Pulse width modulation for the optimization of mass ranges in a mass spectrometer

Abstract

Disclosed are systems, methods, and other implementations, including a method of operating a time-of-flight (TOF) mass analyzer, that includes introducing a plurality of ions into the mass analyzer, applying a plurality of voltage pulses to a pusher electrode of the mass analyzer to direct at least a portion of the plurality of ions into an acceleration region of the mass analyzer to generate accelerated ions, using an ion detector to detect the accelerated ions after passage thereof through a field-free region so as to generate ion detection data during a data acquisition period, and adjusting a pulse duration of the voltage pulses during the data acquisition period such that ion detection data is acquired during the data acquisition period at two or more different voltage pulse durations.

Description

PULSE WIDTH MODULATION FOR THE OPTIMIZATION OF MASS RANGES IN AMASS SPECTROMETERRelated Applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 625,617 filed on January 26, 2024, the contents of which are incorporated herein by reference in their entirety.Technical Field

[0002] The present disclosure relates generally to systems and methods for performing mass spectrometry, and more particularly to such systems and methods that utilize time-of-flight (ToF) mass analyzers.Background

[0003] The present disclosure provides systems and methods for performing mass spectrometry using a time-of-flight (TOF) mass analyzer, and particularly such systems and methods that allow optimizing the performance of a (TOF) mass analyzer for detection of ions spanning a range of m / z ratios through control of the duration of voltage pulses used for accelerating ions in the TOF mass analyzer.

[0004] Mass spectrometry (MS) is an analytical technique for determining the structure of test chemical substances with both qualitative and quantitative applications. MS can be useful for identifying unknown compounds, determining the composition of atomic elements in a molecule, determining the structure of a compound by observing its fragmentation, and quantifying the amount of a particular chemical compound in a mixed sample. Mass spectrometers detect chemical entities as ions such that a conversion of the analytes to charged ions must occur.

[0005] Time-of-flight mass spectrometry relies on different arrival times for separate ions having different m / z ratios. In such systems, the mass analyzer can include a pusher electrode to which voltage pulses can be applied to direct ions arrived at the pusher electrode into an acceleration region in which the ions are accelerated via an electric field. The accelerated ions enter a field- free ion drift region in which they travel to reach an ion detector that detects the ions. The time required for the ions to pass through the drift region to reach the ion detector depends on their m / z ratios, thereby allowing the ions to be separated based on their m / z ratios.Summary

[0006] The present disclosure is directed to a proposed framework that implements pulse width modulation to vary the duration of sequential electrical pulses applied by a pusher electrode (of an accelerator section / module of a mass spectrometer apparatus) to a sample of ions being analyzed by a mass spectrometer apparatus, thus allowing more optimal processing of ions within different m / z ranges. In various embodiments, the framework implements ionprocessing cycles that include pulses with short duration and long duration pulse widths in order to optimize the performance of mass spectrometry for low mass and high mass ions simultaneously present within an ion sample being analyzed. As the pulsing frequency of the voltage pulses applied to the pusher electrode of a TOF mass analyzer increases (e.g., > 50kHz) and the path length of ions within the TOF mass analyzer gets much shorter than the path length within an N geometry configuration of the analyzer, a one-size-fits-all approach with respect to the pulse duration may not produce satisfactory data due to sub-optimality of a particular pulse duration for certain m / z ranges (e.g., due to the configuration, physical attributes (such as geometry) of the apparatus being used).

[0007] Thus, in various embodiments, after acquiring a short pulse duration spectrum (and, in some example embodiments, eliminating the poor high mass data), and subsequently acquiring a long pulse duration spectrum and eliminating poor low mass data, the two (filtered) spectra can then reassembled to provide one composite spectrum that covers the broader m / z range in a usable manner, retaining the high quality data while discarding the poor quality data that was eliminated from the individual low-mass and high-mass spectra.

[0008] In various embodiments, the proposed framework implements high pulsing speed on a shorter ToF configuration by using a pulse width modulation optimization method. It corrects for peak smearing that may occur at higher m / z ratios and missing mass peaks at lower m / z ratios due to non-optimal pulse widths.

[0009] Therefore, in some embodiments, the pulse duration applied during sequential data acquisition periods may be varied (modulated) by using short pulses to detect low mass ions (i.e., for ions within a relatively low m / z values), while using longer pulses to detect high mass ions (for ions falling within a range of m / z values higher than that used for the low mass ions). One advantage of using a higher pulsing frequency is that the number of MSMS or MS spectra thatcan be acquired increases with the pulsing frequency (thus improving the quality of peak statistics that can be determined from acquired MS spectra).

[0010] In one aspect, a method of operating a time-of-flight (TOF) mass analyzer is disclosed, that includes introducing a plurality of ions into the mass analyzer, applying a plurality of voltage pulses to a pusher electrode of the mass analyzer to direct at least a portion of the plurality of ions into an acceleration region of the mass analyzer to generate accelerated ions, using an ion detector to detect the accelerated ions after passage thereof through a field-free region so as to generate ion detection data during a data acquisition period, and adjusting a pulse duration of the voltage pulses during the data acquisition period such that ion detection data is acquired during the data acquisition period at two or more different voltage pulse durations.

[0011] In various embodiments, the method can further include analyzing the ion detection data to generate a mass spectrum of the at least the portion of the plurality of ions.

[0012] In various embodiments, the step of analyzing the ion detection data can include generating a first mass spectrum corresponding to a first range of m / z ratios associated with a first one of said two or more different voltage pulse durations, generating a second mass spectrum corresponding to a second range of m / z ratios associated with a second one of said two or more different voltage pulse durations, and combining the first and the second mass spectra to obtain a mass spectrum of the at least a portion of the said plurality of ions. The first range of m / z ratios and the second range of m / z ratios can be partially overlapping.

[0013] In various embodiments, the first range of m / z ratios can include one or more m / z ratios that are less than one or more m / z ratios in the second range of m / z ratios. The first one of said two or more different voltage pulse durations can be less than the second one of said two or more different voltage pulse durations.

[0014] In various embodiments, the step of adjusting the pulse duration of the voltage pulses can include maintaining the pulse duration at a first one of the two or more different voltage pulse durations during a first portion of said data acquisition period and maintaining the pulse duration at a second one of the two or more different voltage pulse durations during a second portion of said data acquisition period. The first portion and the second portion of the data acquisition period can be partially overlapping.

[0015] In various embodiments, the step of adjusting the pulse duration of the voltage pulses can include changing the pulse duration alternatingly between a first one and a second one of said two or more different voltage pulse durations.

[0016] In another aspect, a method of operating a time-of-flight (TOF) mass analyzer is disclosed that includes configuring a mass filter to allow passage of ions having m / z ratios within a first m / z range, introducing ions passing through the mass filter into a downstream time-of- flight (TOF) mass analyzer, applying a plurality of voltage pulses having a first pulse duration selected based on the first m / z range to a pusher electrode of the mass analyzer to direct at least a portion of the ions received by the mass analyzer into an acceleration region of the mass analyzer to generate accelerated ions, and using an ion detector to detect the accelerated ions after passage thereof through a field-free region so as to generate ion detection data during a data acquisition period.

[0017] In various embodiments, the method can further include reconfiguring the mass filter to allow passage of ions having m / z ratios within a second m / z range and adjusting the pulse duration of the voltage pulses applied to the pusher electrode to a second pulse duration.

[0018] In various embodiments, the first and the second m / z ranges can be partially overlapping.

[0019] In various embodiments, the one or more m / z ratios in the first range can be less than one or more m / z ratios in the second range.

[0020] In various embodiments, the second pulse duration can be greater than the first pulse duration.

[0021] In a further aspect, a mass spectrometer is provided that includes a time-of-flight (TOF) mass analyzer for receiving ions, at least one voltage source for applying voltage pulses to a pusher electrode of the TOF mass analyzer to direct at least a portion of the ions received by the mass analyzer into an acceleration region of the mass analyzer to generate accelerated ions, and a controller in communication with the at least one voltage source. The controller is configured to adjust pulse durations of the voltage pulses applied to the pusher electrode of the TOF mass analyzer such that ion detection data is acquired during the data acquisition period at two or more different voltage pulse durations.

[0022] In various embodiments, the controller can further be configured to analyze the ion detection data to generate a mass spectrum of the received ions, including to: generate a first mass spectrum corresponding to a first range of m / z ratios associated with a first one of said pulse durations, generate a second mass spectrum corresponding to a second range of m / z ratios associated with a second one of said pulse durations, and combine the first and the second mass spectra to obtain a mass spectrum of said received ions.

[0023] In various embodiments, the first range of m / z ratios and the second range of m / z ratios can be partially overlapping.

[0024] In various embodiments, the first one of said pulse durations can be less than the second one of said pulse durations.

[0025] In various embodiments, the mass spectrometer can further include a mass filter, positioned upstream of the mass analyzer, configured to receive a plurality of ions and to allow passage of a portion of the plurality of ions having m / z ratios within a bandwidth thereof. The controller can be configured to set the bandwidth of the mass filter and can further be configured to adjust the pulse durations of the voltage pulses applied to the pusher electrode of the TOF mass analyzer based on the bandwidth of the mass filter.

[0026] In a further aspect, a mass spectrometer is provided that includes a mass filter configured to receive a plurality of ions and to allow passage of ions having m / z ratios within a bandwidth thereof, a time-of-flight (TOF) mass analyzer positioned downstream of the mass filter for receiving ions passing through the mass filter, at least one voltage source for applying voltage pulses to a pusher electrode of the TOF mass analyzer to direct at least a portion of the ions received by the mass analyzer into an acceleration region of the mass analyzer to generate accelerated ions, and a controller in communication with the mass filter and the at least one voltage source. The controller is configured to set a bandwidth of the mass filter and is further configured to adjust a pulse duration of the voltage pulses applied to the pusher electrode of the TOF mass analyzer based on the bandwidth of the mass filter.

[0027] In various embodiments, the controller can be further configured to adjust the bandwidth of the mass filter such that any two consecutive bandwidths are partially overlapping.

[0028] In various embodiments, the controller can be further configured to increase the pulse duration of the voltage pulses as an average of m / z ratios contained within the bandwidth of the mass filter increases.

[0029] In various embodiments, the mass spectrometer can further include an ion detector positioned at a distal end of a field-free region of the TOF mass analyzer to receive the accelerated ions after passage thereof through the field-free region and to generate ion detection data.

[0030] In various embodiments, the mass spectrometer can further include a data acquisition and analysis module configured to receive the ion detection data and to process the ion detection data to generate mass spectra data. The data acquisition and analysis module can be further configured to process the ion detection data to generate at least two mass spectra each corresponding to one of at least two different pulse durations.

[0031] Further understanding of various aspects of the present teachings can be obtained by reference to the following detailed description in conjunction with the associated drawings, which are described briefly below.Brief Description of the Drawings

[0032] The skilled person in the art will understand that the drawings, described below, are for illustration purposes only. The drawings are not intended to limit the scope of the applicant’s teachings in any way.

[0033] FIG. 1 is a schematic representation of an example mass spectrometry system configured to implement pulse width modulation.

[0034] FIG. 2 is a schematic diagram of an example implementation of a linear ToF mass analyzer that may be used in conjunction with the mass spectrometry system of FIG. 1.

[0035] FIG. 3 is a schematic diagram of a linear ToF mass analyzer.

[0036] FIG. 4 includes a graph of a high-frequency voltage pulse train (applied to a pulser of a mass analyzer) with short pulse widths, and a resulting mass spectrum.

[0037] FIG. 5 includes a graph of a high-frequency voltage pulse train with long pulse widths, and a resulting mass spectrum.

[0038] FIG. 6 is a mass spectrum graph on which the spectra data obtained with pulse width of 0.9ps, and the spectra data obtained with a pulse width of 2.5ps are overlaid.

[0039] FIGS. 7A-7B present spectra graphs obtained from measurements performed at high frequency with a 0.9 ps pulse, and a 2.5 ps in which the portions of the graph containing nonideal performance results have been parsed.

[0040] FIG. 8 presents a graph of a composite spectrum combining two spectra obtained using two different pulse widths.

[0041] FIG. 9 includes examples of alternating voltage pulse sequences applied to the pusher plate.

[0042] FIG. 10 is an example of a user- interface screen to control mass parsing in the quad sections prior to the time-of-flight portion of a mass spectrometer.

[0043] FIG. 11 is a flowchart of another example procedure for operating a time-of-flight (TOF) mass analyzer and acquiring ion spectra data.

[0044] FIG. 12 is a flowchart of an example procedure for operating a mass spectrometer and acquiring ion spectra data.Detailed Description

[0045] It will be appreciated that for clarity, the following discussion will explicate various aspects of embodiments of the applicant’s teachings, while omitting certain specific details wherever convenient or appropriate to do so. For example, discussion of like or analogous features in alternative embodiments may be somewhat abbreviated. Well-known ideas or concepts may also, for brevity, not be discussed in any great detail. The skilled person will recognize that some embodiments of the applicant’s teachings may not require certain of the specifically described details in every implementation, which are set forth herein only to provide a thorough understanding of the embodiments. Similarly, it will be apparent that the described embodiments may be susceptible to alteration or variation according to common generalknowledge without departing from the scope of the disclosure. The following detailed description of embodiments is not to be regarded as limiting the scope of the applicant’s teachings in any manner.

[0046] As used herein, the terms "about" and "substantially equal" refer to variations in a numerical quantity that can occur, for example, through measuring or handling procedures in the real world; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of compositions or reagents; and the like. Typically, the terms "about" and "substantially" as used herein means 10% greater or less than the value or range of values stated or the complete condition or state. For instance, a concentration value of about 30% or substantially equal to 30% can mean a concentration between 27% and 33%. The terms also refer to variations that would be recognized by one skilled in the art as being equivalent so long as such variations do not encompass known values practiced by the prior art.

[0047] As used herein the term "and / or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as " / ".

[0048] As noted above, in a time-of-flight (TOF) mass analyzer, a pusher electrode to which voltage pulses are applied is employed to direct ions received by the mass analyzer into an acceleration region and then into a field- free region. The ions travel through the field- free region and are detected by a downstream ion detector. As the frequency of the voltage pulses applied to the pusher electrode increases, the number of MS or MS / MS spectra that can be acquired also increases. The increase in the number of acquired MS or MS / MS spectra can be advantageous in that it can enhance the dynamic range for ion detection as well as lead to improved mass peak statistics (due to larger number of available spectra for mass analysis).

[0049] However, in some TOF mass analyzers, e.g., those in which the ion path lengths are short enough for the pulse width of the accelerator to overlap with the ion detection window, as the pulsing frequency exceeds a certain threshold (e.g., for pulsing frequencies greater than about 50 kHz), the use of the same pulse width for directing ions of both low and high m / z ratios may lead to smearing of the mass peaks in the resultant mass spectra. In fact, in some cases, such smearing of the mass peaks can in fact render the mass spectra unusable for mass analysis. In other words, the pulse widths that may be optimal for processing ions having m / z ratios less than a threshold, may not be optimal for processing of ions having higher m / z ratios. For example,shorter pulses may not provide sufficient time for heavier ions to clear one or more acceleration regions.

[0050] As discussed in more detail below, in some embodiments, the m / z range associated with ions for which mass analysis is desired can be split into two or more regions, and an optimal duration for voltage pulses to be applied to the pusher electrode can be selected for processing of ions within each m / z region. By way of example, the m / z range associated with the ions may be split into two portions such that the m / z ratios in the lower m / z region would be less than an m / z threshold and the m / z ratios in the higher m / z region would be equal to or more than the threshold. In this example, the duration of the voltage pulses applied to the pusher electrode for processing of the ions in the lower m / z region will be less than the respective duration of the voltage pulses applied to the pusher electrode for processing of the ions in the higher m / z region. In such cases, the mass peaks corresponding to high m / z ions that appear in the short pulse duration mass spectrum, which may exhibit poor characteristics, can be eliminated to generate a low m / z spectrum. Similarly, the mass peaks corresponding to low m / z ions that appear in the long pulse duration spectrum, which may also exhibit poor characteristics, can be eliminated to generate a high m / z spectrum. The low m / z and the high m / z spectra can be combined (stitched together) to generate a full spectrum of the ions.

[0051] Accordingly, in various embodiments, a proposed approach for processing an ion sample comprising ions groups spanning two or more m / z ranges is implemented herein (e.g., using a time-of-flight (TOF) mass analyzer). The proposed approach includes introducing a plurality of ions into the mass analyzer, and applying a plurality of voltage pulses (typically at frequencies of at least 50 kHz) to a pusher electrode of the mass analyzer to direct at least a portion of the received ions into an acceleration region of the mass analyzer to generate accelerated ions. An ion detector is then used to detect the accelerated ions after passage thereof through a field-free region to generate ion detection data during a data acquisition period. The proposed approach further includes adjusting a pulse duration of the voltage pulses during the data acquisition period such that ion detection data is acquired during the data acquisition period at two or more different voltage pulse durations. Different data processing procedures can then be applied to respective acquired mass spectrometry spectra resulting from the different pulse lengths. For example, when two different pulse lengths are used (e.g., a first voltage pulse width of 0.9 ps followed by a second voltage pulse of 2.5 ps), different portions of each acquiredspectrum can be omited (to produce resultant truncated or parsed spectra), and the truncated spectra (omiting the “less reliable” (aka unusable) data, but retaining the good quality data) are combined.

[0052] More particularly, and with reference to FIG. 1, a schematic diagram of an example mass spectrometer 100, implemented according to the proposed framework described herein, is shown. The example mass spectrometer 100 is a liquid chromatography (LC) / mass spectrometry (MS) system that uses a linear TOF mass analyzer 150 to analyze the ions in an ion stream. However, in some embodiments, other types of the mass spectrometers (analyzers) may be used, such as capillary electrophoresis (CE)-mass spectrometer, infusion-type mass spectrometer, nano-spray mass spectrometer, etc. The LC-MS spectrometric system 100 includes a liquid chromatography (LC) column that can receive a sample and deliver the eluate exiting the LC column to an ion source (not shown) that is in communication with the LC column. The ion source can ionize one or more analytes within the received eluate to generate a plurality of ions that can be received by an ion guide 110 (a QJet ®ion guide in the example of FIG. 1) via an orifice 102 of the mass spectrometer. The QJet ion guide 110 includes a set of rods 112 arranged in a quadrupole configuration, two of which 112a / l 12b are depicted in FIG. 1. Generally, the QJet ion guide 110 employs a combination of gas dynamics and radio frequency fields to cause focusing of the ions.

[0053] As further shown in FIG. 1, the ions exiting the QJet ion guide 110 are focused by an ion lens IQ0 118 into an ion guide Q0 120, which includes a set of quadrupole rods 122, two of which 122a / 122b are visible in FIG. 1, to which RF voltages can be applied for causing radial confinement of the ions of an ion beam, which is in turn received by an ion mass filter QI 130. The ion guides QJet®, Q0, and the mass filter QI are disposed in differentially-pumped chambers that are maintained at progressively lower pressures. For example, QJet® ion guide can operate at a pressure of, for example, about 1-10 Torr, a Q0 focusing ion guide can operate at a pressure of, for example, about 1-100 mTorr, and a mass filter QI can operate at a pressure of, for example, less than 1x1 O'4Torr.

[0054] An ion lens IQ1 128 focuses the ions exiting the Q0 ion guide 120 into the mass filter QI 130. The mass filter QI 130 includes a stubby lens 134 formed by a set of quadrupole rods (two of which 134a / 134b are depicted in FIG. l) to which RF voltages can be applied to causefocusing of the ions. The mass filter QI 130 further includes a set of quadrupole rods 132, two of which 132a / 132b are visible in the figure, to which a combination of RF and DC voltages can be applied to allow the selection of one or more precursor ions, e.g., all precursor ions of interest when the mass spectrometer is operating in a DIA mode, having m / z ratios within a target m / z range for transmission to a downstream ion dissociation device Q2 140, e.g., a collision cell in this example via an ion lens IQ2 138. A stubby lens 136 that includes a set of quadrupole rods (two of which 136a / 136b are visible in the figure) positioned downstream of the quadrupole rod set 132 helps focus the selected precursor ion into the downstream electron ion dissociation device Q2 140.

[0055] The mass filter QI 130 is thus configured to select an ion of interest and / or a range of ions of interest. By way of example, the quadrupole rod set for QI can be provided with RF / DC voltages suitable for operation in a mass-resolving mode, e.g., in accordance with a controller 170 to dynamically select an m / z ratio range that is to pass through the mass filter. Taking the physical and electrical properties of QI into account, parameters for an applied RF and DC voltage can be selected so that QI establishes a transmission window of chosen m / z ratios, such that these ions can traverse QI largely unperturbed. Ions having m / z ratios falling outside the window, however, do not attain stable trajectories within the quadrupole and can be prevented from traversing the quadrupole rod set QI . As will be discussed in greater detail below, users may interact and provide controlling commands and instructions through a user interface (which may be rendered, for example, on a display device coupled to the data processing module 160). For example, a user may specify a mass range that it wishes to examine. Based on the specified mass range, the controller 170 may determine the RF and DC voltages that need to be applied to the quadrupole rods of the mass filter QI 130 to cause ions within that range to pass through towards the downstream mass analyzer 150.

[0056] Additionally, in various embodiments, the controller 170 (or a separate dedicated controller) and / or the data processing module may determine pulse characteristics (e.g., pulse width) to generate a sequence of pulses with a pulse width suitable for the m / z range determined for the mass filter. That is, pre-knowledge of the m / z range for the ions about to be processed is used to configure the pulse sequence that will be applied to the pulser of the TOF mass analyzer to establish an electric field to act on the ions that were allowed to pass through the mass filter tobe received by the downstream TOF mass analyzer. The controller 170 may cause a pulse train with a fixed pulse width to be generated based on this pre-knowledge of the m / z range (if the incoming ion stream comprises low mass ions, the controller will be configured to cause generation of relatively short pulse width). Alternatively, in various embodiments, when the m / z range is too broad, the controller 170 can be configured to generate a pulse train with alternating pulses of different widths that have been determined to generate good quality spectra data for the sub-ranges within the m / z range set for the mass filter.

[0057] It is to be noted that with the selection of a band-limited m / z range by the mass filter (which will forward only ions in that range), it may not be necessary to modulate the pulse width for the voltage pulses since a single pulse width may provide good quality data acquisition over the entire limited m / z range that the mass filter establishes. However, in some situations, in order to obtain more refined results, the limited m / z range established by the mass filter may be sub-divided to multiple sub-ranges (2, 3, or more), each of which will have an optimal pulse width (as may be determined for the specific m / z sub-range, taking into account operating conditions and characteristics of the mass spectrometer, including specifications of the mass analyzer) that will result in acquisition of more refined (higher quality) spectra data within the associated sub-range. Then, spectra data acquired through application of a pulse with a particular pulse width that falls outside the associated sub-range may be discarded. The high-quality spectra data for each subrange is subsequently combined to form a composite spectrum (as will become apparent below).

[0058] As further shown in FIG. 1, a DC voltage source 172 and an RF voltage source 174 operating under control of a controller 170, are configured to controllab ly apply RF and DC voltages to the one or more of the sections of the mass spectrometer 100, including to controllably apply DC and RF voltages to the QJet® section, the Q0 section, the mass filter QI 130, and / or any of the other sections / modules of the mass spectrometer 100. The voltage sources 172 and 174 are generally independently electrically coupled to any of the mass spectrometer’s sections so as to independently control those sections’ operations (using the controller 170). For example, the controller 170 may be configured to control the RF voltage source 174 so that the RF voltage applied to the rods of the QI mass filter can have a frequency in a range of about 200 kHz to about 1.2 MHz and a peak-to-peak amplitude (Vpp) in a range of about 100 volts to about 10 kilovolts (kV).

[0059] With continued reference to FIG. 1, in various embodiments, the collision cell Q2 140 includes a set of rods 142, two of which 142a / 142b are visible in the figure, which are arranged in a quadrupole configuration. The collision cell is pressurized via introduction of, for example, nitrogen gas to allow collisional fragmentation of the ions received by the collision cell Q2. The RF frequency applied to the rods of the Q2 collision cell can be, for example, in a range of about 1 MHz to about 5 MHz. In various embodiments, the Q2 cell can be employed for collisional focusing, where higher RF frequencies, e.g., 5 MHz, can be employed.

[0060] The ions exiting the Q2 cell 140 are focused by a set of ion focusing optics 144 into a time-of-flight (TOF) mass analyzer 150 (an example embodiment of a suitable mass analyzer is the linear TOF mass analyzer 200, discussed in greater detail below with respect to FIG. 2). The mass analyzer 150 includes an ion detector 152, which generates ion detection data in response to the detection of ions incident thereon (e.g., generating electrical pulses representative of ion intensity, and producing a sequence of detection signals as a function of time). The ion detection signals generated by the ion detector can be processed using a data processing module 160 to generate the mass spectrum of the received ions.

[0061] As further illustrated in FIG. 1, the controller 170 of the mass spectrometry system 100 is additionally configured to control / actuate a pulser voltage source 180 (configured to generate electrical pulses over a range of different frequencies, and with controllable amplitude, width, and / or shape) to apply voltage pulses to a pusher plate (also referred to as a pulser plate) 154 at an upstream location of the mass analyzer 150 (e.g., proximate to the entrance to the mass analyzer 150). The voltage pulses applied to the pusher plate (e.g., an electrode, such as the electrode 302 depicted in FIG. 3) establishes an electric field between the pusher plate and a companion plate paired with the pusher plate to cause ions introduced into the accelerator to accelerate. Different ions having different m / z values will experience different accelerations, thus resulting in different time-of-flight behaviors for those different ions.

[0062] The controller 170 is configured to generate, inter alia, control signals (e.g., an ON signal that remains active for the desired duration of the electrical pulse to be applied to the pusher) to cause the pulser voltage source 180 to generate a pulse with a width determined according to the control signal provided by the controller 170. It is to be noted that the controller 170 in combination with the pulser voltage source 180 may be configured to also controllably modulate,for example, the frequency of the voltage pulses. In some embodiments, the pulser voltage source may be configured to tune the amplitude applied to the pusher (pulser) plate 154 during system tune-up time. However, once the appropriate voltage / amplitude is determined, that voltage level will generally remain fixed and will not change. Typically, though, for a particular set of measurements of an ion sample, the frequency and amplitude will be set to a fixed value (e.g., the pulse frequency may be set to a fixed value in the range of 25 kHz to 1 MHz), in which case the controller 170 (or some other dedicated controller) will primarily control the pulse widths of the pulses applied to the pusher / pulser plate 154.

[0063] In some embodiments, the data processing module 160 (or alternatively the ion detector 152) may be in electrical communication with the pulse width modulation and be configured to control, at least partly, operation of the pulse width modulation controller 170. For example, the data processing module 160 may be implemented to include a user interface through which users can interact with the system 100, to control various modes of system operation. For instance, a user interface rendered on a screen attached to the data processing modules may provide input prompts to specify (e.g., from a look-up table) a sequence of pusher (acceleration) pulses and their durations, e.g., to repeatedly generate a short pulse, that results in more optimal acquisition of spectra data for lighter ions, followed by a long pulse that results in a more optimal acquisition of spectra data for heavier ions. In another example, the pulse width modulation controller 170 may be configured to generate an initial pulse (or a sequence of pulses) of some pre-determined duration that results in acquisition of spectra data covering a relatively large portion of the mass spectrum of the ion sample being analyzed. That spectra data can be used to make an initial coarse estimate of the various ions present in the sample, based on which a suitable sequence of different pulse widths can be determined that, when applied in sequence by the controller 170 and the pulser 180, would provide more accurate (and with better mass resolution) spectra data for m / z sub-ranges corresponding to the ions identified to be in the sample. The specific pulse widths can be determined a priori (off-line), based, for example, on mathematical equations governing the motion of ions with different m / z values inside a mass spectrometer, or based on predicted values generated through a trained machine learning system that outputs appropriate pulse characteristics for specified mass ranges and / or operating conditions.

[0064] As noted, controller 170 may be implemented to control the mass filter 130. Based on input from the user, or based on initial measurements of the composition of the ions beinganalyzed, a resultant m / z range may be determined to let ions within the resultant m / z range pass through the filter en route to the collision cell 140 and the mass analyzer 150, while suppressing or inhibiting passage of ions outside the determined m / z range. In some examples, the m / z range to be used by the mass filter may be computed according to input parameter(s) provided as input by a user. For example, the user may provide pulse width values (or other available input param eter(s)), resulting in automatic determination (e.g., by one of the controllers, or the data processing module) of an appropriate m / z range compatible with the input values chosen by the user. Conversely, the user may specify the m / z (or mass) ranges, which in turn causes the controller 170 to compute suitable pulse width values (and / or other operating parameter values), or to select such values from a table of pre-determined values.

[0065] In various examples, the data processing module 160 may also be configured to process spectra measurement data acquired from the mass analyzer 150 based on the specific pulse width that was applied to obtain the spectra measurement data. For example, the processing module 160 may be configured to remove a portion of the spectra data corresponding to heavier ions (e.g., remove spectra data for values above a pre-determined m / z threshold value). Conversely, for spectra data captured as a result of applying a long pulse width, the processing module 160 may be configured to remove a portion of the spectra data corresponding to lighter ions, e.g., remove spectra data for m / z values below a cutoff threshold value (which may be the same or different cutoff threshold than that used to remove spectra data for lighter ions). The remainder portions of the spectra data (i.e., the retained portions) can subsequently be combined (concatenated) to produce a composite spectrum covering, for example, a portion of the spectra data corresponding to low m / z ratios retained from measurement data resulting from application of a short pulse can be combined with a portion of the spectra data corresponding to high m / z ratios retained from measurement data resulting from application of a long pulse. In some examples, spectra data for multiple different m / z ranges / bands, produced from application of pulse sequences with three or more different pulse lengths, can be generated.

[0066] With reference next to FIG. 2, a diagram of an example implementation of a linear ToF mass analyzer 200 that may be used in conjunction with the mass spectrometry system of FIG. 1 is shown. Further details regarding the implementation of a linear ToF mass analyzer such as the one depicted in FIG. 2 are provided in provisional application serial No. 63 / 590,600, entitled“Time of Flight Mass Spectrometer” and filed October 16, 2023, the content of which is herein incorporated by reference in its entirety.

[0067] Various ion acceleration regions of the ToF mass analyzer 200 can be implemented by employing a stack of electrodes to which voltages are applied to generate a desired electric field within that region. For example, the first ion acceleration region (<77) of the ToF mass analyzer 200 includes a pulser electrode 202, e.g., in the form of a solid conductive planar element, for deflecting the ions received by the ToF mass analyzer in an orthogonal direction and a pair of stacked electrodes 204, 206, e.g., in the form of solid conductive planar elements having central openings through which ions can pass. Various voltages can be applied to electrodes 204 and 206 to establish a desired electric field within the first acceleration region (<77).

[0068] A plurality of spacers 203A and 203B separate, respectively, the electrodes 202 / 204 and 204 / 206 from one another. The thickness of the spacers can be chosen to achieve a desired length of the first acceleration region (<77).

[0069] The mass analyzer 200 further includes a second ion acceleration region (<73) and a first field-free ion drift region (<72) that separates the first and the second ion acceleration regions. The second ion acceleration region (<73) includes electrically conductive electrodes 208, 210, 212, 214, 216, 218 and 220, for example, each in the form of a planar surface having a central opening through which ions can pass, which are stacked relative to one another and are pairwise separated via a plurality of electrically insulating separators 207, 209, 211, and 213. Voltages applied to the electrically conductive electrodes can establish an electric field within the second ion acceleration region. The thickness of the insulating separators and / or ring electrode thicknesses can be selected to achieve a desired effective length for the second ion acceleration region.

[0070] In the first field-free ion drift region (<72), two grid electrodes 240 and 242 are in electrical contact with electrodes 206 and 208, respectively. These grid electrodes provide openings through which ions can pass. To establish the field-free ion drift region, the electrodes 206 and 208 and the respective grid electrodes 240 and 243 may be maintained at the same voltage. In various embodiments, the grid electrodes can facilitate the formation of sharp transitions in the magnitude of the electric field between the ion acceleration regions and the adjacent field-free ion drift regions.

[0071] A second field-free ion drift region ( ) extends from the second ion acceleration region (d3) to an ion detector 250. The ions exiting the second ion acceleration region (d3) pass through a grid electrode to propagate through the final field-free ion drift region to reach the ion detector 250. The voltage applied to the grid electrode positioned between the second ion acceleration region (d3) and the second field-free ion drift region (d ) is the same as the voltage applied to the liner of the second field-free ion drift region and in various embodiments, it can create a distinct and sharp transition between the second ion acceleration region and the second field-free ion drift region. The second field-free ion drift region is surrounded by a liner, which can be maintained, for example, at the ground electric potential or at a floated voltage.

[0072] By selecting the lengths associated with the two ion acceleration regions and the two field-free ion drift regions as well as the voltages VI and V3 applied across the first and the second ion acceleration regions, respectively, a combination of a fast data acquisition rate and good (particularly for short-linear mass spectrometer instruments) mass resolution (i.e., the ability of a mass spectrometer to distinguish between ions of different mass-to-charge ratios (m / z) having similar masses) can be achieved. By way of example, and without limitation, in various embodiments, a data acquisition rate of at least 1 kHz together with a mass resolution of at least 3000 can be obtained.

[0073] FIG. 3 is a schematic diagram of a linear ToF mass analyzer 300 which may be similar to the linear ToF depicted in FIG. 2. The mass analyzer 300 includes an inlet 301 for receiving a plurality of ions propagating along a transverse axis (TA) and a deflector electrode 302 (also referred to as a pusher electrode) to which voltage pulses can be applied. In the embodiments of FIG. 3, each voltage pulse can cause the deflection of a portion of ions arrived at the TOF mass analyzer into an orthogonal direction along a longitudinal axis (LA) into a first ion acceleration region 304 established between the deflector electrode 302 and a downstream grid electrode 306. More specifically, a voltage differential (VI) applied via a controllable pulser voltage source 305 (which may be similar in configuration in implementation to the pulser voltage source 180 of FIG. 1) operating under control of a controller 307 (which may be similar to the controller 170 of FIG. 1) between the deflector electrode 302 and the downstream grid electrode 306 can generate an electric field El in the region between the deflector electrode 302 and the grid electrode 306, thereby establishing a first ion acceleration region 304 in which ions can be accelerated under theinfluence of the electric field El to a first kinetic energy (KE1). As noted, the electric pulses applied between the deflector plate 302 and the grid electrode 306 are controllab ly varied to produce pulses with widths that have been determined (during design-time or during run-time) to optimally produce high quality spectra data for certain m / z sub-ranges (bands), thus allowing for high-quality portions of spectra data, resulting from application of different pulse widths, to be combined while removing (discarding) low-quality or noisy data portions of the spectra data.

[0074] The linear TOF mass analyzer 300 further includes another grid electrode 310 that is positioned downstream from the grid electrode 306 and is held at the same electrical potential as the grid electrode 306 (in this embodiment, both grid electrodes 306 and 310 are maintained at the ground electric potential) so as to establish a first field-free ion drift region 308 between the two grid electrodes 306 and 310. As no electric field is applied to the ions as they travel across the field-free ion drift region 308, ions having the same electric charge, but different masses, will undergo some degree of spatial separation before exiting the first field-free ion drift region. In other words, because the ions entering the first field-free ion drift region have the same kinetic energy (KE1), ions with different masses will have different velocities that determine the time required for the ions to traverse the field- free ion drift region.

[0075] In some embodiments, a second ion acceleration region 312 is positioned downstream of and adjacent to the first field-free ion drift region 308. The second ion acceleration region 312 is established via application of a voltage differential between the grid electrode 310 and a downstream grid electrode 314. More specifically, a DC power supply 315, which may also operate under the control of the controller 307, applies a voltage differential (V2) across the grid electrodes 310 and 314, which results in the generation of an electric field E3 in the region between the two grid electrodes 310 and 314. The ions exiting the field-free drift region 308 enter the second ion acceleration region 312 established between the grid electrodes 310 and 314 and are accelerated under the influence of the electric field in this region to achieve a kinetic energy KE2, which is greater than the kinetic energy KE1.

[0076] The linear TOF mass analyzer further includes a second field-free ion drift region 316 that is positioned downstream of the second ion acceleration region 312 and is enclosed within a shell 317 (herein also referred to as a liner) that is maintained at the same electric potential asthe grid electrode 314. More specifically, the second field-free ion drift region 316 extends from the grid electrode 314 to an ion detector 318 that can detect ions passing through the second field- free ion drift region 316 and generate ion detection data. The ion detection data can, in turn, be received by a digital data processing module 320 (herein also referred to as the computer data system), which may be similar to the data processing module 160 of FIG. 1, that can operate on the ion detection data to generate a mass spectrum associated with the ions detected by the mass analyzer.

[0077] In the configuration of the mass analyzer depicted in FIGS. 2 and 3, the flight time (FT) of an ion having a mass-to-charge ratio denoted by m / z through the mass analyzer can be obtained using the following relation:Eq- (1)Where:• y denotes the ion location in the first acceleration region with y = 0 being the location adjacent to the first electrode (i.e., the deflector electrode), and y=dl being coincident with the exit grid of the first acceleration region.• dl denotes the length of the first ion acceleration region,• d2 denotes the length of the first field- free ion drift region,• d3 denotes the length of the second ion acceleration region,• d4 denotes the length of the second field- free ion drift region,• VI denotes the voltage applied across the first ion acceleration region, and• V3 denotes the voltage applied across the second ion acceleration region.

[0078] In various embodiments, by setting the values of the ion path length associated with the first ion acceleration region, namely, (di), and the ion path length associated with the second ion acceleration region, namely, (d3), as well as the voltages VI and V3 to be applied across the first and the second ion acceleration regions, the values of the lengths associated with the first and the second field- free ion drift regions can be obtained according to the following relationships:and

[0079] Thus, the dimensions of various regions of the mass analyzer (e.g., the mass analyzer 300) can be determined by selecting the dimensions of two regions of the mass analyzer and the voltages applied across the two ion acceleration regions. The ion path length through the mass analyzer (i.e., the path length of an ion from the deflector electrode 302 to the ion detector 318) and the voltages applied across the two ion acceleration regions can be chosen to obtain a desired resolution. The rate of the pulser (i.e., the rate at which voltages are applied to the deflector electrode) can then be adjusted to provide the maximum pulser frequency possible for the desired length and resolution configurations. Furthermore, the choice of the dl-d4 lengths and the voltages can affect the overall resolution and the limits of the maximum pulser frequency that can be utilized, but it does not directly change the pulser frequency. By changing the frequency of the pulser itself can the acquisition rate be changed. More generally, by selecting the values of four of the above parameters, the values for the other two parameters can be derived from the above relations (Eqs. (2) and (3)).

[0080] In addition to determining various operating parameters of the mass spectrometer system (e.g., voltages to be applied), suitable pulse characteristics (e.g., pulse widths) for the voltage pulses applied between electrodes in the acceleration region(s) can be selected to obtain higher quality detection data for particular m / z sub-ranges. A desired m / z range can also be specified or determined, and that range can be used to determine appropriate operating parameters for a mass filter (such as the RF and DC voltage to be applied to quadrupole rods of the mass filter in order to pass ions in that selected range).

[0081] Thus, in various examples, a mass spectrometer is provided that includes a time-of- flight (TOF) mass analyzer for receiving ions, and at least one voltage source for applying voltage pulses to a pusher electrode of the TOF mass analyzer to direct at least a portion of the ions received by the mass analyzer into an acceleration region of the mass analyzer to generate accelerated ions. The mass spectrometer additionally includes a controller in communication with the at least one voltage source. The controller is configured to adjust pulse durations of the voltage pulses applied to the pusher electrode of the TOF mass analyzer such that ion detection data is acquired during data acquisition periods at two or more different voltage pulse durations.

[0082] In some examples, the controller may further be configured to analyze the ion detection data to generate a mass spectrum of the received ions, including to generate a first mass spectrum corresponding to a first range of m / z ratios associated with a first one of said pulse durations, generate a second mass spectrum corresponding to a second range of m / z ratios associated with a second one of said pulse durations, and combine the first and the second mass spectra to obtain a mass spectrum of said received ions. In such embodiments, the first range of m / z ratios and the second range of m / z ratios may be partially overlapping. In some examples, the first one of said pulse durations may be less than the second one of said pulse durations.

[0083] It should be noted that terminating one pulse in the sequence (i.e., switching the pulse off), induces noise spike that can result in noisy detection output. As a result, two large peaks are generated at the start of each acquisition period that should be ignored. This is known as the veto window. For embodiments involving a fixed window, the data prior to the end of the veto window should therefore not be saved. Thus, in various embodiments, in order to mitigate this problem, recordation of data acquisition (by the detector) is timed such that the noise occurring from the pulse switching off is not recorded.

[0084] In some embodiments the implementation of the proposed framework allows for control of a mass filter (positioned upstream of the mass analyzer) to restrict the ions being passed to the downstream analyzer to a particular band / range of m / z values. Accordingly, in such embodiments, a mass spectrometer is provided that includes a mass filter (such as the QI mass filter 130) configured to receive a plurality of ions and to allow passage of ions having m / z ratios within a particular (pre-determined) bandwidth. The mass spectrometer also includes a time-of- flight (TOF) mass analyzer (such as the TOF analyzers 150, 200, or 300 depicted in FIGS. 1-3)that is positioned downstream of the mass filter, and is configured to receive ions passing through the mass filter (in embodiments of FIG. 1, the ions first pass through a collision cell Q2 140). The mass spectrometer further includes at least one voltage source (e.g., the pulser voltage sources 180 and 305 illustrated in FIGS. 1 and 3) for applying voltage pulses to a pusher electrode of the TOF mass analyzer to direct at least a portion of the ions received by the mass analyzer into an acceleration region of the mass analyzer to generate accelerated ions. The mass spectrometer additionally includes a controller (such as the controller 170 or 307, shown in FIGS. 1 and 3) in communication with the mass filter and the at least one voltage source. The controller is configured to adjust a pulse duration of the voltage pulses applied to the pusher electrode of the TOF mass analyzer based, for example, on the bandwidth of the mass filter.

[0085] In embodiments of the mass spectrometer that include the controllable mass filter the controller is configured to adjust the duration of the pulser such that the duration of the pulse adequately covers the mass range being passed by the mass filter. If the pulser duration is either too long or too short, then the pulser will modify the pulse widths. This can be done in a static manner from a lookup table or the like. For example, if the quad has 2 hops (as it does covering masses 100-1000) then there would be a need for a short pulse and a long pulse to generate quality spectra across this mass range. Conversely, if there is only one quad hop (as in a scan of masses 400-1000) then a single pulser duration for the experiments in question may be sufficient. In various examples, the controller is configured to increase the pulse duration of the voltage pulses as an average of m / z ratios contained within the bandwidth of the mass filter increases. The mass spectrometer may further include an ion detector positioned at a distal end of a field- free region of the TOF mass analyzer to receive the accelerated ions after passage thereof through the field-free region and to generate ion detection data. In some examples, the mass spectrometer may further include a data acquisition and analysis module that is configured to receive the ion detection data and to process the ion detection data to generate mass spectra data. The data acquisition and analysis module may be configured to process the ion detection data to generate at least two mass spectra each corresponding to one of at least two different pulse durations.

[0086] As described herein, under the proposed framework the pulse widths of voltage pulses used to accelerate ions within a time-of-flight are controllably varied in order to obtain higher quality data for different m / z sub-ranges within the overall ion sample spectrum (bandwidth). More particularly, in various embodiments, when running the mass analyzer pulserat speeds above ~50 kHz, a short pulse, which is advantageous for lower masses, may not be ideal for higher masses >500amu. This may be manifested as a smearing of the mass peaks above ~500amu to a point that these peaks are unusable. Without being bound to any particular theory, such smearing occurs because the shorter duration pulse does not allow enough time for the higher mass ions to clear the dl portion of the accelerator. At the other end of the spectrum, it is advantageous to have a longer pulse width from the pulser to allow for the high mass ions to clear the dl portion of the accelerator. Because the ion flight path can correspond to a fraction (e.g., roughly l / 3rd) of the ion path length in an N geometry configuration, the fact that the ions do not need to slow down and change directions (as happens when using ion mirrors), and the fact that the acceleration voltage (e.g., 10 kV) provided by the voltage source accelerates the ions, some timing issues may arise. When the pulse duration gets to be too long, or rather long enough to optimize the higher mass ions, then the veto signal which prevents the large peaks (and subsequent ringing from the pulser) being detected as “signal” begins to overlap with the flight times of the low mass ions. Furthermore, in some situations, because the TOF is short, a long duration pulse may result in low mass ions hitting the detector before the pulser has even shut off.

[0087] To illustrate, consider FIG. 4 which includes a graph 410 of a high-frequency voltage pulse train (applied to a pulser of a mass analyzer) with short pulse widths, and a resulting mass spectrum 420 (the data points for the graphs of FIGS. 4-9 were generally collected using a working linear TOF spectrometer, with some added simulated data to help clarify the pulse widths and pulse length variations). At pulser frequencies > 50kHz, a 0.9ps pulse width clears low mass ions out of the accelerator, but the pulse is not long enough and shuts off before the higher masses clear the dl region. This manifests itself as smeared peaks for masses >~500amu (e.g., mass 732, marked as reference numeral 422) includes a sharp front to the peak representing ions which have cleared the accelerator at the end of the pulse while the smear at the backside of the pulse represents a portion of the mass 732 ions that had not cleared the accelerator at the end of the pulse. For larger masses, it gets to the point where none of the ions at a specific mass are capable of making it out of the accelerator by the end of the pulse. FIG. 5 includes a graph 510 of a high-frequency voltage pulse train with long pulse widths, and a resulting mass spectrum 520. In contrast to the situation illustrated in FIG. 4, at pulser frequencies > 50 kHz, a 2.5ps pulse width clears all masses out of the accelerator, but due to the high pulse rate and very short flight times the low masses getclipped by the veto pulse, or hit the detector before the pulse has even ended. This is manifested as an absence of peaks below ~500amu for larger pulse widths.

[0088] FIG. 6 presents mass spectra graph 610 on which the spectra data of graph 420 (obtained with pulse width of 0.9ps) and the spectra data of graph 520 (obtained with a pulse width of 2.5ps) are overlaid. The composite spectrum of FIG. 6 shows that it is possible to have the entire target mass range of interest covered if one were to use two different pulse durations during an acquisition period. FIG. 6 also shows spectra high mass peak smears occurring for peaks beyond 600 amu. If a pulse duration compromise were to be used (e.g., with duration between 0.9 and 2.5 ps), the resultant spectra data would not provide satisfactory results at either end of spectrum in terms of mass identification. The alternative of using slower pulsing speeds can undermine the advantages of using a linear ToF configuration (namely, to allow faster and more plentiful ToF measurements, which can in turn provide better statistical computations to determine the masses being detected in the ion sample).

[0089] Thus, one solution for overcoming the pulse duration mass bias would be to discard the zones of non-ideal behavior in the short pulse duration and high pulse duration spectra and combine the two to arrive at a full spectrum. FIG. 7A includes a spectra graph 710 obtained from measurements performed at high frequency with a 0.9 ps pulse, in which the portion of the graph containing non-ideal performance results (namely, the high ion mass portion) has been parsed (filtered out, as indicated by shade area). Accordingly, the high mass smear that was present in the graph 420 is removed. Conversely, FIG. 7B includes spectra graph 720 obtained from measurements performed at high frequency with a 2.5 ps pulse, the lower portion of the graph containing non-ideal performance results (corresponding to the low mass spectra results) is filtered out (removed) as indicated by the shaded area occupying the low mass spectra portion of the graph 720.

[0090] Once the parsed spectra (comprising the retained high mass and low mass portions obtained from the long and short pulses, respectively) are combined, a composite spectrum is obtained, such as the composite (combined) spectrum 800 shown in FIG. 8.

[0091] It is to be noted that by using two different pulse durations and removing non-ideal performance results portions from resultant spectra, the pulsing (and thus measurement) frequency may be effectively cut in half (e.g., because only half the sample measurements are used todetermine each of the low mass and high mass spectra). Nevertheless, this reduction in effective sampling frequency is more than offset by the potential benefits uncovered by the present proposed framework, such as the pulse duration optimization across the mass range.

[0092] Because in various embodiments, as illustrated in FIGS. 7A-B, only spectra portions that contain usable spectra data are retained, it may not be necessary, in such embodiments, to alternate short and long pulse lengths and collecting data across the entire mass range if the spectra data above mass 500 is being removed. With this in mind, in some embodiments, a way to further optimize the pulse width modulation approach is to shorten the listening period (data acquisition period) of the short pulse, and leave the long pulse as full scan. An example of pulse sequencing that can be used in such embodiments is provided in graph 920 of FIG. 9, showing an alternating short and long pulse width sequence. For comparison purposes, a second alternating short and long pulse width sequence is provided in graph 910 positioned above the graph 920. It can be seen from a comparison of the pulse sequences shown in the graphs 910 and 920 that the optimized alternating short and long pulse width doubles the effective measurement sampling frequency (relative to the frequency of pulse sequence of the graph 910).

[0093] Another feature that can be considered when using the varied pulse duration and / or the procedure to vary the lengths of time between pulses (e.g., to shorten or lengthen the listening / detection period by the ion detector) is to tie these procedures to the mass range parsing procedure / algorithm. Under this approach appropriate pulse durations and / or listening durations can be determined according to user-specified selections (e.g., the mass range the user is interested in analyzing) and / or the behavior of the mass range parsing procedure (e.g., the procedure to control what portion of a spectrum, given the pulse duration and / or pulse frequency, to retain, and what portion to remove). For example, if the user selects a mass range that does not warrant the use of either a short duration or high duration pulse length, then the mass range parsing procedure may be omitted (i.e., the entire resultant spectrum of detected masses is retained), and the pulse train characteristics (pulse width duration, duration of listening period, etc.) may be automatically adjusted in accordance with the requested mass range. The determination of the appropriate pulse train characteristics may be based on a look-up table that matches pre-determined pulse characteristics values to mass ranges (and / or other information) provided by the user. In some examples, the determination of pulse characteristics may be performed using a machine learning implementation, trained using training data that associates pulse characteristics to different user-specified selections (such as mass ranges). In further examples, optimal, or near optimal pulse characteristic values can be computed according to mathematical relationships tying user-specified selections to, for example, voltage pulse characteristics. FIG. 10 is an example of a user-interface screen 1000 (rendered on a display device electrically coupled to a data processing module such as the data processing module 160 of FIG. 1) where the user may enter some of the information for the various fields (e.g., the mass ranges to be determined in separate transmission windows), and the pulse characteristics are then automatically determined and used for generating appropriate voltage pulses (e.g., by the pulser plate 154) applied to the accelerator plates of the mass analyzer (e.g., the mass analyzer 150 of FIG. 1).

[0094] With reference now to FIG. 11, a flowchart of a procedure 1100 for operating a time-of-flight (TOF) mass analyzer, and for acquiring ion spectra data, is shown. The procedure 1100 includes introducing 1110 a plurality of ions into the mass analyzer, applying 1120 a plurality of voltage pulses to a pusher electrode of the mass analyzer to direct at least a portion of the plurality of ions into an acceleration region of the mass analyzer to generate accelerated ions, using 1130 an ion detector to detect the accelerated ions after passage thereof through a field- free region so as to generate ion detection data during a data acquisition period, and adjusting 1140 a pulse duration of the voltage pulses during the data acquisition period such that ion detection data is acquired during the data acquisition period at two or more different voltage pulse durations.

[0095] In various examples, adjusting the pulse duration of the voltage pulses may include maintaining the pulse duration at a first one of the two or more different voltage pulse durations during a first portion of said data acquisition period and maintaining the pulse duration at a second one of the two or more different voltage pulse durations during a second portion of said data acquisition period. In such examples, the first portion and the second portion of the data acquisition period may be partially overlapping. In some embodiments, adjusting the pulse duration of the voltage pulses may include changing the pulse duration alternatingly between a first one and a second one of said two or more different voltage pulse durations.

[0096] In some embodiments, the procedure 1100 may further include analyzing the ion detection data to generate a mass spectrum of the at least the portion of the plurality of ions. Analyzing the ion detection data may include generating a first mass spectrum corresponding to a first range of m / z ratios associated with a first one of said pulse durations, a second mass spectrumcorresponding to a second range of m / z ratios associated with a second one of said pulse durations and combining the first and the second mass spectra to obtain a mass spectrum of the at least the portion of said plurality of ions. The first range of m / z ratios and the second range of m / z ratios may be partially overlapping. In some embodiments, the first range of m / z ratios may include one or more m / z ratios that are less than one or more m / z ratios in the second range of m / z ratios. The first one of said pulse durations may be less than the second one of said pulse durations.

[0097] FIG. 12 is a flowchart of another example procedure 1200 for operating a mass spectrometer and acquiring ion spectra data. As in the procedure 1100, the procedure 1200 is also predicated on controllably varying (modulating) pulse widths of voltage pulses applied to the pulser (pusher plate) of a ToF mass analyzer, but further includes using information from a mass filter, positioned upstream of the mass analyzer, to select an m / z range, or band, to allow ions in that range pass through to the mass analyzer while suppressing (deflecting) ions outside the dynamically controlled m / z range. The subsequent pulse width modulation performed by the mass analyzer is applied to a narrower and more defined m / z range, thus allowing acquisition of more refined data, and performance of more refined operation and analysis by the mass analyzer on the ions falling in the resultant m / z range set for the mass filter.

[0098] Accordingly, the procedure 1200 includes configuring 1210 a mass filter to allow passage of ions having m / z ratios within a first m / z range, introducing 1220 ions passing through the mass filter into a downstream time-of-flight (TOF) mass analyzer, applying 1230 a plurality of voltage pulses having at least a first pulse duration selected based on the first m / z range (pulse sequences with multiple pulse widths that may be determined independently for every particular m / z range determined by the mass filter) to a pusher electrode of the mass analyzer to direct at least a portion of the ions received by the mass analyzer into an acceleration region of the mass analyzer to generate accelerated ions, and using 1240 an ion detector to detect the accelerated ions after passage thereof through a field-free region so as to generate ion detection data during a data acquisition period.

[0099] The selection of a particular mass range (by the mass filter) will typically result in the determination of suitable pulse widths to improve the spectra results obtained for sub-ranges within the selected mass filter m / z range, with resultant detection data for the sub-ranges then being combined in the manner discussed above, e.g., removing noisy or inadequate spectra data-Tl-corresponding to each the multiple (e.g., two or more) sub-ranges within the selected mass filter range, and combining the retained spectra data portions to produce a composite spectrum.

[0100] In some examples of the procedure 1200, the procedure may further include reconfiguring the mass filter to allow passage of ions having m / z ratios within a second m / z range and adjusting the pulse durations of the voltage pulses applied to the pusher electrode to a second pulse durations. The first and the second m / z ranges may be, in some embodiments, partially overlapping. In various embodiments, one or more m / z ratios in the first range are less than one or more m / z ratios in the second range. The second pulse duration may be greater than the first pulse duration.

[0101] The descriptions herein of various implementations of the present teachings have been presented for purposes of illustration and description. It is not exhaustive and does not limit the present teachings to the precise form disclosed. Modifications and variations are possible in light of the above teachings or may be acquired from practicing of the present teachings. Additionally, the described implementation includes software, though the present teachings may be implemented as a combination of hardware and software or in hardware alone. The present teachings may be implemented with both object-oriented and non-object-oriented programming systems.

[0102] The section headings used herein are for organizational purposes only and are not to be construed as limiting. While the applicant’s teachings are described in conjunction with various embodiments, it is not intended that the applicant’s teachings be limited to such embodiments. On the contrary, the applicant’s teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art.

Claims

What is claimed is:

1. A method of operating a time-of-flight (TOF) mass analyzer, comprising: introducing a plurality of ions into the mass analyzer; applying a plurality of voltage pulses to a pusher electrode of the mass analyzer to direct at least a portion of the plurality of ions into an acceleration region of the mass analyzer to generate accelerated ions; using an ion detector to detect the accelerated ions after passage thereof through a field- free region so as to generate ion detection data during a data acquisition period; and adjusting a pulse duration of the voltage pulses during the data acquisition period such that ion detection data is acquired during the data acquisition period at two or more different voltage pulse durations.

2. The method of Claim 1, further comprising analyzing the ion detection data to generate a mass spectrum of the at least the portion of the plurality of ions.

3. The method of Claim 2, wherein the step of analyzing the ion detection data comprises generating a first mass spectrum corresponding to a first range of m / z ratios associated with a first one of said two or more different voltage pulse durations, generating a second mass spectrum corresponding to a second range of m / z ratios associated with a second one of said two or more different voltage pulse durations, and combining the first and the second mass spectra to obtain a mass spectrum of the at least a portion of the said plurality of ions.

4. The method of Claim 3, wherein the first range of m / z ratios and the second range of m / z ratios are partially overlapping.

5. The method of Claim 4, wherein the first range of m / z ratios include one or more m / z ratios that are less than one or more m / z ratios in the second range of m / z ratios.

6. The method of Claim 5, wherein the first one of said two or more different voltage pulse durations is less than the second one of said two or more different voltage pulse durations.

7. The method of any one of Claims 1 to 6, wherein the step of adjusting the pulse duration of the voltage pulses comprises maintaining the pulse duration at a first one of the two or more different voltage pulse durations during a first portion of said data acquisition period and maintaining the pulse duration at a second one of the two or more different voltage pulse durations during a second portion of said data acquisition period.

8. The method of Claim 7, wherein the first portion and the second portion of the data acquisition period are partially overlapping.

9. The method of any one of Claims 1 to 6 and 8, wherein the step of adjusting the pulse duration of the voltage pulses comprises changing the pulse duration alternatingly between a first one and a second one of said two or more different voltage pulse durations.

10. A method of operating a time-of-flight (TOF) mass analyzer, comprising: configuring a mass filter to allow passage of ions having m / z ratios within a first m / z range; introducing ions passing through the mass filter into a downstream time-of-flight (TOF) mass analyzer; applying a plurality of voltage pulses having a first pulse duration selected based on the first m / z range to a pusher electrode of the mass analyzer to direct at least a portion of the ions received by the mass analyzer into an acceleration region of the mass analyzer to generate accelerated ions; and using an ion detector to detect the accelerated ions after passage thereof through a field- free region so as to generate ion detection data during a data acquisition period.

11. The method of Claim 10, further comprising reconfiguring the mass filter to allow passage of ions having m / z ratios within a second m / z range and adjusting the pulse duration of the voltage pulses applied to the pusher electrode to a second pulse duration.

12. The method of Claim 11, wherein the first and the second m / z ranges are partially overlapping.

13. The method of Claim 11, wherein one or more m / z ratios in the first range are less than one or more m / z ratios in the second range.

14. The method of Claim 13, wherein the second pulse duration is greater than the first pulse duration.

15. A mass spectrometer, comprising: a time-of-flight (TOF) mass analyzer for receiving ions; at least one voltage source for applying voltage pulses to a pusher electrode of the TOF mass analyzer to direct at least a portion of the ions received by the mass analyzer into an acceleration region of the mass analyzer to generate accelerated ions; and a controller in communication with the at least one voltage source, wherein the controller is configured to adjust pulse durations of the voltage pulses applied to the pusher electrode of the TOF mass analyzer such that ion detection data is acquired during data acquisition periods at two or more different voltage pulse durations.

16. The mass spectrometer of Claim 15, wherein the controller is further configured to analyze the ion detection data to generate a mass spectrum of the received ions, including to: generate a first mass spectrum corresponding to a first range of m / z ratios associated with a first one of said pulse durations, generate a second mass spectrum corresponding to a second range of m / z ratios associated with a second one of said pulse durations, and combine the first and the second mass spectra to obtain a mass spectrum of said received ions.

17. The mass spectrometer of Claim 16, wherein the first range of m / z ratios and the second range of m / z ratios are partially overlapping.

18. The mass spectrometer of Claim 16, wherein the first one of said pulse durations is less than the second one of said pulse durations.

19. The mass spectrometer of any one of Claims 15 to 18, further comprising: a mass filter, positioned upstream of the mass analyzer, configured to receive a plurality of ions and to allow passage of a portion of the plurality of ions having m / z ratios within a bandwidth thereof, wherein the controller is configured to set the bandwidth of the mass filter and is further configured to adjust the pulse durations of the voltage pulses applied to the pusher electrode of the TOF mass analyzer based on the bandwidth of the mass filter.

20. A mass spectrometer, comprising: a mass filter configured to receive a plurality of ions and to allow passage of ions having m / z ratios within a bandwidth thereof; a time-of-flight (TOF) mass analyzer positioned downstream of the mass filter for receiving ions passing through the mass filter; at least one voltage source for applying voltage pulses to a pusher electrode of the TOF mass analyzer to direct at least a portion of the ions received by the mass analyzer into an acceleration region of the mass analyzer to generate accelerated ions; and a controller in communication with the mass filter and the at least one voltage source, wherein the controller is configured to set a bandwidth of the mass filter and is further configured to adjust a pulse duration of the voltage pulses applied to the pusher electrode of the TOF mass analyzer based on the bandwidth of the mass filter.

21. The mass spectrometer of Claim 20, wherein the controller is further configured to adjust the bandwidth of the mass filter such that any two consecutive bandwidths are partially overlapping.

22. The mass spectrometer of Claim 20, wherein the controller is further configured to increase the pulse duration of the voltage pulses as an average of m / z ratios contained within the bandwidth of the mass filter increases.

23. The mass spectrometer of Claim 22, further comprising an ion detector positioned at a distal end of a field-free region of the TOF mass analyzer to receive the accelerated ion after passage thereof through the field-free region and to generate ion detection data.

24. The mass spectrometer of Claim 23, further comprising a data acquisition and analysis module configured to receive the ion detection data and to process the ion detection data to generate mass spectra data.

25. The mass spectrometer of Claim 24, wherein the data acquisition and analysis module is further configured to process the ion detection data to generate at least two mass spectra each corresponding to one of at least two different pulse durations.

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