the filter 424 can be controlled in any of the modes described herein to allow only ions having a mass-to-charge ratio within a specified range of mass-to-charge ratios to pass into the ion trap 418. In some such embodiments, the mass-to-charge ratio filter 424 can be arranged upstream and downstream of the ion trap 418. In such an embodiment, the mass-to-charge ratio filter 424 upstream of the ion trap 418 can be controlled, for example, to allow only ions having a mass-to-charge ratio within a selected range of mass-to-charge ratios to pass through, and the mass-to-charge ratio filter 424 downstream of the ion trap 418 can be controlled to allow only ions having a mass-to-charge ratio within a subset of the selected range of mass-to-charge ratios to pass through. Alternatively, the two mass-to-charge ratio filters 424 can be controlled to allow only ions having a mass-to-charge ratio within the same range of mass-to-charge ratios 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 the selected range of mass-to-charge ratios to pass into the trap 418, and the mass-to-charge ratio filter 424 downstream of the ion trap 418 can be used to enable the ions going out of the ion trap 418 to be temporally separated when they pass through it on the way to the detector 434.

[0097]

[0116] In some alternative embodiments, a conventional drift tube is used for the mass-to-charge ratio Replace, i.e., be replaceable with, filter 424. In some such embodiments, the axial passage defined through the drift tube can have a constant cross-sectional area. In some such embodiments, the drift tube is configured and controlled using one or more voltages created by voltage source 450 and can radially concentrate ions moving axially therethrough. In another embodiment, at least a portion of the drift tube near the ion exit end of the drift tube can be funnel-shaped, i.e., such that the cross-sectional area of the axial passage decreases in the direction towards the ion exit. In some embodiments, at least the funnel portion is configured and controlled using one or more voltages created by voltage source 450 to radially concentrate ions moving axially therethrough, and in another embodiment, the entire drift tube is configured and controlled using one or more voltages created by voltage source 450 to radially concentrate ions moving axially therethrough. In some such embodiments, plate or grid 426 can be substituted for the conventional ion carpet defining the central opening therethrough, and the ion carpet is configured and controlled using one or more voltages created by voltage source 450 to further concentrate ions to pass through the opening and towards the opening of the next stage of apparatus 400.

[0098]

[0117] Apparatus 400 is further coupled to the ion exit of mass-to-charge ratio filter 424 including a fourth differently pumped region 428 having an ion inlet that is either incorporated or integrated. A fourth pump P4 is operably coupled to the region 428 and is configured to pump in the region 428 to a pressure lower than the pressure of the filter 424. In the exemplary embodiment, the fourth differently pumped region 428 includes an ion lens and deflector 430, followed by a conventional energy analyzer 432, which is electrically connected to the voltage output V8 of the voltage source 450. In one embodiment, the energy analyzer 432 is a dual hemispherical deflection energy analyzer (HDA) and is configured to send a narrow band of ion energies centered at a nominal ion energy of 130 eV / z. In an alternative embodiment, the energy analyzer 432 can be implemented in another conventional form and / or configured to send ion energies centered at another ion energy value. configured to send a narrow band of ion energies centered at a nominal ion energy per ion energy. In an alternative embodiment, the energy analyzer 432 can be implemented in another conventional form and / or configured to send ion energies centered at another ion energy value.

[0099]

[0118] The apparatus 400 further includes an ion mass and charge detector 434, which In this exemplary embodiment, it is provided in the form of a single stage electrostatic linear ion trap (ELIT). The configuration of the ELIT is generally one stage of the ELIT 14 illustrated in FIGS. 1-2B and described in detail above. For example, the ELIT 434 includes spaced end caps 436, 438, each of which represents, by way of example, opposite halves of the ion mirror MX illustrated in FIGS. 2A and 2B, with a detection cylinder 440 disposed therebetween. The ELIT 434 is operably coupled to a pump P5, which is configured and controlled to establish a pressure, e.g., a vacuum, within a fifth differently pumped region defined by the ELIT chamber. In one embodiment, the pump P5 is controlled to establish a pressure of about 10 -9 mbar within the ELIT 434, although in another embodiment, the pump P5 can be controlled to establish a higher or lower pressure within the ELIT chamber.

[0100]

[0119] The input of a conventional charge sensitive preamplifier 442 supplies a current to the charge detection cylinder 440. The preamplifier 442 is electrically connected to the input of a conventional processor 444, with the output of the preamplifier 442 electrically coupled to an input of the processor 444. The processor 444 illustratively includes or is coupled to a memory 446, which stores instructions executable by the processor 444 to control the operation of the apparatus 444 as described below. In some embodiments, the processor 444 is operably coupled to one or more peripheral devices PD 448 via P number of signal paths, where P can be any positive integer. In some embodiments, the processor 444 can also be electrically coupled to a voltage source 450 via M number 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 can itself be programmable and / or manually controllable. In either case, the charge sensitive preamplifier 442, processor 444, memory 446, and peripheral device(s) 448 are, by way of example, all as described above with respect to FIG.

[0101]

[0120] The voltage output V9 of the voltage source 450 is electrically connected to the ion mirror 436. Another voltage output V10 of voltage source 450 is electrically connected to ion mirror 438. It will be understood that each of voltages V9 and V10 includes a number of different switchable voltages for controlling the operation of individual ones of the ion mirrors 436, 438, as shown by way of example in Figures 2A and 2B and described in detail above, and that the operation of the ELIT 434 under control of such voltages V9 and V10 is also as described with respect to each of the stages depicted in Figures 1-4E.

[0102]

[0121] 10 and 11, pulsed operation of the CDMS device 400 includes at least the selective control of voltages V5, V9, and V10. Voltage V5, which causes ions to be trapped and stored within ion trap 418, i.e., corresponding to the ion storage or trapping state in the case of the voltage of V5, or in the case of ion mirrors 436, 438, the ion trapping or reflection state, i.e., voltages V9 and V10 that cause ion mirrors 436, 438 to operate in their reflection modes to receive ions from charge detection cylinder 440 therein, the high states of voltages V5, V9, and V10 reverse the direction of ion movement and cause the ions to accelerate back through charge detection cylinder 440 and towards another mirror. As described above, it will be understood that the ions are trapped within ELIT 434 and oscillate back and forth between ion mirrors 436, 438, passing through detection cylinder 440 each time. The low states of voltages V5, V9, and V10 correspond to the transmission state, i.e., the voltage at which ions are released from ion trap 418, which, as described above, causes ion mirrors 436, 438 to operate in their transmission modes to allow the ions to pass through them.

[0103]

[0122] Ion source 404 responds to voltage V1 created by voltage source 450 ​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 an alternative embodiment, the voltage source 450 can itself be programmed to do so, and the voltage source 450 can be manually controlled to produce V1. In any case, the generated ions go through the source region 408 and into the ion trap 418. In embodiments where the source region 408 includes the interface 410, the voltage source 450 is operable to produce one or more voltages V2 to control the interface 410 such that ions pass through it, as briefly described above. In any case, the voltage V3 produced by the voltage source 450 controls the ion inlet of the ion trap 418 to set the energy of the ions entering from the source region 408 to a target energy, for example, about 130 eV / z. First, as shown in FIG. 11, the voltage (one or more) V5 is set to a trapping state for capturing, trapping, and accumulating the generated ions in the ion trap 418, and the voltages V9 and V10 are set to a transmission state to clear the ELIT 434 by allowing any ions moving towards the ELIT 434 to pass through it.

[0104]

[0123] The pulsed operation of the apparatus 400 switches to the transmission state only for the pulse width period tw Starting from voltage (1 or greater) V5, voltage (1 or greater) V5 is then switched so as to return to the trapping state again. The pulse width period tw is selectable, i.e., adjustable, and during this time, the ions stored in ion trap 418 are released or ejected therefrom and move into region 424 in response to the electric field established by voltages V5 and V7, and move towards ELIT 434. In embodiments where region 424 includes a mass-to-charge ratio filter, only ions having a value of mass-to-charge ratio selected for passage by voltage (1 or greater) V6 pass through region 424 and proceed into region 428. Ions having energy within a narrow band of energy per transmission energy of energy analyzer 432 pass through region 428 and proceed into ion mirror 436 of ELIT 434, and ions having energy outside this narrow band are deflected away from the ion inlet of ELIT 434.

[0105]

[0124] Voltage (1 or greater) V5 for the ion transmission state to release ions from ion trap 418 The delay time t following the transition of voltage (1 or greater) V5 D1 expires, the voltage V10 to the rear ion mirror or end cap 438 is switched from the transmission state to the trapping or reflecting state. Thereafter, the ions coming from charge detection cylinder 440 into the rear ion mirror or end cap 438 are thus reversed in direction by the ion reflection electric field established therein and accelerated by the ion reflection electric field to return through charge detection cylinder 440 towards the front mirror or end cap 436. Another delay time t following the transition of voltage (1 or greater) V5 to the ion transmission state to release ions from ion trap 418 D2When it expires, the voltage V9 to the front ion mirror or end cap 436 is switched from the transmission state to the trapping or reflection state. The ions in the charge detection cylinder 440 or in the rear ion mirror or end cap 438 during such a switching of the voltage V9 to the trapping or reflection state are thus trapped in the ELIT 434, and when both the ion mirrors 436, 438 are in their reflection modes, as described above, the trapped ion(s) oscillate back and forth between the ion mirrors 436, 438, inducing the corresponding charge there each time through the charge detection cylinder 440. The ion(s) remain trapped in the ELIT 434 for only the trapping time period t trap shown in FIG. 11, and at the end of the trapping time period t trap , the voltages V9 and V10 return to their transmission states, emptying the ELIT 434 before starting the sequence again. The resulting charge detection signal created by the charge preamplifier 442 in response to the detection of the charge induced in the charge detection cylinder by the ion(s) passing through the charge detection cylinder is processed by the processor 444 to determine the mass and charge of the trapped ion(s), as described above. In some embodiments, the voltage is controlled as described herein to trap one ion in the ELIT 434, and in other embodiments, the voltage can be controlled to trap more than one ion in the ELIT 434. The pulse mode operation of the CDMS device 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 such that the arrival of the ions at the ELIT 434 is synchronized with the opening and closing (transmission mode and reflection mode, respectively) of the ion mirrors 436, 438.

[0106]

[0125] As illustrated in FIG. 10, the ion exit of the ion trap 418 and the charge detection port are such that the arrival of the ions at the ELIT 434 is synchronized with the opening and closing (transmission mode and reflection mode, respectively) of the ion mirrors 436, 438.

[0107]

[0126] As illustrated in FIG. 10, the ion exit of the ion trap 418 and the charge detection There is a substantial distance D1 (e.g., 0.86 m) between the front end of the extraction cylinder 440. In one embodiment, D1 is about 0.86 meters, but in alternative embodiments, D1 can be longer or shorter than 0.86 meters. In any case, the time required for the ions to travel D1 depends on their kinetic energy and their mass-to-charge ratio (m / z). Since the energy analyzer 432 transmits only ions within a narrow kinetic energy distribution, this transit or travel time depends primarily on the m / z of the ions. When the pulse width period tw is short, one range of m / z values is trapped between a given total delay time t D1 while t D is the transition of the voltage (1 or greater) V5 to the ion transmission mode corresponding to opening the ion exit of the ion trap 418 and releasing or ejecting the ions therefrom, i.e., the fall of V5 at tw, and the closing of the ion mirror 436 of the ELIT 434, i.e., corresponding to the reflection mode, and the transition of the voltage V9 to the ion trapping or reflection state corresponding to the trapping of the ion(s) in the ELIT 434, i.e., the rise of V9 following the subsequent rise of V5 at tw, and thus, t D = t D1 + t D2 is. The maximum mass-to-charge ratio m / z MAX (i.e., the slowest) ions that can be trapped are those that have just entered the detection cylinder when the front end cap has switched to the reflection mode under these circumstances.

[0108]

[0127] m / z MAX = 2eE[t D 2 / d1 2 (1)

[0109]

[0128] In Equation 1, the elementary charge E is the ion energy, and d1 is as described above and is shown in FIG. 10. The minimum mass-to-charge ratio m / z that can be trapped MINThe fastest (i.e., fastest) ions are those traveling through the charge detection cylinder 440 when voltage V9 switches to the reflective state, are reflected by the rear ion mirror or end cap 438, travel back through the charge detection cylinder 440, and are about to exit through the front ion mirror or end cap 436.

[0110]

[0129] m / z MIN = 2eE[t D 2 / (d1+ 2d2+ d3) 2 ] (2)

[0111]

[0130] In Equation 2, d2 is the length of the charge detection cylinder 440, and d3 is the is the distance between the inlet / outlet of each ion mirror 436, 438 and the corresponding end of the charge detection cylinder 440. 2d2 in equation (2) is so because ions travel both forward and backward through the charge detection cylinder 440, and d3 is determined from the time spent in the end caps. In some embodiments of the ELIT 434, d2=d3, and therefore the time spent by an ion traveling through the charge detection cylinder 440 is equal to the time spent traveling through each end cap 436, 438. In such embodiments, equation (2) can be reduced to:

[0112]

[0131] m / z MIN = 2eE[t D 2 / (d1+ 3d2) 2 ] (3)

[0113]

[0132] Therefore, the ratio of the maximum and minimum m / z that can be trapped is given by the following formula: can be done.

[0114]

[0133] m / z MAX / m / z MIN = (d1+ 3d2) 2 / d1 2 (4)

[0115]

[0134] Therefore, the range of m / z values that can be trapped is independent of the ion energy and the delay time t D From. When the delay time is long, the m / z window shifts to larger m / z values, but the relative width of the m / z window remains the same. For the CDMS device 400 where d2 = d3 as described above, the ratio of the maximum to minimum m / z values is 1.38. Therefore, the width of the m / z window that can be trapped using one delay time t D is from m / z MIN to 1.38 × m / z MIN . For example, if the delay time t D is set so that the minimum m / z value that can be trapped is 25 kDa, ions with m / z values up to 34.5 kDa can be trapped simultaneously.

[0116]

[0135] Example

[0117]

[0136] The truncated hepatitis B virus (HBV) capsid protein (C p149) was assembled in 300 mM sodium chloride for 24 hours, dialyzed into 100 mM ammonium acetate (Sigma Aldrich, 99.999% trace metal basis), and stored for at least one week before use (to allow assembly error time for self-correction). The initial concentration of the capsid protein was 1 mg / mL. The assembly yielded mainly an icosahedral T = 4 capsid (about 32 nm in diameter) composed of 120 capsid protein dimers, accompanied by a small amount (about 5% in this case) of an icosahedral T = 3 capsid with 90 protein dimers. The pseudo critical concentration for HBV assembly in 300 mM NaCl is 3.7 μM. Therefore, the final capsid concentration is about It is 0.22 μM. Samples of the stock solution were purified by size exclusion chromatography (SEC) with a 6 kDa cutoff. An aliquot of the purified liquid was then diluted with 100 mM ammonium acetate to the required concentration ranging from 0.05 μg / mL to 100 μg / mL.

[0118]

[0137] Pyruvate kinase (PK) was prepared in ammonium acetate at 10 mg / ml An aliquot of the stock solution was purified by SEC with a 6 kDa cutoff. The purified liquid was then diluted with 100 mM ammonium acetate to 2 mg / mL.

[0119]

[0138] FIG. 12A shows portions of two representative mass distributions of an HBV sample measured using the CDMS device 400 illustrated in FIG. 10 and described above. Results for two concentrations are shown, with 100 μg / mL (100-fold dilution of the HBV stock solution) shown as 500 in FIG. 12A and 0.5 μg / mL (2000-fold dilution) shown as 502 in FIG. 12A. The CDMS distribution shown in FIG. 12A was recorded for 16.6 minutes (10,000 trapping events) and plotted on a 25 kDa bin. At a concentration of 10 μg / mL (represented as 500), there is a prominent peak at a mass of approximately 4.05 MDa, which is close to the predicted mass for the T = 4 capsid of HBV Cp149. At a concentration of 0.5 μg / mL (represented as 502), the peak has almost disappeared. Note that since the ions are measured for a relatively long time (100 ms), the rate of spurious signals in CDMS is very low. Ions of the HBV T = 4 capsid have approximately 140 elementary charges, and the probability that a random noise signal could masquerade as an ion signal of this magnitude over a 100 ms time period is quite small. Thus, the background noise in the target range is also quite small.

[0120]

[0139] The number of analytes contained in electrospray droplets can affect the detection efficiency. Note that the estimate of the average number of capsids present in the droplets can be obtained, for example, from the concentration and droplet size. Also, the average size of the main electrospray droplets can be estimated from the electrospray conditions. When the estimated droplet size is 70 nm, the average number of capsids per droplet is approximately 0.025 (i.e., 1 out of 40 droplets contains a capsid) at the concentration of the HBV stock solution (1 mg / mL).

[0121]

[0140] Figure 12B shows a log-log plot 504 of the integrated counts in the range from 3.8 MDa to 4.4 MDa for HBV concentrations from 0.5 μg / mL to 10 μg / mL. The points are the measured values and the line is, for example, a least-squares fit. A slope of 1.0 is expected for the log-log plot of the response versus concentration and a slope close to 1.0 is observed. In the plot 504 of Figure 12B, for example, the slope is 1.031. Based on these results, the limit of detection for the HBV T = 4 capsid can be taken to be approximately 0.5 μg / mL. This corresponds to 1.1×10 mol / L or 6.6×10 -10 particles / mL. During a collection period of 16.6 minutes, approximately 1.3 μL of liquid was electrosprayed. Taking this into account, the limit of detection is thus approximately 0.14 femtomoles or 8.6×10 10 particles. During the 16.6-minute data acquisition time, 19 ions were detected. Thus, the detection efficiency for the HBV T = 4 capsid is approximately 2.2×10 7 as follows. -7

[0122]

[0141] Figure 13A shows the standard for the HBV capsid at a concentration of 1 μg / mL ​Comparison of the mass distributions measured by the CDMS device 400 in both the quasi-mode (i.e., non-pulsed type) (represented by 602 in FIG. 13A) and the pulsed mode (represented by 600 in FIG. 13A) described herein is shown. Clearly, the intensity in the distribution 600 measured in the pulsed mode is much larger than the intensity in the distribution 602 measured in the standard (non-pulsed) mode. The standard mode distribution contains 15 ions, and the pulsed type contains 3695. Thus, the intensity gain in this example is 246.

[0123]

[0142] FIG. 13B shows another comparison of the mass distributions between the standard (non-pulsed) mode 606 and the pulsed mode 604. In this case, the standard mode distribution 606 was measured at a concentration of 0.5 μg / mL, and the pulsed mode distribution 604 was measured at a concentration of 0.05 μg / mL. The standard mode distribution 606 contains 8 ions, and the pulsed mode distribution 604 contains 145. Thus, the intensity gain is 181 (considering the concentration difference).

[0124]

[0124]

[0143] The intensity gain depends on the trapping efficiency, the pulse width period tw, and the delay times t D1 and t D2 (all shown in FIG. 11). It was found that the signal from the ions trapped in the ion trap 418 persists for longer than 20 seconds after the electrospray source 404 is turned off, indicating that ions are efficiently trapped in the ion trap 418. If the pulse width tw 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 tw is too long, the benefit of accumulating ions in the ion trap 418 is lost, and the signal approaches the value for the non-pulsed mode. The pulse width tw and the delay times t D1 and t D2When optimized, the intensity gain obtained from the pulsed-mode operation was found to have an average of about 200. Regarding an m / z of 2800 Da, it should be noted that in the non-pulsed mode of operation of the CDMS device 400, only about 1 out of 620 ions can be trapped. By operating in the pulsed mode as described above, much of the signal lost in the non-pulsed mode can be recovered. When performing the pulsed-mode operation illustrated and described here, the detection limit for the T = 4 capsid of HBV is about 200 times lower, at 5.5×10 - 13 mol / L or 3.3×10 8 particles / mL. This corresponds to about 4.3×10 5 particles or about 0.7 attomoles for a 1.3 μL sample. The detection efficiency for the T = 4 capsid of HBV in the pulsed-mode operation is about 4.4×10 -5 (i.e., 200 times the detection efficiency in the non-pulsed mode).

[0125]

[0144] In the case of high sensitivity obtained by pulsed-mode CDMS, many ions are in E It is relatively easy to inject simultaneously into the LIT. However, while multiple ion-trapping events can be analyzed to determine the m / z values and charges of small amounts of simultaneously trapped ions, the ion-ion interactions within the ELIT434 can vary the trajectories and energies, which degrades the m / z resolution. Trapping multiple ions with similar m / z values can cause errors in data analysis, and the measurements depicted in the attached drawings are limited to samples in which, on average, one ion is trapped per trapping event. The distribution of trapped ions is a Poisson distribution, and when the average trapping efficiency is about 1, approximately one-third of the trapping events are empty, another one-third contain one ion, and the remaining one-third contain two or more ions. For a sample concentration of 10 μg / mL, the number of ions trapped in pulse mode is considerably more than one per event on average, and the sample must be diluted in order for the measurements depicted in the attached drawings to be made.

[0126]

[0145] As described above, the assembly of the HBV capsid protein, in addition to T = 4 , resulting in a small amount of small T = 3 capsids. 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 is within the range that can be trapped simultaneously. In this regard, FIG. 14 shows the CDMS mass distributions 700, 702 for HBV measured using the CDMS device 400, showing a peak of T = 3 at about 3.0 MDa and a peak of T = 4 at about 4.05 MDa. Distribution 702 was measured using the CDMS device 400 under standard operating conditions (i.e., non-pulsed mode), and distribution 700 was measured using the CDMS device 400 operating in pulse mode as described above. The concentration of the HBV protein was 100 μg / mL for the non-pulsed type (distribution 702) and 1 μg / mL for the pulsed type (distribution 700). The portion of the T = 3 capsid (from the integrated counts) is 0.0435 for the standard mode distribution 702 and 0.0470 for the pulse mode distribution 700. However, larger (i.e., slower) ions spend more time in the trapable region of ELIT434, so the detection efficiency in the standard mode distribution 702 is proportional to (m / z) 1 / 2 . In the pulse mode operation of the CDMS device 400, all ions in the trapable region of ELIT434 are trapped, and the detection efficiency for these ions does not depend on the m / z ratio. After correcting the ratio of the standard mode with respect to the detection efficiency, the ratio increases to 0.0461 (compared to 0.0470 for the pulse mode). Therefore, the ratio of intensities is not significantly affected by the pulse mode operation.

[0127]

[0146] The m / z distribution is from the above m / z MIN to 1.38×m / z MIN window is wider, the total delay time t Dcan be adjusted to trap another portion of the distribution. For example, FIG. 15 shows the CDMS mass distribution for a pyruvate kinase (PK) sample measured using the CDMS apparatus 400. The mass distribution 804 was measured under standard (i.e., non-pulsed) conditions, and peaks due to the tetramer (230 kDa), octamer (460 kDa), dodecamer (690 kDa), and hexadecamer (920 kDa) of PK are clearly visible. It is not possible to simultaneously transmit all multimers in pulse mode. However, by adjusting the delay time t D it is possible to transmit different m / z bands. The mass distribution 800 was measured in pulse mode using a delay time t D optimized to transmit m / z values that include the tetramer (m / z values in the range of about 6600 Da to 9150 Da are transmitted), and the mass distribution 802 was measured in pulse mode using a delay time t optimized to transmit the octamer and dodecamer D . In both cases, the ratio of the minimum to maximum mass-to-charge ratio transmitted is close to the predicted value (1.38) described above. The ability to select some portions of the m / z distribution is beneficial in many applications. For example, since individual ions are processed by CDMS, it is beneficial not to consume time processing ions that do not contain useful information. Thus, as described above, distinguishing portions of the m / z distribution that do not contain useful information is beneficial. Many samples contain a large number of low-mass ions that can be distinguished for use of this approach.

[0128]

[0147] In the exemplary embodiment of the apparatus 400 described herein, ion mass and charge detection Detector 434 is provided in the form of a single-stage electrostatic linear ion trap (ELIT). In another embodiment, however, ion mass and charge detector 434 may alternatively be provided in the form of a multi-stage ELIT, such as ELIT 14 described herein with respect to FIGS. 1-4E, or multiple single-stage ELITs, such as those described herein with respect to FIGS. 6-8F, or, in some embodiments, one or more orbitraps, such as those disclosed in co-pending International Patent Application No. PCT / US2019 / 013278, below. In the first two cases, the operation of apparatus 400 can be modified without conflicting with the description of systems 10, 200 above, to supply ions to the multi-stage ELIT or stages of ELIT in sequence. In the case of the multi-stage ELIT of the type illustrated and described above with respect to FIGS. 1-4E, it should be noted that each ELIT region (e.g., E1, E2, and E3) is spaced apart from the ion trap 418 by successively greater distances such that the minimum and maximum mass-to-charge ratio values are somewhat different respectively. Further, it should be noted that the range of mass-to-charge ratios that can be trapped within each of the ELIT regions decreases gradually as the distance from the ion trap 418 to the ELIT region increases, as given by equation (4) above.

[0129]

[0148] The ELIT and / or array 14, 2 illustrated and described above with reference to the accompanying drawings 05, 302, 434, or any combination thereof, the dimensions of the various components can be selected, for example, to establish a desired duty cycle of ion oscillations therein and / or within each ELIT or ELIT region E1 - E3, which corresponds to the ratio of the time consumed by ions (one or more) in the individual charge detection cylinders (one or more) CD1 - CD3 to the total time consumed by ions (one or more) across the combination of the ion mirror corresponding to one complete oscillation cycle and the individual charge detection cylinders (one or more) CD1 - CD3. For example, a duty cycle of about 50% may be desirable in one or more of the ELIT or ELIT regions for the purpose of reducing noise in the quantification of the magnitude of the fundamental frequency resulting from the harmonic frequency components of the measurement signal. Details related to the consideration of such dimensions to achieve a desired duty cycle, such as 50%, are exemplified and described in International Patent Application No. PCT / US2019 / 013251, filed on January 11, 2019, entitled "ELECTROSTATIC LINEAR ION TRAP DESIGN FOR CHARGE DETECTION MASS SPECTROSCOPY", the disclosure of which is hereby expressly incorporated herein by reference in its entirety. International Patent Application No. PCT / US2019 / 013251, the disclosure of which is hereby expressly incorporated herein by reference in its entirety.

[0130]

[0149] Further, any It will be understood that a charge calibration or resetting device can be used with one or more charge detection cylinders (one or more) and / or in any one or more of the regions (one or more) E1 - E3 of the ELIT or ELIT array. An example of one such charge calibration or resetting device is illustrated and described in International Patent Application No. PCT / US2019 / 013284 filed on January 11, 2019 and International Patent Application No. PCT / US2019 / 035381 filed on June 4, 2019, both of which have the title "APPARATUS AND METHOD FOR CALIBRATING OR RESETTING A CHARGE DETECTOR", and the entire disclosures of these applications are hereby expressly incorporated herein by reference will be.

[0131]

[0150] Further, for trigger trapping or other charge detection events, it will be understood that one or more charge detection optimization techniques can be used with any one or more of the EL IT and / or arrays 14, 205, 302, 434 and / or with one or more regions E1 - E3 of such ELIT and / or ELIT arrays. Examples of some such charge detection optimization devices and techniques are illustrated and described in International Patent Application No. PCT / US2019 / 0132 80 filed on January 11, 2019 and having the title "APPARATUS AND METHOD FOR CAPTURING IONS IN AN ELECTROSTATIC LINEAR ION TRAP", the disclosure of which is hereby expressly incorporated herein by reference in its entirety.

[0132]

[0151] Further, together with one or more embodiments of the ion source 12 illustrated and described herein It is understood that ion source optimization apparatuses and / or techniques of 1 or more can be used, some examples of which are illustrated and described in International Patent Application No. PCT / US2019 / 013274 filed on January 11, 2019 and International Patent Application No. PCT / US2019 / 035379 filed on June 4, 2019, both of which have the title "HYBRID ION FUNNEL-ION CARPET (FUNPET) ATMOSPHERIC PRESSURE INTERFACE FOR CHARGE DETECTION MASS SPECTROMETRY", and the disclosures of these applications are hereby expressly incorporated herein by reference in their entirety.

[0133]

[0152] Further, it is understood that the ion mass detection systems 10, 60, 80, 2 00, 300, 400 can be implemented according to real-time analysis and / or real-time control techniques, some examples of which are illustrated and described in International Patent Application No. PCT / US2019 / 013277 filed on January 11, 2019 with the title "CHARGE DETECTION MASS SPECTROMETRY WITH REAL TIME ANALYSIS AND SIGNAL OPTIMIZATION", and the disclosure of this application is hereby expressly incorporated herein by reference in its entirety.

[0134]

[0153] Further, the ion mass detection systems 10, 60, 80, 2 It is understood that the ELITs 14, 300, 400 can be configured to deliver 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 are operable to measure the mass and charge of multiple ions at once, some examples of which are disclosed in co-pending application Ser. No. 09 / 023,313, filed on Jan. 11, 2019, and entitled “APPARATUS AND METHOD FOR SIMULTANEOUSLY ANALYZING MULTIPLE IONS WITH AN ELECTROSTATIC LINEAR ION TRAP.” No. PCT / US2019 / 013285, the disclosure of which is expressly incorporated herein by reference in its entirety.

[0135]

[0154] Furthermore, the ion mass detection systems 10, 60, 80, 200 and 220 illustrated and described herein It is understood that in one or more of 00, 300, 400, at least one ELIT can alternatively be provided in the form of an Orbitrap, some examples of which are illustrated and described in co-pending International Patent Application No. PCT / US2019 / 013278, filed January 11, 2019, and entitled "ORBITRAP FOR SINGLE PARTICLE MASS SPECTROMETRY," the disclosure of which is expressly incorporated herein by reference in its entirety.

[0136]

[0155] Further, the CDMS apparatus 400 may additionally be configured as illustrated in FIG. 5A and described above. It will be understood that the CDMS device 400 is included as an alternative ion mass detection device embodiment (i.e., as an alternative to the ion mass detection systems 10, 200, 300). Similarly, the CDMS device 400 may be used in addition to the ion mass detection device embodiment illustrated in FIG. 5B and described above. It will be understood that these are included as alternatives (i.e., as alternatives to the ion mass detection systems 10, 200, 300).

[0137]

[0156] Although the invention has been illustrated and described in detail in the above drawings and description, this is considered to be an example shown and not a limitation of features, only its exemplary embodiments are shown and described, and it is understood that protection is desired for all changes and modifications within the spirit of the invention.

Claims

1. A charge detection mass spectrometer, comprising: 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) located away from the ion trap and including a first ion mirror, a second ion mirror, and a charge detection cylinder disposed therebetween; means for selectively controlling the ion trap to release at least some of the stored ions therefrom and move them into the ELIT, and for controlling the first ion mirror and the second ion mirror to trap one of the ions passing through the ELIT, and vibrate the trapped ion back and forth between the first ion mirror and the second ion mirror, and pass through the charge detection cylinder each time to induce a corresponding charge; A charge detection mass spectrometer comprising the above.

2. The charge detection mass spectrometer according to Claim 1, further comprising: a charge-sensitive amplifier having an input and an output coupled to the charge detection cylinder, and configured to generate a corresponding charge detection signal at the output in response to detection of a charge induced in the charge detection cylinder by the trapped ions passing through the charge detection cylinder; means for processing a plurality of the charge detection signals and determining the mass and charge of the trapped ions from the processing. A charge detection mass spectrometer further comprising the above.

3. The charge detection mass spectrometer according to Claim 1, further comprising: a mass-to-charge ratio filter disposed between the ion trap and the ELIT, configured such that only ions having a mass-to-charge ratio above a mass-to-charge ratio threshold, or below a mass-to-charge ratio threshold, or within a selected range of mass-to-charge ratios pass therethrough. A charge detection mass spectrometer further comprising the above.

4. A charge detection mass spectrometer, comprising: an ion source configured to generate ions from a sample; at least one voltage source configured to generate a plurality of output voltages. An ion trap coupled to the plurality of output voltages of the first set, configured to receive and store the generated ions therein according to its trapping state, and to selectively release the stored ions therefrom according to its transmission state; An electrostatic linear ion trap (ELIT) remote from the ion trap, including a front ion mirror and a rear ion mirror, and a charge detection cylinder disposed therebetween, the front ion mirror and the rear ion mirror being coupled to the second set and the third set of the plurality of output voltages respectively, configured to allow ions to pass therethrough according to its transmission state, and to reflect ions entering therein from the charge detection cylinder back into the charge detection cylinder according to its reflection state; A processing circuit that controls the first set of voltages to its transmission state to release at least some of the ions stored in the ion trap and cause them to move through the front ion mirror into the ELIT, and then the second set of voltages subsequent to which controls the third set of voltages to its reflection state to trap one of the ions moving therethrough and cause the trapped ion to oscillate back and forth between the front ion mirror and the rear ion mirror, passing through the charge detection cylinder each time and inducing a corresponding charge; A charge detection mass spectrometer including the processing circuit.

5. The charge detection mass spectrometer according to claim 4, further comprising a charge-sensitive amplifier having an input and an output coupled to the charge detection cylinder, and configured to generate a charge detection signal at the output in response to detection of the charge induced in the charge detection cylinder by the ions passing through the charge detection cylinder; wherein the processing circuit is configured to process a plurality of the charge detection signals and determine from the processing the mass and charge of the trapped ions. A charge detection mass spectrometer.

6. The charge detection mass spectrometer according to claim 4, A mass-to-charge ratio filter disposed between the ion trap and the ELIT, configured such that only ions having a mass-to-charge ratio above a mass-to-charge ratio threshold, or below a mass-to-charge ratio threshold, or within a selected range of mass-to-charge ratios pass therethrough A charge detection mass spectrometer further comprising the same

7. The charge detection mass spectrometer according to claim 4, wherein the processing circuit is configured to control the first set of voltages from the trapping state to the transmission state during the pulse width period and, in response to the expiration of the pulse width period, to control the first set of voltages from the transmission state to the trapping state

8. The charge detection mass spectrometer according to claim 7, wherein the processing circuit is configured to control the third set of voltages from the transmission state to the reflection state when a first delay time from the control of the first set of voltages from the trapping state to the transmission state has elapsed, the processing circuit is configured to control the second set of voltages from the transmission state to the reflection state when a second delay time from the control of the first set of voltages from the trapping state to the transmission state has elapsed, the second delay time being greater than the first delay time A charge detection mass spectrometer

9. The charge detection mass spectrometer according to claim 8, wherein the mass-to-charge ratio of the ions trapped in the ELIT is proportional to the sum of the first delay time and the second delay time, the sum of the first delay time and the second delay time is controlled by the processing circuit so as to select a corresponding mass-to-charge ratio range of the ions trapped in the ELIT A charge detection mass spectrometer

10. A method of operating a charge detection mass spectrometer including an electrostatic linear ion trap (ELIT) having a charge detection cylinder disposed between a front ion mirror and a rear ion mirror, and an ion trap remote from the front ion mirror, the method comprising: generating ions from a sample; storing the generated ions in the ion trap; controlling the ion trap to release at least some of the stored ions therefrom and move them through the front ion mirror into the ELIT and After controlling the ion trap to release the trapped ions, the rear ion mirror is controlled to a reflective state so that the rear ion mirror reflects ions entering from the charge detection cylinder to the rear ion mirror back through the charge detection cylinder towards the front ion mirror. After controlling the rear ion mirror to its reflective state, the front ion mirror is controlled to a reflective state so that the front ion mirror reflects ions entering from the charge detection cylinder to the front ion mirror back through the charge detection cylinder towards the rear ion mirror, traps one of the ions released from the ion trap in the ELIT, and causes the trapped ion to oscillate between the front ion mirror and the rear ion mirror, inducing corresponding charges each time it passes through the charge detection cylinder. A method comprising the above.

11. The method of claim 10, using a processor to process the detection of the plurality of induced charges and determine from the processing the mass and charge of the trapped ions. A method further comprising the above.

12. The method of claim 10, for the ions released from the ion trap, performing a filtering process only for ions having a mass-to-charge ratio above or below a mass-to-charge ratio threshold or within a selected range of mass-to-charge ratios before passing them into the ELIT. A method further comprising the above.

13. The method of claim 10, wherein the range of mass-to-charge ratios of ions that can be trapped within the ELIT is a function of the distance between the ion trap and the ELIT and the axial dimension inside the ELIT.

14. The method of claim 13, configuring the analyzer to trap within the ELIT by establishing a corresponding distance between the ion trap and the ELIT for a selected range of mass-to-charge ratios. A method further comprising the above.

15. A charge detection mass analyzer, an ion source configured to generate ions from a sample, An ion trap configured to receive and store the generated ions therein and to selectively release the stored ions therefrom; An electrostatic linear ion trap (ELIT) remote from the ion trap, including a first ion mirror and a second ion mirror, and a charge detection cylinder disposed therebetween, the first ion mirror facing the ion trap, an ion exit of the ion trap being spaced from a first end of the charge detection cylinder facing the first ion mirror by a first distance, a length of the charge detection cylinder between the first end of the charge detection cylinder and a second end of the charge detection cylinder facing the second ion mirror defining a second distance, the first distance and the second distance being selected to define a range of mass-to-charge ratios of ions that can be trapped within the ELIT; Means for selectively controlling the ion trap to release at least some of the stored ions therefrom and move them toward the ELIT, and for controlling the first ion mirror and the second ion mirror to trap at least one of the ions moving therein in the ELIT and vibrate the trapped at least one ion back and forth between the first ion mirror and the second ion mirror, passing through the charge detection cylinder each time to induce a corresponding charge; A charge detection mass spectrometer.

16. The charge detection mass spectrometer according to claim 15, Further including a charge-sensitive amplifier having an input and an output coupled to the charge detection cylinder, and configured to create a charge detection signal at the output in response to detection of a charge induced in the charge detection cylinder by the at least one ion passing through the charge detection cylinder; The processing circuit being configured to process a plurality of the charge detection signals and determine from the processing the mass and charge of the trapped at least one ion; A charge detection mass spectrometer.

17. The charge detection mass spectrometer according to claim 15, A mass-to-charge ratio filter disposed between the ion trap and the ELIT, configured such that only ions having a mass-to-charge ratio above a mass-to-charge ratio threshold, or below a mass-to-charge ratio threshold, or within a selected range of mass-to-charge ratios pass therethrough. A charge detection mass spectrometer further comprising the same.

18. The charge detection mass spectrometer according to claim 15, wherein the processing circuit is configured to control a first set of voltages from its trapping state to a transmission state during a pulse width period, and in response to the expiration of the pulse width period, control the first set of voltages from the transmission state to the trapping state. Charge detection mass spectrometer.

19. The charge detection mass spectrometer according to claim 18, wherein the processing circuit is configured to control a third set of voltages from its transmission state to a reflection state when a first delay time from the control of the first set of voltages from the trapping state to the transmission state elapses. The processing circuit is configured to control a second set of voltages from its transmission state to a reflection state when a second delay time from the control of the first set of voltages from the trapping state to the transmission state elapses, and the second delay time is greater than the first delay time. Charge detection mass spectrometer.

20. A method of operating a charge detection mass spectrometer including an electrostatic linear ion trap (ELIT) having a charge detection cylinder disposed between a front ion mirror and a rear ion mirror, and an ion trap remote from the front ion mirror, comprising: selecting a first distance between an ion exit of the ion trap and an end of the charge detection cylinder facing the front ion mirror of the ELIT, and a second distance between opposite ends of the charge detection cylinder to establish a range of mass-to-charge ratios of ions that can be trapped within the ELIT; generating ions from a sample; storing the generated ions in the ion trap; controlling the ion trap to release at least some of the stored ions therefrom and move them through the front ion mirror into the ELIT; After controlling the ion trap to release the stored ions, the rear ion Control the on-mirror to the reflective state so that the rear ion mirror reflects ions entering from the charge detection cylinder to the rear ion mirror back through the charge detection cylinder towards the front ion mirror. After controlling the rear ion mirror to its reflective state, control the front ion mirror to the reflective state so that the front ion mirror reflects ions entering from the charge detection cylinder to the front ion mirror back through the charge detection cylinder towards the rear ion mirror, trap at least one of the ions released from the ion trap in the ELIT, and cause the trapped at least one ion to oscillate back and forth between the front ion mirror and the rear ion mirror, passing through the charge detection cylinder each time to induce a corresponding charge. A method comprising the above.

21. The method of claim 20, using a processor to process the detection of the plurality of induced charges and determine from the processing the mass and charge of the trapped at least one ion. A method further comprising the above.

22. The method of claim 20, for the ions released from the ion trap, performing a filtering process only for ions having a mass-to-charge ratio above or below a mass-to-charge ratio threshold, or within a selected range of mass-to-charge ratios, before passing them into the ELIT. A method further comprising the above.

Images