Apparatus and method for calibrating or resetting a charge detector - Patents.com

Abstract

To provide an apparatus and method for calibrating charge detection equipment.SOLUTION: A charge detection mass spectrometer (CDMS) may include an electrostatic linear ion trap (ELIT) having a charge detection cylinder (CD), a charge generator for generating a high frequency charge (HFC), a charge sensitive preamplifier (CP) having an input coupled to the CD and an output configured to produce a charge detection signal (CHD) in response to a charge induced on the CD, and a processor. The processor is configured to (a) control the charge generator to induce an HFC on the CD, (b) control operation of the ELIT to cause a trapped ion to oscillate back and forth through the CD each time inducing a charge thereon, and (c) process the CHD to (i) determine a gain factor as a function of the HFC induced on the CD, and (ii) modify a magnitude of a portion of the CHD resulting from the charge induced on the CD by the trapped ion passing through the CD as a function of the gain factor.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] Cross-reference to related applications

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 680,272, filed June 4, 2018, and is a continuation-in-part of International Patent Application No. PCT / US2019 / 013284, filed January 11, 2019. These patent applications are incorporated herein by reference in their entireties.

[0002] Technical Field This disclosure relates generally to charge detection instruments, and more particularly to apparatus and methods for calibrating such instruments.

[0003]

[0003] Mass spectrometry allows the identification of chemical components of a substance by separating the gaseous ions of the substance according to ion mass and charge. Various instruments and techniques have been developed to determine the mass of such separated ions, one such technique being known as charge detection mass spectrometry (CDMS). In CDMS, ion mass is determined as a function of the measured ion mass-to-charge ratio, commonly referred to as "m / z," and the measured ion charge. Summary of the Invention [Problem to be solved by the invention]

[0004]

[0004] Early CDMS detectors had high levels of uncertainty in m / z and charge measurements, leading to the development of electrostatic linear ion traps (ELITs). This led to the development of a charge trap detector, which traps ions back and forth across a charge detection cylinder. The multiple passes of the ions through the charge detection cylinder provide for multiple measurements per ion, with the uncertainty in the charge measurement being n 1 / 2 It has been shown that the charge measurement error decreases with n, where n is the number of charge measurements. However, challenges can arise in distinguishing valid, detectable charge from charge detector noise due to spurious, extraneous, and / or other charges being picked up on the charge detector, and this effect becomes more pronounced as the charge signal level approaches the noise floor of the charge detector. It is therefore desirable to seek improvements in the design and / or operation of ELITs that would expand the range of valid, detectable charge measurements beyond those measurements that can be obtained using current ELIT designs. [Means for solving the problem]

[0005]

[0005] The present disclosure may 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 a first aspect, a charge detection mass spectrometer (CDMS) with gain drift compensation comprises first and second The present invention can include an electrostatic linear ion trap (ELIT) having a charge detection cylinder disposed between two ion mirrors, an ion source configured to supply ions to the ELIT, a charge generator configured to generate a radio frequency charge, a charge sensitive preamplifier having an input coupled to the charge detection cylinder and an output configured to generate a charge detection signal corresponding to the charge induced on the charge detection cylinder, and a processor, wherein the processor (a) controls the charge generator to induce a radio frequency charge on the charge detection cylinder, (b) controls operation of the first and second ion mirrors to trap ions from the ion source therein and thereafter oscillate the trapped ions back and forth between the first and second ion mirrors each time the trapped ions pass the charge detection cylinder and induce a corresponding charge thereon, and (c) controls the charge sensitive preamplifier to generate a charge detection signal corresponding to the charge induced on the charge detection cylinder. and (ii) processing the charge detection signal generated by the charge generator to (i) determine a gain factor as a function of the radio frequency charge induced on the charge detection cylinder by the charge generator, and (ii) modifying, as a function of the gain factor, the magnitude of a portion of the charge detection signal attributable to charge induced on the charge detection cylinder by the passage of the trapped ions through the charge detection cylinder. It is done.

[0006]

[0006] In a second aspect, the ion separation system may comprise a CDMS as described in any one of claims 1 to 11, wherein the CDMS has an ion source configured to generate ions from a sample, and at least one ion separation device configured to separate the generated ions as a function of at least one molecular property, and ions ejected from the at least one ion separation device are supplied to the ELIT.

[0007]

[0007] In a third aspect, an ion separation system comprises an ion source configured to generate ions from a sample, a first mass spectrometer configured to separate the generated ions as a function of mass to charge ratio, an ion dissociation stage positioned to receive ions exiting the first mass spectrometer and configured to dissociate the ions exiting the first mass spectrometer, a second mass spectrometer configured to separate the dissociated ions exiting the ion dissociation stage as a function of mass to charge ratio, and a charge detection mass spectrometer (C) according to any one of claims 1 to 11. and a charge detection mass spectrometer (CDMS) coupled in parallel to the ion dissociation stage such that the CDMS can receive ions exiting either the first mass spectrometer or the ion dissociation stage, wherein the mass of precursor ions exiting the first mass spectrometer is measured using the CDMS, the mass to charge ratio of dissociated ions of the precursor ions having a mass value less than a threshold mass is measured using the second mass spectrometer, and the mass to charge ratio and charge value of dissociated ions of the precursor ions having a mass value equal to or greater than the threshold mass are measured using the CDMS. [Brief description of the drawings]

[0008] [Figure 1] FIG. 1 is a simplified diagram of an ion mass detection system including an embodiment of an electrostatic linear ion trap (ELIT) with associated control and measurement components, including an apparatus for calibrating or resetting its charge detectors. [Figure 2A] Figure 2A is an enlarged view of the ion mirror M1 of the ELIT shown in Figure 1. The mirror electrodes of M1 are controlled to generate an ion-permeable electric field inside. [Figure 2B] Figure 2B is an enlarged view of the ion mirror M2 of the ELIT shown in Figure 1. The mirror electrodes of M2 are controlled to generate an ion reflecting electric field inside. [Figure 3A] FIG. 3A is a plot of charge versus time on a charge detection cylinder showing two different charge detection threshold levels compared to a noisy charge reference on the charge detection cylinder. [Figure 3B] FIG. 3B is a plot of charge versus time on the charge detection cylinder and shows a lower charge detection threshold compared to FIG. 3A compared to a calibrated charge reference on the charge detection cylinder. [Figure 4] Figures 4A-E are simplified schematics of the ELIT of Figure 1, clearly showing the sequencing and operation of the ion mirrors and charge generators to calibrate or reconfigure the charge detector between ion measurement events. [Figure 5A] FIG. 5A is a simplified diagram of the ELIT of FIG. 1, clearly showing the control and operation of the charge generator to calibrate or reconfigure the charge detector between ion measurement events. [Figure 5B] FIG. 5B is a simplified schematic of the ELIT of FIG. 1, clearly showing the control and operation of the charge generator to calibrate or reconfigure the charge detector between ion measurement events. [Figure 5C]FIG. 5C is a simplified schematic of the ELIT of FIG. 1, clearly showing the control and operation of the charge generator to calibrate or reconfigure the charge detector between ion measurement events. [Figure 5D] FIG. 5D is a simplified schematic of the ELIT of FIG. 1, clearly showing the control and operation of the charge generator to calibrate or reconfigure the charge detector between ion measurement events. [Figure 5E] FIG. 5E is a simplified schematic of the ELIT of FIG. 1, clearly showing the control and operation of the charge generator to calibrate or reconfigure the charge detector between ion measurement events. [Figure 5F] FIG. 5F is a simplified schematic of the ELIT of FIG. 1, clearly showing the control and operation of the charge generator to calibrate or reconfigure the charge detector between ion measurement events. [Figure 6A] FIG. 6A is a simplified block diagram of an embodiment of an ion separation device including an ELIT as shown and described herein, and shows an example of an ion processing device that may form part of an ion source upstream of the ELIT and / or may be positioned downstream of the ELIT for further processing of ion(s) ejected from the ELIT. [Figure 6B] FIG. 6B is a simplified block diagram of another embodiment of an ion separation apparatus including an ELIT as shown and described herein, illustrating an example implementation combining conventional ion processing equipment with any of the embodiments of an ion mass detection system as shown and described herein. [Figure 7] FIG. 7 is a simplified flowchart of an embodiment of a process for selectively inducing radio frequency charges on the charge detection cylinder during normal operation of the ELIT to measure the mass and charge of charged particles, processing the detected radio frequency charges, and using the information provided thereby to control the charge generator of FIG. 1 to compensate for any drift in the gain of the charge preamplifier over time. [Figure 8]FIG. 8 is a plot of charge detection signal versus frequency illustrating an example of a charge detection signal that includes a charge peak corresponding to detection of a charge induced on the charge detection cylinder of the ELIT by a passing charged particle, and an additional charge peak corresponding to detection of a high frequency charge simultaneously induced on the charge detection cylinder by a charge generator according to the process shown in FIG. [Figure 9] FIG. 9 is a plot of the peak magnitude over time of the fundamental frequency of the high frequency charge induced on the charge detection cylinder by the charge generator. [Figure 10] Figure 10 is a plot of the moving average of the N-sample data set over time of the peak magnitude signal shown in Figure 9. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009]

[0021] For the purposes of promoting an understanding of the principles of the present disclosure, reference will now be made to a number of exemplary embodiments illustrated in the accompanying drawings, and specific language will be used to describe the same.

[0010]

[0022] The present disclosure relates to an electrostatic linear ion trap (ELIT) including an apparatus for calibrating or resetting a charge detector, and means and methods for controlling both. In one embodiment, the calibration apparatus is controlled to calibrate or reset a charge detector of the ELIT to a predefined reference charge level during an ion measurement event, an example of which is described in detail below with respect to Figures 3A-3E. In another embodiment, the calibration apparatus is controlled to calibrate or reset a charge detector of the ELIT to a predefined reference charge level during a charge detection event, an example of which is described in detail below with respect to Figures 5A-5F. For purposes of this disclosure only, the phrase "charge detection event" is defined as the detection of charge associated with a single passage of an ion through a charge detector of the ELIT, and the phrase "ion measurement event" is defined as the detection of a charge associated with a selected number of passages or a selected period of time of a selected number of charge detections or a selected period of time. It is defined as the collection of charge detection events that occur due to the back and forth oscillation of ions across the detector.

[0011]

[0023] 1, a charge detection mass spectrometer (CDMS) 10 is shown that includes an embodiment of an electrostatic linear ion trap (ELIT) 14 to which control and measurement components are coupled, including apparatus for calibrating or resetting the charge detector of the ELIT 14. In the illustrated embodiment, the CDMS 10 includes an ion source 12 operably coupled to the entrance of the ELIT 14. As will be further described with respect to FIG. 6A, the ion source 12 illustratively includes any conventional device or apparatus for generating ions from a sample, and may also include one or more devices and / or instruments for separating, collecting, filtering, fragmenting, and / or normalizing the ions according to one or more molecular properties. As one illustrative example, which should in no way be construed as limiting, the ion source 12 may include a conventional electrospray ionization source, a matrix-assisted laser desorption ionization (MALDI) source, or the like, coupled to the entrance of a conventional mass spectrometer. The mass spectrometer may be of any conventional design, such as a time-of-flight (TOF) mass spectrometer, a reflectron mass spectrometer, a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer, or a reflectron mass spectrometer. ELIT 14. Examples of suitable mass spectrometers include, but are not limited to, a quadrupole mass spectrometer, a triple quadrupole mass spectrometer, a magnetic field mass spectrometer, and the like. In any case, the ion exit port of the mass spectrometer is operably coupled to the ion entrance port of the ELIT 14. The sample from which ions are generated may be any biological or other material.

[0012]

[0024] In the illustrated embodiment, the ELIT 14 illustratively includes a charge detector CD surrounded by a ground chamber or cylinder GC and operably coupled to opposing ion mirrors M1, M2. The ion mirrors M1, M2 are positioned at opposite ends of the charge detector CD. The ion mirror M1 is operably positioned between the ion source 12 and one end of the charge detector CD, and the ion mirror M2 is operably positioned at the opposite end of the charge detector CD. Each ion mirror M1, M2 defines a respective ion mirror region R1, R2 therein. The regions R1, R2 of the ion mirrors M1, M2, the charge detector CD, and the space between the charge detector CD and the ion mirrors M1, M2 collectively define a longitudinal axis 22 through the center. The longitudinal axis 22 illustratively represents an ideal ion travel path through the ELIT 14 and passing between the ion mirrors M1, M2, as will be described in more detail below.

[0013]

[0025] In the illustrated embodiment, voltage sources V1, V2 are electrically connected to the ion mirrors M1, M2, respectively. Each voltage source V1, V2 illustratively comprises one or more switchable DC voltage sources. The DC voltage sources can be controlled or programmed to selectively generate N programmable or controllable voltages, where N can be any positive integer. Illustrative examples of such voltages for establishing one of two different operating modes of each of the ion mirrors M1, M2, as described in more detail below, are described below with respect to FIGS. 2A and 2B. In either case, ions move within the EFLIT 14 along a longitudinal axis 22. The longitudinal axis 22 extends through the center of the charge detector CD and the ion mirrors M1, M2 under the influence of electric fields established by the voltage sources V1, V2, respectively.

[0014]

[0026] Voltage sources V1, V2 are illustratively shown electrically connected by P signal paths to a conventional processor 16. Processor 16 includes a memory 18 having instructions stored therein. The instructions, when executed by processor 16, cause processor 16 to control voltage sources V1, V2 to generate desired DC output voltages to selectively establish ion transmission and ion reflection fields TEF, REF, respectively, within regions R1, R2 of respective ion mirrors M1, M2. P may be any positive integer. In an alternative embodiment, either or both of voltage sources V1, V2 may be programmed to selectively generate one or more constant output voltages. In another alternative embodiment, voltage sources V1, V2 may be programmed to selectively generate one or more constant output voltages. Either or both of V1 and V2 may be configured to generate one or more time-varying output voltages of any desired shape, it being understood that in alternative embodiments, more or fewer voltage sources may be electrically connected to the mirrors M1, M2.

[0015]

[0027] The charge detector CD is illustratively provided in the form of a conductive cylinder. The conductive cylinder is electrically connected to a signal output of a charge-sensitive preamplifier (or charge-sensitive amplifier) ​​CP, which is electrically connected to the processor 16. The charge preamplifier CP is illustratively conventionally operable to receive a charge signal (CH) corresponding to a charge induced thereon by ions passing through the charge detection cylinder CD, generate a corresponding charge detection signal (CHD), and provide the charge detection signal CHD to the processor 16. In an embodiment, the charge preamplifier CP may include conventional feedback components, such as one or more resistors and / or other conventional feedback circuits, coupled between its output and at least one of its inputs. In an alternative embodiment, the charge preamplifier CP may not include any resistive feedback components at all, and in yet another alternative embodiment, the charge preamplifier CP may not include any feedback components at all. In either case, the processor 16 itself is illustratively operable to receive and digitize the charge detection signal CHD generated by the charge preamplifier CP and store the digitized charge detection signal CHD in memory 18. Additionally, the processor 16 is illustratively coupled to one or more peripheral devices 20 (PD) that provide input signal(s) to the processor 16 and / or to which the processor 16 provides signal output(s). In one embodiment, the peripheral devices 20 include at least one of a conventional display monitor, a printer, and / or other output device, and in such embodiment, the memory 18 has instructions stored therein that, when executed by the processor 16, cause the processor 16 to control one or more such output peripheral devices 20 to display and / or record an analysis of the stored digitized charge detection signal.

[0016]

[0028] Voltage sources V1, V2 are illustratively controlled, as described in more detail below, to selectively trap ions entering the ELIT 14 and cause the trapped ions to oscillate back and forth between ion mirrors M1, M2 and repeatedly pass through charge detection cylinder CD. A number of charge and oscillation period values ​​are measured at charge detection cylinder CD and the recorded results are processed to determine the mass-to-charge ratio, charge, and mass values ​​of the ions trapped in the ELIT 14.

[0017]

[0029] 2A and 2B, there is shown an embodiment of each of the ion mirrors M1, M2 of the ELIT 14 shown in FIG. 1. Illustratively, the ion mirrors M1, M2 are identical to one another and each includes a cascaded arrangement of four spaced apart conductive mirror electrodes. For each of the ion mirrors M1, M2, the first mirror electrode 301 has a thickness W1 and defines a centrally therethrough passage of diameter P1. An end cap 32 is fixedly or otherwise coupled to an outer surface of the first mirror electrode 301 and defines a centrally therethrough aperture A1. The aperture A1 serves as an entrance and / or exit for ions to and / or from the corresponding ion mirror M1, M2, respectively. In the case of the ion mirror M1, the end cap 32 is coupled to or is part of the ion exit port of the ion source 12 shown in FIG. 1. The aperture A1 of each end cap 32 illustratively has a diameter P2.

[0018]

[0030] The second mirror electrode 302 of each ion mirror M1, M2 is spaced from the first mirror electrode 301 by a space having a width W2. The second mirror electrode 302, like the mirror electrode 301, has a thickness W1 and defines a passageway through its center with a diameter P2. The third mirror electrode 303 of each ion mirror M1, M2 is similarly spaced from the second mirror electrode 302 by a space of width W2. The third mirror electrode 303 has a thickness W1 and defines a passage therethrough centrally of width P1.

[0019]

[0031] The fourth mirror electrode 304 is spaced from the third mirror electrode 303 by a space of width W2. The fourth mirror electrode 304 is illustratively formed by the respective ends of a grounded cylinder GC having a thickness of W1 and arranged around the charge detector CD. The fourth mirror electrode 304 defines an aperture A2 through its center. The aperture A2 is illustratively cone-shaped and increases linearly between the inner and outer surfaces of the grounded cylinder GC from a diameter P3 defined at the inner surface of the grounded cylinder GC to a diameter P1 at the outer surface of the grounded cylinder GC (which is also the inner surface of each ion mirror M1, M2).

[0020]

[0032] The spaces defined between the mirror electrodes 301-304 may in some embodiments be air gaps, i.e., vacuum gaps, while in other embodiments such spaces may be filled with one or more non-conductive, e.g., dielectric materials. The mirror electrodes 301-304 and the end caps 32 are axially aligned, i.e., collinear, such that the longitudinal axis 22 passes through the centres of each aligned passageway and also passes through the centres of the apertures A1, A2. In embodiments in which the spaces between the mirror electrodes 301-304 include one or more non-conductive materials, such materials similarly define respective passageways therethrough. These passageways are axially aligned, i.e., collinear, with the passageways defined through the mirror electrodes 301-304. Illustratively, P1>P3>P2, although other relative diameter configurations are possible in other embodiments.

[0021]

[0033] A region R1 is defined between the apertures A1 and A2 of the ion mirror M1, and another region R2 is similarly defined between the apertures A1 and A2 of the ion mirror M2. The regions R1 and R2 are illustratively identical in shape and volume to each other.

[0022]

[0034] As explained above, the charge detector CD is illustratively provided in the form of an elongated conductive cylinder positioned between respective ones of the ion mirrors M1, M2 and spaced apart by a space of width W3. In one embodiment, W1>W3>W2 and P1>P3>P2, although other relative width configurations are possible in other alternative embodiments. In either case, illustratively, the longitudinal axis 22 passes through the center of the path defined through the charge detection cylinder CD such that the longitudinal axis 22 passes through the center of the combination of the path defined by the regions R1, R2 of the ion mirrors M1, M2 and the path defined through the charge detection cylinder CD. In operation, the ground cylinder GC is illustratively controlled to ground potential such that the fourth mirror electrode 304 of each ion mirror M1, M2 is always at ground potential. In an alternative embodiment, the fourth mirror electrode 304 of either or both of the ion mirrors M1, M2 may be set to any desired DC reference potential, or to a switchable DC or other time-variable voltage source.

[0023]

[0035] In the embodiment shown in Figures 2A and 2B, voltage sources V1, V2 are each configured to generate four DC voltages D1-D4 and supply the voltages D1-D4 to respective mirror electrodes 301-304 of respective ion mirrors M1, M2. In embodiments in which one or more of the mirror electrodes 301-304 are constantly held at ground potential, one or more of such mirror electrodes 301-304 may instead be electrically connected to the ground reference of the respective voltage source V1, V2, and the corresponding one or more voltage outputs D1-D4 may be omitted. Alternatively or additionally, in embodiments in which any two or more of the mirror electrodes 301-304 are controlled to the same non-zero DC value, any such two or more mirror electrodes 301-304 may be electrically connected to one of the voltage outputs D1-D4, and the extra ones of the output voltages D1-D4 may be omitted.

[0024]

[0036] Each ion mirror M1, M2 is illustratively controllable and switchable between an ion transmission mode (FIG. 2A) and an ion reflection mode (FIG. 2B) by selective application of voltages D1-D4. In the ion transmission mode, the voltages D1-D4 generated by the respective voltage sources V1, V2 establish an ion transmission field (TEF) in the respective region R1, R2, and in the ion reflection mode, the voltages D1-D4 generated by the respective voltage sources V1, V2 establish an ion reflection field (REF) in the respective region R1, R2. As shown by way of example in FIG. 2A, once ions from the ion source 12 pass through the entrance aperture A1 of the ion mirror M1 and enter the region R1 of the ion mirror M1, the ions are focused toward the longitudinal axis 22 of the ELIT 14 by the ion transmission field TEF established in the region R1 of the ion mirror M1 by selective control of the voltages D1-D4 of V1. As a result of the focusing effect of the transmission field TEF in region R1 of ion mirror M1, ions exiting region R1 of ion mirror M1 through aperture A2 of grounded chamber GC achieve a narrow trajectory into and through charge detector CD, i.e., maintain a path of ion travel through charge detector CD close to the longitudinal axis 22. The same ion transmission field TEF may be selectively established in region R2 of ion mirror M2 by similar control of voltages D1-D4 of voltage source V2. In the ion transmission mode, ions entering region R2 from charge detector cylinder CD through aperture A2 of M2 are focused by the ion transmission field TEF in region R2 towards the longitudinal axis 22, such that the ions exit ion mirror M2 through aperture A1 of ion mirror M2.

[0025]

[0037] 2B, the ion reflecting field REF established in region R2 of ion mirror M2 by selective control of voltages D1-D4 of V2 acts to slow and stop ions passing through ion entrance aperture A2 of M2 through charge detection cylinder CD into ion region R2, to accelerate ions in the reverse direction through aperture A2 of M2 to the end of charge detection cylinder CD adjacent M2 as shown by ion trajectory 42, and to focus the ions toward central longitudinal axis 22 within region R2 of ion mirror M2 and maintain a narrow trajectory for the ions passing through charge detector CD back toward ion mirror M1. The same ion reflecting field REF may be selectively established in region R1 of ion mirror M1 by similar control of voltages D1-D4 of voltage source V1. In the ion reflection mode, ions passing through aperture A2 of M1 into region R1 from charge detection cylinder CD are decelerated and stopped by the ion reflection field REF established within region R1, and then accelerated in the reverse direction through aperture A2 of M1 to the end of charge detection cylinder CD adjacent to M1, and focused within region R1 of ion mirror M1 towards central longitudinal axis 22, maintaining the ion's narrow trajectory back through charge detector CD towards ion mirror M2. As just described, ions reflected by the ion reflection field REF in ion regions R1, R2 are considered trapped within the ELIT14, allowing the ions to traverse the length of the ELIT14 and continue to move back and forth in the charge detection cylinder CD between ion mirrors M1, M2.

[0026]

[0038] Several example sets of output voltages D1-D2 generated by voltage sources V1, V2, respectively, to control each ion mirror M1, M2 in the aforementioned ion transmission and reflection modes are shown below in Table 1. It should be understood that the following values ​​for D1-D4 are presented by way of example only, and that other values ​​may be used instead for one or more of D1-D4.

[0027] [Table 1]

[0028]

[0039] 1-2B as defining a cylindrical passage therethrough, it will be appreciated that in alternative embodiments, either or both of the ion mirrors M1, M2, and / or the charge detection cylinder CD may define a non-cylindrical passage therethrough, such that one or more of the passage(s) through which the longitudinal axis 22 passes centrally exhibits a cross-sectional area and circumference that is not circular. In still other embodiments, the cross-sectional area of ​​the passage defined through ion mirror M1 may be different from the passage defined through ion mirror M2, regardless of the shape of the cross-sectional circumference.

[0029]

[0040] Voltage sources V1, V2 illustratively allow ions to enter the ELIT 14 from the ion source 12, selectively trap ions within the ELIT 14, and selectively establish ion transmission and reflection electric fields within regions R1 and R2 of the ion mirror M2 such that the trapped ions repeatedly pass through the charge detector CD while oscillating within the ELIT 14 between the ion mirrors M1 and M2. The charge induced on the charge detector CD for each ion passage is detected by the charge preamplifier CP, and a corresponding charge detection signal (CHD) is generated by the charge preamplifier CP. The amplitude and timing of the charge detection signal (CHD) generated by the charge preamplifier CP are recorded by the processor 16 for each charge detection event as defined herein. The record of each charge detection event illustratively includes an ion charge value corresponding to the magnitude of the detected charge and an oscillation period value corresponding to the elapsed time between the charge detection events, and the record of each charge detection event is stored by the processor 16 in the memory 18. The collection of charge detection events performed by oscillating the ion back and forth in the charge detector CD at a selected number of times or for a selected period of time, i.e., a period that constitutes an ion measurement event as defined herein, is then processed to determine the charge, mass-to-charge ratio and mass value of the ion.

[0030]

[0041] In one embodiment, the ion measurement event data is processed by the processor 16 by calculating a Fourier transform of the collection of recorded charge detection events. The processor 16 is illustratively operable to calculate such a Fourier transform using any conventional digital Fourier transform (DFT) technique, such as, but not limited to, a conventional fast Fourier transform (FFT) algorithm. In either case, illustratively the processor 16 is then operable to calculate an ion mass-to-charge ratio value (m / z), an ion charge value (z), and an ion mass value (m), each as a function of the calculated Fourier transform. The processor 16 is illustratively operable to store the calculated results in the memory 18 and / or to control one or more of the peripheral devices 20 to display the results for viewing and / or further analysis.

[0031]

[0042] It is generally understood that the mass-to-charge ratio (m / z) of an ion oscillating back and forth in the charge detector CD of the ELIT between the opposing ion mirrors M1 and M2 of the ELIT is inversely proportional to the square of the fundamental frequency ff of the oscillating ion, according to the following equation:

[0032]

[0043] m / z=C / ff 2

[0033]

[0044] where C is a constant that is a function of the ion energy and also of the dimensions of the respective ELIT, and the fundamental frequency ff is determined directly from the calculated Fourier transform. The value z of the ion charge is proportional to the amplitude FTMAG of the fundamental frequency ff, taking into account the number of ion oscillation cycles. In some cases, the amplitude (s) of one or more of the harmonic frequencies of the FFT may be added to the amplitude of the fundamental frequency for the purpose of determining the ion charge z. In any case, the ion mass m is then calculated as the product of m / z and z. Thus, the processor 16 calculates m / z=Cff 2, z=F(FTMAG), and m=(m / z)(z). For every individual sample from which ions are generated by the ion source 12, multiple, e.g., hundreds or thousands or more, ion capture events are typically performed and an ion mass-to-charge, ion charge, and ion mass value is determined / calculated for each such ion capture event. In turn, the ion mass-to-charge, ion charge, and ion mass values ​​for multiple such ion capture events are combined to form spectral information about the sample. Such spectral information may illustratively be in different forms, including, but not limited to, ion count vs. mass-to-charge ratio, ion charge vs. ion mass (e.g., in the form of an ion charge / mass scatter plot), ion count vs. ion mass, ion count vs. ion charge, etc.

[0034]

[0045] 1, the illustrated ELIT 14 further includes a charge generator CG electrically connected to the processor 16 and further electrically connected to a charge generator voltage source VCG. In the illustrated embodiment, the charge generation voltage source VCG is programmable or artificially controllable to generate one or more DC voltages, voltage pulses, and / or voltage waveforms of any amplitude, shape, duration, and / or frequency. In an alternative embodiment, the charge generation voltage source VCG can be programmable or artificially controllable by the processor 16 to generate one or more DC voltages, voltage pulses, and / or voltage waveforms of any amplitude, shape, duration, and / or frequency. The processor 16 may be operatively coupled to the charge generating voltage source VCG to control the charge generator CG to generate one or more DC voltages, voltage pulses, and / or voltage waveforms of the charge generator CG. In the illustrated embodiment, illustratively, at least one charge drain passage 24 of the charge generator CG penetrates the ground chamber GC such that a charge drain port 26 of the charge drain passage 24 is in fluid communication with a space 36 defined between an inner surface of the ground chamber GC and an outer surface of the charge detection cylinder CD. Although one charge drain passage 24 is shown penetrating the ground chamber GC in the illustrated embodiment, in alternative embodiments, multiple charge drain passages may penetrate the ground chamber GC. In such an embodiment, two or more charge drain passages may be spaced apart axially and / or radially along the charge detection cylinder CD, either singly or in groups of two or more.

[0035]

[0046] In one embodiment, the charge generator CG is configured, in response to a control signal C generated by the processor 16, to generate free charges 28 that pass through charge drain ports 26 of one or more charge drain passages 24 into a space 36 defined between the inner surface of the grounded chamber or cylinder GC and the outer surface of the conductive charge detection cylinder CD. In the illustrated embodiment, the charges 28 generated by the charge generator are positive charges, although the charge generator CG may be configured in alternative embodiments to generate negative charges or to selectively generate positive or negative charges.

[0036]

[0047] In one embodiment, the charge generator CG is configured or controllable using conventional control circuitry and / or techniques to generate and deliver a predictable number of free charges 28 per unit time, within any desired tolerance level, to the space 36 of the ELIT 14 in response to activation of a control signal C generated by the control circuit 16. The unit time is: The period of the control signal C may have any desired duration. In such an embodiment, the total number of charges 28 provided by the charge generator CG to the spaces 36 in the ELIT 14 in response to a single activation of the control signal C is therefore controllable as a function of the number of charges 28 generated by the charge generator CG per unit time and period, i.e., as a function of the pulse width of the active portion of the control signal C. In alternative embodiments, the charge generator CG may be configured to generate a programmable number of charges 28 per unit time. In yet other embodiments, the charge detector CG may be configured such that the number of charges 28 generated in response to the control signal C is constant, predictable or programmable within any desired tolerance level, regardless of and independent of the period of the control signal C. In such an embodiment, the number of charges 28 supplied by the charge generator CG to the space 36 within the ELIT 14 in response to any one activation of the control signal C is therefore constant and predictable, and the total number of charges 28 that can be supplied by the charge generator CG to the space 36 within the ELIT 14 is controllable as a function of the total number of charges 28 generated by each activation of the control signal C and the total number of activations of the control signal C generated by the processor 16.

[0037]

[0048] The charge generator CG may be provided in the form of any conventional charge generator. As an example, the charge generator CG may be or include a conventional filament that generates and produces free charge 28 in response to a voltage or current applied thereto. As another example, the charge generator CG may be or include a conductive mesh or lattice that generates and produces free charge 28 in response to a voltage or current applied thereto. In yet another example, the charge generator CG may be or include a particle charge generator configured to generate free charge in the form of charged particles from a sample source. Examples of such particle charge generators may include, but are not limited to, an electrospray ionization (ESI) source, a matrix-assisted laser desorption ionization (MALDI) source, and the like. In either case, the charge generator CG is operable to generate and supply charge to the space 36 within the ELIT 14 through a charge drain port(s) of one or more charge drain passages extending into and / or fluidly coupled to the space 36.

[0038]

[0049] When there is no charge induced on the charge detector CD by a charged particle passing through the charge detector or by one or more free charges 28 generated by the charge generator GC, the charge detection cylinder CD illustratively has a reference charge level CH REF When the charge detection cylinder CD is unpowered or grounded, the reference charge level CH REF is typically less than a few tens of charges (i.e., the elementary charge "e"), but in some applications, the reference charge level CH REF may be more than several tens of charges.

[0039]

[0050] As mentioned above, the charge generator CG generates charges 28 of a desired polarity in response to control signals C generated by the processor 16 or other control signal generating circuitry, which charges 28 penetrate into a space 36 between the inner surface of the ground cylinder GC and the outer surface of the charge detection cylinder CD. Since the ground cylinder GC is normally maintained at ground potential and the charge detection cylinder CD is typically operated at or near ground potential, the space 36 is a substantially field-free region. In an embodiment, the one or more charge drain passages 24 and / or the body of the charge generator CG illustratively include one or more regions within which an electric field of suitable direction is established by a voltage source VCG (or some external power source(s)) for the purpose of accelerating the generated charges 28 into the field-free region 36 and for the accelerated charges 28 to exit the field-free region 36 toward the charge detection cylinder CD and contact its outer surface. When such charges 28 contact the outer surface of the charge detection cylinder CD, they impart their respective charges onto the charge detection cylinder CD. In this regard, the generation of charge 28 by charge generator GC and the passage of the generated charge through field free region 36 toward and into contact with the outer surface of the charge detection cylinder are The movement of the charge detector 28 from the charge detector 20 to the charge detector cylinder 22 defines a "charge injection" process, through which the generated charges 28, in one embodiment, calibrate or reset the charge detector cylinder CD and / or the charge sensitive preamplifier CP. Charges so injected can illustratively be removed from the charge detector cylinder CD by applying an equal amount of opposite charge, and thus, illustratively, can be used to calibrate and / or reset the charge detector cylinder in some applications, and / or to calibrate or reset the charge preamplifier in other applications.

[0040]

[0051] The just-described "charge injection" process is different from the "charge induction" process. In the charge induction process, a charge can be induced on the charge detection cylinder CD by establishing a voltage difference between the charge detection cylinder CD and a voltage reference, e.g., ground potential. One exemplary technique for inducing a charge on the charge detection cylinder CD without physically coupling one or more wires and / or one or more electronic devices to the charge detection cylinder CD is to configure the charge generator GC such that the voltage source VCG establishes a potential of a desired polarity on the at least one charge drain passage 24. Establishing a DC potential on the at least one charge drain passage 24 without generating a charge 28 typically creates an electric field between the at least one charge drain passage 24 and the charge detection cylinder CD, i.e., induces a DC voltage, which then induces a charge on the charge detection cylinder CD. The magnitude of the induced charge is generally The magnitude of the voltage applied to the at least one charge drain passage 24 by the voltage source VCG depends on the strength of the electric field that is established. The charge that is generated can illustratively be removed or altered by applying a different voltage, e.g., ground or other potential, to the charge detection cylinder CD, and thus can be used for offsetting to switch the voltage applied to the ion mirror(s) M1 and / or M2, and in an embodiment, to calibrate the charge preamplifier CP. In alternative embodiments of the charge generator CG described above, in which the charge generator CG is operable to generate free charge, the charge generator CG can thus also be configured to operate as a charge-inducing antenna. In such an embodiment, the voltage source VCG is illustratively controlled by the processor 16 to generate a DC voltage, a voltage pulse or a series of voltage pulses, or a voltage waveform. The DC voltage, voltage pulse or a series of voltage pulses, or a voltage waveform, is applied to the charge drain passage(s) 24 to create or establish one or more corresponding electric fields between the charge drain passage(s) 24 overall (and in an embodiment, the charge drain port(s) 26 specifically) and the charge detection cylinder CD, thereby generating one or more corresponding electric fields on the charge detection cylinder CD. In such an embodiment, the charge drain passage(s) 24 may, but need not, include one or more charge drains 26 in fluid communication with the space 36. In some embodiments, for example when the charge generator CG is configured strictly for charge induction, the charge drain passage(s) 24 may be or include one or more conductive rods, probes, filaments, etc. that do not include any drains for distributing or otherwise generating free charge. In other embodiments where the charge generator CG is configured to operate as a charge induction device and a charge injection device, the charge drain passage(s) 24 illustratively include one or more charge drains 24 as described above for distributing or otherwise generating free charge 28.

[0041]

[0052] Thus, in one embodiment, the charge generator CG is illustratively configured to operate strictly as a charge injection device, in which case the charge generator CG is configured to generate charges 28 of a suitable polarity in response to a control signal C, accelerate the generated charges 28 through at least one charge discharge port 26 of at least one charge discharge passage 24 into a field-free region 36, pass the generated charges 28 through the field-free region 36 toward the charge detection cylinder CD, contact its outer surface, and dispense their charges onto the charge detection cylinder CD. In an alternative embodiment, the charge generator CG is illustratively configured to operate strictly as a charge inducing device, in which case the charge generator CG, in response to a control signal C, applies at least one voltage of suitable amplitude and polarity to establish a corresponding electric field in a region 36 between at least one charge drain passage 24 and the charge detection cylinder CD, inducing a DC voltage, i.e., charge, on the charge detection cylinder CD. In other alternative embodiments, the charge generator CD is illustratively configured to operate both as a charge injection device and as a charge induction device (e.g., simultaneously or separately), in which case the charge generator CG, in response to control signals C generated by the processor 16, generates charges 28 of suitable polarity and / or applies one or more voltages of suitable amplitude and polarity to establish an electric field in a region 36 between at least one charge drain passage 24 and the charge detection cylinder CD to (i) induce a DC voltage and thus a charge on the charge detection cylinder CD, and (ii) further under the influence of the electric field established in the region 36, accelerate the generated charges 28 towards the charge detection cylinder CD, contact its outer surface, and impart their charge onto the charge detection cylinder CD. The charge generator CG may thus be configured and operable strictly as a charge injector, strictly as a charge inducer, or as a combination charge injector and charge inducer.

[0042]

[0053] In an embodiment in which the charge generator CG is configured and operable as a charge injector to generate a controlled number of charges 28, and in which the charges are moved or transported to contact the outer surface of the charge detection cylinder CD, such charges are illustratively directed to a target charge level CH T In one embodiment, the number and polarity of the charges 28 generated are CH REF A target charge level CH greater than T For example, CH REF and a constant target charge level CH above any induced noise. T In other embodiments, the number and polarity of the charges 28 generated may be selected to achieve REF Lower target charge level CH T For example, a target charge level CH at or near the zero charge level may be provided. T In embodiments in which the charge generator CG is configured and operable as a charge inducer to controllably establish an electric field that induces a DC voltage or potential on the charge detection cylinder CD, such DC voltage or potential may illustratively be selected to achieve a target charge level CH of suitable amplitude and polarity on the charge detection cylinder CD. T In embodiments where the charge generator CG is configured and operable as a combination charge injector and charge inducer, the net charge induced and dispensed onto the charge detection cylinder is a target charge CH of suitable magnitude and polarity. T It becomes.

[0043]

[0054] Reference charge level CH on the charge detection cylinder CD REF may be subject to one or more potentially significant charge noise sources, which may introduce uncertainty into the charge detection events as a result of the uncertainty in the reference charge level at any one time. Referring to FIG. 3A, for example, a plot of charge CH on a charge detection cylinder CD versus time is shown. While there are no charge detection events on the plot, an example charge noise waveform 50 is shown with a reference charge level CH REF1. In embodiments in which the charge sensitive preamplifier CP does not include a feedback component, one such source of such charge noise 50 is the accumulation of charge on the charge detection cylinder CD, i.e., at the input of the charge sensitive preamplifier CP during its normal operation. In this and other embodiments, the capacitance of the charge detector CD also contributes, as do spurious noise contributions due to external events and extraneous charge induced on the charge detection cylinder due to switching of either or both of the ion mirrors M1, M2 between ion transmission and ion reflection modes of operation.

[0044]

[0055] Such charge noise 50, from either source, is undesirable because it can cause false charge detection events and / or require the charge detection threshold to be set higher than desired. As an example of the former case, the plot of FIG. 3A further illustrates the case where a valid charge detection event is not detected by a reference charge level CH REF To distinguish from the charge detection thresholds, an example of a charge detection threshold CH implemented in the ion mass detection system 10 is shown. TH1 In the illustrated example, REF The two peaks 52 and 54 of the charge noise 50 around it are CH TH1 , and thus be erroneously or erroneously detected as a valid charge detection event, thereby corrupting the ion measurement event data for the ion(s) being evaluated. Second Example of Charge Detection Threshold at 3A TH2 5, which is illustratively safely positioned above the highest peak of the charge noise 50 so as to avoid spurious charge detection events of the kind just described. However, the upper charge detection threshold CH TH2 is CH TH2 and C.H. REF, leaving an undesirably wide range where detectable charge values ​​cannot be detected without a high level of charge noise 50.

[0045]

[0056] 1 , the charge generator CG is illustratively implemented and controlled to selectively generate a target number of charges 28 that are transported through a field-free region 36 toward and in contact with the outer surface of the charge detection cylinder CD, e.g., under the influence of one or more appropriately oriented electric fields at or within the charge generator CG as described above. The charges 28 deposited on the charge detection cylinder CD illustratively combine with any charge noise carried on the charge detection cylinder CD to produce a substantially constant, predictable and repeatable target charge level CH on the charge detection cylinder CD. T In one example embodiment, the target number and polarity of charges 28 generated is set to a target charge level CH on the charge detection cylinder. T can be selected to dispense a target charge level CH T The magnitude of the reference charge level CH REF and any charge noise on the charge detection cylinder CD. That is, the target charge level CH T is CH REF and any combination of charge noise is enveloped and nullified, T Alternatively or additionally, the charge generator CG can be controlled to induce appropriate charges on the charge detection cylinder CD by controlling the voltage source VCG to apply one or more corresponding voltages to the charge generator CG.

[0046]

[0057] In an alternative embodiment, the target number and polarity of the charges 28 generated is determined based on a reference charge level CH REF and neutralizing at least one or a combination of any charge noise on the charge detection cylinder CD, e.g., to a target charge level CH T In order to achieve this, REFThe final charge detection level CH, which is less than or close to the zero charge level T on the charge detection cylinder CD. Such a result may be obtained, illustratively, by controlling the charge generator CG to first inject positive charge and then to inject negative charge, or alternatively by controlling the voltage source VCG to apply one or more corresponding voltages to the charge generator CG to induce the appropriate charge on the charge detection cylinder CD. In embodiments in which the amount of charge noise 50 at the input of the charge sensitive preamplifier CP is specifically targeted (e.g., in embodiments in which the charge sensitive preamplifier does not include any feedback components as previously described), the target charge level CH T may be a charge magnitude and / or polarity which, when deposited or dispensed onto the charge detection cylinder CD, acts to clear such charge noise 50 therefrom, i.e., from the input of the charge preamplifier, and to reset the charge sensitive preamplifier CP to a predictable operating state.

[0047]

[0058] In either case, the target number of charges 28 generated by the charge generator CG and transported to the charge detection cylinder CD and in contact with its outer surface, and / or the charge induced on the charge detection cylinder CD by the operation of the charge generator CG, are intended to substantially maintain the charge detection cylinder CD at a predictable and repeatable target charge level CH, as shown by example in FIG. 3B. T The target charge level CH T establishes a "new" reference charge level against which subsequent charge detection events are measured. New Reference Charge Level CH T is substantially repeatable, and the charge detection threshold CH TH3 and C.H. T A large reduction in the charge difference between the ions can be achieved, as shown in FIG. 3B, which increases the range of detectable ionic charges compared to conventional ELIT.

[0048]

[0059] 4A-4E, a simplified diagram of the ELIT 14 of FIG. 1 is shown, clearly illustrating the sequence control and operation of the ion mirrors M1, M2 and the charge generator CG as described above to calibrate or reconfigure the charge detection cylinder CD during an ion measurement event. Referring to FIG. 4A, the ELIT 14 has just finished an ion measurement event, an ion has been captured by the ELIT 14, and the processor 16 was operable to control the voltage sources V1, V2 to control the ion mirrors M1, M2 in an ion-reflecting mode of operation (R). In the ion-reflecting mode of operation (R), an ion-reflecting electric field was established in the regions R1, R2 of the respective ion mirrors M1, M2. The ions thus oscillated back and forth between M1 and M2 each time they passed the charge detection cylinder CD, and the charge induced on the charge detection cylinder CD was detected by the charge preamplifier CP, and the ion detection event was recorded by the processor 16. After ions have oscillated back and forth between ion mirrors M1, M2 through the ELIT 14 a selected number of times or for a selected period of time, the processor 16 was operable to maintain ion mirror M1 in an ion reflecting mode (R) while controlling ion mirror M2 in an ion transmitting mode of operation (T) by controlling voltage source V2 to establish an ion transmitting electric field in region R2 of ion mirror M2, as shown in Figure 4A. As a result, trapped ions exit ion mirror M2 through aperture A2 of M2, as shown by ion trajectory 60 in Figure 4A.

[0049]

[0060] When the ELIT 14 has been operated in the state shown in FIG. 4A for a selected period of time or for a selected period of time and no charge detection event has occurred, the processor 16 is operable to provide a control signal C to the charge generator CG to cause the charge generator CG to controllably generate a target number of free charges 28 and provide the free charges 28 to a space 36 defined between the ground cylinder GC and the charge detection cylinder CD, as shown in FIG. 4B. In a charge injection operation of the charge generator CG, the generated free charges 28 pass through the field-free region 36 toward and contact the outer surface of the charge detection cylinder CD, as previously described. In a charge induction operation, an electric field established by the charge generating voltage source VCG or other field generating structure induces a charge on the charge detection cylinder CD. Because the ion mirror M1 was in a reflective operating mode (R) and the ion mirror M2 was in a transmissive operating mode (T) for a period of time sufficient to clear ions from the ELIT 14, no ions are transported through the charge detection cylinder CD. This is because free charges 28 are generated and transferred to the charge detection cylinder CD during the charge injection operation. Thus, the target number of charges 28 generated by the charge generator CG that contact and impart charge to the outer surface of the charge detection cylinder CD, as previously described, is used to charge the charge detection cylinder CD to a substantially constant, predictable and repeatable target charge level CH T In a charge induction operation, the charge induced on the charge detection cylinder CD by the electric field established by the charge generator CG can likewise be used for calibration and / or resetting.

[0050]

[0061] Referring now to FIG. 4C, the charge detection cylinder CD is rotated to a target charge level CH TAfter calibrating to ion mirror M1, processor 16 is operable to control ion mirror M1 in an ion transmission mode of operation (T) by controlling voltage source V1 to establish an ion transmission electric field in region R1 of ion mirror M1 while also maintaining ion mirror M2 in an ion transmission mode of operation (T). As a result, ions generated by ion source 12 and incident on ion mirror M1 pass through ion mirror M1, through charge detection cylinder CD, through ion mirror M2, and exit ion mirror M2 through aperture A1 of ion mirror M2, as described above and illustrated by ion trajectory 62 in FIG. 4C. In one embodiment, a conventional ion detector 25, such as one or more microchannel plates A detector is positioned adjacent to the ion exit aperture A1 of the ion mirror M2 and ion detection information provided by the detector 25 to the processor 16 can be used to adjust one or more of the components and / or operating conditions of the ELIT 14 to ensure proper detection of ions passing through the charge detection cylinder CD.

[0051]

[0062] 4D, after both ion mirrors M1, M2 have been operated in the ion transmission mode of operation for a selected period of time, the processor 16 is operable to control the voltage source V2 to maintain the ion mirror M1 in the ion transmission mode of operation (T) while controlling the ion mirror M2 in the ion reflection mode of operation (R) by establishing an ion reflection field in the region R2 of the ion mirror M2 as shown. As a result, ions generated by the ion source 12 and entering the ion mirror M1 pass through the ion mirror M1, pass through the charge detection cylinder CD, and enter the ion mirror M2. Here, the ions are reflected back to the charge detection cylinder CD by the ion reflection field (R) established in the region R2 of M2, as shown by ion trajectory 64 in FIG. 4D.

[0052]

[0063] 4E, the processor 16 is operable to control the ion mirror M1 in an ion-reflecting mode of operation (R) by controlling the voltage source V1 to establish an ion-reflecting electric field in a region R1 of the ion mirror M1 as shown, while maintaining the ion mirror M2 in an ion-reflecting mode of operation (R). In one embodiment, the processor 16 is illustratively operable, i.e., programmed, to control the ELIT 14 in a "random trapping mode." In the random trapping mode, the processor 16 is operable to control the ion mirror M1 in a reflecting mode of operation (R) after the ELITs have operated in the state shown in FIG. 4D, i.e., with M1 in an ion-transmitting mode and M2 in an ion-reflecting mode, for a selected period of time. The ELIT 14 is controlled to operate in the state shown in FIG. 4D until the selected period of time has elapsed. In an alternative embodiment, the processor 16 is operable, i.e., programmed, to control the ELIT 14 in a "trigger trapping mode." In the triggered trapping mode, the processor 16 is operable to control the ion mirror M1 in a reflective mode of operation (R) until an ion is detected at the charge detector CD. Until such detection, the ELIT 14 is controlled to operate in the state shown in FIG. 4D. Detection of a charge by the processor 16 on the charge detector CD indicates that an ion has passed the charge detector CD towards the ion mirror M1 or towards the ion mirror M2, and serves as a trigger event to trap the ion in the ELIT 14 by causing the processor 16 to control the voltage source V1 to switch the ion mirror M1 to an ion-reflective mode of operation (R).

[0053]

[0064] By controlling both ion mirrors M1, M2 in the ion-reflecting mode of operation (R), ions are caused to oscillate back and forth between the regions R1 and R2 of the respective ion mirrors M1 and M2 by the ion-reflecting electric fields established in the regions R1 and R2 of the ion mirrors M1 and M2, as shown by the ion trajectory 66 described above and depicted in FIG. 4E. In one embodiment, the processor 16 is operable to maintain the operating state shown in FIG. 4E until the ions have passed through the charge detection cylinder CD a selected number of times. In an alternative embodiment, the processor 16 is operable to maintain the operating state shown in FIG. 4E for a selected period of time after controlling M1 in the ion-reflecting mode of operation (R). When the ions have passed the charge detection cylinder CD a selected number of times, or have oscillated back and forth between the ion mirrors M1, M2 for a selected period of time, the processor 16 is operable, i.e. programmed, to maintain the ion mirror M1 in an ion reflecting mode of operation (R) while controlling the voltage source V2 to control the ion mirror M2 in an ion transmitting mode of operation (T) by establishing an ion transmitting electric field in the region R2 of the ion mirror M2, as shown in Figure 4A. This process is then repeated as many times as desired.

[0054]

[0065] 4A-4E may alternatively or additionally be implemented with the ELIT 14 during a charge detection event. However, in such an embodiment, the dimensions of the ELIT 14 and the axial lengths of the ion mirrors M1, M2 are adjusted to accommodate, among other things, the activation and subsequent generation of free charge 28 by the charge generator GC, the deposition of the generated free charge 28 on the outer surface of the charge detection cylinder CD, and the final target charge level CH on the charge detection cylinder CD. T and / or induce a charge on the charge detection cylinder CD by a suitably established electric field, all between the time that a trapped ion traveling through the ELIT 14 leaves the charge detection cylinder CD and the time that the ion is reflected back into the charge detection cylinder by one of the ion mirrors M1, M2.

[0055]

[0066] 5A-5F, there is shown a simplified diagram of the ELIT 14 of FIG. 1, clearly illustrating the sequence control and operation of the ion mirrors M1, M2 and charge generator CG as previously described, to calibrate or reconfigure the charge detection cylinder CD during such a charge detection event. Referring to FIG. 5A, one ion 70 is shown passing through the ELIT 14 at time T1 in the direction of arrow A from region R1 of ion mirror M1 towards the charge detection cylinder CD. The detected charge signal 80 is compared to the charge reference CH as shown in the attached plot of charge CH on the charge detection cylinder CD versus time. REF In Fig. 5B the ion 70 is shown at a subsequent time T2, where the ion has travelled along the direction of travel A and has entered the charge detection cylinder CD. The detected charge signal 80 thus indicates a step before T2, and indicates the detection of a charge induced thereon by the ion 70 contained within the charge detection cylinder CD. At a further subsequent time T3, the ion 70 has travelled further along the direction of travel A and is approaching the end of the charge detection cylinder CD, as shown in Fig. 5C. The peak of the charge detection signal 80 is thus reaching its end at T3.

[0056]

[0067] At a further subsequent time T4, the ion 70, still moving in the direction A, has just exited the charge detection cylinder CD and is poised to enter the region R2 of the ion mirror M2, as shown in FIG. 5D. Upon detecting an associated falling edge of the charge detection signal 80 at time T4 as the ion passes through the charge detection cylinder CD and induces its charge on the charge detection cylinder, i.e., upon detecting the absence of the charge detection signal generated by the charge preamplifier CP, the processor 16 is operable to generate a control signal C at time T5 to enable the charge generator CG, as indicated by a rising edge of the control signal 90. At a further subsequent time T6, the charge generator CG, in response to the control signal C, generates a selected number of free charges 28, which then pass through the field-free region 36 to contact the outer surface of the charge detection cylinder CD and deposit a target number of free charges 28 thereon. Alternatively or additionally, the charge generator CG may generate an electric field between the at least one charge drain passage 24 and the charge detection cylinder CD in response to a control signal C. This electric field induces a corresponding charge on the charge detection cylinder CD.

[0057]

[0068] At a subsequent time T7, the ion reflecting field (R) established in region R2 of ion mirror M2 traps ion 70 and reverses its direction so that the ion is now moving in the opposite direction B toward the entrance of charge detection cylinder CD adjacent ion mirror M2, as shown in FIG. 5E. As indicated by the falling edge of control signal 90, processor 16 has disabled control signal C at T7. In response to disabling control signal C, charge generator CG stops generating free charges 28, and the last of the generated charges 28 are shown in FIG. 5E moving toward the outer surface of charge detection cylinder CD. Alternatively or additionally, charge generator CG may have been deactivated at T7. In response to control signal C, the generation of the aforementioned electric field may be stopped. Thereafter, at time T8, ion 70 moving in direction B is again incident on charge detection cylinder CD as indicated by the rising edge of charge detection signal 80 at T8, as shown in FIG. 5F. Between T7 and T8, the free charge 28 that was created and deposited on charge detection cylinder CD settles and stabilizes to a final target charge level CH on charge detection cylinder CD. T Similarly, as shown in FIG. 5F, this target charge level CH T becomes the new charge reference for the charge detection signal 80. Alternatively or additionally, calibration or resetting can be accomplished by charge induction, as described above. The same process as shown in Figures 5A-5F occurs at the opposite end of the ELIT 14 and continues for each oscillation of ions 70 within the ELIT 14 until ion mirror M2 is opened to allow ions 70 to exit aperture A1.

[0058] example

[0069] The following examples are presented to illustrate three specific applications: controlling the charge generator CG to selectively generate free charges 28 as part of a charge injection process that deposits or imparts a net charge, respectively, onto the charge detection cylinder CD; controlling the charge generator CG as part of a charge induction process that selectively induces charges onto the charge detection cylinder; and controlling the charge generator CG as part of a charge preamp calibration process to selectively induce high frequency charges onto the charge detection signal during normal operation of the ELIT to measure the mass and charge of charged particles, process the detected high frequency charges, and use the information provided thereby to compensate over time for any drift in the gain of the charge preamp. It will be understood that these applications are presented by way of example only and should in no way be understood to limit the concepts described herein.

[0059]

[0070] The first application example specifically relates to an embodiment in which the charge sensitive preamplifier does not include any feedback components, or at least a feedback component operable to bleed, i.e., dissipate or remove, charge that may build up, i.e., accumulate, on the charge detection cylinder CD as charge is induced by the passage of trapped ions. In such an embodiment, charge that accumulates or builds up on the charge detection cylinder raises the reference charge level at the input of the charge sensitive preamplifier, thus causing the output of the charge preamplifier to drift upwards and eventually to the level of the supply voltage of the charge sensitive preamplifier. In such an embodiment, the charge generator GC is configured to operate in a charge injection mode, and the processor 16 is operable to control the charge generator CG to generate free charges 28 of appropriate polarity and quantity, which, as they are deposited or dispensed onto the charge detection cylinder CD, counteract the built-up or accumulated charge, thereby raising the charge level of the charge detection cylinder CD, and the input of the charge sensitive preamplifier, to the reference charge level CH. REF or reset to some other selectable charge level.

[0060]

[0071] The second application example is specifically directed to embodiments in which the charge generator is configured to operate in a charge induction mode to counteract or at least reduce the charge induced on the charge detection cylinder CD by the electric field transients generated when switching either or both of the ion mirrors M1, M2 between ion transmission and ion reflection modes, as described above. In general, each time the voltage sources V1 and / or V2 are controlled by the processor 16 to change the respective voltages applied to the ion mirrors M1 and / or M2 to switch the ion transmission electric field TEF to the ion reflection electric field REF, or vice versa, a switching from one electric field to the other results in an electric field transient that induces a corresponding transient charge on the charge detection cylinder CD. This transient charge, in at least some instances, saturates the output of the charge sensitive preamplifier for a period of time, and in other instances, saturates the output of the charge sensitive preamplifier. In either instance, such an output generated by the charge sensitive preamplifier does not correspond to a charge induced thereon by the passage of trapped ions through the charge detection cylinder CD, and following such switching of either the ion mirrors M1, M2, or simultaneous switching of both ion mirrors M1, M2, charge detection data collection by the processor 16 is conventionally paused or delayed for a period of time to allow the transient charge induced on the charge detection cylinder CD to dissipate. In this regard, the processor 16 in this second instance controls the charge generator CG and / or the voltage source VCG to generate a counter-pulse each time one or both of the ion mirrors M1, M2 are switched between the ion transmission and reflection modes. , such a counter-pulse induces an equal or nearly equal and opposite charge on the charge detection cylinder CD to the transient charge induced on the charge detection cylinder CD by switching of the ion mirror(s) M1 and / or M2 to cancel or at least reduce the net transient charge induced on the charge detection cylinder by such switching of the ion mirror(s) M1 and / or M2. Illustratively, the shape, duration, and / or amplitude of the voltage counter-pulse generated by the voltage source VCG is controlled to form an electric field between the charge generator CG and the charge detection cylinder CD having a corresponding shape, duration, and / or amplitude to induce an equal and opposite charge on the charge detection cylinder to the transient charge induced on the charge detection cylinder CD by switching of the ion mirror(s) M1, M2. Such counter-pulsing by the voltage source VCG illustratively prevents the charge preamplifier CP from saturating. In either case, subsequent switching of the ion mirror(s) M1 and / or M2 allows for much faster processing of charge detection data than in conventional ELIT and / or CDMS instruments.

[0061]

[0072] It will be appreciated that the transient charge induced on the charge detection cylinder CD by switching the ion mirror M1 may be different from that induced by switching the ion mirror M2, either of which may be different from that induced when both ion mirrors M1, M2 are switched simultaneously, and any such transient charge induced on the charge detection cylinder CD when either or both of the ion mirrors M1, M2 are switched from a transmissive mode to a reflective mode may be different from that when switched from a reflective mode to a transient mode. Thus, in this example application, depending on which and how ion mirror M1, M2 (or both) are switched, the processor 16 may be programmed to differentially control the shape, duration and / or amplitude of the voltage reverse pulse generated by the voltage source VCG to selectively form an appropriate electric field between the charge generator CG and the charge detection cylinder CD having a corresponding shape, duration and / or amplitude to induce an equal and opposite charge on the charge detection cylinder CD to any such transient charge induced on the charge detection cylinder CD by such switching of the ion mirror(s) M1 and / or M2.

[0062]

[0073] The third application example is specifically targeted to embodiments in which the charge sensitive preamplifier may be susceptible to drift in gain over time, for example, but not limited to, due to one or any combination of the amplifier operating temperature, the amplifier operating temperature gradient, and signal history. In such an embodiment, illustratively during normal operation of the ELIT 14, in which the mass and charge of a charged particle are measured by the ELIT 14 as described herein, the charge generator CG is controlled to selectively induce high frequency charges on the charge detection cylinder CD, process the detected high frequency charges, and use the information provided thereby to compensate for any drift in the gain of the charge sensitive preamplifier CP over time. In this regard, the simplified flow chart of FIG. 7 illustrates a method for continuously inducing high frequency charges on the charge detection cylinder CD and using corresponding information in the resulting charge detection signal CHD to compensate for gain drift over time in the charge sensitive preamplifier. An example process 200 for controlling the generation voltage source VCG and / or the charge generator CG is shown, illustratively stored in the memory 18 in the form of instructions executable by the processor 16 to control the operation of the charge generation voltage source VCG and / or the charge generator CG and process the charge detection signal CHD as just described.

[0063]

[0074] In this regard, the process 200 begins at step 202, where the processor 16 is operable to set a counter j equal to one or some other starting value. Thereafter, at step 204, the processor 16 is operable to control the voltage source VCG and / or the charge generator CG to generate a suitable constant or stable amplitude high frequency voltage to form a corresponding high frequency electric field between the outlet 26 of the charge generator CG, e.g., in the form of an antenna or other suitable structure, and the charge detection cylinder CD, which induces a corresponding high frequency charge on the charge detection cylinder CD. The term "high frequency", as used in this embodiment, refers to a frequency domain charge detection signal CHD that, during normal operation of the ELIT 14, is a detection of charges induced by charged particles, i.e., ions, passing through the charge detection cylinder. The term "high frequency" is understood to mean a frequency at least high enough to be distinguishable from the portion of the CHD resulting from the emission. In this regard, "high frequency" may be at least higher than the highest oscillation frequency of any ion oscillating back and forth in the ELIT 14 as explained above. The high frequency voltage generated by the VCG and / or CG may be of any shape, e.g., square, sinusoidal, triangular, etc., and may have any desired duty cycle. In one example embodiment, which should not be taken as limiting in any way, the high frequency voltage generated at the antenna 26 is a square wave and includes only the fundamental frequency and odd harmonics in the frequency domain.

[0064]

[0075] Following step 204, the process 200 proceeds to step 206 where the processor 16 is operable to measure the charge CI induced on the charge detector CD by the radio frequency signal generated at the antenna 26 by processing a corresponding charge detection signal CHD generated by the charge sensitive preamplifier CP. Thereafter, in step 208, the processor 16 converts the time domain charge detection signal CHD into a frequency domain charge detection signal CI using any conventional signal transformation technique, such as, for example, a discrete Fourier transform (DFT), a fast Fourier transform (FFT), or other conventional technique. F Then, in step 210, the processor 16 is operable to determine a peak amplitude PM of the fundamental frequency of the charge detection signal CIF. Then, in step 212, the processor 16 is operable to compare the counter value j to a target value N. In general, N is a sample size of a data set that includes a plurality of sequentially measured values ​​of PM, and defines the size of a moving average window that is used to track drift of the charge sensitive preamplifier CP. In this regard, N may have any positive value. In general, the smaller the value of N, the more responsive but less smooth the moving average will be, and the larger the value of N, the greater the moving average will be. Conversely, the smaller the N, the less responsive but smoother the moving average will be. Typically, N is selected based on the application. In one example application, which should not be considered limiting in any way, N is 100, but in other applications N may be less than 100, hundreds, thousands, or even thousands.

[0065]

[0076] If, in step 212, the processor 16 determines that j is less than or equal to N, the process 200 proceeds to step 214, where the processor 16 is operable to add MP(j) to the N-sample data set stored in the memory 18. Thereafter, in step 216, the processor is operable to increment the counter j and then return to step 206. If, in step 212, the processor 216 determines, conversely, that j is greater than N, the process 200 proceeds to step 218, where the processor 16 increments the N-sample data set value PM I-N In one embodiment, processor 16 is operable to determine an average AV of PM 1-N Although it is possible to compute the algebraic average of In embodiments, processor 16 may be operable to calculate the AV in step 218 using one or more other conventional averaging techniques or processes.

[0066]

[0077] Steps 202-218 of process 200 are illustratively performed prior to operation of the instrument 10 to measure the mass and charge spectrum of ions generated from a sample as described herein. In this regard, the purpose of steps 202-218 is to construct an N-sample data set of peak magnitude values ​​PM prior to normal operation of the ELIT 14 to measure the mass and charge of ions as described herein. and determining a baseline gain or gain coefficient AV of the charge sensitive preamplifier CP. However, it will be appreciated that in other embodiments, steps 202-218 may be re-performed at any time, e.g., randomly, periodically, or selectively, to re-determine the baseline gain or gain coefficient.

[0067]

[0078] Following step 218, processor 16 may illustratively select, for example, an ELI ELIT 14. The processor 16 is operable to initiate a CDMS analysis of the sample by the instrument 10, as described herein, by controlling the voltage sources V1 and V2 to measure the mass and charge of ions generated from the sample by the ELIT 14. Thereafter, in step 222, as such operation of the instrument 10 and the ELIT 14 occurs, and as the charge generator CG is continually controlled to induce a high frequency charge HFC on the charge detection cylinder CD, the processor 16 (a) determines PM, for example, according to steps 206-210 or other conventional processes for determining PM, for each charge detection signal CHD generated by the charge sensitive preamplifier in response to a charge induced thereon by a charged particle passing therethrough, and (b) adds the PM to an N-sample data set, deleting the oldest PM value and generating a 1 data set. (c) determine a new average NAV of the now updated N-sample data set, e.g., according to step 218 or other conventional averaging techniques; (d) determine a gain calibration factor GCF for the charge sensitive preamplifier as a function of AV and NAV; and (e) modify the portion of the charge detection signal CHD generated by the charge sensitive preamplifier in response to charge induced thereon by the passage of the charged particle through the charge detection cylinder CD as a function of GCF to compensate for any drift in the gain of the charge sensitive preamplifier CP.

[0068]

[0079] It will be appreciated that any of a variety of conventional techniques may be used by processor 16 to determine GCF in step 222(d). In one embodiment, for example, GCF may be a ratio GCF=NAV / AV or GCF=AV / NAV. In other embodiments, AV may be normalized, for example, to a value of 1 or some other value, and NAV may similarly be normalized as a function of the normalized AV to generate GCF in the form of a normalized multiplier. Other techniques will occur to those skilled in the art, and it will be appreciated that any such other techniques are intended to fall within the scope of the present disclosure. In any case, processor 16 is illustratively operable in step 222(e) to compensate for any drift in the gain of charge sensitive preamplifier CP by modifying a portion of charge detection signal CHD generated by the charge sensitive preamplifier in response to charge induced thereon by the passage of a charged particle through charge detection cylinder CD, and multiplying the peak amplitude of this portion of charge detection signal CH by GCF. However, those skilled in the art will recognize other techniques for performing step 222(e), such as for including other coefficients in the GCF that can affect the gain of the CP, for including one or more weighting coefficients that boost or weaken the gain of the CP based on one or more coefficients, etc.

[0069]

[0080] Referring now to FIG. 8, the charge detection signal processed in step 222(a) is 8 shows an example plot of CHD versus frequency representing an example output signal CDH. The charge detection signal CHD includes a charge peak 300 corresponding to the detection of a charge induced on the charge detection cylinder CD of the ELIT 14 by a charged particle passing thereon, and an additional charge peak 400 corresponding to the detection of a high frequency charge HFC simultaneously induced on the charge detection cylinder CD by the charge generator CG. As explained herein, the frequency of the high frequency charge induced on the charge detection cylinder CD by the antenna 26 of the charge generator CG is at least sufficiently higher than the oscillation frequency of the charged particle oscillating back and forth through the ELIT 14 so that the two sources of charge can be distinguished from one another. The peak magnitude Ipeak magnitude)PM of the fundamental frequency of the induced high frequency charge HFC determined in step 222(a) of the process 200 is also shown in FIG.

[0070]

[0081] 9, an example plot of the peak amplitude PM of the fundamental frequency of the high frequency charge HFC induced on the charge detection cylinder CG by the charge generator versus time 410 is shown. The example plot includes the baseline gain value AV calculated in step 218, and also includes an example of drift in the gain of the charge sensitive preamplifier CP over time during operation of the device 10. It is understood that although FIG. 9 illustrates the gain drift as increasing linearly over time, the gain drift may instead be nonlinear or partially linear, and / or may decrease over time, or may increase at some times and decrease at other times. In any case, the baseline gain value AV calculated in step 218 occurs during a time window W1 between times T0 and T1, step 220 is performed at time T1, and the gain of the charge sensitive preamplifier subsequently drifts between T1 and T3. 9 also illustrates the progressive movement of the N-sample time windows repeatedly performed in step 222(b), i.e., the respective charge detection signals CHD resulting from the charges induced thereon by the passage of the charged particles through the charge detection cylinder CD. An example of such a time window, W2, is shown extending from midway between T0 and T1 to T2, and another example time window, W3, spanning between times T2 and T is also shown.

[0071]

[0082] 10, there is shown a plot of the moving average (NAV) 420 of an N-sample data set. This is the moving average (NAV) 420 over time of the peak amplitude signal 410 shown in FIG. 9, as determined by the processor 16 in step 222(c) of process 200. In the illustrated example, the moving average NAV smoothes the peak amplitude signal 410 into a linear increasing function from a baseline gain or gain factor AV. As previously explained, the NAV and AV are illustratively used by the processor 16 in steps 222(d) and 222(e) to correct a portion of the charge detection signal CHD generated by the charge sensitive preamplifier in response to charge induced thereon by the passage of a charged particle through the charge detection cylinder CD, to compensate for any drift in the gain of the charge sensitive preamplifier CP by multiplying the peak amplitude of this portion of the charge detection signal CH by the GCF.

[0072]

[0083] 6A, a simplified diagram of an embodiment of an ion separation apparatus 100 is shown. The ion separation apparatus 100 may include an ELIT 14 as shown and described herein, may include a charge detection mass spectrometer (CDMS) 10 as shown and described herein, may include any number of ion processing devices that may form part of an ion source 12 upstream of the ELIT 14, and / or may be located downstream of the ELIT 14 for further processing of ion(s) exiting the ELIT 14. In this regard, the ion source 12 is shown in FIG. 6A as including Q ion source stages IS1-IS1. Q The ion source stages IS1 through IS Q may be the ion source 12 or form part of the ion source 12. Alternatively or additionally, the ion processing device 110 may be In A, the ion processing device 110 is shown coupled to the ion exit port of the ELIT 14 and may include any number of ion processing stages OS1 to OS R where R can be any positive integer.

[0073]

[0084] Focusing on the ion source 12, the ion source 12 for ions entering the ELIT 14 is made up of ion source stages IS1 to IS Q It will be understood that the ion source may be or include one or more conventional ion sources as described above, in one or more forms, and may further include 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, 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 quadrupoles, hexapoles, and / or other ion traps), filtering ions (e.g., according to one or more molecular properties such as ion mass, ion mass-to-charge, ion mobility, ion retention time, etc.), fragmenting or otherwise dissociating ions, normalizing or shifting ion charge states, etc. It will be understood that ion source 12 may include one or any combination of any such conventional ion sources, ion separation devices, and / or ion processing devices in any order, and that an embodiment may include a plurality of adjacent or spaced apart any such conventional ion sources, ion separation devices, and / or ion processing devices. In any embodiment that includes one or more mass spectrometers, any one or more such mass spectrometers may be implemented in any of the forms described herein.

[0074]

[0085] Turning now to the ion processing device 110, the device 110 has ion processing stages OS1 to OS Rone or more conventional instruments for separating ions according to one or more molecular properties (e.g., according to ion mass, ion mass-to-charge, ion mobility, ion retention time, etc.), in the form of one or more of: It will be understood that the ion processing device 110 may be or include one or more conventional ion processing devices such as a mass spectrometer, a mass analyzer ...

[0075]

[0086] In one specific embodiment of the ion separation apparatus 100 shown in FIG. 6A, the ion source 12 illustratively includes three stages and excludes the ion processing apparatus 110. This should not be considered limiting in any way. In this example embodiment, the ion source stage IS1 is The ion source stage IS2 is a conventional ion source, e.g., electrospray, MALDI, etc., the ion source stage IS2 is a conventional ion filter, e.g., a quadrupole or hexapole ion guide, and the ion source stage IS3 is a mass spectrometer of any of the types previously described herein. In this embodiment, the ion source stage IS2 is conventionally controlled to preselect ions having desired molecular characteristics for analysis by a downstream mass spectrometer and to pass only these preselected ions to the mass spectrometer, such that the ions analyzed by the ELIT14 become preselected ions that are separated by the mass spectrometer according to their mass to charge ratio. As the preselected ions exit the ion filter, ions having a specified ion mass or mass-to-charge ratio, a specified ion quality, The selected ions may be ions having ion masses or ion mass-to-charge ratios higher and / or lower than the specified ion mass or ion mass-to-charge ratio, ions having ion masses or ion mass-to-charge ratios within a specified ion mass or ion mass-to-charge ratio range, etc. In an alternative embodiment of this example, the ion source stage IS2 may be a mass spectrometer and the ion source stage IS3 may be an ion filter, which may otherwise be operable as just described to preselect ions exiting the mass spectrometer with desired molecular characteristics for analysis downstream by the ELIT 14. In another alternative embodiment of this example, the ion source stage IS2 may be an ion filter and the ion source stage IS3 may include a mass spectrometer preceded by another ion filter, each of which operates as just described.

[0076]

[0087] In another specific embodiment of the ion separation device 100 shown in Figure 6A, the ion source 12 illustratively includes two stages, and the ion processing device 110 is again excluded. This should not be considered limiting in any way. In this example embodiment, the ion source stage IS1 is a conventional ion source, e.g., electrospray, MALDI, etc., and the ion source stage IS2 is a conventional mass spectrometer of any of the types previously described. This is the embodiment previously described with respect to Figure 1, where the ELIT 14 is operable to analyze ions exiting the mass spectrometer.

[0077]

[0088] As yet another specific embodiment of the ion separation device 100 shown in FIG. The ion source 12 illustratively includes two stages and excludes the ion processing device 110. This should not be considered limiting in any way. In this example embodiment, the ion source stage IS1 is a conventional ion source, e.g., electrospray, MALDI, etc., and the ion processing stage OS2 is a conventional single or multi-stage ion mobility spectrometer. In this embodiment, the ion mobility spectrometer is operable to separate ions produced by the ion source stage IS1 over time according to one or more functions of ion mobility, and the ELIT 14 is operable to analyze ions exiting the ion mobility spectrometer. In an alternative embodiment of this example, the ion source 12 may include only one stage IS1 in the form of a conventional ion source, and the ion processing equipment 110 is a conventional single or multi-stage ion mobility spectrometer. An ion mobility spectrometer as the only stage OS1 (or a multi-stage instrument 110 In this alternative embodiment, the ELIT14 is operable to analyze ions produced by the ion source stage IS1, and the ion mobility spectrometer OS1 is operable to separate ions exiting the ELIT14 over time according to one or more functions of ion mobility. In another alternative embodiment of this example, single or multiple stage ion mobility spectrometers may follow both the ion source stage IS1 and the ELIT14. In this alternative embodiment, the ion mobility spectrometer following the ion source stage IS1 is operable to separate ions produced by the ion source stage IS1 over time according to one or more functions of ion mobility, the ELIT14 is operable to analyze ions exiting the ion source stage ion mobility spectrometer, and the ion mobility spectrometer of the ion processing stage OS1 following the ELIT14 is operable to separate ions exiting the ELIT14 over time according to one or more functions of ion mobility. In any of the implementations of the embodiments described in this section, additional variations can include a mass spectrometer operably positioned upstream and / or downstream of the single or multi-stage ion mobility spectrometer in the ion source 12 and / or ion processing device 110.

[0078]

[0089] In yet another specific embodiment of the ion separation device 100 shown in FIG. 6A, the ion source 12 illustratively includes two stages and excludes the ion processing device 110, but this should not be considered limiting in any way. In this example embodiment, the ion source stage IS1 is a conventional liquid chromatograph, e.g., a stage for separating molecules in a solution according to molecular retention time. and the ion source stage IS1 is a conventional ion source, e.g., an electrospray, etc. In this embodiment, the liquid chromatograph is operable to separate molecular components in the solution, the ion source stage IS2 is operable to generate ions from a solution stream exiting the liquid chromatograph, and the ELIT14 is operable to analyze the ions generated by the ion source stage IS2. In an alternative embodiment of this example, the ion source stage IS1 may instead be a conventional size-exclusion chromatograph (SEC) operable to separate molecules in the solution by size. In another alternative embodiment, the ion source stage IS1 may comprise a conventional liquid chromatograph followed by a conventional SEC, or vice versa. In this embodiment, ions are generated from the solution separated twice by the ion source stage IS2, once according to molecular retention time followed by a second separation according to molecular size, or vice versa. In any of the implementations of the embodiments described in this section, an additional variant may include a mass spectrometer operably positioned between the ion source stage IS2 and the ELIT14.

[0079]

[0090] 6B, there is shown a simplified block diagram of another embodiment of an ion separation device 120. Illustratively, the ion separation device 120 includes a multi-stage mass spectrometry device 130, which further includes a charge detection mass spectrometer (CDMS) 10 as shown and described herein and implemented as a high-mass ion analysis component. In the illustrated embodiment, the multi-stage mass spectrometry instrument 130 includes an ion source (IS) 12 as illustrated and described herein, followed by and coupled to a first conventional mass spectrometer (MS1) 132 followed by and coupled to a conventional ion dissociation stage (ID) 134 operable to dissociate ions exiting the mass spectrometer 132, for example by one or more of collision induced dissociation (CID), surface induced dissociation (SID), electron capture dissociation (ECD), and / or photoinduced dissociation (PID), followed by and coupled to a second conventional mass spectrometer (MS2) 136 followed by a conventional ion detector (D) 138, such as, for example, a microchannel plate detector or other conventional ion detector. The CDMS 10 is in parallel with and coupled to the ion dissociation stage 134 such that the CDMS 10 can selectively receive ions from the mass spectrometer 136 and / or the ion dissociation stage 132 .

[0080]

[0091] For example, MS / MS using only an ion separation instrument 130 is a well-established technique in which precursor ions of a particular molecular weight are separated by a first mass spectrometer 132 (MS1) based on their m / z value. The mass-selected precursor ions are fragmented in an ion dissociation stage 134, for example by collision-induced dissociation, surface-induced dissociation, electron capture dissociation, or light-induced dissociation. The fragment ions are then analyzed by a second mass spectrometer 136 (MS2). In both MS1 and MS2, only the m / z values ​​of the precursor and fragment ions are measured. For high mass ions, the charge state is not resolved, and therefore it is not possible to select precursor ions of a particular molecular weight based on m / z value alone. However, by coupling the instrument 130 to a DMS 10, it becomes possible to select a narrow range of m / z values ​​and then use the CDMS 10 to determine the mass of the m / z-selected precursor ions. The mass spectrometers 132, 136 may be, for example, one or any combination of magnetic sector mass spectrometers, time-of-flight mass spectrometers, or quadrupole mass spectrometers, although in alternative embodiments other types of mass spectrometers may be used. In either case, precursor ions exiting MS1, selected by m / z and having known mass, may be fragmented in ion dissociation stage 134, and the resulting fragment ions may then be analyzed by MS2 (where only the m / z ratio is measured) and / or by the CDMS instrument 10 (where m / z ratio and charge are measured simultaneously). Low mass fragments, i.e., fragments below a threshold mass value, e.g., 10,000 Da (or The fragment ions of the precursor ion, which have a mass value lower than the threshold mass value (other mass values), can therefore be analyzed by conventional MS using MS2, while the high mass fragments (charge state unresolved), i.e., fragment ions of the precursor ion, which have a mass value equal to or greater than the threshold mass value, can be analyzed by CDMS10.

[0081]

[0092] It will be appreciated that the dimensions of the various components of the ELIT 14, and the magnitude of the electric field established therein, implemented in any of the systems 10, 100, 120 shown in the accompanying drawings and described above, can be selected to establish a desired duty cycle of ion oscillation, illustratively within the ELIT 14, corresponding to the ratio of the time spent by an ion in the charge detection cylinder CD to the total time spent by an ion traversing the combination of the ion mirrors M1, M2 and the charge detection cylinder CD during one complete oscillation cycle. For example, a duty cycle of about 50% may be desirable for the purpose of reducing noise in fundamental frequency amplitude determinations obtained from harmonic frequency components of the measurement signal. Details regarding such dimensions and operational considerations to achieve a desired duty cycle, such as 50%, are shown and described in co-pending U.S. Patent Application No. 62 / 616,860, filed January 12, 2018, co-pending U.S. Patent Application No. 62 / 680,343, filed June 4, 2018, and co-pending International Patent Application No. PCT / US2019 / 013251, filed January 11, 2019, all of which are incorporated herein by reference in their entirety. No. 6,393,633, entitled "Electrostatic Linear Ion Trap Design for Mass Spectroscopic Analysis," which are expressly incorporated herein by reference in their entireties.

[0082]

[0093] It will be further understood that one or more charge detection optimization techniques may be used in conjunction with the ELIT 14 in any of the systems 10, 100, 120, for example, to trigger capture or other charge detection events. Some examples of such charge detection optimization techniques are shown and described in co-pending U.S. patent application Ser. No. 62 / 680,296, filed Jun. 4, 2018, and co-pending International Patent Application No. PCT / US2019 / 013280, filed Jan. 11, 2019, both of which are incorporated herein by reference in their entirety. No. 6,399,363, which are hereby expressly incorporated herein by reference in their entireties.

[0083]

[0094] Furthermore, it will be appreciated that the charge detection cylinder calibration or resetting apparatus and techniques illustrated in the accompanying drawings and described herein may be used in applications involving at least one ELIT array having two or more ELITs or having two or more ELIT regions in each of the two or more ELITs and / or in each of the two or more ELIT regions. Examples of several such ELITs and / or ELIT arrays are illustrated and described in co-pending U.S. Patent Application No. 62 / 680,315, filed June 4, 2018, and co-pending International Patent Application No. PCT / US2019 / 013283, filed January 11, 2019, both of which are incorporated herein by reference in their entirety for purposes of illustration only and are not intended to be limiting ... No. 6,399,326, entitled "Ion Trap Array for Mass Spectroscopy Using a Single Crystal," which are hereby expressly incorporated herein by reference in their entireties.

[0084]

[0095] It will be further understood that one or more ion source optimization devices and / or techniques may be used with one or more embodiments of the ion source 12 as part of or in combination with any of the systems 10, 100, 120 shown in the accompanying drawings and described herein, some examples of which are incorporated herein by reference in their entirety. N CARPET (FUNPET) ATMOSPHERIC PRESSURE INTERFACE FOR CHARGE DETECTION MASS SPECTROMETRY No. 62 / 680,223, filed on Jan. 11, 2019, entitled INTERFACE FOR TRANSPORTING IONS FROM AN ATMOSPHERIC PRESSURE ENVIRONMENT TO A LOW PRESSURE ENVIRONMENT, and in co-pending International Patent Application No. PCT / US2019 / 013274, filed on Jan. 11, 2019, entitled INTERFACE FOR TRANSPORTING IONS FROM AN ATMOSPHERIC PRESSURE ENVIRONMENT TO A LOW PRESSURE ENVIRONMENT, the contents of which are expressly incorporated herein in their entirety by reference.

[0085]

[0096] It will further be appreciated that any of the systems 10, 100, 120 illustrated in the accompanying drawings and described herein may be implemented in or as part of a system configured to operate in accordance with real-time analysis and / or real-time control techniques, some examples of which are shown and described in co-pending U.S. patent application Ser. No. 62 / 680,245, filed Jun. 4, 2018, and co-pending International Patent Application No. PCT / US2019 / 013277, filed Jan. 11, 2019, both of which are entitled CHARGE DETECTION MASS SPECTROMETRY WITH REAL TIME ANALYSIS AND SIGNAL OPTIMIZATION, the contents of which are expressly incorporated herein in their entireties by reference.

[0086]

[0097] It will further be understood that in any of the systems 10, 100, 120 shown in the accompanying drawings and described herein, the ELIT 14 may be replaced with an orbitrap, and the charge detection cylinder calibration or resetting apparatus and techniques shown in the accompanying drawings and described herein may be used with such an orbitrap. Examples of such orbitraps are shown and described in co-pending U.S. patent application Ser. No. 62 / 769,952, filed Nov. 20, 2018, and co-pending International Patent Application No. PCT / US2019 / 013278, filed Jan. 11, 2019, both of which are entitled ORBITRAP FOR SINGLE PARTICLE MASS SPECTROMETRY, the contents of which are expressly incorporated herein in their entirety by reference.

[0087]

[0098] It will further be appreciated that one or more ion injection trajectory control devices and / or techniques may be used with the ELIT 14 of any of the systems 10, 100, 120 illustrated in the accompanying drawings and described herein to accommodate simultaneous measurement of multiple individual ions within the ELIT 14. Examples of some such ion injection trajectory control devices and / or techniques are illustrated and described in co-pending U.S. patent application Ser. No. 62 / 774,703, filed Dec. 3, 2018, and co-pending International Patent Application No. PCT / US2019 / 013285, filed Jan. 11, 2019, both of which are incorporated herein by reference in their entirety, and are incorporated herein by reference in their entirety. No. 6,399,363, which is incorporated herein by reference in its entirety, and which is hereby expressly incorporated herein by reference in its entirety.

[0088]

[0099] While the present disclosure has been particularly illustrated and described in the drawings and foregoing description, it will be understood that this is to be regarded as illustrative in nature and not restrictive, that exemplary embodiments thereof have been shown and described only, and that all changes and modifications that fall within the spirit of the disclosure are desired to be protected. For example, it will be understood that the ELIT 14 shown in the accompanying drawings and described herein is provided by way of example only, and that the concepts, structures, and techniques described above may be directly implemented in ELITs of various alternative designs. Such alternatives may be implemented in any manner that is suitable for use in a variety of applications. Any alternative ELIT design may include any one or more combinations of, for example, two or more ELIT regions, more, fewer, and / or differently shaped ion mirror electrodes, more or fewer voltage sources, more or fewer DC or time-varying signals generated by one or more of the voltage sources, one or more ion mirrors defining additional electric field regions, etc. As another example, although the concepts, structures, and / or techniques of the present disclosure have been described as being implemented in an electrostatic linear ion trap (ELIT), it will be understood that such concepts, structures, and / or techniques are not intended to be limited to ELITs and variants thereof, but rather are intended to be applicable to any conventional charge detector or charge detection device. Thus, any conventional charge detector or charge detection device embodying the concepts, structures, and / or techniques illustrated in the accompanying drawings and described herein is intended to fall within the scope of the present disclosure.

Claims

1. 1. A charge detection mass spectrometer (CDMS) including reconfiguration or calibration of a charge detector, comprising: an electrostatic linear ion trap (ELIT) having a charge detection cylinder disposed between first and second ion mirrors; A charge generator; and an area between the charge generator and the charge detection cylinder; 1. A processor comprising: (i) generating a target number of free charges and accelerating said generated target number of free charges through said region between said charge generator and said charge detection cylinder and into contact with said charge detection cylinder and depositing said target number of free charges thereon, thereby calibrating or resetting said charge detection cylinder to a corresponding target charge level; or (ii) generating at least one electric field in the region, the at least one electric field inducing a target charge on the charge detection cylinder for calibrating the charge detection cylinder; a processor configured to control the charge generator so as to 1. A charge detection mass spectrometer comprising:

2. 10. The CDMS of claim 1, further comprising an ion source configured to provide ions to the ELIT; a charge detection cylinder configured to detect charges on the charge detection cylinder and to cause the charge detection cylinder to detect charges on the charge detection cylinder.

3. 3. The CDMS of claim 2, further comprising at least one voltage source operatively coupled to the processor and the first and second ion mirrors and configured to generate voltages to selectively establish an ion transmission field or an ion reflection field therein, the ion transmission field configured to focus ions passing through each of the first and second ion mirrors toward a longitudinal axis passing through a center of each of the first and second ion mirrors and the charge detection cylinder, and the ion reflection field configured to stop ions entering each of the first and second ion mirrors from the charge detection cylinder and to focus the ions toward the longitudinal axis while accelerating the ions back through the charge detection cylinder toward the other of the first and second ion mirrors, a charge detection cylinder configured to detect a charge on a charge detector cylinder and a charge-detecting cylinder configured to detect a charge on the ...

4. 4. The CDMS of claim 3, wherein the processor is configured to calibrate or reconfigure the charge detection cylinder during each pass of the ions by controlling the charge generator to generate the target number of free charges following each pass of the ions through the charge detection cylinder when the ions are within each of the first and second ion mirrors.

5. 5. The CDMS of claim 4, further comprising a charge preamplifier having an input coupled to the charge detection cylinder and an output coupled to the processor, the charge preamplifier configured to generate a charge detection signal in response to charge induced thereon by ions passing through the charge detection cylinder; A CDMS, wherein the processor is configured to control the charge generator to generate the target number of free charges upon detection of an absence of the charge detection signal at the output of the charge preamplifier.

6. 6. The CDMS of claim 5, wherein no feedback components are electrically connected between the input and output of the charge preamplifier; A CDMS, wherein the target number of free charges deposited on the charge detection cylinder is selected such that, when detected by the charge preamplifier, resets the charge detection cylinder and the charge preamplifier to their respective repeatable operating states by eliminating the amount of charge noise accumulated on the charge detection cylinder due to charge induced due to the passage of trapped charges.

7. 7. The CDMS according to claim 5 or 6, further comprising a memory, a processor configured to receive the charge detection signal from the charge preamplifier and to record the received charge detection signal in the memory over the duration of an ion measurement event in which the ions oscillate back and forth between the first and second ion mirrors a predetermined number of times or for a predetermined period of time.

8. The CDMS of claim 7 , wherein the processor is configured to process the recorded charge detection signals to determine ion charge values ​​and at least one of ion mass-to-charge ratios and ion masses.

9. 8. The CDMS of claim 7, wherein the processor controls at least one of the first and second ion mirrors to eject the trapped ions from the ELIT after the ion measurement event; a processor configured to control the charge generator to generate the target number of free charges after the trapped ions exit the ELIT, thereby calibrating or reconfiguring the charge detection cylinder after the ion measurement event.

10. 10. The CDMS of claim 9, wherein the processor is configured to control at least one of the first and second ion mirrors to control the at least one voltage source to eject the trapped ions from the ELIT by establishing the ion transmission electric field in at least one of the first and second ion mirrors such that the trapped ions exit the ELIT through an ion entrance aperture defined in the first ion mirror or through an ion exit aperture defined in the second ion mirror.

11. 11. The CDMS of claim 9 or 10, wherein the processor (i) controls the first and second ion mirrors to trap ions in the ELIT and oscillate the trapped ions back and forth between the first and second ion mirrors during an ion measurement event, and then (ii) controls at least one of the first and second ion mirrors to eject the trapped ions from the ELIT, and (iii) repeats (i) and (ii) for a number of successive ion measurement events. A CDMS, wherein the processor is configured to control the charge generator to generate the target number of free charges to calibrate or reconfigure the charge detection cylinder during each of the number of successive ion measurement events.

12. 4. The CDMS of claim 2 or 3, wherein the processor is configured to: (i) control operation of the first and second ion mirrors to trap ions from the ion source therein; (ii) thereafter oscillate the trapped ions back and forth between the first and second ion mirrors each time the trapped ions pass the charge detection cylinder and induce a corresponding charge thereon; (iii) oscillate the trapped ions back and forth between the first and second ion mirrors for a predetermined number of times or for a predetermined period of time that defines an ion measurement event; and (iv) thereafter eject the trapped ions from the ELIT; a processor configured to control the charge generator to generate the target number of free charges after the trapped ions exit the ELIT, thereby calibrating or reconfiguring the charge detection cylinder after the ion measurement event.

13. 13. The CDMS of claim 12, further comprising a charge preamplifier having an input coupled to the charge detection cylinder and an output coupled to the processor, the charge preamplifier configured to generate a charge detection signal in response to charge induced thereon by ions passing through the charge detection cylinder; no feedback component is electrically connected between the input and output of the charge preamplifier; A CDMS, wherein the target number of free charges deposited on the charge detection cylinder is selected such that, when detected by the charge preamplifier, resets the charge detection cylinder and the charge preamplifier to their respective repeatable operating states by eliminating the amount of charge noise accumulated on the charge detection cylinder due to charge induced due to the passage of trapped charges.

14. 14. The CDMS of claim 13, further comprising a memory, wherein the processor is configured to receive the charge detection signal from the charge preamplifier and to record the received charge detection signal in the memory for the duration of the ion measurement event.

15. 15. The CDMS of claim 14, wherein the processor is configured to process the recorded charge detection signals to determine ion charge values ​​and at least one of ion mass-to-charge ratios and ion masses.

16. 16. The CDMS of claim 12, wherein the processor is configured to repeat (i) through (iv) for a number of successive ion measurement events; A CDMS, wherein the processor is configured to control the charge generator to generate the target number of free charges to calibrate or reconfigure the charge detection cylinder during each of the number of successive ion measurement events.

17. 17. The CDMS of claim 1, wherein the charge generator comprises: A filament; a voltage or current source operably coupled to the filament; Equipped with A CDMS, wherein the processor is configured to control the voltage or current source to apply a selected voltage or current to the filament, the filament generating the target number of free charges in response to the selected voltage or current.

18. 17. The CDMS of claim 1, wherein the charge generator comprises: a conductive mesh or grid; a voltage or current source operably coupled to the mesh or grid; Equipped with A CDMS, wherein the processor is configured to control the voltage or current source to apply a selected voltage or current to the mesh or grid, the mesh or grid responding to the selected voltage or current to generate the target number of free charges.

19. 17. The CDMS of claim 1, wherein the charge generator comprises: A charged particle generator; and A sample source; wherein the processor is configured to control the charged particle generator to generate the target number of free charges from the sample source in the form of charged particles of the sample.

20. 4. The CDMS of claim 3, further comprising a charge generator voltage source; switching an electric field established on either or both of the first and second ion mirrors between the ion transmitting electric field and the ion reflecting electric field induces a corresponding transient charge on the charge detection cylinder; a charge generator voltage source configured to apply a voltage pulse to the charge generator when the electric field established in at least one of the first and second ion mirrors is switched from the ion transmitting electric field to the ion reflecting electric field or vice versa, the voltage pulse being selected to form a corresponding electric field in the region having at least one of a selected shape, amplitude, and duration and to induce a corresponding charge on the charge detection cylinder that is approximately equal and opposite to the corresponding transient charge induced on the charge detection cylinder by the switching of the electric field established in at least one of the first and second ion mirrors.

21. 1. An ion separation system comprising:

21. The CDMS of claim 2, wherein the ion source is configured to generate ions from a sample; and at least one ion separation device configured to separate the generated ions as a function of at least one molecular property; Equipped with An ion isolation system, wherein ions ejected from the at least one ion isolation device are provided to the ELIT.

22. 22. The system of claim 21 , wherein the ELIT is configured and controlled such that ions trapped inside the ELIT oscillate back and forth through the charge detection cylinder between the first and second ion mirrors with a duty cycle of about 50% that corresponds to a ratio of the time spent by an ion moving through the charge detection cylinder to the total time spent by an ion traversing the combination of the first and second ion mirrors and the charge detection cylinder during one complete oscillation cycle.

23. 23. The system of claim 21 or 22, wherein the ELIT is operably coupled to the ion source and the processor, the ELIT including an ELIT array having two or more ELIT regions, and the processor is configured to control the ELIT array to trap a single ion in each of the two or more ELIT regions.

24. 23. The system of claim 21 or 22, wherein the ELIT comprises an ELIT array operatively coupled to the processor, the ELIT array having two or more ELITs; The system, wherein the processor is configured to control the ELIT array to trap a single ion in each of the two or more ELITs.

25. 25. The system of claim 21, wherein the at least one ion separation device comprises one or any combination of at least one device that separates ions as a function of mass to charge ratio, at least one device that separates ions in time as a function of ion mobility, at least one device that separates ions as a function of ion retention time, and at least one device that separates ions as a function of molecular size.

26. 26. The system of claim 25, wherein the at least one ion separation instrument comprises one or a combination of a mass spectrometer and an ion mobility spectrometer.

27. 27. The system of claim 21, further comprising at least one ion processing device positioned between the ion source and the at least one ion separation device, the at least one ion processing device positioned between the ion source and the at least one ion separation device comprising one or any combination of at least one device for collecting or storing ions, at least one device for filtering ions according to molecular properties, at least one device for dissociating ions, and at least one device for normalizing or transferring ion charge states.

28. 28. The system of claim 21, further comprising at least one ion processing device positioned between the at least one ion separation device and the ELIT, the at least one ion processing device positioned between the at least one ion separation device and the ELIT including one or any combination of at least one device for collecting or storing ions, at least one device for filtering ions according to molecular properties, at least one device for dissociating ions, and at least one device for normalizing or transferring ion charge states.

29. 29. The system of claim 21, wherein the ELIT is configured to allow ions to exit therefrom; The system further comprises at least one ion separation device positioned to receive ions exiting the ELIT and separate the received ions as a function of at least one molecular property.

30. 30. The system of claim 29, further comprising at least one ion processing device positioned between the ELIT and the at least one ion separation device, the at least one ion processing device positioned between the ELIT and the at least one ion separation device including one or any combination of at least one device for collecting or storing ions, at least one device for filtering ions according to molecular properties, at least one device for dissociating ions, and at least one device for normalizing or transferring ion charge states.

31. 30. The system of claim 29, further comprising at least one ion processing device positioned to receive ions exiting the at least one ion separation device, the at least one ion separation device positioned to receive ions exiting the ELIT, the at least one ion processing device positioned to receive ions exiting the at least one ion separation device positioned to receive ions exiting the ELIT comprising one or any combination of at least one device for collecting or storing ions, at least one device for filtering ions according to molecular properties, at least one device for dissociating ions, and at least one device for normalizing or transferring ion charge states.

32. 30. The system of claim 21, wherein the ELIT is configured to allow ions to exit therefrom; The system further comprises at least one ion processing device positioned to receive ions ejected from the ELIT, the at least one ion processing device positioned to receive ions ejected from the ELIT including one or any combination of at least one device for collecting or storing ions, at least one device for filtering ions according to molecular properties, at least one device for dissociating ions, and at least one device for normalizing or transferring ion charge states.

33. 1. An ion separation system comprising: an ion source configured to generate ions from the sample; a first mass spectrometer configured to separate the generated ions as a function of mass to charge ratio; an ion dissociation stage positioned to receive ions exiting the first mass spectrometer and configured to dissociate ions exiting the first mass spectrometer; a second mass spectrometer configured to separate dissociated ions exiting the ion dissociation stage as a function of mass to charge ratio; 2. The CDMS of claim 1 , wherein the CDMS is coupled in parallel with the ion dissociation stage such that the CDMS can receive ions exiting either the first mass spectrometer or the ion dissociation stage; Equipped with 1. An ion separation system, comprising: a mass of a precursor ion exiting the first mass spectrometer is measured using a CDMS; a mass-to-charge ratio of dissociated ions of the precursor ion having a mass value less than a threshold mass is measured using the second mass spectrometer; and a mass-to-charge ratio and charge value of dissociated ions of the precursor ion having a mass value equal to or greater than the threshold mass are measured using the CDMS.

34. 1. A method of resetting or calibrating a charge detector of a charge detection mass spectrometer (CDMS), the charge detector comprising an electrostatic linear ion trap (ELIT) having a charge detection cylinder disposed between first and second ion mirrors, the method comprising: controlling, by a processor, a charge generator; (i) generating a target number of free charges, accelerating said generated target number of free charges through a field free region defined between said charge generator and said charge detection cylinder, contacting said charge detection cylinder and depositing said target number of free charges thereon, thereby calibrating or resetting said charge detection cylinder to a corresponding target charge level; or (ii) generating at least one electric field in the field-free region to induce a target charge on the charge detection cylinder for calibrating the charge detection cylinder; A method comprising:

35. 35. The method of claim 34, wherein accelerating the generated target number of free charges through the field free region includes controlling, by the processor, a voltage source coupled to the charge generator to selectively generate a potential to establish a charge acceleration field outside of the charge free region, the charge acceleration field being oriented to accelerate the generated target number of free charges into the field free region and toward the charge detection cylinder.

36. 36. The method of claim 34 or 35, wherein the ELIT is configured to trap ions therein and oscillate the ions back and forth between the first and second ion mirrors each time the ions pass through the charge detection cylinder and induce a corresponding charge thereon; wherein controlling the charge generator to generate the target number of free charges comprises calibrating or resetting the charge detection cylinder between each pass of the ions by controlling the charge generator to generate the target number of free charges following each pass of the ions through the charge detection cylinder when the ions are within each of the first and second ion mirrors.

37. 36. The method of claim 35, wherein the charge detector comprises a charge preamplifier having an input coupled to the charge detection cylinder and an output coupled to the processor, the charge preamplifier configured to generate a charge detection signal in response to charge induced thereon by ions passing through the charge detection cylinder; The method, wherein controlling the charge generator to generate the target number of free charges comprises controlling the charge generator to generate the target number of free charges upon detection of an absence of the charge detection signal at the output of the charge preamplifier.

38. 37. The method of claim 36, wherein no feedback components are electrically connected between the input and output of the charge preamplifier; The method further includes the step of selecting a target number of free charges deposited on the charge detection cylinder such that, when detected by the charge preamplifier, resets the charge detection cylinder and the charge preamplifier to their respective repeatable operating states by eliminating an amount of charge noise accumulated on the charge detection cylinder due to charge induced due to the passage of trapped charge.

39. 39. The method of claim 35, wherein the trapped ions are oscillated back and forth between the first and second ion mirrors for an ion measurement event period defined by a predetermined time period or a predetermined number of oscillations, and the ions are ejected from the ELIT after the ion measurement event; The method, wherein controlling the charge generator to generate the target number of free charges comprises controlling the charge generator to generate the target number of free charges after ejection of the ions from the ELIT.

40. 40. The method of claim 39, wherein the ELIT is controlled to continuously trap ions therein over an ion measurement event period and to allow the ions to exit the ELIT multiple times; The method of claim 1, wherein controlling the charge generator to generate the target number of free charges comprises controlling the charge generator to generate the target number of free charges after each ion exits the ELIT.

41. 36. The method of claim 34 or 35, wherein the ELIT is configured to: (i) trap the ion therein such that the ion oscillates back and forth between the first and second ion mirrors each time the ion passes through the charge detection cylinder and induces a corresponding charge thereon; (ii) oscillate the trapped ion back and forth between the first and second ion mirrors for an ion measurement event period defined by a predetermined period of time or a predetermined number of oscillations; and (iii) allow the trapped ion to exit the ELIT after the ion measurement event period has ended; The method, wherein controlling the charge generator to generate the target number of free charges comprises controlling the charge generator to generate the target number of free charges after ejection of the ions from the ELIT.

42. 42. The method of claim 41, wherein the ELIT is controlled to repeat (i) through (iii) for a plurality of consecutive ion measurement events; The method of claim 1, wherein controlling the charge generator to generate the target number of free charges comprises controlling the charge generator to generate the target number of free charges after each ejection of each ion from the ELIT.

43. 43. The method of any one of claims 39 to 42, wherein the charge detector comprises a charge preamplifier having an input coupled to the charge detection cylinder and an output coupled to the processor, the charge preamplifier configured to generate a charge detection signal in response to charge induced thereon by ions passing through the charge detection cylinder; no feedback component is electrically connected between the input and output of the charge preamplifier; The method further includes the step of selecting the target number of free charges such that, when detected by the charge preamplifier, the target number of charges deposited on the charge detection cylinder resets the charge detection cylinder and the charge preamplifier to repeatable respective operating states by eliminating an amount of charge noise accumulated on the charge detection cylinder due to charge induced due to the passage of trapped charges.

44. 44. The method of claim 39 or 43, further comprising: recording, by the processor, the charge detection signal in a memory for the duration of the ion measurement event; processing, by the processor, the recorded charge detection signals to determine ion charge values ​​and at least one of ion mass-to-charge ratios and ion masses; A method comprising:

45. 35. The method of claim 34, wherein at least one ion mirror voltage source is operatively coupled to the first and second ion mirrors and configured to generate voltages to selectively establish an ion transmission field or an ion reflection field therein, the ion transmission field configured to focus ions passing through each of the first and second ion mirrors toward a longitudinal axis passing through a center of each of the first and second ion mirrors and the charge detection cylinder, and the ion reflection field is also configured to stop ions entering each of the first and second ion mirrors from the charge detection cylinder and focus the ions toward the longitudinal axis while accelerating the ions back through the charge detection cylinder toward the other of the first and second ion mirrors, the at least one ion mirror voltage source is configured to selectively vary the voltage generated by the at least one ion mirror voltage source to thereby switch the electric field established in either or both of the first and second ion mirrors between the ion transmitting electric field and the ion reflecting electric field; switching the electric field established in either or both of the first and second ion mirrors between the ion transmitting electric field and the ion reflecting electric field induces a corresponding transient charge on the charge detection cylinder; the step of controlling the charge generator also includes controlling a charge generator voltage source to apply a voltage pulse to the charge generator when switching the electric field established on at least one of the first and second ion mirrors from the ion transmitting electric field to the ion reflecting electric field or vice versa to generate the at least one electric field in the field free region, the voltage pulse being selected to form a corresponding electric field in the field free region having at least one of a selected shape, amplitude, and duration and to induce a corresponding charge on the charge detection cylinder that is approximately equal and opposite to the corresponding transient charge induced on the charge detection cylinder by switching the electric field established on at least one of the first and second ion mirrors.

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