Apparatus and method for calibrating or resetting a charge detector

Abstract

The CDMS may include: an ELIST 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 generate a charge detection signal (CHD) in response to charge induced on the CD; and a processor configured to (a) control the charge generator to induce an HFC on the CD, (b) control operation of the ELIST to cause trapped ions to oscillate back and forth through the CD each time the charge is induced on the CD, and (c) process the CHD to (i) determine a gain coefficient from the HFC induced on the CD, and (ii) modify the size of the portion of CHD generated by the charge induced thereon as the trapped ions pass through the CD as a function of the gain coefficient.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 680,272, filed on June 4, 2018, and is a continuation-in-part of International Patent Application No. PCT / US2019 / 013284, filed on January 11, 2019, the disclosures of both of which are incorporated herein by reference in their entirety. Technical Field

[0002] The present disclosure relates generally to charge detection instruments, and more particularly to apparatus and methods for calibrating such instruments. Background Art

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

[0004] The high uncertainty in m / z and charge measurements with early CDMS detectors has led to the development of electrostatic linear ion trap (ELIT) detectors, in which ions are oscillated back and forth through a charge detection cylinder. Multiple passes of ions through such a charge detection cylinder provide multiple measurements for each ion, and results have shown that the uncertainty in charge measurements is in the order of n. 1 / 2 , where n is the number of charge measurements. However, extraneous and / or other charges picked up on the charge detector may present challenges in distinguishing valid and detectable charge from charge detector noise, and this effect may become even more pronounced as the charge signal level approaches the noise floor of the charge detector. It is therefore desirable to seek improvements in ELIT design and / or operation that extend the range of valid, detectable charge measurements beyond what is achievable using current ELIT designs. Summary of the invention

[0005] The present disclosure may include one or more of the features recited in the accompanying claims and / or one or more of the following features and combinations thereof. In a first aspect, a charge detection mass spectrometer (CDMS) including gain drift compensation may include: an electrostatic linear ion trap (ELIT) having a charge detection cylinder disposed between a first ion mirror and a second ion mirror; an ion source configured to supply ions to the ELIT; a charge generator for generating high frequency charges; 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 generated on the charge detection cylinder; and a processor configured to: (a) control the charge generator to (a) controlling the operation of a first ion mirror and a second ion mirror to capture ions from an ion source therein and thereafter causing the trapped ions to oscillate back and forth between the first ion mirror and the second ion mirror each time the trapped ions pass through the charge detection cylinder and induce corresponding charges thereon, and (c) processing a charge detection signal generated by a charge sensitive preamplifier to (i) determine a gain factor based on the high frequency charges induced on the charge detection cylinder by a charge generator, and (ii) modify the size of a portion of the charge detection signal caused by the charges induced thereon by the trapped ions passing through the charge detection cylinder based on the gain factor.

[0006] In a second aspect, a system for separating ions may include: a CDMS according to any one of claims 1 to 11, wherein the ion source is configured to generate ions from a sample; and at least one ion separation instrument, which is configured to separate the generated ions according to at least one molecular characteristic, wherein the ions leaving the at least one ion separation instrument are supplied to the ELIT.

[0007] In a third aspect, a system for separating ions may include: an ion source configured to generate ions from a sample; a first mass spectrometer configured to separate the generated ions according to a mass-to-charge ratio; an ion dissociation stage positioned to receive ions leaving the first mass spectrometer and configured to dissociate ions leaving the first mass spectrometer; a second mass spectrometer configured to separate the dissociated ions leaving the ion dissociation stage according to a mass-to-charge ratio; and a CDMS according to any one of claims 1 to 11, coupled in parallel with and to the ion dissociation stage so that the CDMS can receive ions leaving either the first mass spectrometer and the ion dissociation stage, wherein the mass of precursor ions leaving the first mass spectrometer is measured using the CDMS, the mass-to-charge ratio of the dissociated ions of the precursor ions having a mass value below a threshold mass is measured using the second mass spectrometer, and the mass-to-charge ratio and charge value of the dissociated ions of the precursor ions having a mass value equal to or above the threshold mass are measured using the CDMS. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 is a simplified diagram of an ion mass detection system including an embodiment of an electrostatic linear ion trap (ELIT) having control and measurement components coupled thereto and including apparatus for calibrating or resetting its charge detector.

[0009] Figure 2A yes Figure 1 An enlarged view of the ion mirror M1 of the ELIT is shown, wherein the mirror electrodes of M1 are controlled to generate an ion transport electric field therein.

[0010] Figure 2B yes Figure 1 An enlarged view of the ion mirror M2 of the ELIT is shown, wherein the mirror electrodes of M2 are controlled to generate an ion reflecting electric field therein.

[0011] Figure 3A is a graph of charge detection cylinder charge versus time illustrating two different charge detection thresholds compared to a noisy charge reference on the charge detection cylinder.

[0012] Figure 3B is a graph of the charge detection cylinder charge versus time, and Figure 3A In contrast, it illustrates the lower charge detection threshold compared to a calibrated charge reference on the charge detection cylinder.

[0013] FIG. 4A to FIG. 4E yes Figure 1 Simplified diagram of the ELIT showing the sequential control and operation of the ion mirrors and charge generators for calibrating or resetting the charge detector between ion measurement events.

[0014] FIG. 5A to FIG. 5F yes Figure 1 A simplified diagram of the ELIT showing the control and operation of the charge generator for calibrating or resetting the charge detector between charge detection events, the sequential control and operation.

[0015] Fig. 6A is a simplified block diagram of an embodiment of an ion separation instrument including the ELIT shown and described herein, and illustrating an example ion processing instrument which may form part of an ion source upstream of the ELIT and / or may be disposed downstream of the ELIT to further process ion(s) leaving the ELIT.

[0016] Figure 6B is a simplified block diagram of another embodiment of an ion separation instrument, including an ELIT shown and described herein, and illustrates an example implementation that combines a conventional ion processing instrument with any embodiment of an ion mass detection system shown and described herein.

[0017] Figure 7 is a simplified flow chart of an embodiment of a process for controlling Figure 1 The charge generator selectively induces high frequency charge on the charge detection cylinder during normal operation of the ELIT in which the mass and charge of the charged particles are thereby measured, to process the detected high frequency charge, and to use the information thereby provided to compensate for any drift in the gain of the charge preamplifier over time.

[0018] Figure 8 is a graph of charge detection signal versus frequency depicting an example of a charge detection signal including a charge peak corresponding to detection of charge induced thereon by a charged particle passing through a charge detection cylinder of the ELIT and a charge peak corresponding to detection of charge induced thereon by a charge generator according to Figure 7 The process shown simultaneously induces the detection of the high frequency charge corresponding to the additional charge peak on the charge detection cylinder.

[0019] Fig. 9 It is a graph of the peak magnitude of the fundamental frequency of the high frequency charge induced by the charge generator on the charge detection cylinder over time.

[0020] Fig.10 yes Fig. 9 A graph showing the moving average of an N-sample data set of the peak magnitude signal versus time. DETAILED DESCRIPTION

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

[0022] The present disclosure relates to an electrostatic linear ion trap (ELIT) including an apparatus for calibrating or resetting its charge detector and to means and methods for controlling both. In one embodiment, an example of this embodiment will be described below with reference to FIG. 3A to FIG. 4E In further detail, the calibration device is controlled in such a way that the charge detector of the ELIT is calibrated or reset to a predefined reference charge level between ion measurement events. In another embodiment, an example of this embodiment will be described below with reference to FIG. 5A to FIG. 5F In detail, the calibration device is controlled in such a way that the charge detector of the ELIT is calibrated or reset to a predetermined reference charge level between charge detection events. For the purposes of this disclosure, the phrase "charge detection event" is defined as the detection of the charge associated with a single pass of an ion through a charge detector of the ELIT, and the phrase "ion measurement event" is defined as a collection of charge detection events caused by the oscillation of ions passing back and forth through the charge detector a selected number of times or within a selected time period.

[0023] Reference Figure 1 , shows a charge detection mass spectrometer (CDMS) 10 that includes an embodiment of an electrostatic linear ion trap (ELIT) 14 having control and measurement components coupled thereto and includes a device for calibrating or resetting the charge detector of the ELIT 14. In the embodiment shown, the CDMS 10 includes an ion source 12 operably coupled to an inlet of the ELIT 14. As will be further referenced Fig. 6A Described, ion source 12 illustratively comprises any conventional device or equipment for generating ions from sample, and can further comprise one or more devices and / or instruments for separating, collecting, filtering, fragmenting and / or standardizing ions according to one or more molecular characteristics.As an illustrative example (it should not be considered to have restriction in any aspect), ion source 12 can comprise conventional electrospray ionization source, matrix-assisted laser desorption ionization (MALDI) source etc. coupled to the entrance of conventional mass spectrometer.Mass spectrometer can have any conventional design, for example, including but not limited to time-of-flight (TOF) mass spectrometer, reflectometer, Fourier transform ion cyclotron resonance (FTICR) mass spectrometer, quadrupole mass spectrometer, triple quadrupole mass spectrometer, magnetic sector mass spectrometer etc.In any case, the ion outlet of mass spectrometer is operably coupled to the ion inlet of ELIT14.The sample from which ions are generated can be any biological or other materials.

[0024] In the illustrated embodiment, the ELIT 14 illustratively includes a charge detector CD, which is surrounded by a grounded chamber or cylinder GC and is operably coupled to relative ion mirrors M1, M2, respectively, positioned at opposite ends thereof. 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 corresponding ion mirror region R1, R2 therein. The regions R1, R2 of the ion mirrors M1, M2, the electron detector CD and the charge detector CD together with the space between the ion mirrors M1, M2 define a longitudinal axis 22 through the center thereof, which illustratively represents an ideal ion travel path through the ELIT 14 and between the ion mirrors M1, M2, as described in more detail below.

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

[0026] Illustratively, voltage sources V1 and V2 are electrically connected to a conventional processor by a signal path of number P, and the conventional processor 16 includes a memory 18 having instructions stored therein, which, when executed by the processor 16, causes the processor 16 to control the voltage sources V1 and V2 to generate a desired DC output voltage so as to selectively establish ion transmission and ion reflection electric fields TEF and REF in the regions R1 and R2 of the corresponding ion mirrors M1 and M2, respectively. P can be any positive integer. In some alternative embodiments, either or both of the voltage sources V1 and V2 can be programmable to selectively generate one or more constant output voltages. In other alternative embodiments, either or both of the voltage sources V1 and V2 can be configured to generate one or more time-varying output voltages of any desired shape. It will be understood that in alternative embodiments, more or fewer voltage sources can be electrically connected to the ion mirrors M1 and M2.

[0027] The charge detector CD is illustratively provided in the form of a conductive cylinder electrically connected to the signal input of a charge sensitive preamplifier (or charge sensitive amplifier) ​​CP, and the signal output of the charge preamplifier CP is electrically connected to the processor 16. The charge preamplifier CP is illustratively operable in a conventional manner to receive a charge signal (CH) corresponding to the charge induced on the ion by the charge detection cylinder CD, thereby generating a charge detection signal (CHD) corresponding thereto and supplying the charge detection signal CHD to the processor 16. In some embodiments, the charge preamplifier CP may include a conventional feedback component coupled between the output and at least one of its inputs, such as one or more resistors and / or other conventional feedback circuits. In some alternative embodiments, the charge preamplifier CP may not include any resistive feedback component, and in other alternative embodiments, the charge preamplifier CP may not include any feedback component at all. In any case, the processor 16 is further 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 the memory 18. Processor 16 may further illustratively be coupled to one or more peripheral devices 20 (PD) for providing signal input(s) to processor 16 and / or for processor 16 to provide signal output(s) to the peripheral devices. In some embodiments, peripheral device 20 includes at least one of a conventional display monitor, printer, and / or other output device, and in such embodiments, memory 18 has instructions stored therein that, when executed by processor 16, cause processor 16 to control one or more such output peripheral devices 20 to display and / or record analysis of the stored, digitized charge detection signals.

[0028] The voltage sources V1, V2 are illustratively controlled in a manner described in detail below, which selectively captures ions entering the ELIT 14 and causes the captured ions to oscillate back and forth between the ion mirrors M1, M2 so that they repeatedly pass through the charge detection cylinder CD. A plurality of charge and oscillation period values ​​are measured at the charge detection cylinder CD, and the recorded results are processed to determine the mass-to-charge ratio, charge and mass values ​​of the ions captured in the ELIT 14.

[0029] Now refer to Figure 2A and Figure 2B , respectively showing Figure 1An embodiment of the ion mirrors M1, M2 of the ELIT 14 depicted in . Illustratively, the ion mirrors M1, M2 are identical to one another in that each comprises a cascade arrangement of four spaced-apart, electrically conductive mirror electrodes. For each of the ion mirrors M1, M2, a first mirror electrode 301 has a thickness W1 and defines a passage through its center having a diameter P1. An end cap 32 is fixed or otherwise coupled to an outer surface of the first mirror electrode 301 and defines a hole A1 through its center, which hole A1 serves as an ion inlet to and / or an ion outlet from the corresponding ion mirrors M1, M2, respectively. In the case of the ion mirror M1, the end cap 32 is coupled to Figure 1 1 and 2. The ion outlet of the ion source 12 shown in FIG.

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

[0031] The fourth mirror electrode 304 is separated from the third mirror electrode 303 by a space of width W2. The fourth mirror electrode 304 illustratively has a thickness of W1 and is formed by the respective ends of the ground cylinder GC arranged around the charge detector CD. The fourth mirror electrode 304 defines an aperture A2 through its center, which aperture A2 is illustratively conical in shape and increases linearly between the inner and outer faces of the ground cylinder GC from a diameter P3 defined at the inner face of the ground cylinder GC to a diameter P1 defined at the outer face of the ground cylinder GC (which is also the inner face of the respective ion mirrors M1, M2).

[0032] The space defined between the mirror electrodes 301 to 304 may be a void, i.e., a vacuum gap, in some embodiments, and in other embodiments, such a space may be filled with one or more non-conductive materials (e.g., dielectric materials). The mirror electrodes 301 to 304 and the end cap 32 are axially aligned, i.e., co-linear, such that the longitudinal axis 22 passes through the center of each aligned passage and also through the center of the holes A1, A2. In embodiments where the space between the mirror electrodes 301 to 304 includes one or more non-conductive materials, such materials will also define corresponding passages therethrough that are axially aligned, i.e., co-linear, with passages defined by the mirror electrodes 301 to 304 and illustratively having a diameter of P2 or greater. Illustratively, P1>P3>P2, although in other embodiments, other corresponding diameter arrangements are possible.

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

[0034] As described above, the charge detector CD is illustratively provided in the form of an elongated conductive cylinder, which is positioned between corresponding ion mirrors in the ion mirrors M1, M2 and is separated from the corresponding ion mirror by a space of width W3. In one embodiment, W1>W3>W2, and P1>P3>P2, although in alternative embodiments, other relative width arrangements are also possible. In any case, the longitudinal axis 22 illustratively extends through the center of the passage defined by the charge detection cylinder CD, so that the longitudinal axis 22 extends through the center of the combination of the passage defined by the regions R1, R2 of the ion mirrors M1, M2 and the passage defined by the charge detection cylinder CD. In operation, the ground cylinder GC is illustratively controlled to ground potential so that the fourth mirror electrode 304 of each ion mirror M1, M2 is always at ground potential. In some alternative embodiments, the fourth mirror electrode 304 of either or both of the ion mirrors M1, M2 can be set to any desired DC reference potential or a switchable DC or other time-varying voltage source.

[0035] exist Figure 2A and Figure 2B In the embodiment shown in , the voltage sources V1, V2 are each configured to generate four DC voltages D1 to D4 respectively, and supply the voltages D1 to D4 to corresponding mirror electrodes in the mirror electrodes 301 to 304 of the corresponding ion mirrors M1, M2. In some embodiments in which one or more of the mirror electrodes 301 to 304 are always maintained at a ground potential, the one or more such mirror electrodes 301 to 304 may alternatively be electrically connected to the ground reference of the corresponding voltage sources V1, V2, and the corresponding one or more voltage outputs D1 to D4 may be omitted. Alternatively or additionally, in embodiments in which any two or more of the mirror electrodes 301 to 304 may be controlled to the same non-zero DC value, any such two or more mirror electrodes 301 to 304 may be electrically connected to a single voltage output in the voltage outputs D1 to D4, and redundant output voltages in the output voltages D1 to D4 may be omitted.

[0036] By selective application of voltages D1 to D4, in ion transmission mode ( Figure 2A ) and ion reflectron mode ( Figure 2B), each ion mirror M1, M2 is illustratively controllable and switchable, in ion transmission mode, the voltages D1 to D4 generated by the corresponding voltage sources V1, V2 establish an ion transmission electric field (TEF) in its corresponding region R1, R2, and in ion reflection mode, the voltages D1 to D4 generated by the corresponding voltage sources V1, V2 establish an ion reflection electric field (REF) in its corresponding region R1, R2. Figure 2A As shown in the example in, once the ions from the ion source 12 fly into the region R1 of the ion mirror M1 through the entrance aperture A1 of the ion mirror M1, the ions are concentrated through the longitudinal axis 22 toward the ELIT 14 by the ion transmission electric field TEF established in the region R1 of the ion mirror M1 by selectively controlling the voltages D1 to D4 of V1. Due to the concentrating effect of the transmission electric field TEF in the region R1 of the ion mirror M1, the ions leaving the region R1 of the ion mirror M1 through the aperture A2 of the ground chamber GC obtain a narrow trajectory 36 to enter into and pass through the charge detector CD, i.e., so as to keep the ions traveling through the path of the charge detector CD close to the longitudinal axis 22. The same ion transmission electric field TEF can be selectively established in the region R2 of the ion mirror M2 via the same control of the voltages D1 to D4 of the voltage source V2. In ion transmission mode, ions entering region R2 from charge detection cylinder CD via aperture A2 of M2 are focused toward longitudinal axis 22 by the ion transmission electric field TEF within region R2, causing the ions to exit ion mirror M2 through aperture A1 thereof.

[0037] like Figure 2BAs shown in the example in, the ion reflection electric field REF established in the region R2 of the ion mirror M2 by selectively controlling the voltages D1 to D4 of V2 is used to decelerate and stop the ions entering the ion region R2 from the charge detection cylinder CD through the ion entrance aperture A2 of M2, so that the ions are accelerated in the opposite reverse direction back through the aperture A2 of M2 and enter the end of the charge detection cylinder CD adjacent to M2 as depicted by the ion trajectory 42, and the ions are concentrated toward the central longitudinal axis 22 within the region R2 of the ion mirror M2, so as to maintain a narrow trajectory for the ions to return through the charge detector CD toward the ion mirror M1. The same ion reflection electric field REF can be selectively established in the region R1 of the ion mirror M1 by the same control of the voltages D1 to D4 of the voltage source V1. In ion reflection mode, ions entering region R1 from the charge detection cylinder CD via aperture A2 of M1 are slowed down and stopped by the ion reflection electric field REF established within region R1, and then accelerated in the opposite direction back through aperture A2 of M1 and into the end of the charge detection cylinder CD adjacent to M1, and focused toward the central longitudinal axis 22 within region R1 of ion mirror M1 so as to maintain a narrow trajectory of the ions backward through the charge detector CD and toward ion mirror M2. As described, ions that travel the length of ELIT 14 and are reflected by the ion reflection electric field REF in ion regions R1, R2 in a manner that enables the ions to continue traveling back and forth between ion mirrors M1, M2 through the charge detection cylinder CD are considered to be trapped within ELIT 14.

[0038] An example set of output voltages D1 to D4, generated by voltage sources V1, V2, respectively, for controlling the corresponding ion mirrors in ion mirrors M1, M2 to the ion transmission mode and ion reflection mode described above, are shown in Table I below. It will be understood that the following values ​​of D1 to D4 are provided by way of example only, and other values ​​of one or more of D1 to D4 may be used instead.

[0039] Table I

[0040] Although in Figures 1 to 2B Ion mirrors M1, M2 and charge detection cylinder CD are shown as defining a cylindrical passage therethrough, but it will be understood that in alternative embodiments, either or both of ion mirrors M1, M2 and / or charge detection cylinder CD may define a non-cylindrical passage therethrough such that one or more of the (multiple) passages through whose centers the longitudinal axis 22 passes represents a non-circular cross-sectional area and profile. In still other embodiments, regardless of the shape of the cross-sectional profile, the cross-sectional area of ​​the passage defined by ion mirror M1 may be different from the passage defined by ion mirror M2.

[0041] The voltage sources V1 and V2 are illustratively controlled in the following manner: this manner selectively establishes an ion transmission electric field and an ion reflection electric field in the region R1 of the ion mirror M1 and in the region R2 of the ion mirror M2 in a manner that allows ions to enter the ELIT 14 from the ion source 12 and causes the ions to be selectively captured in the ELIT 14, so that the captured ions repeatedly pass through the charge detector CD while oscillating in the ELIT 14 between the ion mirrors M1 and M2. Each time the ion passes through the charge detector CD, the charge induced thereon is detected by the charge preamplifier CP, and a corresponding charge detection signal (CHD) is generated by the charge preamplifier CP. For a charge detection event, the timing size and timing of the charge detection signal (CHD) generated by the charge preamplifier CP are recorded by the processor 16, as the term is defined herein. Each charge detection event record illustratively includes an ion charge value corresponding to the size of the detected charge and an oscillation period value corresponding to the time elapsed between charge detection events, and each charge detection event record is stored in the memory 18 by the processor 16. The collection of charge detection events resulting from the ion oscillating back and forth through the charge detector CD a selected number of times or for a selected time period (i.e., constituting an ion measurement event, as that term is defined herein) is then processed to determine the ion's charge, mass-to-charge ratio, and mass value.

[0042] In one embodiment, the ion measurement event data is processed by calculating the Fourier transform of the recorded charge detection event set using the processor 16. The processor 16 is illustratively operable to calculate such a Fourier transform using any conventional digital Fourier transform (DFT) technique (such as, for example, but not limited to, a conventional fast Fourier transform (FFT) algorithm). In any case, the processor 16 is then illustratively operable to calculate an ion mass-to-charge ratio value (m / z), an ion charge value (z), and an ion mass value (m), each of which is based on the calculated Fourier transform. The processor 16 is illustratively operable to store the calculation results in the memory 18 and / or control one or more of the peripheral devices 20 to display the results for viewing and / or further analysis.

[0043] It is generally understood that the mass-to-charge ratio (m / z) of an ion oscillating back and forth between its opposing ion mirrors M1, M2 by the charge detector CD of the ELIT is inversely proportional to the square of the fundamental frequency ff of the oscillating ion, according to the equation: m / z = C / ff 2, where C is a constant that is a function of the ion energy and also of the size of the corresponding ELIT, and the fundamental frequency ff is determined directly from the calculated Fourier transform. Taking into account the number of ion oscillation cycles, the value of the ion charge z is proportional to the magnitude of the fundamental frequency ff, FTMAG. In some cases, in order to determine the ion charge z, the magnitude of one or more of the harmonic frequencies of the FFT can be added to the magnitude of the fundamental frequency. In any case, the ion mass m is then calculated as the product of m / z and z. The processor 16 is therefore operable to calculate m / z=C / ff 2 , z=F(FTMAG) and m=(m / z)(z). Multiple (e.g., hundreds or thousands or more) ion capture events are typically performed for any particular sample from which ions are generated by the ion source 12, and ion mass-to-charge values, ion charge values, and ion mass values ​​are determined / calculated for each such ion capture event. The ion mass-to-charge values, ion charge values, and ion mass values ​​for such multiple ion capture events are then combined to form spectral information related to the sample. Such spectral information can illustratively take different forms, examples of which include, but are not limited to, ion counts relative to mass-to-charge ratios, ion charge relative to ion mass (e.g., in the form of an ion charge / mass scatter plot), ion counts relative to ion mass, ion counts relative to ion charge, and the like.

[0044] Refer again Figure 1 , the ELIT 14 shown further includes a charge generator CG, which is electrically connected to the processor 16 and electrically connected to a charge generator voltage source VCG. In the embodiment shown, the charge generator voltage source VCG is programmable or manually controllable to generate one or more DC voltages, voltage pulses and / or voltage waveforms of any size, shape, duration and / or frequency. In an alternative embodiment, the charge generator voltage source VCG can be operably coupled to the processor 16 so that the processor 16 can control the charge generator voltage source VCG to generate one or more DC voltages, voltage pulses and / or voltage waveforms of any size, shape, duration and / or frequency. In the embodiment shown, at least one charge outlet channel 24 of the charge generator CG illustratively extends through the ground chamber GC so that the charge outlet 26 of the charge outlet channel 24 is in fluid communication with the space 36 defined between the inner surface of the ground chamber GC and the outer surface of the charge detection cylinder CD. In the embodiment shown, a single charge outlet channel 24 extending through the ground chamber GC is shown, although in alternative embodiments, multiple charge outlet channels may extend through the ground chamber GC. In such an embodiment, two or more charge outlet channels may be spaced apart individually, or in groups of two or more, axially and / or radially along the charge detection cylinder CD.

[0045] In one embodiment, the charge generator CG is configured to generate free charges 28 in response to a control signal C generated by the processor 16, which pass through the charge outlet 26 of the one or more charge outlet channels 24 into the 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 embodiment shown, the charge 28 generated by the charge generator is a positive charge, although in alternative embodiments, the charge generator CG can be configured to generate a negative charge or selectively generate a positive or negative charge.

[0046] In one embodiment, the charge generator CG may be configured or controllable using conventional control circuitry and / or conventional control techniques to generate a predictable number of free charges 28 per unit time within any desired tolerance level and supply it to the space 36 within the ELIT 14 in response to activation of a control signal C generated by the control circuit 16. The time unit may have any desired duration. In such an embodiment, the total number of charges 28 supplied to the space 36 within the ELIT 14 by the charge generator CG in response to a single activation of the control signal C may thus be controlled according to the number of charges 28 generated by the charge generator CG per unit time and duration (i.e., 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 other embodiments, the charge detector CG may be configured such that the number of charges 28 thus generated in response to the control signal C is constant and predictable or programmable within any desired tolerance level, regardless of and independent of the duration of the control signal C. In such an embodiment, the amount of charge 28 supplied to the space 36 within the ELIT 14 by the charge generator CG in response to any single activation of the control signal C is therefore constant and predictable, and the total amount of charge 28 that can be supplied by the charge generator CG to the space 36 within the ELIT 14 can be controlled based on the total amount of charge 28 generated with each single activation of the control signal C and the total number of activations of the control signal C generated by the processor 16.

[0047] The charge generator CG can be provided in the form of any conventional charge generator. As an example, the charge generator CG can be or include a conventional filament that responds to a voltage or current applied thereto to generate and produce free charges 28. As another example, the charge generator CG can be or include a conductive mesh or grid that responds to a voltage or current applied thereto to generate or produce free charges 28. As yet another example, the charge generator CG can be or include a particle charge generator that is configured to generate free charges in the form of charged particles from a sample source. Examples of such particle charge generators can include, but are not limited to, an electrospray ionization (ESI) source, a matrix-assisted laser desorption ionization (MALDI) source, and the like. In any case, the charge generator CG is operable to generate charges and supply the charges to the space 36 within the ELIT 14 via (multiple) charge outlets extending into the space 36 and / or fluidically coupled to one or more charge outlet channels of the space 36.

[0048] In the absence of an induced charge on the charge detector CD by charged particles passing through the charge detector CD or by one or more free charges 28 generated by the charge generator GC, the charge detection cylinder CD is illustratively at a reference charge level CH REF Since the charge detection cylinder CD is not powered or grounded, the reference charge level CH REF Typically a few tens of charges (i.e., elementary charge "e") or less, although in some applications the reference charge level CH REF There may be more than a few dozen charges.

[0049] As described above, the charge generator CG is responsive to the control signal C generated by the processor 16 or other control signal generating system to generate charges 28 of the desired polarity, which then enter the space 36 between the inner surface of the ground chamber GC and the outer surface of the charge detection cylinder CD. Since the ground cylinder GC is generally maintained at ground potential and the charge detection cylinder CD is generally operated at or near ground potential, the space 36 is substantially a field-free region. In some embodiments, the one or more charge outlet channels 24 and / or the body of the charge generator CG illustratively include one or more regions in which an electric field of a suitable direction is established by the voltage source VCG (or by some other source(s)) in order to accelerate the generated charges 28 into the field-free region 36 so that the accelerated charges 28 then travel through the field-free region 36 toward the outer surface of the charge detection cylinder CD and contact it. When such charges 28 contact the outer surface of the charge detection cylinder CD, they transfer their respective corresponding charges to the charge detection cylinder CD. In this regard, the charge 28 is generated by the charge generator GC, and the generated charges travel through the field-free region 36 toward the outer surface of the charge detection cylinder and contact it to thereby transfer their charge to the charge detection cylinder, which defines a "charge injection" process, through which the generated charge 28 calibrates or resets the charge detection cylinder CD and / or the charge sensitive preamplifier CP in some embodiments thereof. This injected charge can illustratively be removed from the charge detection cylinder CD by applying an equal amount of opposite charge, and can therefore illustratively be used to calibrate and / or reset the charge detection cylinder in some applications and / or calibrate or reset the charge preamplifier in other applications.

[0050] The "charge injection" process just described is different from the "charge induction" process, in which 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 (such as ground potential). An illustrative technique for inducing 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 so that the voltage source VCG establishes a potential of the desired polarity on the at least one charge outlet channel 24. Establishing a DC potential on the at least one charge outlet channel 24 without generating charge 28 will generally establish an electric field between the at least one charge outlet channel 24 and the charge detection cylinder CD, thereby inducing a DC voltage and, in turn, inducing charge on the charge detection cylinder CD. The magnitude of the induced charge will generally depend on the strength of the established electric field, and therefore on the magnitude of the voltage applied to the at least one charge outlet channel 24 by the voltage source VCG. By applying a different voltage (e.g., ground potential or other potential) to the charge detection cylinder CD, such induced charge can be illustratively removed or modified, and can therefore be used to compensate for the switching voltage applied to the (multiple) ion mirrors M1 and / or M2, and in some embodiments thereof, for calibrating the charge preamplifier CP. In alternative embodiments of the charge generator CG described above (in these embodiments, the charge generator CG is operable to generate free charge), the charge generator CG can therefore be configured to operate as a charge sensing 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, which is applied to the (multiple) charge outlet channels 24 to generally create or establish one or more corresponding electric fields between the (multiple) charge outlet channels 24 (and in some embodiments, specifically the (multiple) charge outlets 26) and the charge detection cylinder CD, so as to thereby induce one or more corresponding charges on the charge detection cylinder. In such an embodiment, the (multiple) charge outlet channels 24 may not need to include one or more charge outlets 26 that are in fluid communication with the space 36. In some embodiments, for example, in those embodiments, the charge generator CG is strictly configured for charge induction, the charge outlet channel (s) 24 may be or include one or more conductive rods, probes, filaments, etc., which do not include any outlet 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 outlet channel (s) 24 will illustratively include one or more charge outlets 24 as described above for distributing or otherwise generating free charge 28.

[0051] Thus, in some embodiments, the charge generator CG is illustratively configured to operate strictly as a charge injection device, in which the charge generator CG is responsive to the control signal C to generate charges 28 of suitable polarity and to accelerate the generated charges 28 away from the at least one charge outlet 26 of the at least one charge outlet channel 24 and into the field-free region 36, such that the generated charges 28 travel through the field-free region 36 toward and contact the outer surface of the charge detection cylinder CD to exert their charge on the charge detection cylinder CD. In alternative embodiments, the charge generator CG may be illustratively configured to operate strictly as a charge induction device, in which the charge generator CG is responsive to the control signal C to apply at least one voltage of suitable magnitude and polarity to establish a corresponding electric field in the region 36 between the at least one charge outlet channel 24 and the charge detection cylinder CD to induce a DC voltage on the charge detection cylinder CD, and thus induce a charge on the charge detection cylinder CD. In other alternative embodiments, the charge generator CD may illustratively be configured to operate both as a charge injection device and as a charge induction device (e.g., simultaneously or separately) in which the charge generator CG is responsive to a control signal C generated by the processor 16 to generate charges 28 of suitable polarity, and / or to apply one or more voltages of suitable magnitude and polarity to establish an electric field within a region 36 between the at least one charge outlet channel 24 and the charge detection cylinder CD, thereby (i) inducing a DC voltage on the charge detection cylinder CD and thereby inducing charge on the charge detection cylinder CD, and (ii) under the influence of the electric field established within the region 36, also causing the generated charges 28 to accelerate toward and contact the outer surface of the charge detection cylinder CD to impart their charge on the charge detection cylinder CD. Thus, the charge generator CG may be configured and operated strictly as a charge injector, strictly as a charge induction device, or as a combination of a charge injector and a charge induction device.

[0052] In an embodiment where the charge generator CG is configured and operated as a charge injector to generate a controlled amount of charge 28 which then travels to or is delivered to and contacts the outer surface of the charge detection cylinder CD, such charge illustratively sets the target charge level CH T is applied to the charge detection cylinder CD. In one embodiment, the amount and polarity of the generated charge 28 can be selected to apply a charge greater than CH REF The target charge level CH T , for example to achieve a value higher than CH REF The constant charge level CH T and any noise induced thereon, and in other embodiments, the amount and polarity of the generated charge 28 may be selected to impose a voltage less than CH REFThe target charge level CH T , for example to achieve a target charge level CH at or near a zero charge level T In embodiments where the charge generator CG is configured and operable as a charge inductor to controllably establish an electric field that induces a DC voltage or potential on the charge detection cylinder CD, such DC voltage or potential illustratively induces a target charge level CH of suitable magnitude and polarity on the charge detection cylinder CD. T In embodiments where the charge generator CG is configured and operable as a combination of a charge injector and a charge sensor, the net charge induced and applied on the charge detection cylinder is a target charge CH of appropriate magnitude and polarity. T .

[0053] Reference charge level CH on the charge detection cylinder CD REF is subject to one or more potentially significant sources of charge noise which may introduce uncertainty into the charge detection event due to the uncertainty of the reference charge level at any point in time. Figure 3A , for example, shows a graph of charge CH on a charge detection cylinder CD versus time, wherein there is no charge detection event, but wherein a reference charge level CH is superimposed. REF 5. An example charge noise waveform 50 is shown in FIG. 5. In embodiments where the charge sensitive preamplifier CP does not include feedback components, one such source of such charge noise 50 is charge accumulation on the charge detection cylinder CD and, therefore, at the input of the charge sensitive preamplifier CP during normal operation thereof. In this and other embodiments, the capacitance of the charge detector CD also plays a role, as does parasitic noise caused by 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.

[0054] Such charge noise 50 from any source is undesirable because it may produce false charge detection events and / or may require setting the charge detection threshold higher than desired. As an example of the former case, Figure 3A The graph of further illustrates an example charge detection threshold CH implemented in the ion mass detection system 10. TH1 , to distinguish between a valid charge detection event and the reference charge level CH REF In the example shown, in CH REF The two peaks 52 and 54 of the charge noise 50 appearing at and near CH TH1, and will therefore be incorrectly or erroneously detected as a valid charge detection event, thereby corrupting the ion measurement event data for the ion(s) being evaluated. As an example of the latter case, Figure 3A A second example charge detection threshold CH is also illustrated in TH2 , this second example charge detection threshold is illustratively and safely positioned above the highest peak of the charge noise 50 in order to avoid false charge detection events of the type described above. However, the higher charge detection threshold CH TH2 In CH TH2 and CH REF This leaves an undesirably large range of undetectable charge values ​​in between, which would otherwise be detectable except for the high level of charge noise 50 .

[0055] exist Figure 1 In the illustrated embodiment of the ELIT 14, the charge generator CG is illustratively implemented and controlled to selectively generate a target amount of charge 28 that is delivered through the field-free region 36 to and in contact with the outer surface of the charge detection cylinder CD, such as at the charge generator CG or under the influence of one or more appropriately oriented electric fields within the charge generator CG as described above. The charge 28 deposited on the charge detection cylinder CD is illustratively combined 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 amount and polarity of the generated charge 28 may be selected to impose a target charge level CH on the charge detection cylinder. T , the target charge level is greater than the reference charge level CH REF and any charge noise present on the charge detection cylinder CD. In this example embodiment, the target charge level CH T Therefore, enveloping and overriding CH REF and any charge noise, leaving CH T Alternatively or additionally, the charge generator CG may be controlled to induce a suitable charge on the charge detection cylinder CD by applying one or more corresponding voltages to the charge generator CG by controlling the voltage source VCG.

[0056] In an alternative embodiment, the target amount and polarity of the generated charge 28 may be selected to neutralize the reference charge level CH REF and any charge noise present on the charge detection cylinder CD, so as to induce a charge on the charge detection cylinder CD that is less than CH REF The resulting target charge level CHT , for example to achieve the target charge level CH T or near zero charge level. This result may be achieved illustratively by controlling the charge generator CG to first inject positive charge and then negative charge, or alternatively by controlling the voltage source VCG to apply one or more corresponding voltages to the charge generator CG to induce a suitable charge on the charge detection cylinder CD. In some embodiments specifically targeting the amount of charge noise 50 at the input charge sensitive preamplifier CP (e.g., in embodiments where the charge sensitive preamplifier does not include any feedback components described above), the target charge level CH T It may be a charge magnitude and / or polarity which, when deposited or applied on the charge detection cylinder CD, is used to clear such charge noise 50 therefrom and hence from the input of the charge preamplifier to reset the charge sensitive preamplifier CP to a predictable operating condition.

[0057] In any case, the target amount of charge 28 generated by the charge generator CG and delivered to and in contact with the outer surface of the charge detection cylinder CD and / or the charge induced on the charge detection cylinder CD by operation of the charge generator CG operates to set the charge detection cylinder CD to a substantially predictable and repeatable target charge level CH T ,like Figure 3B The target charge level CH T A “new” reference charge level is established against which subsequent charge detection events are measured. T is essentially repeatable, so the charge detection threshold CH TH3 and CH T The charge difference between them can be greatly reduced. Figure 3B This is accomplished as shown, thereby increasing the range of detectable ionic charges compared to conventional ELIT.

[0058] Now refer to FIG. 4A to FIG. 4E , showing Figure 1 A simplified diagram of the ELIT 14 showing the sequential control and operation of the ion mirrors M1, M2 and the charge generator CG as described above for calibrating or resetting the charge detection cylinder CD between ion measurement events. Figure 4A, ELIT 14 has just ended an ion measurement event in which ions were trapped in ELIT 14, and wherein processor 16 is operable to control voltage sources V1, V2 so as to control ion mirrors M1, M2 to an ion reflection mode of operation (R), in which an ion reflection electric field is established in regions R1, R2 of each respective ion mirror M1, M2. The ions thus oscillate back and forth between M1 and M2, each time passing through a charge detection cylinder CD, whereby the charge induced thereby on the charge detection cylinder CD is detected by a charge preamplifier CP, and the ion detection event is recorded by processor 16. After the ions have oscillated back and forth between ion mirrors M1, M2 through ELIT 14 a selected number of times or for a selected time period, processor 16 is operable to control voltage source V2 so as to control ion mirror M2 to an ion transmission mode of operation (T) by establishing an ion transmission field in region R2 of ion mirror M2, while maintaining ion mirror M2 in the ion reflection mode of operation (R), as Figure 4A As a result, the trapped ions leave the ion mirror M2 through the aperture A2 of M2, as shown in Figure 4A The ion trajectory is shown in 60.

[0059] When ELIT 14 is already Figure 4A When operating in the state shown in FIG. 1 for a selected time period or a selected time period in which no charge detection event occurs, the processor 16 is operable to supply a control signal C to the charge generator CG so that the charge generator CG controllably generates a target amount of free charges 28 and supplies the free charges 28 to a space 36 defined between the ground cylinder GC and the charge detection cylinder CD, as shown in FIG. Figure 4B As shown. Under the charge injection operation of the charge generator CG, the generated free charges 28 travel toward and contact the outer surface of the charge detection cylinder CD through the field-free region 36 as described above. Under the charge induction operation, the electric field established by the charge generator voltage source VCG or other electric field generating structure induces charge on the charge detection cylinder CD. Since the ion mirror M1 has been in the reflection operation mode (R) and the ion mirror M2 has been in the transmission operation mode (T) for a period of time sufficient to clear the ELIT 14 of ions, when the free charges 28 are generated and travel to the charge detection cylinder CD during the charge injection operation, no ions are transported through the charge detection cylinder CD. Therefore, the target number of charges 28 generated by the charge generator CG, which contacts the outer surface of the charge detection cylinder CD and applies their charge thereto, operates to calibrate or reset the charge detection cylinder CD to a substantially constant, predictable and repeatable target charge level CH T , as described above. In charge sensing operation, the charge induced on the charge detection cylinder CD by the electric field established by the charge generator CG can also be used for calibration and / or resetting.

[0060] Now refer to Figure 4C , after the charge detection cylinder CD has been calibrated to the target charge level CH T Thereafter, the processor 16 is operable to control the voltage source V1 to control the ion mirror M1 to the ion transmission mode of operation (T) by establishing an ion transmission field within the region R1 of the ion mirror M1, while also maintaining the ion mirror M2 in the ion transmission mode of operation (T). As a result, ions generated by the ion source 12 and entering the ion mirror M1 pass through the ion mirror M1, through the charge detection cylinder CD, through the ion mirror M2 and leave the ion mirror M2 via the aperture A1 of the ion mirror M2, as described above and as Figure 4C ion trajectories 62 in FIG. 1 . In some embodiments, a conventional ion detector 25 (e.g., one or more microchannel plate detectors) 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 adequate detection of ions passing through the charge detection cylinder CD.

[0061] Now refer to Figure 4D , after both ion mirrors M1 and M2 have been operated in the ion transmission operation mode for a selected time period, the processor 16 is operable to control the voltage source V2 to control the ion mirror M2 to the ion reflection operation mode (R) by establishing an ion reflection field in the region R2 of the ion mirror M2, while maintaining the ion mirror M1 in the ion transmission operation mode (T), as shown. As a result, ions generated by the ion source 12 and entering the ion mirror M1 pass through the ion mirror M1, through the charge detection cylinder CD and enter the ion mirror M2, in which they are reflected back into the charge detection cylinder CD by the ion reflection field (R) established in the region R2 of M2, as shown. Figure 4D The ion trajectory in FIG64 is shown.

[0062] Now refer to Figure 4E , the processor 16 is operable to control the voltage source V1 to control the ion mirror M1 to the ion reflection mode of operation (R) by establishing an ion reflection field in the region R1 of the ion mirror M1, while maintaining the ion mirror M2 in the ion reflection mode of operation (R), as shown. In one embodiment, the processor 16 is illustratively operable, i.e., programmed, to control the ELIT 14 in a "random capture mode" in which the ELIT 14 is ... Figure 4D After operating for a selected time period in the state shown (i.e., with M1 in ion transmission mode and M2 in ion reflection mode), the processor 16 is operable to control the ion mirror M1 to the reflection mode of operation (R). Until the selected time period has elapsed, the ELIT 14 is controlled to operate in the state shown in FIG. Figure 4DIn an alternative embodiment, the processor 16 is operable, i.e. programmed, to control the ELIT 14 in a "triggered capture mode" in which the processor 16 is operable to control the ion mirror M1 to a reflectron mode of operation (R) until ions are detected at the charge detector CD. Prior to such detection, the ELIT 14 is controlled to Figure 4D Detection of the charge on the charge detector CD by the processor 16 indicates that ions are passing through the charge detector CD either towards the ion mirror M1 or towards the ion mirror M2, and acts as a trigger event which causes the processor 16 to control the voltage source V1 to switch the ion mirror M1 to the ion reflection mode of operation (R) to thereby trap ions within the ELIT 14.

[0063] With both ion mirrors M1, M2 controlled to the ion reflection mode of operation (R), ions are caused to oscillate back and forth between regions R1 and R2 of the respective ion mirrors M1, M2 by the ion reflection electric fields established in these regions, as described above and as Figure 4E In one embodiment, the processor 16 is operable to maintain Figure 4E , until the ions pass through the charge detection cylinder CD a selected number of times. In an alternative embodiment, the processor 16 may be operable to maintain M1 for a selected time period after controlling M1 to the ion reflection operating mode (R). Figure 4E When the ions have passed through the charge detection cylinder CD for a selected number of times or have oscillated back and forth between the ion mirrors M1 and M2 for a selected time period, the processor 16 is operable, i.e., programmed, to control the voltage source V2 to control the ion mirror M2 to the ion transmission mode of operation (T) by establishing an ion transmission field in the region R2 of the ion mirror M2, while maintaining the ion mirror M1 in the ion reflection mode of operation (R), as shown in FIG. Figure 4A The process is then repeated as many times as desired.

[0064] refer to FIG. 4A to FIG. 4E The described charge cylinder calibration or resetting technique may alternatively or additionally be implemented between charge detection events using the ELIT 14. However, it will be appreciated that in such an embodiment, the dimensions of the ELIT 14 and the axial lengths of the ion mirrors M1, M2 may be specifically configured to allow activation and subsequent generation of free charges 28 by the charge generator GC, deposition of the generated free charges 28 on the outer surface of the charge detection cylinder CD, and stabilization of the resulting target charge level CH on the charge detection cylinder CD. T, and / or charge induction on the charge detection cylinder CD by appropriately established electric fields, all of which occur between the time when a trapped ion traveling through the ELIT 14 leaves the charge detection cylinder CD and is reflected back into the charge detection cylinder by one of the ion mirrors M1, M2.

[0065] Now refer to FIG. 5A to FIG. 5F , showing Figure 1 A simplified diagram of the ELIT 14 showing the sequential control and operation of the ion mirrors M1, M2 and the charge generator CG as described above for calibrating or resetting the charge detection cylinder CD between such ion measurement events. Figure 5A , shows a single ion 70 traveling through the ELIT 14 at time T1 in the direction of arrow A from region R1 of ion mirror M1 toward the charge detection cylinder CD. As shown in the accompanying graph of charge CH on the charge detection cylinder CD versus time, the detected charge signal 80 is at a charge reference CH REF .exist Figure 5B , ions 70 are shown at a subsequent time T2, wherein ions 70 have advanced in the travel direction A and entered the charge detection cylinder CD. Detected charge signal 80 accordingly shows the step just before T2, which indicates the detected charge induced on the charge detection cylinder CD by ions 70 contained in the charge detection cylinder CD. At a further subsequent time T3, ions 70 have further advanced in the travel direction A and have reached the end of the charge detection cylinder CD, as shown in FIG. Figure 5C Therefore, the peak value of the charge detection signal 80 reaches its end at T3.

[0066] Still at a further subsequent time T4, ions 70, still travelling in direction A, have just left the charge detection cylinder CD and are preparing to enter region R2 of ion mirror M2, as shown in FIG. Figure 5DAs shown. When the accompanying falling edge of the charge detection signal 80 is detected at time T4, that is, when the absence of the charge detection signal generated by the charge preamplifier CP when ions pass through the charge detection cylinder CD and induce their charge on the charge detection cylinder is detected by the processor 16, the processor 16 is operable to generate a control signal C at time T5 to activate the charge generator CG indicated by the rising edge of the control signal 90. At a subsequent time T6, the charge generator CG responds to the control signal C to generate a selected number of free charges 28, and such free charges 28 then travel through the field-free region 36 and contact the outer surface of the charge detection cylinder CD to deposit the target number of free charges 28 thereon. Alternatively or additionally, the charge generator CG may respond to the control signal C to generate an electric field between at least one charge outlet channel 24 and the charge detection cylinder CD, which induces a corresponding charge on the charge detection cylinder CD.

[0067] At a subsequent time T7, the ion reflection electric field (R) established in region R2 of ion mirror M2 has captured ion 70 and reversed the direction of ion 70 so that it now travels in the opposite direction B toward the entrance of the charge detection cylinder CD adjacent to ion mirror M2, as shown in FIG. Figure 5E As shown. The processor 16 has disabled the control signal C at T7 as indicated by the falling edge of the control signal 90. In response to the disabling of the control signal C, the charge generator CG has stopped generating free charge 28, and Figure 5E The last of the generated charges 28 moving toward the outer surface of the charge detection cylinder CD is shown in FIG. Alternatively or additionally, the charge generator CG may respond to the control signal C at T7 to stop generating the electric field. Thereafter, at time T8, the ions 70 travelling in direction B have re-entered the charge detection cylinder CD, as shown in FIG. Fig. 5F The rising edge of the charge detection signal 80 at time T8 is shown. Between T7 and T8, the generated free charges 28 deposited on the charge detection cylinder CD settle and stabilize to produce the target charge level CH on the charge detection cylinder CD. T , the target charge level becomes the new charge reference for the charge detection signal 80, also as Fig. 5F Alternatively or additionally, calibration or resetting may be accomplished via charge sensing as described above. FIG. 5A to FIG. 5F The same process as shown in occurs at the opposite end of the ELIT 14 and continues for each oscillation of the ion 70 within the ELIT 14 until the ion mirror M2 opens to allow the ion 70 to exit its aperture A1.

[0068] Example The following examples are provided to illustrate three specific applications; one in which the charge generator CG is controlled to selectively generate free charges 28 as part of a charge injection process for depositing or applying a corresponding net charge on a charge detection cylinder CD, one in which the charge generator CG is controlled as part of a charge induction process for selectively inducing charge on the charge detection cylinder, and one in which the charge generator CG is controlled as part of a charge preamplifier calibration process for selectively inducing high-frequency charge on the charge detection signal during normal operation of the ELIT, wherein the mass and charge of the charged particles are thereby measured, to process the detected high-frequency charge, and to use the information provided thereby to compensate for any drift in the gain of the charge preamplifier over time. It will be understood that such applications are provided by way of example only and should not be construed as limiting the concepts described herein in any way.

[0069] The first example application is specifically directed to embodiments in which the charge sensitive preamplifier does not include any feedback components, or at least in which the charge sensitive preamplifier does not include any feedback components that are operable to discharge or otherwise dissipate or remove charges that may accumulate or otherwise build up on the charge detection cylinder CD when charges are induced thereon by trapped ions as they pass through the charge detection cylinder CD. In such embodiments, the charges that accumulate or build up on the charge detection cylinder raise the base charge level at the input of the charge sensitive preamplifier, thereby causing the output of the charge preamplifier to drift upward and eventually to the level of the supply voltage of the charge sensitive preamplifier. In such embodiments, the charge generator CG 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 that when deposited or applied on the charge detection cylinder CD cancel out the accumulated or built up charges, thereby resetting the charge level of the charge detection cylinder CD and the input of the charge sensitive preamplifier to a reference charge level CH REF or other selectable charge levels.

[0070] The second example application is specifically directed to an embodiment 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 either or both of the ion mirrors M1, M2 are switched between the ion transmission mode and the ion reflection mode as described above. Typically, each time the voltage source V1 and / or V2 is controlled by the processor 16 to modify the corresponding voltage applied to the ion mirror M1 and / or the ion mirror M2 to switch from the ion transmission electric field TEF to the ion reflection electric field REF or from the ion reflection electric field REF to the ion transmission electric field TEF, the switch from one electric field to another creates an electric field transient that induces a corresponding transient charge on the charge detection cylinder CD. This transient charge, at least in some cases, saturates the output of the charge sensitive preamplifier for a period of time, and in other cases, causes the charge sensitive preamplifier to generate one or more pulses that can be detected by the processor 16. In either case, such output produced by the charge sensitive preamplifier does not correspond to the charge induced on the trapped ions as they pass through the charge detection cylinder CD, and after any such switching of either ion mirror M1, M2 or simultaneous switching of both ion mirrors M1, M2, the charge detection data collection of the processor 16 is routinely suspended or delayed for a period of time to allow the transient charge induced on the charge detection cylinder CD to dissipate. In this regard, in this second example, the processor 16 is operable to control the charge generator CG and / or the voltage source VCG to generate a counting pulse whenever one or both of the ion mirrors M1, M2 are switched between ion transmission mode and ion reflection mode, wherein the counting pulse induces on the charge detection cylinder CD a transient charge equal to or approximately equal to and opposite to the transient charge induced on the charge detection cylinder CD by the switching of the (multiple) ion mirrors M1 and / or M2 so as to offset or at least reduce the transient net charge induced on the charge detection cylinder by such switching of the (multiple) ion mirrors M1 and / or M2. Illustratively, the shape, duration and / or size of the voltage counting pulses produced by the voltage source VCG are controlled to create an electric field of corresponding shape, duration and / or size between the charge generator CG and the charge detection cylinder CD to induce a charge on the charge detection cylinder that is equal and opposite to the transient charge induced on the charge detection cylinder CD by the switching of the (multiple) ion mirrors M1, M2. Such counting pulses by the voltage source VCG illustratively avoid saturating the charge preamplifier CP and in any case provide for processing of the charge detection data much faster than in conventional ELIT and / or CDMS instruments after the switching of the (multiple) ion mirrors M1 and / or M2.

[0071] It will be understood that the transient charge induced on the charge detection cylinder CD by switching the ion mirror M1 may be different from the transient charge induced by switching the ion mirror M2, any of these transient charges may be different from the transient charge induced when the two ion mirrors M1 and 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 and M2 are switched from transmission mode to reflection mode may be different from the transient charge induced when switching from reflection mode to transient mode. In this example application, the processor 16 can therefore be programmed to control the shape, duration and / or size of the voltage counting pulses generated by the voltage source VCG in different manners depending on how the ion mirrors M1, M2 (or both) are switched and which ion mirrors M1, M2 (or both) are switched, so as to selectively create an appropriate electric field between the charge generator CG and the charge detection cylinder CD, which electric field has a corresponding shape, duration and / or size to induce charges on the charge detection cylinder that are equal and opposite to any such transient charges induced on the charge detection cylinder CD by such switching of (multiple) ion mirrors M1 and / or M2.

[0072] The third example application is particularly directed to embodiments in which the charge sensitive preamplifier may be subject to gain drift over time, for example, due to one or any combination of amplifier operating temperature, amplifier operating temperature gradient, and signal history, but not limited thereto. In such embodiments, the charge generator CG is illustratively controlled to selectively induce high frequency charge on the charge detection cylinder CD during normal operation of the ELIT 14, during which normal operation the mass and charge of the charged particles are thereby measured as described herein, to process the detected high frequency charge, and to use the information provided thereby to compensate for any gain drift of the charge sensitive preamplifier over time. In this regard, Figure 7 A simplified flow chart of illustrates an example process 200 for controlling a charge generator voltage source VCG and / or a charge generator CG to continuously induce high frequency charge on a charge detection cylinder CD, and using corresponding information in a resulting charge detection signal CHD to compensate for gain drift of a charge sensitive preamplifier over time. The process 200 is illustratively stored in the form of instructions in the memory 18, which are executable by the processor 16 to control the operation of the charge generator voltage source VCG and / or the charge generator CG, and process the charge detection signal CHD as just described.

[0073] In this regard, the process 200 begins at step 202, where the processor 16 is operable to set a counter j equal to 1 or some other starting value. Thereafter, in step 204, the processor 16 is operable to control the voltage source VCG and / or the charge generator CG to generate a high frequency voltage of a suitable constant or stable magnitude, thereby creating 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 that induces a corresponding high frequency charge on the charge detection cylinder CD. The term "high frequency" as used in this embodiment should be understood as a frequency that is at least high enough so that the resulting portion of the frequency domain charge detection signal CHD during normal operation of the ELIT 14 can be distinguished from the portion of CHD generated by the detection of charge reacted by the passage of charged particles (i.e., ions) through the charge detection cylinder. In this regard, the "high frequency" should be at least higher than the highest oscillation frequency of any ion oscillating back and forth in the ELIT 14, as described above. The high frequency voltage generated by the VCG and / or CG can take any shape, such as square, sinusoidal, triangular, and have any desired duty cycle. In one example embodiment (which should not be considered limiting in any way), the high frequency voltage generated at antenna 26 is a square wave that, in the frequency domain, includes only the fundamental frequency and odd harmonics.

[0074] After step 204, process 200 proceeds to step 206, where processor 16 is operable to measure the charge CI induced on charge detector CD by the high frequency signal generated at antenna 26 by processing the corresponding charge detection signal CHD generated by charge sensitive preamplifier CP. Thereafter, at step 208, processor 16 is operable to convert the time domain charge detection signal CHD into a frequency domain charge detection signal CIF, for example using any conventional signal conversion technique, such as discrete Fourier transform (DFT), fast Fourier transform (FFT) or other conventional techniques. Thereafter, at step 210, processor 16 is operable to determine the peak magnitude PM of the fundamental frequency of charge detection signal CIF. Thereafter, at step 212, processor 16 is operable to compare counter value j with a target value. Typically, N will be the sample size of a data set containing multiple sequentially measured values ​​of PM, and will define the size of a moving average window for tracking drift of charge sensitive preamplifier CP. In this regard, N can have any positive value. Typically, lower values ​​of N will produce a more responsive but less smooth moving average, and higher values ​​of N will produce a less responsive but smoother moving average. Typically, N will be selected based on the application. In one example application (which should not be considered limiting in any way), N is 100, although in other applications, N may be less than 100, several hundred, 1000, or several thousand.

[0075] If, in step 212, the processor 16 determines that j is less than or equal to N, then the process 200 proceeds to step 214, where the processor 16 is operable to add PM(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 loop back to step 206. If, in step 212, instead, the processor 216 determines that j is greater than N, then the process 200 proceeds to step 218, where the processor 16 is operable to determine the N sample data set value PM 1-N In one embodiment, in step 218, the processor 16 is illustratively operable to calculate AV as PM 1-N , although in alternative embodiments, the processor 16 may be operable to calculate AV in step 218 using one or more other conventional averaging techniques or processes.

[0076] Steps 202 to 218 of process 200 are illustratively performed prior to operation of instrument 10 to measure a spectrum of mass and charge of ions generated from a sample, as described herein. In this regard, the purpose of steps 202 to 218 is to construct an N-sample data set of peak magnitude values ​​PM and to establish a baseline gain or gain factor AV of the charge sensitive preamplifier CP prior to normal operation of ELIT 14 to measure ion mass and charge, as described herein. However, it will be understood that in other embodiments, steps 202 to 218 may be re-performed at any time (e.g., randomly, periodically, or selectively) to re-establish a baseline gain or gain factor.

[0077] After step 218, processor 16 is illustratively operable to initiate CDMS analysis of the sample by instrument 10 as described herein, for example by controlling voltage sources V1 and V2 to measure the mass and charge of ions generated from the sample by ELIT 14. Thereafter, in step 222, when instrument 10 and ELIT While this operation of 14 is occurring, and while the charge generator CG is being continually controlled to induce high frequency charge HFC on the charge detection cylinder CD, for each charge detection signal CHD generated by the charge sensitive preamplifier in response to the charge induced thereon by the charged particles passing through the charge detection cylinder CD, the processor 16 is operable to: (a) determine PM, for example according to steps 206 to 210 or other conventional processes for determining PM; (b) add PM to the N sample data set and delete the oldest PM value so as to advance the N sample data set "window" by one data point; (c) determine a new average value NAV of the now updated N sample data set, for example according to step 218 or other conventional averaging techniques; (d) determine a charge sensitive preamplifier gain calibration factor GCF based on AV and NAV; and (e) modify the portion of the charge detection signal CHD generated by the charge sensitive preamplifier in response to the charge induced thereon by the charged particles passing through the charge detection cylinder CD based on GCF to compensate for any gain drift of the charge sensitive preamplifier CP.

[0078] It will be appreciated that at step 222(d), any of several conventional techniques may be used by the processor 16 to determine the GCF. In one embodiment, for example, the GCF may be the ratio GCF=NAV / AV or GCF=AV / NAV. In other embodiments, AV may be normalized to a value such as 1 or some other value, and the NAV may be similarly normalized based on the normalized AV to produce a GCF in the form of a normalized multiplier. Other techniques will occur to those skilled in the art, and it will be appreciated that it is intended that any such other techniques are within the scope of the present disclosure. In any case, at step 222(e), the processor 16 is illustratively operable to modify a portion of the charge detection signal CHD generated by the charge sensitive preamplifier in response to the charge induced thereon by the charged particles passing through the charge detection cylinder CD, so as to compensate for any gain drift of the charge sensitive preamplifier CP by multiplying the peak magnitude of this portion of the charge detection signal CH by the GCF. Those skilled in the art will recognize other techniques for performing step 222(e) to include other coefficients in the GCF that may affect the gain of the CP, to include one or more weighting values ​​to enhance or attenuate the gain of the CP based on the one or more coefficients, and so on.

[0079] Now refer to Figure 8, shows an example graph of CHD relative frequency, which depicts an example of a charge detection signal CHD processed at step 222(a), the charge detection signal CHD including a charge peak 300 corresponding to the detection of the charge induced on the charge detection cylinder CD of the ELIT 14 by the charged particle passing therethrough and an additional charge peak 400 corresponding to the detection of the high frequency charge HFC simultaneously induced on the charge detection cylinder CD by the charge generator CG. As described 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 charge sources can be distinguished from each other. Figure 8 Also illustrated in FIG. 2 is the peak magnitude PM of the fundamental frequency of the induced high frequency charge HFC determined at step 222 ( a ) of process 200 .

[0080] Reference Fig. 9 , shows an example graph of the peak magnitude PM of the fundamental frequency of the high frequency charge HFC induced by the charge generator on the charge detection cylinder CG versus time 410, the graph including the baseline gain value AV calculated at step 218, and which includes an example gain drift of the charge sensitive preamplifier CP over time during normal operation of the instrument 10. It will be appreciated that although Fig. 9 The gain drift is depicted as increasing linearly over time, but the gain drift may alternatively be nonlinear or piecewise linear and / or may decrease over time or sometimes increase and sometimes decrease. In any case, the baseline gain value AV calculated at step 218 occurs during a time window W1 between times T0 and T1, step 220 is performed at time T1, and thereafter, the charge sensitive preamplifier gain drifts between T1 and T3. Fig. 9 Further depicted is the progressive movement of the N sample time windows repeatedly performed at step 222(b), i.e., each charge detection signal CHD resulting from the charge induced thereon by the charged particles passing through the charge detection cylinder CD. One such example time window W2 is shown extending from the middle of T0 and T1 to T2, and another example time window W3 is shown extending between times T2 and T.

[0081] Now refer to Fig.10 , shows the N sample data set moving average (NAV) 420 as determined by processor 16 at step 222(c) of process 200. Fig. 94 is a graph of the peak magnitude signal 410 over time as shown. In the example shown, the moving average NAV smoothes the peak magnitude signal 410 as a function that increases linearly from a baseline gain or gain factor AV. As described above, at steps 222(d) and 222(e), NAV and AV are illustratively used by the processor 16 to modify a portion of the charge detection signal CHD generated by the charge sensitive preamplifier in response to the charge induced thereon by the charged particles passing through the charge detection cylinder CD to compensate for any gain drift of the charge sensitive preamplifier CP by multiplying the peak magnitude of this portion of the charge detection signal CH by GCF.

[0082] Now refer to Fig. 6A , shows a simplified block diagram of an embodiment of an ion separation instrument 100, which may include an ELIT 14 as shown and described herein, and may include a charge detection mass spectrometer (CDMS) 10 as shown and described herein, and which may include any number of ion processing instruments that may form part of an ion source 12 upstream of the ELIT 14 and / or which may include any number of ion processing instruments that may be disposed downstream of the ELIT 14 to further process the ions (multiple) exiting the ELIT 14. In this regard, the ion source 12 may be disposed in a manner that is consistent with the ion source 12 of FIG. Fig. 6A It is shown as including a number Q of ion source stages IS1 to IS Q , these ion source stages may be or form part of the ion source 12. Alternatively or additionally, the ion processing instrument 110 may be Fig. 6A 14, wherein the ion processing instrument 110 may include any number of ion processing stages OS1 to OS2. R , where R can be any positive integer.

[0083] Focusing on the ion source 12, it will be appreciated that the source 12 of ions entering the ELIT 14 may be or include ion source stages IS1 to IS2. QOne or more conventional ion sources as described above in the form of one or more of the above, and may further include one or more conventional instruments for separating ions according to one or more molecular properties (e.g., according to ion mass, ion mass-charge, ion mobility, ion retention time, etc.) and / or one or more conventional ion processing instruments for collecting and / or storing ions (e.g., one or more quadrupoles, hexapole and / or other ion traps), for filtering ions (e.g., according to one or more molecular properties, such as ion mass, ion mass-charge, ion mobility, ion retention time, etc.), for fragmenting or dissociating ions, for standardizing or transforming ion charge states, etc. It will be understood that the ion source 12 may include any one or any combination of any such conventional ion sources, ion separation instruments and / or ion processing instruments in any order, and some embodiments may include multiple adjacent or spaced-apart instruments in any such conventional ion sources, ion separation instruments and / or ion processing instruments. In any embodiment including one or more mass spectrometers, any one or more such mass spectrometers may be implemented in any of the forms described herein.

[0084] Turning now to the ion processing instrument 110, it will be appreciated that the instrument 110 may be or include ion processing stages OS1 to OS2. Q One or more conventional instruments for separating ions according to one or more molecular properties (e.g., according to ion mass, ion mass-charge, ion mobility, ion retention time, etc.) and / or one or more conventional ion processing instruments for collecting and / or storing ions (e.g., one or more quadrupoles, hexapole and / or other ion traps), for filtering ions (e.g., according to one or more molecular properties, such as ion mass, ion mass-charge, ion mobility, ion retention time, etc.), for fragmenting or dissociating ions, for standardizing or transforming ion charge states, etc., in the form of one or more of the conventional ion separation instruments and / or ion processing instruments. It will be understood that the ion processing instrument 110 can include any one or any combination of any such conventional ion separation instruments and / or ion processing instruments in any order, and some embodiments can include multiple adjacent or spaced-apart instruments of any such conventional ion separation instruments and / or ion processing instruments. In any embodiment including one or more mass spectrometers, any one or more of such mass spectrometers can be implemented in any of the forms described herein.

[0085] As Fig. 6AIn one specific embodiment of the ion separation instrument 100 shown in , which should not be considered limiting in any way, the ion source 12 illustratively includes 3 stages, and the ion processing instrument 110 is omitted. In this example embodiment, the ion source stage IS1 is a conventional ion source, such as electrospray, MALDI, etc., the ion source stage IS2 is a conventional ion filter, such as a quadrupole or hexapole ion guide, and the ion source stage IS3 is a mass spectrometer of any of the above types. In this embodiment, the ion source stage IS2 is controlled in a conventional manner to pre-select ions having molecular characteristics desired for analysis by a downstream mass spectrometer, and only such pre-selected ions are passed to the mass spectrometer, wherein the ions analyzed by the ELIT 14 will be the pre-selected ions separated by the mass spectrometer according to mass-to-charge ratio. For example, the pre-selected ions leaving the ion filter may be ions having a specified ion mass or mass-to-charge ratio, ions having an ion mass or ion mass-to-charge ratio above and / or below a specified ion mass or ion mass-to-charge ratio, ions having an ion mass or ion mass-to-charge ratio within a specified ion mass or ion mass-to-charge ratio range, etc. In some alternative embodiments of this example, the ion source stage IS2 may be a mass spectrometer, and the ion source stage IS3 may be an ion filter, and the ion filter may additionally operate as just described to pre-select ions leaving the mass spectrometer that have molecular characteristics desired for analysis by the downstream ELIT 14. In other alternative embodiments of this example, the ion source stage IS2 may be an ion filter, and the ion source stage IS3 may include a mass spectrometer preceding another ion filter, wherein the ion filters each operate as just described.

[0086] As Fig. 6A In another specific embodiment of the ion separation instrument 100 shown in FIG. 1 (which should not be considered limiting in any way), the ion source 12 illustratively includes 2 stages, and the ion processing instrument 110 is again omitted. In this example embodiment, the ion source stage IS1 is a conventional ion source, such as electrospray, MALDI, etc., and the ion source stage IS2 is a conventional mass spectrometer of any of the above types. This is the above reference Figure 1 An embodiment is described in which the ELIT 14 is operable to analyse ions exiting a mass spectrometer.

[0087] As Fig. 6AIn yet another specific embodiment of the ion separation instrument 100 shown in (which should not be considered limiting in any way), the ion source 12 illustratively includes 2 stages, and the ion processing instrument 110 is omitted. In this example embodiment, the ion source stage IS1 is a conventional ion source, such as electrospray, MALDI, etc., and the ion processing stage OS2 is a conventional single-stage or multi-stage ion mobility spectrometer. In this embodiment, the ion mobility spectrometer is operable to separate ions generated by the ion source stage IS1 over time according to one or more ion mobility functions, and the ELIT 14 is operable to analyze ions leaving the ion mobility spectrometer. In an alternative embodiment of this example, the ion source 12 may include only a single-stage IS1 in the form of a conventional ion source, and the ion processing instrument 110 may include a conventional single-stage or multi-stage ion mobility spectrometer as a single-stage OS1 (or as stage OS1 of a multi-stage instrument 210). In this alternative embodiment, the ELIT 14 is operable to analyze ions generated by the ion source stage IS1, and the ion mobility spectrometer OS1 is operable to separate ions leaving the ELIT 14 over time according to one or more ion mobility functions. As another alternative embodiment of this example, a single-stage or multi-stage ion mobility spectrometer may follow both the ion source stage IS1 and the ELIT 14. In this alternative embodiment, the ion mobility spectrometer following the ion source stage IS1 is operable to separate ions generated by the ion source stage IS1 over time according to one or more ion mobility functions, the ELIT 14 is operable to analyze ions leaving the ion source stage ion mobility spectrometer, and the ion mobility spectrometer following the ion processing stage OS1 of the ELIT 14 is operable to separate ions leaving the ELIT 14 over time according to one or more ion mobility functions. In any of the embodiments described in this paragraph, additional variations may include a mass spectrometer operably positioned upstream and / or downstream of the single-stage or multi-stage ion mobility spectrometer in the ion source 12 and / or ion processing instrument 110.

[0088] As Fig. 6AIn another specific embodiment of the ion separation instrument 100 shown in (which should not be considered as limiting in any way), the ion source 12 illustratively includes 2 stages, and the ion processing instrument 110 is omitted. In this example embodiment, the ion source stage IS1 is a conventional liquid chromatograph, such as an HPLC configured to separate molecules in a solution according to molecular retention time, and the ion source stage IS2 is a conventional ion source, such as electrospray, etc. In this embodiment, the liquid chromatograph is operable to separate molecular components in a solution, the ion source stage IS2 is operable to generate ions from a solution flow leaving the liquid chromatograph, and the ELIT 14 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 also be a conventional size exclusion chromatography (SEC) instead, which is operable to separate molecules in a solution by size. In another alternative embodiment, the ion source stage IS1 may include a conventional liquid chromatograph, followed by a conventional SEC, or vice versa. In this embodiment, ions are generated by ion source stage IS2 from a solution separated twice; the first time according to molecular retention time, followed by a second time according to molecular size, or vice versa. In any of the embodiments described in this paragraph, additional variations may include a mass spectrometer operably positioned between ion source stage IS2 and ELIT 14.

[0089] Now refer to Figure 6B , a simplified block diagram of another embodiment of an ion separation instrument 120 is shown, which ion separation instrument 120 illustratively includes a multi-stage mass spectrometer instrument 130 and which also includes a charge detection mass spectrometer (CDMS) 10 shown and described herein, which CDMS is implemented as a high mass ion analysis component. In the illustrated embodiment, the multi-stage mass spectrometer instrument 130 includes an ion source (IS) 12 as shown and described herein, followed by a first conventional mass spectrometer (MS1) 132 and coupled to the first conventional mass spectrometer (MS1) 132, followed by a conventional ion dissociation stage (ID) 134 and coupled to the ion dissociation stage (ID) 134, which is operable to dissociate ions leaving 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 photo induced dissociation (PID), etc., followed by a second conventional mass spectrometer (MS2) 136 and coupled to the second conventional mass spectrometer (MS2) 136, followed by a conventional ion detector (D) 138 (e.g., such as a microchannel plate detector or other conventional ion detector), etc. The CDMS 10 is coupled in parallel with and to the ion dissociation stage 134 , such that the CDMS 10 can selectively receive ions from the mass spectrometer 136 and / or from the ion dissociation stage 132 .

[0090] MS / MS, for example using only ion separation instrument 130, is a well-established method in which precursor ions of a specific molecular weight are selected by a first mass spectrometer 132 (MS1) based on their m / z values. In the ion dissociation stage 134, the precursor ions selected by mass are fragmented, for example by collision induced dissociation, surface induced dissociation, electron capture dissociation or photoinduced dissociation. The fragment ions are then analyzed by a second mass spectrometer 136 (MS2). Only the m / z values ​​of the precursor ions and the fragment ions are measured in both MS2 and MS3. For high-mass ions, the charge state cannot be resolved, and therefore, it is impossible to select precursor ions with a specified molecular weight based only on the m / z value. However, by coupling the instrument 130 to the CDMS10 shown and described herein, a narrow range of m / z values ​​can be selected, and then the mass of the precursor ions selected by m / z is determined using CDMS10. For example, mass spectrometers 132, 136 can be one or any combination of magnetic sector mass spectrometers, time-of-flight mass spectrometers, or quadrupole mass spectrometers, although in alternative embodiments, other mass spectrometer types can be used. In any case, the m / z selected precursor ions with known masses leaving MS1 can be fragmented in the ion dissociation stage 134, and the resulting fragment ions can then be analyzed by MS2 (in the case of measuring only the m / z ratio) and / or by the CDMS instrument 10 (in the case of measuring both the m / z ratio and the charge). Low-quality fragments, i.e., dissociated ions of precursor ions having mass values ​​below a threshold mass value (e.g., 10,000Da (or other mass values)), can therefore be analyzed by conventional MS using MS2, while high-quality fragments (in the case of unresolved charge states), i.e., dissociated ions of precursor ions having mass values ​​equal to or above the threshold mass value, can be analyzed by CDMS10.

[0091] It will be appreciated that the dimensions of the various components of the ELIT 14 and the magnitude of the electric field established in the ELIT 14 (as implemented in any of the systems 10, 200, 220 shown in the drawings and described above) may be illustratively selected to establish a desired duty cycle of ion oscillations within the ELIT 14, the duty cycle corresponding to the ratio of the time that the ions spend in the charge detection cylinder CD to the total time that the ions spend passing through the combination of the ion mirrors M1, M2 and the charge detection cylinder CD in one complete oscillation cycle. For example, a duty cycle of approximately 50% may be desirable in order to reduce noise in the determination of the magnitude of the fundamental frequency caused by harmonic frequency components of the measurement signal. Details regarding such sizing and operational considerations for achieving a desired duty cycle (e.g., such as 50%) are illustrated and described in co-pending U.S. patent application serial number 62 / 616,860 filed on January 12, 2018, co-pending U.S. patent application serial number 62 / 680,343 filed on June 4, 2018, and co-pending international patent application number PCT / US2019 / / 013251 filed on January 11, 2019, all of which are entitled “ELECTROSTATIC LINEAR ION TRAP DESIGN FOR CHARGE DETECTION MASSSPECTROMETRY,” the disclosures of which are expressly incorporated herein by reference.

[0092] It will be further understood that one or more charge detection optimization techniques may be used with the ELIT 14 in any of the systems 10, 100, 120, for example, to trigger a trapping or other charge detection event. Examples of some such charge detection optimization techniques are illustrated 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 entitled “APPARATUS AND METHOD FOR CAPTURING IONS IN AN ELECTROSTATICLINEAR ION TRAP”, the disclosures of both applications being expressly incorporated herein by reference.

[0093] It will also be further understood that the charge detection cylinder calibration or resetting apparatus and techniques shown in the drawings and described herein can be used in each of two or more ELITs and / or in each of two or more ELIT regions in an application including at least one ELIT array having two or more ELITs or having two or more ELIT regions. Examples of some such ELITs and / or ELIT arrays are illustrated and described in co-pending U.S. patent application Ser. No. 62 / 680,315 filed on Jun. 4, 2018 and co-pending International Patent Application No. PCT / US2019 / 013283 filed on Jan. 11, 2019, both entitled “ION TRAP ARRAY FOR HIGHTHROUGHPUT CHARGE DETECTION MASS SPECTROMETRY”, the disclosures of both applications being expressly incorporated herein by reference.

[0094] 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 conjunction with any of the systems 10, 100, 120 shown in the figures and described herein, some examples of which are disclosed in co-pending U.S. patent application Ser. No. 62 / 680,223, filed on Jun. 4, 2018, entitled “HYBRID ION FUNNEL-ION CARPET (FUNPET) ATMOSPHERIC PRESSURE INTERFACE FOR CHARGE DETECTION MASS SPECTROMETRY” and in co-pending U.S. patent application Ser. No. 62 / 680,223, filed on Jan. 11, 2019, entitled “INTERFACE FOR TRANSPORTING IONS FROM AN ATMOSPHERIC PRESSURE ENVIRONMENT TO A LOW PRESSURE SYSTEM”. The present invention is described and illustrated in the co-pending International Patent Application No. PCT / US2019 / 013274 entitled "INTERFACE FOR TRANSPORTING IONS FROM ATMOSPHERIC PRESSURE ENVIRONMENT TO LOW PRESSURE ENVIRONMENT", the disclosures of both applications being expressly incorporated herein by reference.

[0095] It will also be further understood that any of the systems 10, 100, 120 shown in the figures and described herein may be implemented in or as part of a system configured to operate according to real-time analysis and / or real-time control techniques, some examples of such systems being illustrated and described in co-pending U.S. patent application serial number 62 / 680,245 filed on June 4, 2018 and co-pending international patent application number PCT / US2019 / 013277 filed on January 11, 2019, both applications being entitled “CHARGE DETECTION MASS SPECTROMETRY WITH REAL TIMEANALYSIS AND SIGNAL OPTIMIZATION,” the disclosures of both applications being expressly incorporated herein by reference.

[0096] It will also be further understood that in any of the systems 10, 100, 120 shown in the drawings and described herein, the ELIT 14 can be replaced with an orbital trap, and the charge detection cylinder calibration or reset apparatus and techniques shown in the drawings and described herein can be used with such an orbital trap. An example of such an orbital ion trap is illustrated 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 entitled “ORBITRAP FOR SINGLE PARTICLE MASS SPECTROMETRY,” the disclosures of both applications being expressly incorporated herein by reference.

[0097] It will also be further understood that one or more ion entrance trajectory control devices and / or techniques may be used with the ELIT 14 of any of the systems 10, 100, 120 shown in the figures and described herein to provide simultaneous measurement of multiple individual ions within the ELIT 14. Examples of some such ion entrance 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 entitled “APPARATUS AND METHOD FOR SIMULTANEOUSLY ANALYZING MULTIPLE IONS WITH ANELECTROSTATIC LINEAR ION TRAP,” the disclosures of both of which are expressly incorporated herein by reference.

[0098] Although the present disclosure has been illustrated and described in detail in the above figures and descriptions, such illustrations and descriptions are considered to be illustrative and non-restrictive in nature, it is to be understood that only illustrative embodiments thereof have been shown and described, and it is expected that all changes and modifications within the spirit of the present disclosure are protected. For example, it will be understood that the ELIT 14 shown in the drawings and described herein is provided only by way of example, and the above-mentioned concepts, structures and techniques can be directly implemented in ELITs of various alternative designs. For example, any such alternative ELIT design can include two or more ELIT regions, more, fewer and / or ion mirror electrodes of different shapes, 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 that define 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 it is intended that such concepts, structures and / or techniques are not limited to ELITs or variations thereof, but are intended to be applicable to any conventional charge detector or charge detection device. Therefore, any conventional charge detector or charge detection device that implements the concepts, structures and / or techniques shown in the figures and described herein is within the scope of the present disclosure.

Claims

1. A charge detection mass spectrometer (CDMS) including charge detector reset or calibration, the CDMS comprising: an electrostatic linear ion trap (ELIT) having a charge detection cylinder disposed between a first ion mirror and a second ion mirror, Charge generator, the region between the charge generator and the charge detection cylinder, and a processor configured to control the charge generator to (i) generate a target amount of free charges and cause the target amount of free charges to travel through the region and contact the charge detection cylinder to deposit the target amount of free charges thereon and thereby calibrate or reset the charge detection cylinder to a corresponding target charge level, or (ii) generate at least one electric field in the region, the at least one electric field inducing a target charge on the charge detection cylinder to calibrate the charge detection cylinder.

2. The CDMS of claim 1, further comprising an ion source configured to supply ions to the ELIT, in, The processor is configured to control the operation of the first ion mirror and the second ion mirror to capture ions from the ion source therein and thereafter cause the trapped ions to oscillate back and forth between the first ion mirror and the second ion mirror each time the ions pass through the charge detection cylinder and induce corresponding charges thereon.

3. The CDMS according to claim 2 further comprises at least one voltage source, which is operably coupled to the processor and the first and second ion mirrors and is configured to generate a voltage to selectively establish an ion transmission electric field or an ion reflection electric field therein, wherein the ion transmission electric field is configured to concentrate ions passing through a corresponding one of the first and second ion mirrors toward a longitudinal axis, wherein the longitudinal axis passes through the first and second ion mirrors and the center of each of the charge detection cylinders, and the ion reflection electric field is configured to stop and accelerate ions entering a corresponding one of the first and second ion mirrors from the charge detection cylinder in opposite directions, return through the charge detection cylinder and toward the other of the first and second ion mirrors, while also concentrating the ions toward the longitudinal axis, in, The processor is configured to control the operation of the first ion mirror and the second ion mirror to capture ions from the ion source therein by first controlling the at least one voltage source to establish the ion transmission electric field in at least the first ion mirror so that ions supplied by the ion source flow into the ELIT through the ion entrance hole defined in the first ion mirror and then controlling the at least one voltage source to establish the ion reflection electric field in the first ion mirror and the second ion mirror to thereby capture the ions in the ELIT, and causing the trapped ions to oscillate back and forth between the first ion mirror and the second ion mirror each time they pass through the charge detection cylinder and induce corresponding charges thereon.

4. The CDMS according to claim 2 or claim 3, wherein: The processor is configured to control the charge generator to generate the target number of free charges when the ions are located within a respective one of the first ion mirror and the second ion mirror after each passage of the ions through the charge detection cylinder, thereby calibrating or resetting the charge detection cylinder between each passage of the ions through the charge detection cylinder.

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 being configured to generate a charge detection signal in response to charge induced thereon by ions passing through the charge detection cylinder, wherein The processor is configured to control the charge generator to generate the target amount of free charge each time an absence of the charge detection signal is detected at the output of the charge preamplifier.

6. The CDMS according to claim 5, wherein: no feedback component is electrically connected between the input and the output of the charge preamplifier, And wherein the target amount of free charge is selected so that when detected by the charge preamplifier, the target amount of charge deposited on the charge detection cylinder clears a certain amount of charge noise accumulated on the charge detection cylinder through the charge induced thereon caused by the captured charge passing through the charge detection cylinder, thereby resetting the charge detection cylinder and the charge preamplifier to repeatable corresponding operating states.

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

8. The CDMS according to claim 7, wherein: The processor is configured to process the recorded charge detection signals to determine an ion charge value and at least one of an ion mass-to-charge ratio and an ion mass.

9. The CDMS according to claim 7, wherein: The processor is configured to control at least one of the first ion mirror and the second ion mirror to cause the trapped ions to leave the ELIT after the ion measurement event, And wherein the processor is configured to control the charge generator to generate the target amount of free charges after the trapped ions exit from the ELIT to thereby calibrate or reset the charge detection cylinder after the ion measurement event.

10. The CDMS according to claim 9, wherein: The processor is configured to control at least one of the first ion mirror and the second ion mirror by controlling the at least one voltage source to establish the ion transmission electric field in at least one of the first ion mirror and the second ion mirror, so that the trapped ions leave the ELIT through the ion entrance hole defined in the first ion mirror or through the ion exit hole defined in the second ion mirror.

11. A CDMS according to claim 9 or claim 10, wherein: The processor is configured to (1) control the first ion mirror and the second ion mirror to trap ions in the ELIT and cause the trapped ions to oscillate back and forth between the first ion mirror and the second ion mirror for a duration of an ion measurement event, and then (2) control at least one of the first ion mirror and the second ion mirror to cause the trapped ions to leave the ELIT, and (3) repeat (1) and (2) for a plurality of consecutive ion measurement events, And wherein the processor is configured to control the charge generator to generate the target amount of free charges to thereby calibrate or reset the charge detection cylinder between each of the plurality of consecutive ion measurement events.

12. The CDMS according to claim 2 or claim 3, wherein: The processor is configured to (i) control the operation of the first ion mirror and the second ion mirror to capture ions from the ion source therein, (ii) thereafter cause the trapped ions to oscillate back and forth between the first ion mirror and the second ion mirror each time the trapped ions pass through the charge detection cylinder and induce corresponding charges thereon, (iii) cause the trapped ions to oscillate back and forth between the first ion mirror and the second ion mirror a predefined number of times or a predefined time period to define an ion measurement event, and (iv) thereafter cause the trapped ions to leave the ELIT, And wherein the processor is configured to control the charge generator to generate the target amount of free charges after the trapped ions exit from the ELIT to thereby calibrate or reset the charge detection cylinder after the ion measurement event.

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 being configured to generate a charge detection signal in response to charge induced thereon by ions passing through the charge detection cylinder, wherein no feedback component is electrically connected between the input and the output of the charge preamplifier, And wherein the target amount of free charge is selected so that when detected by the charge preamplifier, the target amount of charge deposited on the charge detection cylinder clears a certain amount of charge noise accumulated on the charge detection cylinder through the charge induced thereon by the captured charge passing through the charge detection cylinder, thereby resetting the charge detection cylinder and the charge preamplifier to repeatable corresponding operating states.

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

15. The CDMS according to claim 14, wherein: The processor is configured to process the recorded charge detection signals to determine an ion charge value and at least one of an ion mass-to-charge ratio and an ion mass.

16. The CDMS according to any one of claims 12 to 15, wherein: The processor is configured to repeat (i) to (iv) for a plurality of consecutive ion measurement events, And wherein the processor is configured to control the charge generator to generate the target amount of free charges to thereby calibrate or reset the charge detection cylinder between each of the plurality of consecutive ion measurement events.

17. The CDMS according to any one of claims 1 to 16, wherein: The charge generator comprises: Filament, and a voltage or current source operably coupled to the filament, The processor is configured to control the voltage or current source to apply a selected voltage or current to the filament, and the filament responds to the selected voltage or current to generate the target amount of free charges.

18. The CDMS according to any one of claims 1 to 17, wherein: The charge generator comprises: a conductive mesh or grid, and a voltage or current source operatively coupled to the net or grid, Wherein, the processor is configured to control the voltage or current source to apply a selected voltage or current to the net or mesh, and the net or mesh responds to the selected voltage or current to generate the target amount of free charges.

19. The CDMS according to any one of claims 1 to 16, wherein: The charge generator comprises: Charged particle generators, and Sample source, Wherein, the processor is configured to control the charged particle generator to generate the target amount of free charges in the form of charged particles of the sample from the sample source.

20. The CDMS of claim 3, further comprising a charge generator voltage source wherein: switching the electric field established in either or both of the first ion mirror and the second ion mirror between the ion transmission electric field and the ion reflection electric field to induce corresponding transient charges on the charge detection cylinder, And wherein, the processor is configured to control the charge generator voltage source to apply a voltage pulse to the charge generator, at which time the electric field established in at least one of the first ion mirror and the second ion mirror is switched from the ion transmission electric field to the ion reflection electric field or from the ion reflection electric field to the ion transmission electric field, and the voltage pulse is selected to create a corresponding electric field in the region, and the electric field has at least one of a selected shape, size and duration, thereby inducing corresponding charges on the charge detection cylinder, and the charges are approximately equal to and opposite to the corresponding transient charges induced on the charge detection cylinder by switching the electric field established in at least one of the first ion mirror and the second ion mirror.

21. A system for separating ions, the system comprising: A CDMS according to any one of claims 2 to 20, wherein the ion source is configured to generate ions from a sample, and at least one ion separation instrument configured to separate the generated ions according to at least one molecular characteristic, Therein, ions leaving the at least one ion separation instrument are supplied to the ELIT.

22. The system of claim 21, wherein: The ELIT is configured and controlled so that trapped ions therein oscillate back and forth between the first ion mirror and the second ion mirror through the charge detection cylinder with an approximate 50% duty cycle corresponding to the ratio of the time it takes the ions to move through the charge detection cylinder to the total time it takes the ions to pass through the combination of the first and second ion mirrors and the charge detection cylinder during one complete oscillation cycle.

23. A system according to claim 21 or claim 22, wherein: The ELIT is operably coupled to the ion source and the processor, and wherein the ELIT comprises a plurality of axially aligned charge detection cylinders, each charge detection cylinder being disposed between respective ion mirrors to form one of a corresponding plurality of cascaded ELIT regions, and wherein the processor is configured to control the ELIT to sequentially capture a single ion in each of the plurality of ELIT regions.

24. A system according to claim 21 or claim 22, wherein: the ELIT comprising a plurality of ELITs each operably coupled to the processor, and further comprising means for directing ions from said at least one ion separation instrument to each of said plurality of ELITs, And wherein the processor is configured to control the ELIT and the means for directing ions from the at least one ion separation instrument to each of the plurality of ELITs to successively trap single ions in each of the plurality of ELITs.

25. A system according to any one of claims 21 to 24, wherein: The at least one ion separation instrument includes one or any combination of at least one instrument for separating ions according to mass-to-charge ratio, at least one instrument for separating ions in time according to ion mobility, at least one instrument for separating ions according to ion retention time, and at least one instrument for separating ions according to molecular size.

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. A system according to any one of claims 21 to 26, further comprising at least one ion processing instrument positioned between the ion source and the at least one ion separation instrument, the at least one ion processing instrument positioned between the ion source and the at least one ion separation instrument comprising one or any combination of at least one instrument for collecting or storing ions, at least one instrument for filtering ions according to molecular properties, at least one instrument for dissociating ions, and at least one instrument for standardizing or transforming ion charge states.

28. A system according to any one of claims 21 to 27, further comprising at least one ion processing instrument positioned between the at least one ion separation instrument and the ELIT, the at least one ion processing instrument positioned between the at least one ion separation instrument and the ELIT comprising one or any combination of at least one instrument for collecting or storing ions, at least one instrument for filtering ions according to molecular properties, at least one instrument for dissociating ions, and at least one instrument for standardizing or transforming the charge state of ions.

29. A system according to any one of claims 21 to 28, wherein: The ELIT is configured to allow ions to leave therefrom, And wherein the system further comprises at least one ion separation instrument positioned to receive ions exiting the ELIT and to separate the received ions according to at least one molecular characteristic.

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

31. A system according to claim 29, further comprising at least one ion processing instrument positioned to receive ions leaving the at least one ion separation instrument which is itself positioned to receive ions leaving the ELIT, the at least one ion processing instrument positioned to receive ions leaving the at least one ion separation instrument which is itself positioned to receive ions leaving the ELIT comprising one or any combination of at least one instrument for collecting or storing ions, at least one instrument for filtering ions according to molecular properties, at least one instrument for dissociating ions, and at least one instrument for standardizing or transforming the charge state of ions.

32. A system according to any one of claims 21 to 29, wherein: The ELIT is configured to allow ions to leave therefrom, And wherein the system further includes at least one ion processing instrument positioned to receive ions leaving the ELIT, the at least one ion processing instrument positioned to receive ions leaving the ELIT including one or any combination of at least one instrument for collecting or storing ions, at least one instrument for filtering ions based on molecular properties, at least one instrument for dissociating ions, and at least one instrument for standardizing or transforming the charge state of ions.

33. A system for separating ions, the system comprising: an ion source configured to generate ions from the sample, a first mass spectrometer configured to separate the generated ions according to 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 the dissociated ions leaving the ion dissociation stage according to mass-to-charge ratio, and The CDMS of claim 1, coupled in parallel with and to the ion dissociation stage such that the CDMS can receive ions exiting either of the first mass spectrometer and the ion dissociation stage, wherein the mass of the precursor ions leaving the first mass spectrometer is measured using the CDMS, the mass-to-charge ratio of the dissociated ions of the precursor ions having a mass value below a threshold mass is measured using the second mass spectrometer, and the mass-to-charge ratio and charge value of the dissociated ions of the precursor ions having a mass value equal to or above the threshold mass are measured using the CDMS.

34. 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 a first ion mirror and a second ion mirror, the method comprising: controlling the charge generator (i) to generate a target amount of free charge using a processor, and The target amount of free charges generated is accelerated through a region defined between the charge generator and the charge detection cylinder and into contact with the charge detection cylinder to deposit the target amount of free charges thereon and thereby calibrate or reset the charge detection cylinder to a corresponding target charge level, or (ii) generate at least one electric field in the region to induce a target charge on the charge detection cylinder to calibrate the charge detection cylinder.

35. The method of claim 34, wherein: Accelerating the generated target number of free charges to cross the field-free region includes: using the processor to control a voltage source coupled to the charge generator to selectively generate an electric potential, thereby establishing a charge accelerating electric field outside the field-free region, and the charge accelerating electric field is oriented to cause the generated target number of free charges to enter the field-free region and toward the charge detection cylinder.

36. A method according to claim 34 or claim 35, wherein: the ELIT being configured to trap ions therein such that the ions oscillate back and forth between the first ion mirror and the second ion mirror each time the ions pass through the charge detection cylinder and a corresponding charge is induced thereon, And wherein, controlling the charge generator to generate the target number of free charges includes: controlling the charge generator to generate the target number of free charges when the ions are located in a corresponding one of the first ion mirror and the second ion mirror after each time the ions pass through the charge detection cylinder, so as to thereby calibrate or reset the charge detection cylinder between each time the ions pass through the charge detection cylinder.

37. The method of claim 35, wherein: the charge detector comprising a charge preamplifier having an input coupled to the charge detection cylinder and an output coupled to the processor, the charge preamplifier being configured to generate a charge detection signal in response to charge induced thereon by ions passing through the charge detection cylinder, Wherein, controlling the charge generator to generate the target amount of free charges comprises: controlling the charge generator to generate the target amount of free charges each time it is detected that the charge detection signal is absent at the output of the charge preamplifier.

38. The method of claim 36, wherein: no feedback component is electrically connected between the input and the output of the charge preamplifier, And wherein, the method further includes: selecting the target number of free charges so that when detected by the charge preamplifier, the target number of free charges deposited on the charge detection cylinder clears a certain amount of charge noise accumulated on the charge detection cylinder through the charges induced thereon by the captured charges passing through the charge detection cylinder, thereby resetting the charge detection cylinder and the charge preamplifier to repeatable corresponding operating states.

39. The method according to any one of claims 35 to 38, wherein: The trapped ions oscillate back and forth between the first ion mirror and the second ion mirror for an ion measurement event duration defined by a predefined time duration or a predetermined number of oscillations, and after the ion measurement event duration, the ions leave the ELIT, And wherein controlling the charge generator to generate the target amount of free charges includes: controlling the charge generator to generate the target amount of free charges after the ions leave the ELIT.

40. The method of claim 39, wherein: the ELIT being controlled to continuously trap ions therein for the duration of an ion measurement event and to allow the ions to exit the ELIT a plurality of times, And wherein controlling the charge generator to generate the target amount of free charges includes: controlling the charge generator to generate the target amount of free charges after the corresponding ions leave the ELIT each time.

41. The method of claim 34 or claim 35, wherein: The ELIT is configured to (i) trap ions therein so that the ions oscillate back and forth between the first ion mirror and the second ion mirror each time the ions pass through the charge detection cylinder and induce corresponding charges thereon, (ii) cause the trapped ions to oscillate back and forth between the first ion mirror and the second ion mirror for an ion measurement event duration defined by a predefined duration or a predetermined number of oscillations, and (iii) allow the trapped ions to leave the ELIT after the ion measurement event duration is derived, And wherein controlling the charge generator to generate the target amount of free charges includes: controlling the charge generator to generate the target amount of free charges after the ions leave the ELIT.

42. The method according to claim 41, wherein: The ELIT is controlled to repeat (i) to (iii) for a plurality of consecutive ion measurement events, And wherein controlling the charge generator to generate the target amount of free charges includes: controlling the charge generator to generate the target amount of free charges after the corresponding ions leave the ELIT each time.

43. A method according to any one of claims 39 to 42, wherein: the charge detector comprising a charge preamplifier having an input coupled to the charge detection cylinder and an output coupled to the processor, the charge preamplifier being configured to generate a charge detection signal in response to charge induced thereon by ions passing through the charge detection cylinder, wherein no feedback component is electrically connected between the input and the output of the charge preamplifier, And wherein, the method further comprises: selecting the target amount of free charges so that when detected by the charge preamplifier, the target amount of charges deposited on the charge detection cylinder clears a certain amount of charge noise accumulated on the charge detection cylinder through the charges induced thereon by the captured charges passing through the charge detection cylinder, thereby resetting the charge detection cylinder and the charge preamplifier to repeatable corresponding operating states.

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

45. The method of claim 34, wherein: At least one ion mirror voltage source is operably coupled to the first ion mirror and the second ion mirror and is configured to generate a voltage for selectively establishing an ion transmission electric field or an ion reflection electric field therein, the ion transmission electric field being configured to concentrate ions passing through a corresponding one of the first ion mirror and the second ion mirror toward a longitudinal axis passing through the first ion mirror and the second ion mirror and the center of each of the charge detection cylinders, the ion reflection electric field being configured to stop and accelerate ions entering a corresponding one of the first ion mirror and the second ion mirror from the charge detection cylinder in opposite directions, return through the charge detection cylinder and toward the other of the first ion mirror and the second ion mirror, while also concentrating the ions toward the longitudinal axis, and wherein the at least one ion mirror voltage source is configured to selectively modify a voltage generated thereby to switch an electric field established in either or both of the first ion mirror and the second ion mirror between the ion transmission electric field and the ion reflection electric field, and wherein the electric field established in either or both of the first ion mirror and the second ion mirror is switched between the ion transmission electric field and the ion reflection electric field to induce corresponding transient charges on the charge detection cylinder, And wherein, controlling the charge generator to generate the at least one electric field in the region includes controlling the charge generator voltage source to apply a voltage pulse to the charge generator, while also switching the electric field established in at least one of the first ion mirror and the second ion mirror from the ion transmission electric field to the ion reflection electric field or from the ion reflection electric field to the ion transmission electric field, the voltage pulse being selected to create a corresponding electric field in the region, the electric field having at least one of a selected shape, size and duration, thereby inducing corresponding charges on the charge detection cylinder, the charges being approximately equal and opposite to the corresponding transient charges induced on the charge detection cylinder by switching the electric field established in the at least one of the first ion mirror and the second ion mirror.

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