Patent ID: 12255060

DESCRIPTION OF THE ILLUSTRATIVE EMBODIMENTS

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

This disclosure relates to apparatuses and techniques for simultaneously analyzing multiple ions with an electrostatic linear ion trap (ELIT) detector of a charge detection mass spectrometer (CDMS) by controlling the trajectories of ions entering the ELIT in a manner which provides for simultaneous trapping and individual measurement of multiple ions each having a different oscillation trajectory within the ELIT. In one embodiment, the ion entrance trajectories may be controlled in a manner which favors a planar oscillation trajectory geometry within the ELIT in which the trapped ions have a very low likelihood of interacting with one another. In another embodiment, the ion entrance trajectories may be controlled in a manner which favors a cylindrical oscillation trajectory geometry within the ELIT in which the trapped ions do not significantly interact with one another. In any case, such simultaneous analysis of multiple ions with an ELIT may substantially reduce sample analysis times over that achievable using conventional single-ion trapping techniques.

With respect to the operation of an ELIT, and for purposes of this disclosure, the phrase “charge detection event” is defined as detection of a charge associated with an ion passing a single time through a charge detector of the ELIT, and the phrase “ion measurement event” is defined as a collection of charge detection events resulting from oscillation of an ion back and forth through the charge detector a selected number of times or for a selected time period. As the oscillation of an ion back and forth through the charge detector results from controlled trapping of the ion within the ELIT as will be described in detail below, the phrase “ion measurement event” may alternatively be referred to herein as an “ion trapping event” or simply as a “trapping event,” and the phrases “ion measurement event,” “ion trapping event”, “trapping event” and variants thereof shall be understood to be synonymous with one another.

Referring toFIG.1, a CDMS system10is shown including an embodiment of an electrostatic linear ion trap (ELIT)14with control and measurement components coupled thereto. In the illustrated embodiment, the CDMS system10includes an ion source12operatively coupled to an inlet of the ELIT14. The ion source12may illustratively be or include any conventional device, apparatus or technique for generating ions from a sample, e.g., electrospray or other conventional ion generation device, and may further include, for example, one or more devices and/or instruments for separating ions, e.g., based on ion mass, ion mass-to-charge ratio, ion mobility or other molecular characteristic, one or more devices and/or instruments for filtering ions, e.g., based on ion mass-to-charge ratio, ion mobility or other molecular characteristic, one or more devices or instruments for collecting and/or storing ions, e.g., one or more ion traps, one or more devices and/or instruments for dissociating ions, one or more devices or instruments for normalizing or shifting charge states of ions according to one or more molecular characteristics, and/or any combination thereof arranged in any order relative to the direction of ion flow.

In the illustrated embodiment, the ELIT14illustratively includes a charge detector CD surrounded by a ground chamber or cylinder GC and operatively coupled to opposing ion mirrors M1, M2respectively positioned at opposite ends thereof. The ion mirror M1is operatively positioned between the ion source12and one end of the charge detector CD, and ion mirror M2is operatively positioned at the opposite end of the charge detector CD. Each ion mirror M1, M2defines a respective ion mirror region or cavity R1, R2therein. The regions R1, R2of the ion mirrors M1, M2, the charge detector CD, and the spaces between the charge detector CD and the ion mirrors M1, M2together define a longitudinal axis22centrally therethrough which illustratively represents an ideal ion travel path through the ELIT14and between the ion mirrors M1, M2as will be described in greater detail below.

In the illustrated embodiment, voltage sources V1, V2are electrically connected to the ion mirrors M1, M2respectively. Each voltage source V1, V2illustratively includes one or more switchable DC voltage sources which may be controlled or programmed to selectively produce a number, N, of programmable or controllable voltages, wherein N may be any positive integer. Illustrative examples of such voltages will be described below with respect toFIGS.2A and2Bto establish one of two different operating modes of each of the ion mirrors M1, M2as will be described in detail below. In any case, ions move within the ELIT14close to the longitudinal axis22extending centrally through the charge detector CD and the ion mirrors M1, M2under the influence of electric fields selectively established by the voltage sources V1, V2.

The voltage sources V1, V2are illustratively shown electrically connected by a number, P, of signal paths to a conventional processor16including a memory18having instructions stored therein which, when executed by the processor16, cause the processor16to control the voltage sources V1, V2to produce desired DC output voltages for selectively establishing ion transmission and ion reflection electric fields, TEF, REF respectively, within the regions R1, R2of the respective ion mirrors M1, M2. P may be any positive integer. In some alternate embodiments, either or both of the voltage sources V1, V2may be programmable to selectively produce one or more constant output voltages. In other alternative embodiments, either or both of the voltage sources V1, V2may be configured to produce one or more time-varying output voltages of any desired shape. It will be understood that more or fewer voltage sources may be electrically connected to the mirrors M1, M2in alternate embodiments.

The charge detector CD is illustratively provided in the form of an electrically conductive charge detection cylinder which is electrically connected to a signal input of a charge sensitive preamplifier CP, and the signal output of the charge preamplifier CP is electrically connected to the processor16. The voltage sources V1, V2are illustratively controlled in a manner which causes ions to be introduced into the ELIT14from the ion source12, and which selectively captures and confines an ion to oscillate therein such that the captured ion repeatedly passes through the charge detector CD. With an ion captured, i.e., trapped, within the ELIT14and oscillating back and forth between the ion mirrors M1, M2, the charge preamplifier CP is illustratively operable in a conventional manner to detect charges (CH) induced on the charge detection cylinder CD as the ion passes through the charge detection cylinder CD between the ion mirrors M1, M2, and to produce charge detection signals (CHD) corresponding thereto. A plurality of ion charge and oscillation period values are measured at the charge detector CD for each ion captured therein, and the results are recorded and processed to determine ion charge and mass values as will be described in greater detail below.

The processor16is further illustratively coupled to one or more peripheral devices20(PD) for providing peripheral device signal input(s) (PDS) to the processor16and/or to which the processor16provides signal peripheral device signal output(s) (PDS). In some embodiments, the peripheral devices20include at least one of a conventional display monitor, a printer and/or other output device, and in such embodiments the memory18has instructions stored therein which, when executed by the processor16, cause the processor16to control one or more such output peripheral devices20to display and/or record analyses of the stored, digitized charge detection signals.

Referring now toFIGS.2A and2B, embodiments are shown of the ion mirrors M1, M2respectively of the ELIT14depicted inFIG.1. Illustratively, the ion mirrors M1, M2are identical to one another in that each includes a cascaded arrangement of 4 spaced-apart, electrically conductive mirror electrodes. For each of the ion mirrors M1, M2, a first mirror electrode301has a thickness W1and defines a passageway centrally therethrough of diameter P1. An endcap32is affixed or otherwise coupled to an outer surface of the first mirror electrode301and defines an aperture A1centrally therethrough which serves as an ion entrance and/or exit to and/or from the corresponding ion mirror M1, M2respectively. In the case of the ion mirror M1, the endcap32is coupled to, or is part of, an ion exit of the ion source12illustrated inFIG.1. The aperture A1for each endcap32illustratively has a diameter P2.

A second mirror electrode302of each ion mirror M1, M2is spaced apart from the first mirror electrode301by a space having width W2. The second mirror electrode302, like the mirror electrode301, has thickness W1and defines a passageway centrally therethrough of diameter P2. A third mirror electrode303of each ion mirror M1, M2is likewise spaced apart from the second mirror electrode302by a space of width W2. The third mirror electrode303has thickness W1and defines a passageway centrally therethrough of width P1.

A fourth mirror electrode304is spaced apart from the third mirror electrode303by a space of width W2. The fourth mirror electrode304illustratively has a thickness of W1and is formed by a respective end of the ground cylinder, GC disposed about the charge detector CD. The fourth mirror electrode304defines an aperture A2centrally therethrough which is illustratively conical in shape and increases linearly between the internal and external faces of the ground cylinder GC from a diameter P3defined at the internal face of the ground cylinder GC to the diameter P1at the external face of the ground cylinder GC (which is also the internal face of the respective ion mirror M1, M2).

The spaces defined between the mirror electrodes301-304may be voids in some embodiments, i.e., vacuum gaps, and in other embodiments such gaps may be filled with one or more electrically non-conductive, e.g., dielectric, materials. The mirror electrodes301-304and the endcaps32are axially aligned, i.e., collinear, such that the longitudinal axis22passes centrally through each aligned passageway and also centrally through the apertures A1, A2. In embodiments in which the spaces between the mirror electrodes301-304include one or more electrically non-conductive materials, such materials will likewise define respective passageways therethrough which are axially aligned, i.e., collinear, with the passageways defined through the mirror electrodes301-304and which illustratively have diameters of P2or greater. Illustratively, P1>P3>P2, although in other embodiments other relative diameter arrangements are possible.

A region R1is defined between the apertures A1, A2of the ion mirror M1, and another region R2is likewise defined between the apertures A1, A2of the ion mirror M2. The regions R1, R2are illustratively identical to one another in shape and in volume.

As described above, the charge detector CD is illustratively provided in the form of an elongated, electrically conductive cylinder positioned and spaced apart between corresponding ones of the ion mirrors M1, M2by a space of width W3. In one embodiment, W1>W3>W2, and P1>P3>P2, although in alternate embodiments other relative width arrangements are possible. In any case, the longitudinal axis22illustratively extends centrally through the passageway defined through the charge detection cylinder CD, such that the longitudinal axis22extends centrally through the combination of the ion mirrors M1, M2and the charge detection cylinder CD. In operation, the ground cylinder GC is illustratively controlled to ground potential such that the fourth mirror electrode304of each ion mirror M1, M2is at ground potential at all times. In some alternate embodiments, the fourth mirror electrode304of either or both of the ion mirrors M1, M2may be set to any desired DC reference potential, or to a switchable DC or other time-varying voltage source.

In the embodiment illustrated inFIGS.2A and2B, the voltage sources V1, V2are each configured to each produce four DC voltages D1-D4, and to supply the voltages D1-D4to a respective one of the mirror electrodes301-304of the respective ion mirror M1, M2. In some embodiments in which one or more of the mirror electrodes301-304is to be held at ground potential at all times, the one or more such mirror electrodes301-304may alternatively be electrically connected to the ground reference of the respective voltage supply V1, V2and the corresponding one or more voltage outputs D1-D4may be omitted. Alternatively or additionally, in embodiments in which any two or more of the mirror electrodes301-304are to be controlled to the same non-zero DC values, any such two or more mirror electrodes301-304may be electrically connected to a single one of the voltage outputs D1-D4and superfluous ones of the output voltages D1-D4may be omitted.

Each ion mirror M1, M2is illustratively controllable and switchable, by selective application of the voltages D1-D4, between an ion transmission mode (FIG.2A) in which the voltages D1-D4produced by the respective voltage source V1, V2establishes an ion transmission electric field (TEF) in the respective region R1, R2thereof, and an ion reflection mode (FIG.2B) in which the voltages D1-D4produced by the respect voltage source V1, V2establishes an ion reflection electric field (REF) in the respective region R1, R2thereof. As illustrated by example inFIG.2A, once ions from the ion source12fly into region R1of the ion mirror M1through the inlet aperture A1of the ion mirror M1, the ions become focused towards the longitudinal axis22of the ion trap by an ion transmission electric field TEF established in the region R1of the ion mirror M1via selective control of the voltages D1-D4of V1. As a result of the focusing effect of the transmission electric field in region R1of the ion mirror M1on the ion trajectory, ions exiting the region R1of the ion mirror M1through the aperture A2of ion mirror M1attain a narrow trajectory through the charge detector CD, i.e., so as to maintain the path of ion travel through the charge detector CD close to the longitudinal axis22. An identical ion transmission electric field TEF may be selectively established within the region R2of the ion mirror M2via like control of the voltages D1-D4of the voltage source V2. In the ion transmission mode, ions entering the region R2from the charge detection cylinder CD via the aperture A2of M2are focused towards the longitudinal axis by the ion transmission electric field TEF within the region R2through the exit aperture A1of the ion mirror M2.

As illustrated by example inFIG.2B, an ion reflection electric field REF established in the region R2of the ion mirror M2via selective control of the voltages D1-D4of V2acts to decelerate and stop ions entering the ion region R2from the charge detection cylinder CD via the ion inlet aperture A2of M2, to immediately accelerate the stopped ions in the opposite direction back through the aperture A2of M2and into the end of the charge detection cylinder CD adjacent to M2as depicted by the ion trajectory38, and to focus the ions toward the central, longitudinal axis22within the region R2of the ion mirror M2so as to maintain a narrow trajectory of ions through the charge detector CD. An identical ion reflection electric field REF may be selectively established within the region R1of the ion mirror M1via like control of the voltages D1-D4of the voltage source V1. In the ion reflection mode, ions entering the region R1from the charge detection cylinder CD via the aperture A2of M1are decelerated and stopped by the ion reflection electric field REF established within the region R1, then accelerated in the opposite direction back through the aperture A2of M1and into the end of the charge detection cylinder CD adjacent to M1, and focused toward the central, longitudinal axis22within the region R1of the ion mirror M1so as to maintain a narrow trajectory of ions through the charge detector CD. Ions that traverse the length of the ion trap and are reflected by the ion reflection electric field REF in the ion regions R1and R2in a manner that enables the ions to continue traveling back and forth along the length of the trap are considered trapped.

Example sets of output voltages D1-D4produced by the voltage sources V1, V2to control a respective ion mirror M1, M2to and between the ion transmission and reflection modes described above are shown in TABLE I below. It will be understood that the following values of D1-D4are provided only by way of example, and that other values of one or more of D1-D4may alternatively be used.

TABLE IIon Mirror Operating ModeOutput Voltages (volts DC)TransmissionV1: D1 = 0, D2 = 95, D3 = 135, D4 = 0V2: D1 = 0, D2 = 95, D3 = 135, D4 = 0ReflectionV1: D1 = 190, D2 = 125, D3 = 135, D4 = 0V2: D1 = 190, D2 = 125, D3 = 135, D4 = 0

While the ion mirrors M1, M2and the charge detection cylinder CD are illustrated inFIGS.1-2Bas defining cylindrical passageways therethrough, it will be understood that in alternate embodiments either or both of the ion mirrors M1, M2and/or the charge detection cylinder CD may define non-cylindrical passageways therethrough such that one or more of the passageway(s) through which the longitudinal axis22centrally passes represents a cross-sectional area and profile that is not circular. In still other embodiments, regardless of the shape of the cross-sectional profiles, the cross-sectional areas of the passageway defined through the ion mirror M1may be different from the passageway defined through the ion mirror M2.

Referring now toFIG.3, an embodiment is shown of the processor16illustrated inFIG.1. In the illustrated embodiment, the processor16includes a conventional amplifier circuit40having an input receiving the charge detection signal CHD produced by the charge preamplifier CP and an output electrically connected to an input of a conventional Analog-to-Digital (A/D) converter42. An output of the A/D converter42is electrically connected to a first computing device or circuit50(P1). The amplifier40is operable in a conventional manner to amplify the charge detection signal CHD produced by the charge preamplifier CP, and the A/D converter is, in turn, operable in a conventional manner to convert the amplified charge detection signal to a digital charge detection signal CDS. The computing device50illustratively includes or is coupled to a one or more conventional memory units, and the computing device50is illustratively operable to store therein the charge detection signals CDS for each charge detection event in an ion measurement event such that an ion measurement event record stored in the memory of the processor circuit50includes multiple charge detection event measurements.

The processor16illustrated inFIG.3further includes a conventional comparator44having a first input receiving the charge detection signal CHD produced by the charge preamplifier CP, a second input receiving a threshold voltage CTH produced by a threshold voltage generator (TG)46and an output electrically connected to the computing device50. The comparator44is illustratively operable in a conventional manner to produce a trigger signal TR at the output thereof which is dependent upon the magnitude of the charge detection signal CDH relative to the magnitude of the threshold voltage CTH. In one embodiment, for example, the comparator44is operable to produce an “inactive” trigger signal TR at or near a reference voltage, e.g., ground potential, as long as CHD is less than CTH, and is operable to produce an “active” TR signal at or near a supply voltage of the circuitry40,42,44,46,50when CHD is at or exceeds CTH. In alternate embodiments, the comparator44may be operable to produce an “inactive” trigger signal TR at or near the supply voltage as long as CHD is less than CTH, and is operable to produce an “active” trigger signal TR at or near the reference potential when CHD is at or exceeds CTH. Those skilled in the art will recognize other differing trigger signal magnitudes and/or differing trigger signal polarities that may be used to establish the “inactive” and “active” states of the trigger signal TR so long as such differing trigger signal magnitudes and/or different trigger signal polarities are distinguishable by the computing device50, and it will be understood that any such other different trigger signal magnitudes and/or differing trigger signal polarities are intended to fall within the scope of this disclosure. In any case, the comparator44may additionally be designed in a conventional manner to include a desired amount of hysteresis to prevent rapid switching of the output between the reference and supply voltages.

In the illustrated embodiment, the computing device50is operable, i.e., programmed, to control the threshold voltage generator46to produce the threshold voltage CTH. In one embodiment, the threshold voltage generator46is illustratively implemented in the form of a conventional controllable DC voltage source configured to be responsive to a digital threshold control signal THC, e.g., in the form of a single serial digital signal or multiple parallel digital signals, to produce an analog threshold voltage CTH having a polarity and a magnitude defined by the digital threshold control signal THC. In alternate embodiments, the threshold voltage generator46may be provided in the form of a conventional digital-to-analog (D/A) converter responsive to a serial or parallel digital threshold voltage TCH to produce an analog threshold voltage CTH having a magnitude, and in some embodiments a polarity, defined by the digital threshold control signals THC. In some such embodiments, the D/A converter may form part of the processor circuit50. Those skilled in the art will recognize other conventional circuits and techniques for selectively producing the threshold voltage CTH of desired magnitude and/or polarity, and it will be understood that any such other conventional circuits and/or techniques are intended to fall within the scope of this disclosure.

The computing device50is operable to control the voltage sources V1, V2as described above with respect toFIGS.2A,2Bto selectively establish ion transmission and reflection fields within the regions R1, R2of the ion mirrors M1, M2respectively. In one embodiment, the computing device50is illustratively provided in the form of a field programmable gate array (FPGA) programmed as just described to collect and store charge detection signals CDS for charge detection events and for ion measurement events, to produce the threshold control signal(s) THC from which the magnitude and/or polarity of the threshold voltage CTH is determined or derived, and to control the voltage sources V1, V2based on the charge detection signals CHD relative to the threshold voltage CTH as determined by monitoring the trigger output signal TR produced by the comparator44. In this embodiment, the memory18described with respect toFIG.1is integrated into, and forms part of, the programming of the FPGA. In alternate embodiments, the computing device50may include and/or be provided in the form of one or more conventional microprocessors or controllers and one or more accompanying memory units incorporated therein or coupled thereto and having instructions stored therein which, when executed by the one or more microprocessors or controllers, cause the one or more microprocessors or controllers to operate as just described. In other alternate embodiments, the computing device50may be implemented purely in the form of one or more conventional or application-specific hardware circuits designed to operate as described above, or as a combination of one or more such hardware circuits and at least one microprocessor or controller operable to execute instructions stored in memory to operate as described above.

In any case, the embodiment of the processor16depicted inFIG.3further illustratively includes a second computing device52coupled to the first computing device50and also to the one or more peripheral devices20illustrated inFIG.1. In some alternate embodiments, the computing device52may include at least one of the one or more peripheral devices20. In any case, the computing device52is illustratively operable to process the ion measurement event information stored by the first computing device50to determine ion mass information. The computing device52may be or include one or more conventional microprocessors and/or controllers, one or more programmable circuits, e.g., one or more field-programmable gate arrays, and/or one or more application-specific integrated circuits (ASICs). In some embodiments, the computing device52may be provided in the form of any conventional computer or computing device capable of processing the ion measurement event information, i.e., having sufficient computing power, to determine, display, store and conduct at least some amount of analysis of ion mass information. In one embodiment, the computing device52may be provided or included in the form of a conventional personal computer (PC), although in other embodiments the computing device52may be or be included in one or more computers or computing devices with greater or lesser computing power.

The voltage sources V1, V2are illustratively controlled by the computing device50in a manner which selectively establishes ion transmission and ion reflection electric fields in the region R1of the ion mirror M1and in the region R2of the ion mirror M2to cause an ion to be introduced into the ELIT14from the ion source12, and to then cause the introduced ion to be selectively captured and confined to oscillate within the ELIT14such that the captured ion repeatedly passes through the charge detector CD between M1and M2. Referring toFIGS.4A-4C, simplified diagrams of the ELIT14ofFIG.1are shown depicting an example of such sequential control and operation of the ion mirrors M1, M2of the ELIT14. In the following example, the computing device50will be described as controlling the operation of the voltage sources V1, V2in accordance with its programming, although it will be understood that in alternate embodiments the operation of the voltage source V1and/or the operation of the voltage source V1may be controlled, at least in part, by the computing device52in accordance with its programming.

As illustrated inFIG.4A, the ELIT control sequence begins with the computing device50controlling the voltage source V1to control the ion mirror M1to the ion transmission mode of operation (T) by establishing an ion transmission field within the region R1of the ion mirror M1, and also controlling the voltage source V2to control the ion mirror M2to the ion transmission mode of operation (T) by likewise establishing an ion transmission field within the region R2of the ion mirror M2. As a result, an ion generated by the ion source12is drawn into the ion mirror M1and transmitted, i.e., accelerated, through M1into the charge detection cylinder CD by the ion transmission field established in the region R1. The ion then passes through the charge detection cylinder CD and into the ion mirror M2where the ion transmission field established within the region R2of M2transmits, i.e., accelerates, the ion through the exit aperture A1of M2as illustrated by the ion trajectory60depicted inFIG.4A.

Referring now toFIG.4B, after both of the ion mirrors M1, M2have been operating in ion transmission operating mode for a selected time period and/or until successful ion transmission therethrough has been achieved, e.g., by monitoring the charge detection signals CDS captured by the computing device50, the computing device50is illustratively operable to control the voltage source V2to control the ion mirror M2to the ion reflection mode (R) of operation by establishing an ion reflection field within the region R2of the ion mirror M2, while maintaining the ion mirror M1in the ion transmission mode (T) of operation as shown. As a result, an ion generated by the ion source12flies into the ion mirror M1and is transmitted through M1into the charge detection cylinder CD by the ion transmission field established in the region R1as just described with respect toFIG.4A. The ion then passes through the charge detection cylinder CD and into the ion mirror M2where the ion reflection field established within the region R2of M2reflects ions to cause them to travel in the opposite direction and back into the charge detection cylinder CD, as illustrated by the ion trajectory62inFIG.4B.

Referring now toFIG.4C, after the ion reflection electric field has been established in the region R2of the ion mirror M2and the ion is moving within the ELIT14, the processor circuit50is operable to control the voltage source V1to control the ion mirror M1to the ion reflection mode (R) of operation by establishing an ion reflection field within the region R1of the ion mirror M1, while maintaining the ion mirror M2in the ion reflection mode (R) of operation in order to trap the ion within the ELIT14. In some embodiments, the computing device50is illustratively operable, i.e., programmed, to control the ELIT14in a “random trapping mode” or “continuous trapping mode” in which the computing device50is operable to control the ion mirror M1to the reflection mode (R) of operation after the ELIT14has been operating in the state illustrated inFIG.4B, i.e., with M1in ion transmission mode and M2in ion reflection mode, for a selected time period. Until the selected time period has elapsed, the ELIT14is controlled to operate in the state illustrated inFIG.4B.

The probability of trapping an ion in the ELIT14is relatively low using the random trapping mode of operation due to the timed control of M1to the ion reflection mode of operation without any confirmation that an ion is contained within the ELIT14. The number of trapped ions within the ELIT14during the random trapping mode of operation follows a Poisson distribution and, with the ion inlet signal intensity adjusted to maximize the number of single ion trapping events, it can be shown that only about 37% of trapping events in the random trapping mode can contain a single ion. If the ion inlet signal intensity is too small, most of the trapping events will be empty, and if it is too large most will contain multiple ions.

In other embodiments, the computing device50is operable, i.e., programmed, to control the ELIT14in a “trigger trapping mode” which illustratively carries a substantially greater probability of trapping a single ion therein. In a first version of the trigger trapping mode, the computing device50is operable to monitor the trigger signal TR produced by the comparator44and to control the voltage source V1to control the ion mirror M1to the reflection mode (R) of operation to trap an ion within the ELIT14if/when the trigger signal TR changes the “inactive” to the “active” state thereof. In some embodiments, the processor circuit50may be operable to control the voltage source V1to control the ion mirror M1to the reflection mode (R) immediately upon detection of the change of state of the trigger signal TR, and in other embodiments the processor circuit50may be operable to control the voltage source V1to control the ion mirror M1to the reflection mode (R) upon expiration of a predefined or selectable delay period following detection of the change of state of the trigger signal TR. In any case, the change of state of the trigger signal TR from the “inactive” state to the “active” state thereof results from the charge detection signal CHD produced by the charge preamplifier CP reaching or exceeding the threshold voltage CTH, and therefore corresponds to detection of a charge induced on the charge detection cylinder CD by an ion contained therein. With an ion thus contained within the charge detection cylinder CD, control by the computing device50of the voltage source V1to control the ion mirror M1to the reflection mode (R) of operation results in a substantially improved probability, relative to the random trapping mode, of trapping a single ion within the ELIT14. Thus, when an ion has entered the ELIT14via the ion mirror M1and is detected as either passing the first time through the charge detection cylinder CD toward the ion mirror M2or as passing back through the charge detection cylinder CD after having been reflected by the ion reflection field established within the region R2of the ion mirror M2as illustrated inFIG.4B, the ion mirror M1is controlled to the reflection mode (R) as illustrated inFIG.4Cto trap the ion within the ELIT14. It is also desirable to optimize the signal intensity with trigger trapping as briefly described above with respect to the random trapping mode of operation. In trigger trapping mode with optimized ion inlet signal intensity, for example, it has been shown that trapping efficiency, defined as the ratio between single-ion trapping events and all acquired trapping events, can approach 90% as compared to 37% with random trapping. However, if the ion inlet signal intensity is too large the trapping efficiency will be less than 90% and it will be necessary to reduce the ion inlet signal intensity.

In a second version of the trigger trapping mode, the process or step illustrated inFIG.4Bis omitted or bypassed, and with the ELIT14operating as illustrated inFIG.4Athe computing device50is operable to monitor the trigger signal TR produced by the comparator44and to control both voltage sources V1, V2to control the respective ion mirrors M1, M2to the reflection mode (R) of operation to trap or capture an ion within the ELIT14if/when the trigger signal TR changes the “inactive” to the “active” state thereof. Thus, when an ion has entered the ELIT14via the ion mirror M1and is detected as passing the first time through the charge detection cylinder CD toward the ion mirror M2as illustrated inFIG.4A, the ion mirrors M1and M2are both controlled to the reflection mode (R) as illustrated inFIG.4Cto trap the ion within the ELIT14.

In any case, with both of the ion mirrors M1, M2controlled to the ion reflection operating mode (R) to trap an ion within the ELIT14, the ion is caused by the opposing ion reflection fields established in the regions R1and R2of the ion mirrors M1and M2respectively to oscillate back and forth between the ion mirrors M1and M2, each time passing through the charge detection cylinder CD as illustrated by the ion trajectory64depicted inFIG.4C. In one embodiment, the computing device50is operable to maintain the operating state illustrated inFIG.4Cuntil the trapped ion passes through the charge detection cylinder CD a selected number of times. In an alternate embodiment, the computing device50is operable to maintain the operating state illustrated inFIG.4Cfor a selected time period after controlling M1(and M2in some embodiments) to the ion reflection mode (R) of operation. In either embodiment, the ion detection event information resulting from each pass by the ion through the charge detection cylinder CD is temporarily stored in or by the computing device50. When the ion has passed through the charge detection cylinder CD a selected number of times or has oscillated back-and-forth between the ion mirrors M1, M2for a selected period of time, the total number of ion detection events stored in or by the computing device50defines an ion measurement event and, upon completion, the ion measurement event is passed to, or retrieved by, the computing device52. The sequence illustrated inFIGS.4A-4Cthen returns to that illustrated inFIG.4Awhere the voltage sources V1, V2are controlled by the computing device50as described above to control the ion mirrors M1, M2respectively to the ion transmission mode (T) of operation by establishing an ion transmission fields within the regions R1, R2of the ion mirrors M1, M2respectively. The illustrated sequence then repeats for as many times as desired.

In one embodiment, the ion measurement event data are processed by computing, e.g., with the computing device52or with the computing device50, a Fourier Transform of the recorded collection of charge detection events, i.e., of the recorded ion measurement event data. Illustratively, the computing device52is operable to compute 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 computing device52is then illustratively operable to compute an ion mass-to-charge ratio value (m/z), an ion charge value (z) and ion mass values (m), each as a function of the computed Fourier Transform. The computing device52is illustratively operable to store the computed results in the memory18and/or to control one or more of the peripheral devices20to display the results for observation and/or further analysis.

It is generally understood that the mass-to-charge ratio (m/z) of ion(s) oscillating back and forth between opposing ion mirrors M1, M2of an ELIT14is inversely proportional to the square of the fundamental frequency ff of the oscillating ion(s) according to the equation:
m/z=C/ff2,

where C is a constant that is a function of the ion energy and also a function of the dimensions of the respective ELIT14, and the fundamental frequency ff is determined directly from the computed Fourier Transform in a conventional manner. The value of the ion charge, z, is proportional to the magnitude FTMAG of the FT fundamental frequency, taking into account the number of ion oscillation cycles. In some cases, the magnitude(s) of one or more of the harmonic frequencies of the FFT may be added to the magnitude of the fundamental frequency for purposes of determining the ion charge, z. In any case, ion mass, m, is then calculated as a product of m/z and z. The processor circuit52is thus operable to compute m/z=C/ff2, z=F(FTMAG) and m=(m/z)(z).

Multiple, e.g., hundreds or thousands or more, ion trapping events are typically carried out for any particular sample from which the ions are generated by the ion source12, and ion mass-to-charge, ion charge and ion mass values are determined/computed for each such ion trapping event. The ion mass-to-charge, ion charge and ion mass values for such multiple ion trapping events are, in turn, combined to form spectral information relating to the sample. Such spectral information may illustratively take different forms, examples of which include, but are not limited to, ion count vs. mass-to-charge ratio, ion charge vs. ion mass (e.g., in the form of an ion charge/mass scatter plot), ion count vs. ion mass, ion count vs. ion charge, or the like.

Charge detection mass spectrometry (CDMS) is conventionally a single-ion analysis technique in which an ion is directed into an ion detection or measurement stage for measurement of the ion's charge and mass-to-charge ratio (m/z) from which the ion's mass is then determined. This process is repeated multiple times, e.g., hundreds or thousands of times, to produce a mass spectrum of the sample being analyzed. The ion detection or measurement stage may take any of several different forms including, for example, but not limited to an orbitrap mass analyzer, an electrostatic linear ion trap (ELIT) or other single ion measurement stage or instrument. In the case of an ELIT of any design, including that illustrated inFIGS.1-4Cand described in detail above, ions entering the ELIT are typically tightly focused toward the center of the ion inlet aperture such that their entrance trajectories are generally collinear with the longitudinal axis of the ELIT. In conventional ELIT operation, only single ion trapping events are analyzed because two or more trapped ions oscillating back and forth through the ELIT typically have an unacceptably high probability of interacting with one another in a manner which adversely influences the stabilities of their oscillation trajectories within the ELIT, thereby leading to inaccurate m/z and charge measurements.

In order to accurately measure the m/z and charge of an ion in an ELIT, its longitudinal oscillation frequency must be as stable as possible. When multiple ions enter into and are trapped in an ELIT, the trapped ions exert a repulsive force on one another that is proportional to the distance between them. This repulsive force deflects the ion oscillation trajectories within the ELIT, and as ions exchange momentums as a result of such interactions the energies of the oscillating ions also change. Ion oscillation trajectory and energy fluctuations during trapping events are undesirable because they decrease the certainty with which the ion oscillation frequencies can be determined, thereby decreasing the accuracy of the m/z measurements. Ion oscillation trajectory fluctuations also decrease the certainty in ion charge determinations as such fluctuations can affect the distance of ion penetration into the regions R1, R2of the ion mirrors M1, M2, thereby changing the duty cycle of the charge detection signal CH (see, e.g.,FIGS.4A-4C) and decreasing the certainty in the distributions of the signal harmonics.

Referring now toFIGS.5A and6-7, different ion oscillation trajectories within the ELIT14ofFIGS.1-2B and4A-4Care considered in which Coulombic repulsion between multiple trapped ions is minimized. Referring specifically toFIG.5A, a perspective cross-sectional view is shown of the ELIT14ofFIGS.1-2B and4A-40with a three-dimensional Cartesian coordinate system superimposed thereon. In the illustrated example, the z-axis extends centrally through the charge detection cylinder CD and the regions R1and R2of the ion mirrors M1and M2respectively, and is thus collinear with the central longitudinal axis22of the ELIT14as illustrated inFIGS.1and2A-2B. For purposes of this description, the regions R1, R2and the charge detection cylinder CD of the ELIT14are assumed to be cylindrically symmetric such that the x-axis of the coordinate system, running normal to the z-axis, defines a lateral or transverse plane bisecting the regions R1, R2and the charge detection cylinder CD as illustrated by example inFIG.5A. The y-axis of the coordinate system, likewise running normal to the z-axis, defines a medial, (or vertical or longitudinal) plane bisecting the regions R1, R2and the charge detection cylinder CD. The zero intersection of the x, y and z axes is arbitrarily located at the ion inlet A1of the ELIT14flush with the inner wall of the endcap32as best illustrated inFIG.5B.

Two limiting forms of single ion oscillation trajectories within the ELIT14have been identified in which Coulombic repulsion between multiple trapped ions is minimized. One such single ion oscillation trajectory is illustrated by example inFIG.6in the form of a planar ion oscillation trajectory80, and the other is illustrated by example inFIG.7in the form of a cylindrical ion oscillation trajectory90.

The planar ion oscillation trajectory80illustratively represents a planar trajectory of ion travel back and forth through the regions R1, R2and CD of the ELIT14. In the example illustrated inFIG.6, the planar ion oscillation trajectory80includes a planar frustum82with a flared base, an inverted but otherwise identical planar frustum84with a flared base and a generally rectangular plane86joining the frusta82,84. The opposed planar frusta82,84illustratively represent the flared conical ion trajectories within the regions R1, R2of the ion mirrors M1, M2respectively, and the rectangular plane86illustratively represents the planar ion trajectory through the charge detection cylinder CD. An ion in the planar ion oscillation trajectory80illustrated inFIG.6thus oscillates back and forth through the ELIT14with a planar oscillation trajectory extending along the longitudinal (z) axis22such that its oscillation trajectory is largely constrained to a single line in the x-y plane as it moves along the z-axis22. As also illustrated inFIG.6, the planar ion oscillation trajectory80passes through the z-axis22at least once during each oscillation; once in the region R1(although not necessarily through the longitudinal center of the charge detection cylinder CD) and once in the region R2.

The cylindrical ion oscillation trajectory90illustrated by example inFIG.7represents a generally cylindrical trajectory of ion travel back and forth through the regions R1, R2and CD of the ELIT14. In the illustrated example, the cylindrical ion oscillation trajectory90includes a frustum92with a flared base, an inverted but otherwise identical frustum94with a flared base and a central cylinder96joining the frusta92,94. As with the planar trajectory80illustrated inFIG.6, the opposed frusta92,94illustratively represent the flared conical ion trajectories within the regions R1, R2of the ion mirrors M1, M2respectively, and the central cylinder96illustratively represents the cylindrical ion trajectory through the charge detection cylinder CD. An ion in the cylindrical ion oscillation trajectory90illustrated inFIG.7illustratively undergoes an orbital motion in the x-y plane as it oscillates back and forth through the ELIT14along the z-axis22such that the cylindrical oscillation trajectory90extends along and about the z-axis22. As a result of such orbital motion, the cylindrical ion oscillation trajectory90does not pass though the z-axis22in either region R1, R2or in any other region of the ELIT14as also illustrated inFIG.7.

It has been determined that the planar and cylindrical ion oscillation trajectories80,90respectively illustrated inFIGS.6and7each depend in large part upon ion entrance conditions; specifically, upon ion entrance trajectories. As such, the trajectory of an ion entering the aperture A1of the region R1of the ELIT14can be controlled in a manner which favors a planar ion oscillation trajectory of the type illustrated inFIG.6, or which favors a cylindrical ion oscillation trajectory of the type illustrated inFIG.7. In particular, such control of ion entrance trajectory may take the form of one or a combination of controlling an amount or magnitude of radial offset of the entering ion relative to the z-axis22and controlling an angle of ion entrance relative to the z-axis22. The “angle of ion entrance relative to the z-axis” may be alternatively referred to herein as an “angular divergence,” and it will be understood that these two terms are to be considered interchangeable.

The radial offset of an ion entering the ELIT14is generally the distance between the z-axis22and a line parallel with the z-axis22. Referring toFIG.5Bfor example, the dashed line oz is parallel to but offset from the z-axis22, and oz thus represents one example radial offset condition. As illustrated inFIG.5B, the ion70traveling into the aperture A1of the region R1of the ELIT14along the radial offset line oz thus represents an ion entrance trajectory T1having a radial offset only of “oz”, i.e., having substantially no or negligible angular divergence (conversely, having an angular divergence of substantially 0°). The angular divergence of an ion entering the ELIT14, on the other hand, is generally an angle relative to the z-axis22or relative to a radial offset, if any, at which an ion enters the ELIT14. As also illustrated inFIG.5B, the ion72traveling into the aperture A1of the region R1of the ELIT14at an angle DA1relative to the z-axis22thus represents an ion entrance trajectory T1having a divergence angle only of DA1, i.e., having substantially no or negligible radial offset relative to the z-axis22. Finally, the ion74depicted inFIG.5Bas traveling into the aperture A1of the region R1of the ELIT14at an angle DA2relative to the radial offset oz represents an ion entrance trajectory T3having both a radial offset relative to the z-axis22of “oz” and a divergence angle of DA2relative to the radial offset oz. It should be noted that in cases in which the ion entering the ELIT14has a radial offset and an angular divergence, the two may, but need not, be along the same direction in the x-y plane.

The ion entrance trajectory, e.g., in terms of a radial offset and/or an angular divergence, determines whether an ion entering the ELIT14follows a planar or a cylindrical ion oscillation trajectory within the ELIT14. For example, an ion entering the aperture A1of the ion mirror M1at the z-axis22with or without a divergence angle will adopt a planar ion oscillation trajectory of the type illustrated inFIG.6. An ion entering the aperture A1of the ion mirror M1with a radial offset relative to the z-axis22but with no (or negligible) divergence angle, e.g., a collimated entrance trajectory, will likewise adopt a planar ion oscillation trajectory. On the other hand, an ion entering the aperture A1of the ion mirror M1with both a radial offset relative to the z-axis22and a divergence angle pointing in any direction other than the offset axis will adopt a cylindrical ion oscillation trajectory.

Because the ELIT14is assumed to be cylindrically symmetric as described above, the three-dimensional ion reflection electric field (REF) that is induced within the regions R1, R2during the ion reflection mode of operation of the ion mirrors M1, M2can be described with respect to a two-dimensional radial slice at an arbitrary location through the ion mirror M1of the ELIT14along the x-y plane as illustrated by example inFIG.5C. Referring toFIG.5C, an ion78within the region R1of the ion mirror M1is shown radially offset from the z-axis by a radial distance r. Within the region R1(and also within the region R2of the ion mirror M2), the ion reflection electric field REF operates to reflect the ion78entering R1from the charge detection cylinder CD back toward and into the charge detection cylinder CD as described above with respect toFIG.2B. In addition to reflecting the ion78back toward the charge detection cylinder CD, the ion reflection electric field REF also forces the ion toward the z-axis. This force is illustratively represented in the x-y plane ofFIG.5Cby the vector F, and the direction of the vector F, as just described, always points toward the z-axis.

The velocity of the ion78positioned within the region R1of the ion mirror M1is represented in the x-y plane ofFIG.5Cby the vector v. The ion velocity vector v forms an angle αvwith the x-y coordinate system, and the electric field force vector F likewise forms an angle αFwith the x-y coordinate system. The difference between the force vector angle αFand the velocity vector angle αvis the angle β illustrated inFIG.5C, wherein β represents the deviation of the ion78from collinearity of the two vectors F and v. When the velocity vector v is aligned with the force vector F such that the angle β is 0° or 180°, the ion78will assume a planar ion oscillation trajectory of the type illustrated inFIG.6. When, on the other hand, the angle β between the force and velocity vectors v and F respectively is significantly greater or less than 0° or 180°, the ion78will assume a cylindrical ion oscillation trajectory of the type illustrated inFIG.7. If either the angular divergence or the radial offset of an entering ion is zero or sufficiently small when the radial offset and the angular divergence of the entering ion are in the same direction in the x-y plane, then velocity vector v will point toward the z-axis and the ion oscillation trajectory will be planar. However, if the angular divergence and the radial offset are at different angles in the x-y plane, the ion oscillation trajectory will be cylindrical.

By suitably controlling the entrance trajectories of multiple ions entering the ELIT14, it is possible to favor a distribution of planar ion oscillation trajectories in which the likelihood of interactions, and thus Coulombic repulsion, between the multiple trapped ions simultaneously oscillating back and forth through the ELIT14is acceptably low. Referring toFIG.8, for example, a plot is shown which represents a planar distribution of multiple ions100simultaneously trapped and oscillating back and forth within the ELIT14. In the illustrated example, the planar distribution of ions100includes two planar ion oscillation trajectories80,80′ defining an angle ARtherebetween in the x-y plane. Each planar ion oscillation trajectory80,80′ represents a single ion trapped and oscillating within the ELIT14. In the example illustrated inFIG.8, the ELIT14thus has two ions trapped and oscillating back and forth therein, with each ion following one of two different planar ion oscillation trajectories80,80′ each with a unique αFwherein the difference between αFof one ion and αFfor the other ion is the angle AR. In the illustrated example, ARis approximately 90° such that the two planes80,80′ are orthogonal, although it will be understood that ARmay alternatively be greater or less than 90°. As also illustrated inFIG.8, the two ions can potentially interact with one another only along the z-axis where the two planes80,80′ intersect with one another, and in some embodiments the likelihood of interaction between the two ions may therefore be acceptably low. It will be understood that the planar ion distribution of two ions illustrated inFIG.8is provided only by way of example, and that in other implementations the ion entrance trajectories may be controlled to trap two or more ions each having a different planar ion oscillation trajectory that is offset from adjacent planar ion oscillation trajectories by angle ARof less than 90°. Two or more ions having different planar ion oscillation trajectories will thus be angularly offset from one another about the z-axis22by their respective planar angles AR.

Given the ion entrance conditions discussed above with respect toFIGS.5B and5C, ion entrance trajectories which favor a planar distribution of ions within the ELIT14can illustratively be controlled in several different ways. Examples include, but are not limited to, injecting a collimated beam of ions with a large radial distribution of ions into the aperture A1of the ion mirror M1while keeping voltages D1-D4of power supply V1grounded and the central, longitudinal axis of the beam centered on the z-axis22so as to produce a distribution of radial offsets centered at the z-axis22, and injecting a collimated beam of ions into the aperture A1of the ion mirror M1and then varying the focusing power of the ion transmission electric field of the ion region R1in the ion mirror M1by manipulating voltages D1-D4of V1to impart an angular convergence on the ion beam towards a focal point that lies on the z-axis22. Any such control of the ion entrance trajectories will allow for the trapping of two or more ions within the ELIT14which will favor two or more corresponding planar ion oscillation trajectories within the ELIT14each forming an angle ARin the x-y plane relative to adjacent trajectories which extends along the z-axis22. Various single or multiple stage instruments may be implemented as part of the ion source12illustrated inFIG.1, or disposed between the ion source12and the ELIT14, for suitably controlling ion entrance trajectories in a manner which favors a planar distribution of ions oscillating back and forth within the ELIT14. An example embodiment of one such instrument is illustrated inFIG.11and will be described in detail below.

By suitably controlling the entrance trajectories of multiple ions entering the ELIT14, it is also possible to favor a distribution of cylindrical ion oscillation trajectories in which the likelihood of close interactions, and thus Coulombic repulsion, between the multiple trapped ions simultaneously oscillating back and forth through the ELIT14is minimized. Examples include, but are not limited to, focusing a collimated beam of ions into a point along the z-axis22and sweeping the point along a line of radial offsets relative to the z-axis22, focusing a collimated beam of ions into a plane at the aperture A1of the ion mirror M1and offsetting from the z-axis22, and injecting an uncollimated beam of ions into the ELIT14. Referring toFIG.9, for example, a plot is shown which represents a cylindrical distribution of multiple ions110simultaneously trapped and oscillating back and forth within the ELIT14. In the illustrated example, the cylindrical distribution of ions110includes two cylindrical ion oscillation trajectories90,90′ with the cylindrical ion oscillation trajectory90′ completely nested within the cylindrical ion oscillation trajectory90. Each cylindrical ion oscillation trajectory90,90′ represents a single ion trapped and oscillating within the ELIT14. In the example illustrated inFIG.9, the ELIT14thus has two ions trapped and oscillating back and forth therein, with each ion following one of two different cylindrical ion oscillation trajectories90,90′ and with one trajectory90′ completely nested within the other trajectory90. With this configuration, the ion following the trajectory90thus has no opportunity to significantly interact with the ion following the trajectory90′ and vice versa. It will be understood that the cylindrical ion distribution of two ions illustrated inFIG.9is provided only by way of example, and that in other implementations the ion entrance trajectories may be controlled to trap three or more ions with successively nested cylindrical ion oscillation trajectories.

Referring now toFIG.10, the outer cylindrical ion oscillation trajectory90is illustrated as having an inner radius IR1and an outer radius OR1along the section line10-10ofFIG.9, wherein the radial distance between IR1and OR1defines the thickness of the cylindrical trajectory90. The inner cylindrical ion oscillation trajectory90′ similarly has an inner radius IR2and an outer radius OR2along the section line10-10ofFIG.9, wherein the radial distance between IR2and OR2defines the thickness of the cylindrical trajectory90′. The radial distance between the inner radius IR1of the outer cylindrical ion oscillation trajectory90and the outer radius OR2of the inner cylindrical ion oscillation trajectory90′ is DR.

The inner and outer radii of a cylindrical ion oscillation trajectory can be controlled by controlling the magnitude of the radial offset of the ion entrance trajectory relative to the z-axis22. Thus, if multiple ions enter the ELIT14via the aperture A1of the ion mirror M1with a radial distribution, the resulting multiple cylindrical ion oscillation trajectories within the ELIT14will each have different, independent radii, which will contribute to minimizing the likelihood of close interactions between the multiple trapped ions. The thickness of a cylindrical ion oscillation trajectory in relation to the average radius of the trajectory can similarly be controlled by controlling the magnitude of the angular divergence of the ion entrance trajectory relative to the radial offset line parallel with the z-axis22. For example, the thinnest cylindrical ion oscillation trajectories are produced when β approaches 90°. Thin cylindrical ion oscillation trajectories are preferable in embodiments in which it is desirable to nest or stack many cylindrical ion oscillation trajectories within the ELIT14. As compared with planar ion oscillation trajectories, the ELIT14can accommodate substantially more ions simultaneously oscillating back and forth therein with nested cylindrical ion oscillation trajectories because each such nested cylindrical ion oscillation trajectory occupies a unique region within the ELIT14, i.e., a region that is separate and distinct from those occupied by all other cylindrical ion oscillation trajectories.

Given the ion entrance conditions discussed above with respect toFIGS.5B and5C, ion entrance trajectories which favor a cylindrical distribution of ions within the ELIT14can illustratively be controlled in several different ways. Examples include, but are not limited to, one or more of the example techniques described above with respect to the planar distribution of ions but doing so with an uncollimated beam of ions such that the ions not only have a distribution of radial offsets but also a distribution of divergence angles. In any case, as the radial offset of an entering ion increases in radial distance from the z-axis22of the ELIT14, so too does the magnitude of the force vector F (seeFIG.5C) pointing toward the z-axis22. For a particular velocity vector v, the inner radius of a cylindrical ion oscillation trajectory resulting from an ion entering the ELIT14with a relatively greater radial offset is thus less than that of a cylindrical ion oscillation trajectory resulting from an ion entering the ELIT14with a relatively lower radial offset because the magnitude of the force vector F acting on the former is less than that acting on the latter.

Moreover, as the radial offset of an entering ion increases, the angle of divergence, represented by the magnitude of the velocity vector v that points away from the force vector F, of the entering ion must also increase in order to cause the entering ion to adopt a cylindrical ion oscillation trajectory. This is so because if the velocity vector v is pointing along the same plane as the force vector F, i.e., where β is 0 or 180 degrees, the ion motion will be influenced only by the force vector, thereby causing the entering ion to adopt an oscillation trajectory that lies in the same plane as the force vector F as described above with respect toFIG.5C. Any ion velocity vector v component that is not coplanar with the force vector F, i.e., where β is anything larger or smaller than 0 or 180, causes the ion to rotate in the x-y plane while oscillating back and forth along the z-axis22because no force acts on the ion in the direction of its rotation. The magnitude of the force vector F towards the z-axis22experienced by an ion trapped in the ELIT14is directly proportional to the radial offset of the ion. Since the force vector F acting on an ion increases with the radial offset, an ion oscillating farther away from the z-axis22is subjected to a larger force vector F towards the z-axis22which causes its oscillation trajectory to become dominated by the force vector F and becomes more planar. To compensate for this effect and induce the formation of cylindrical ion oscillation trajectories at all radial offsets in the ELIT14, as the magnitude of the force vector F increases, so too must the magnitude of the velocity vector v in a direction that is perpendicular to the force vector F by a commensurate amount which ensures that the entering ion will adopt a cylindrical oscillation trajectory. Various single or multiple stage instruments may be implemented as part of the ion source12illustrated inFIG.1, or disposed between the ion source12and the ELIT14, for suitably controlling ion entrance trajectories in a manner which favors a cylindrical distribution of ions oscillating back and forth within the ELIT14. An example embodiment of one such instrument is illustrated inFIG.11and will be described in detail below.

Based on the foregoing, the nested cylindrical ion oscillation trajectories illustrated by example inFIG.9are superior to the angularly distributed planar ion oscillation trajectories illustrated by example inFIG.8in terms minimizing interactions between multiple ions trapped within the ELIT14. However, while the angularly distributed planar ion oscillation trajectories do not completely eliminate the potential for ion interaction within the ELIT14, the probability of such ion interaction is substantially reduced as compared with conventional ion entrance control techniques. Moreover, based on the design of the ELIT14illustrated inFIGS.1-2Band described above, the oscillation frequency stability of nested cylindrical ion oscillation trajectories is superior to that of the angularly distributed planar ion oscillation trajectories. In other words, fluctuations in ion oscillation frequency during a trapping event within the ELIT14are greater for planar ion oscillation trajectories than for cylindrical ion oscillation trajectories. Since the oscillation frequency within the ELIT14is used to determine ion mass-to-charge ratio (m/z), m/z determination uncertainty is therefore expected to be smaller for cylindrical ion oscillation trajectories than for planar ion oscillation trajectories. This may not be the case for other ELIT designs, and indeed it is to be understood that the concepts illustrated in the attached figures and described herein may be implemented with ELIT designs and configurations different in one or more aspects from the ELIT14illustrated inFIGS.1-2Band described herein. Moreover, it is possible that the design of the ELIT14may be modified and/or that an ELIT or other ion trap may be designed, in a manner which reduces such fluctuations in oscillation frequency.

It is also possible to split the charge detection cylinder CD of the ELIT14into two halves along the longitudinal axis and either connect a separate detection circuit as shown inFIG.3to each charge detection cylinder half and independently analyze the signal coming from each half, or perform a differential measurement between the two charge detection cylinder halves using a differential amplifier. In the former case where a separate circuit is used for each half, the digitized signal for each half may be analyzed by fast Fourier transform and the magnitude of the fundamental frequency peak related to the average proximity of an ion to each charge detection cylinder half over the course of a trapping event. In other words, a cylindrical ion oscillation trajectory with an outer radius such as OR1of90inFIG.10will oscillate at a particular average distance from the two charge detection cylinder halves. The magnitude of the fundamental frequency peak in the Fourier transform depends on how close the ion was to the charge detection cylinder halves. From this, the outer radius of the cylindrical ion oscillation trajectory can be deduced and used to correct the measured ion m/z to account for deviations from the actual ion m/z that result from ion oscillation trajectory distributions. In the latter case, a differential amplifier can be used to monitor the difference in signal between the two charge detection cylinder halves. Ion oscillation frequencies that are very close to the z-axis22, i.e., its outer radius is small, would produce a small difference in signal between the halves because the ion is a similar distance from each half. However, an ion oscillation trajectory that has a large outer radius is much closer to one charge detection cylinder half than the other which will result in a large difference in signal between the two halves. A fast Fourier transform can be employed to measure the fundamental frequency magnitude from the digitized differential amplifier signal and related to the ion oscillation trajectory outer radius, lending this as a method of ascertaining the three-dimensional ion oscillation trajectory to correct for deviations in the measured m/z of an ion that arise from trajectory distributions. Alternatively, the charge detection cylinder CD can be left whole and additional charge detection cylinders can be located in any other region of the trap where the oscillating ion would produce an induced image charge on the additional cylinders that is representative of the ion oscillation trajectory.

As described above, it is possible to tune the ion entrance trajectories, i.e., the trajectories of ions entering the ELIT14, in a manner which favors a distribution of planar or cylindrical ion oscillation trajectories within the ELIT14, and some example techniques for controlling ion entrance trajectories to favor each trajectory are briefly described above. Such examples of controlling ion entrance trajectories to favor a distribution of planar ion oscillation trajectories illustratively include, but are not limited to, injecting a collimated beam of ions with a large radial distribution of ions into the aperture A1of the ion mirror M1while keeping the voltages D1-D4of power supply V1grounded and the central, longitudinal axis of the beam centered on the z-axis22so as to produce a distribution of radial offsets centered at the z-axis22, and injecting a collimated beam of ions into the aperture A1of the ion mirror M1and then varying the focusing power of the ion transmission electric field of the ion region R1in the ion mirror M1by manipulating voltages D1-D4of V1to impart an angular convergence on the ion beam towards a focal point that lies on the z-axis22. Alternatively, focusing a collimated beam of ions into a point along the z-axis22and sweeping the point along a line of radial offsets relative to the z-axis22, focusing a collimated beam of ions into a plane at the aperture A1of the ion mirror M1and offsetting the plane from the z-axis22, and injecting an uncollimated, i.e., convergent or divergent, beam of ions that includes not only a distribution of radial offsets but also a distribution of angular divergence into the aperture A1of the ion mirror M1are example techniques for controlling ion entrance trajectories to favor a distribution of cylindrical ion oscillation trajectories. Any such control of the ion entrance trajectories will allow for the trapping of two or more ions within the ELIT14which will favor a distribution of planar or cylindrical ion oscillation trajectories respectively. In this regard, an embodiment is shown inFIG.11of a charge detection mass spectrometer (CDMS)100which includes the ion source12illustrated inFIG.1and described above, which includes the ELIT14illustrated inFIGS.1-2Band described above and which includes an example embodiment of an ion trajectory control apparatus101for selectively controlling the trajectories of ions exiting the ion source12and entering the ELIT14in a manner which achieves simultaneous trapping of multiple ions in and by the ELIT14and which favors a distribution within the ELIT14of planar or cylindrical ion oscillation trajectories.

Referring now toFIG.11, the ion trajectory control apparatus101illustratively includes a multi-stage ion trajectory control instrument105disposed between the ion source12and the ELIT14and operatively coupled to one or more voltage sources108and to signal detection circuitry110. The one or more voltage sources108may illustratively include any number of conventional voltage sources configured to produce one or more constant or switching DC voltages of selectable polarity and/or magnitude, and any number of conventional voltage sources configured to produce one or more time-varying, i.e., AC, voltages of selectable frequency and/or peak magnitude. One or any combination of the one or more voltage sources108may be manually controllable and/or may be operatively coupled to a conventional processor112for processor control thereof. One or more of the voltage sources108may also be used to control one or more operational features of the ion source12, and in some embodiments the one or more voltage sources108may include the voltage sources V1and V2illustrated inFIG.1and operable to control operation of the ELIT14as described above.

The signal detection circuitry110illustratively includes one or more conventional signal sensors and conventional signal detection circuitry for detecting one or more operating conditions of the ion trajectory control instrument105. In some embodiments, the signal detection circuitry110may include the charge preamplifier CP operatively coupled to the ELIT14as illustrated inFIG.1and described above. In any case, the signal detection circuitry110is operatively coupled to the processor112, and signals detected by the circuitry110are thus provided to the processor112for processing thereof.

The processor112illustratively includes, or is operatively coupled to, at least one conventional memory unit114for storing operating instructions for the processor114and to store data collected and/or processed by the processor112. As it relates to the operation and control of the ion trajectory control instrument105, the memory unit(s)114illustratively has one or more sets of instructions stored therein which, when executed by the processor112, cause the processor112to control one or more of the voltage sources108based, at least in part, on one or more signals produced by the signal detection circuitry110, in a manner which selectively controls the trajectories of ions exiting the ion source12and entering the ELIT14so as to achieve simultaneous trapping of multiple ions in and by the ELIT14and which causes the ions entering the ELIT14to adopt a distribution therein of planar or cylindrical ion oscillation trajectories. The processor112may include one or more conventional computing devices in the form of any one or combination of one or more conventional microprocessors and/or controllers, one or more field programmable gate arrays (FPGAs), one or more application specific integrated circuits (ASICs), one or more conventional personal, lap top, desk top, tablet or other computers, or the like.

In the illustrated embodiment, the ion trajectory control instrument105includes a number of cascaded ion trajectory control stages. It will be understood that such stages are illustrated only by way of example, and that alternate embodiments of the instrument105may include more or fewer ion trajectory control stages. In any case, the instrument105depicted inFIG.11illustratively includes an image charge detection array stage102having an ion inlet at one end configured to receive ions generated by the ion source12and an ion outlet at an opposite end that is operatively coupled to an ion inlet of an ion deflector/offset stage104having an ion outlet operatively coupled to an ion inlet of an ion focusing stage106. An ion outlet of the ion focusing stage106is operatively coupled to the ion inlet aperture A1of the ion mirror M1of the ELIT14such that ions exiting the ion focusing stage106enter the ELIT14via the aperture A1of the ion mirror M1.

The image charge detection array stage102illustratively includes at least two spaced-apart arrays102A,102B of conventional image charge detectors. As ions exit the ion source12in the form of a beam and pass sequentially through the image charge detector arrays102A,102B, conventional image charge detection circuitry included as part of the signal detection circuitry110provides respective image charge detection signals to the processor112from which the processor112is operable to determine the positions of the ions passing sequentially through each array102A,102B. From this information, the trajectory of the ion beam exiting the stage102can be determined. It will be understood that although the image charge detection array stage102is illustrated inFIG.11and described herein as including only two spaced-apart image charge detector arrays, alternate embodiments of the stage102may include more or fewer spaced-apart image charge detector arrays.

The ion deflector/offset stage104illustratively includes one or more conventional ion deflectors and/or one or more conventional ion offset apparatuses. Based on the computed trajectory of the ion beam exiting the stage102, the processor112is illustratively operable to compute, e.g., in real-time, adjustments to the ion beam trajectory required to achieve an ion entrance trajectory which will favor a selected planar or cylindrical distribution of ion oscillation trajectories within the ELIT14as described in detail hereinabove. Such computed adjustments are illustratively fed to the one or more ion deflectors and/or one or more ion offset apparatuses in the stage104in the form of control signals, and the one or more ion deflectors and/or one or more ion offset apparatuses are responsive to such control signals to selectively alter the trajectory of the ion beam passing therethrough, e.g., by controlling either or both of a radial offset of the ion beam relative to the z-axis22and an angle of the ion beam relative to the z-axis22and/or relative to an axis that passes through the ELIT14and that is parallel with the z-axis22.

The ion focusing stage106illustratively includes one or more conventional ion focusing elements. The adjusted ion beam trajectory exiting the ion deflector/offset stage104is suitably focused as it passes through the one or more ion focusing elements, and the ion beam emerging from the ion focusing stage106is passed into the ELIT14via the ion inlet aperture A1of the ion mirror M1as described above.

As illustrated by dashed-line representation inFIG.11, one example ion entrance trajectory produced by the ion trajectory control instrument105may be a collimated ion beam120which is radially offset from the z-axis22of the ELIT14and which is suitably manipulated using any of the techniques described above so as to favor a distribution of planar ion oscillation trajectories within the ELIT14. As also illustrated by dashed-line representation inFIG.11, another example ion entrance trajectory produced by the ion trajectory control instrument105may be an uncollimated ion beam130which is radially offset from the z-axis22of the ELIT14and includes a distribution of divergence angles, and which is suitably manipulated using any of the techniques described above so as to favor a distribution of cylindrical ion oscillation trajectories within the ELIT14.

In some alternate embodiments, the ion trajectory control instrument105may be or include at least one conventional ion trap that is controlled by the processor112in a conventional manner to collect ions therein, to focus the collected ion toward the z-axis22passing through the ion trap, and to then selectively release the collected ions. Upon release, the exiting ions will expand radially about the z-axis22and may thereafter be focused by one or more focusing elements into the ELIT14. In this embodiment, the ion beam exiting the ion trap will include an angular distribution of ions distributed radially about the z-axis22, and such an ion entrance trajectory will thus favor a distribution of cylindrical ion oscillation trajectories.

In addition to or in place of the ion trajectory control instrument105, one or more magnetic and electric field generators may suitably positioned relative to the ELIT14and selectively controlled in a manner which controls or guides the ion oscillation trajectories within the ELIT14. If, for example, the generated magnetic field lines extend along the z-axis22, ions trapped within the ELIT14will undergo a cyclotron motion as they oscillate back and forth through the ELIT14. Also, a collimated ion beam can be injected into a magnetic lens positioned between the ion source12and ELIT14aligned with the ELIT14z-axis22. The lens would impart a radial Lorentz force on the ions as they travel through the lens that can give them a radial velocity with a magnitude that is proportional to the ion distance from the z-axis22and in a direction that may give rise to cylindrical ion oscillation trajectories. The magnetic field strength of the lens can be adjusted by varying the electric current in the lens coil so as to cause ions to enter the ELIT14with trajectories that favor the formation of planar or cylindrical ion oscillation trajectories. Such control may induce or enhance a desired ion oscillation trajectory or distribution of ion oscillation trajectories within the ELIT14.

Those skilled in the art will recognize other conventional instruments and combinations of conventional instruments that may be used to guide and control ion inlet trajectories according to ion inlet conditions described herein which result in planar or cylindrical distributions of ion oscillation trajectories with an electrostatic linear ion trap such as the ELIT14illustrated in the attached figures and described herein. It will be understood that any such other conventional instruments and combinations thereof are contemplated by, and are intended to fall within the scope of, this disclosure.

In any case, with multiple ions oscillating back and forth through the ELIT14with either a planar or cylindrical distribution of ion oscillation trajectories, charges induced on the charge detection cylinder CD of the ELIT14by the multiple ions passing therethrough are detected by the charge preamplifier CP, and corresponding charge detection signals CHD are passed to the processor16for the duration of a trapping event as described above with respect toFIGS.1-4C. When the stored collection of charge detection signals for a trapping event are processed using a conventional Fourier transform algorithm as described above, multiple fundamental frequency peaks will emerge, each corresponding to a respective one of the multiple trapped ions. The harmonic peaks associated with each such fundamental peak may then be easily identified, and ion charge, mass-to-charge and mass may then be determined as described above for each of the multiple trapped ions.

Referring now toFIG.12A, a simplified block diagram is shown of an embodiment of an ion separation instrument200which may include the ELIT14illustrated and described herein, and which may include the charge detection mass spectrometer100illustrated and described herein, and which may include any number of ion processing instruments which may form part of the ion source12upstream of the ELIT14and/or which may include any number of ion processing instruments which may be disposed downstream of the ELIT14to further process ion(s) exiting the ELIT14. In this regard, the ion source12is illustrated inFIG.12Aas including a number, Q, of ion source stages IS1-ISQwhich may be or form part of the ion source12, where Q may be any positive integer. Alternatively or additionally, an ion processing instrument202is illustrated inFIG.12Aas being coupled to the ion outlet of the ELIT14, wherein the ion processing instrument210may include any number, R, of ion processing stages OS1-OSR, where R may be any positive integer.

Turning now to the ion source12, it will be understood that the source12of ions entering the ELIT may be or include, in the form of one or more of the ion source stages IS1-ISQ, one or more conventional sources of ions as described above, and may further include one or more conventional instruments for separating ions according to one or more molecular characteristics (e.g., according to ion mass, ion mass-to-charge, ion mobility, ion retention time, or the like) and/or one or more conventional ion processing instruments for collecting and/or storing ions (e.g., one or more quadrupole, hexapole and/or other ion traps), for filtering ions (e.g., according to one or more molecular characteristics such as ion mass, ion mass-to-charge, ion mobility, ion retention time and the like), for fragmenting or otherwise dissociating ions, for normalizing or shifting ion charge states, and the like. It will be understood that the ion source12may include one or any combination, in any order, of any such conventional ion sources, ion separation instruments and/or ion processing instruments, and that some embodiments may include multiple adjacent or spaced-apart ones of any such conventional ion sources, ion separation instruments and/or ion processing instruments.

Turning now to the ion processing instrument202, it will be understood that the instrument202may be or include, in the form of one or more of the ion processing stages OS1-OSR, one or more conventional instruments for separating ions according to one or more molecular characteristics (e.g., according to ion mass, ion mass-to-charge, ion mobility, ion retention time, or the like), one or more conventional instruments for collecting and/or storing ions (e.g., one or more quadrupole, hexapole and/or other ion traps), one or more conventional instruments for filtering ions (e.g., according to one or more molecular characteristics such as ion mass, ion mass-to-charge, ion mobility, ion retention time and the like), one or more conventional instruments for fragmenting or otherwise dissociating ions, one or more conventional instruments for normalizing or shifting ion charge states, and the like. It will be understood that the ion processing instrument202may include one or any combination, in any order, of any such conventional ion separation instruments and/or ion processing instruments, and that some embodiments may include multiple adjacent or spaced-apart ones of any such conventional ion separation instruments and/or ion processing instruments. In any implementation which the ion source12and/or the ion processing instruments202includes one or more mass spectrometers, any one or more such mass spectrometers may be of any conventional design including, for example, but not limited to a time-of-flight (TOF) mass spectrometer, a reflectron mass spectrometer, a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer, a quadrupole mass spectrometer, a triple quadrupole mass spectrometer, a magnetic sector mass spectrometer, or the like.

As one specific implementation of the ion separation instrument200illustrated inFIG.12A, which should not be considered to be limiting in any way, the ion source12illustratively includes 3 stages, and the ion processing instrument202is omitted. In this example implementation, the ion source stage IS1is a conventional source of ions, e.g., electrospray, MALDI or the like, the ion source stage IS2is a conventional ion filter, e.g., a quadrupole or hexapole ion guide, and the ion source stage IS3is a mass spectrometer of any of the types described above. In this embodiment, the ion source stage IS2is controlled in a conventional manner to preselect ions having desired molecular characteristics for analysis by the downstream mass spectrometer, and to pass only such preselected ions to the mass spectrometer, wherein the multiple ions simultaneously analyzed by the ELIT14will be the preselected ions separated by the mass spectrometer according to mass-to-charge ratio. The preselected ions exiting the ion filter may, for example, be ions having a specified ion mass or mass-to-charge ratio, ions having ion masses or ion mass-to-charge ratios above and/or below a specified ion mass or ion mass-to-charge ratio, ions having ion masses or ion mass-to-charge ratios within a specified range of ion mass or ion mass-to-charge ratio, or the like. In some alternate implementations of this example, the ion source stage IS2may be the mass spectrometer and the ion source stage IS3may be the ion filter, and the ion filter may be otherwise operable as just described to preselect ions exiting the mass spectrometer which have desired molecular characteristics for analysis by the downstream ELIT14. In other alternate implementations of this example, the ion source stage IS2may be the ion filter, and the ion source stage IS3may include a mass spectrometer followed by another ion filter, wherein the ion filters each operate as just described.

As another specific implementation of the ion separation instrument200illustrated inFIG.12A, which should not be considered to be limiting in any way, the ion source12illustratively includes 2 stages, and the ion processing instrument202is again omitted. In this example implementation, the ion source stage IS1is a conventional source of ions, e.g., electrospray, MALDI or the like, the ion source stage IS2is a conventional mass spectrometer of any of the types described above. In this implementation, the instrument200takes the form of the charge detection mass spectrometer (CDMS)100in which the ELIT14is operable to simultaneously analyze multiple ions exiting the mass spectrometer.

As yet another specific implementation of the ion separation instrument200illustrated inFIG.12A, which should not be considered to be limiting in any way, the ion source12illustratively includes 2 stages, and the ion processing instrument202is omitted. In this example implementation, the ion source stage IS1is a conventional source of ions, e.g., electrospray, MALDI or the like, and the ion source stage IS2is a conventional single or multiple-stage ion mobility spectrometer. In this implementation, the ion mobility spectrometer is operable to separate ions, generated by the ion source stage IS1, over time according to one or more functions of ion mobility, and the ELIT14is operable to simultaneously analyze multiple ions exiting the ion mobility spectrometer. In an alternate implementation of this example, the ion processing instrument202may include a conventional single or multiple-stage ion mobility spectrometer as a sole stage OS1(or as stage OS1of a multiple-stage instrument). In this alternate implementation, the ELIT14is operable to simultaneously analyze multiple ions generated by the ion source stage IS1, and the ion mobility spectrometer OS1is operable to separate ions exiting the ELIT14over time according to one or more functions of ion mobility. As another alternate implementation of this example, single or multiple-stage ion mobility spectrometers may follow both the ion source stage IS1and the ELIT14. In this alternate implementation, the ion mobility spectrometer following the ion source stage IS1is operable to separate ions, generated by the ion source stage IS1, over time according to one or more functions of ion mobility, the ELIT14is operable to simultaneously analyze multiple ions exiting the ion source stage ion mobility spectrometer, and the ion mobility spectrometer of the ion processing stage OS1following the ELIT14is operable to separate ions exiting the ELIT14over time according to one or more functions of ion mobility. In any implementations of the embodiment described in this paragraph, additional variants may include a mass spectrometer operatively positioned upstream and/or downstream of the single or multiple-stage ion mobility spectrometer in the ion source12and/or in the ion processing instrument202.

As still another specific implementation of the ion separation instrument200illustrated inFIG.12A, which should not be considered to be limiting in any way, the ion source12illustratively includes 2 stages, and the ion processing instrument202is omitted. In this example implementation, the ion source stage IS1is a conventional liquid chromatograph, e.g., HPLC or the like configured to separate molecules in solution according to molecule retention time, and the ion source stage IS2is a conventional source of ions, e.g., electrospray or the like. In this implementation, the liquid chromatograph is operable to separate molecular components in solution, the ion source stage IS2is operable to generate ions from the solution flow exiting the liquid chromatograph, and the ELIT14is operable to simultaneously analyze multiple ions generated by the ion source stage IS2. In an alternate implementation of this example, the ion source stage IS1may instead be a conventional size-exclusion chromatograph (SEC) operable to separate molecules in solution by size. In another alternate implementation, the ion source stage IS1may include a conventional liquid chromatograph followed by a conventional SEC or vice versa. In this implementation, ions are generated by the ion source stage IS2from a twice separated solution; once according to molecule retention time followed by a second according to molecule size, or vice versa. The ability to analyze trapping events containing multiple simultaneously trapped ions is highly valuable in experiments where the mass spectrometer is coupled to a chromatographic technique. When molecules are sufficiently separated in the chromatograph, they elute from the chromatograph in bursts, each on the order of seconds to minutes in duration, where each burst occurs only once for each molecule per sample injection into the chromatograph. The abundance of ions exiting the chromatograph as a function of the elution time can be considered the elution profile. When these bursts are introduced into the mass spectrometer, the ion beam intensity becomes a function of the chromatographic elution profile. Unlike conventional CDMS implementation which only analyzes single-ion trapping events and requires over an hour to collect sufficient data for the generation of a mass spectrum, simultaneous trapping of multiple ions and the subsequent analysis of multiple-ion trapping events significantly decrease the time necessary to collect a mass spectrum, making it possible to acquire a mass spectrum in several minutes. This also means that bursts in the ion beam intensity that coincide with the elution of separated molecules from the chromatograph can be characterized by CDMS in the same timeframe as the elution profile. In any implementations of the embodiment described in this paragraph, additional variants may include a mass spectrometer operatively positioned between the ion source stage IS2and the ELIT14.

Referring now toFIG.12B, a simplified block diagram is shown of another embodiment of an ion separation instrument210which illustratively includes a multi-stage mass spectrometer instrument220and which also includes the CDMS100including the ELIT14and, in some embodiments, the ion trajectory control apparatus105as described above, implemented as a high-mass ion analysis component. In the illustrated embodiment, the multi-stage mass spectrometer instrument220includes an ion source (IS)12, as illustrated and described herein, followed by and coupled to a first conventional mass spectrometer (MS1)204, followed by and coupled to a conventional ion dissociation stage (ID)206operable to dissociate ions exiting the mass spectrometer204, e.g., by one or more of collision-induced dissociation (CID), surface-induced dissociation (SID), electron capture dissociation (ECD) and/or photo-induced dissociation (PID) or the like, followed by and coupled to a second conventional mass spectrometer (MS2)208, followed by a conventional ion detector (D)212, e.g., such as a microchannel plate detector or other conventional ion detector. The CDMS100, is coupled in parallel with and to the ion dissociation stage206such that the CDMS100may selectively receive ions from the mass spectrometer204and/or from the ion dissociation stage206.

MS/MS, e.g., using only the ion separation instrument220, is a well-established approach where precursor ions of a particular molecular weight are selected by the first mass spectrometer204(MS1) based on their m/z value. The mass selected precursor ions are fragmented, e.g., by collision-induced dissociation, surface-induced dissociation, electron capture dissociation or photo-induced dissociation, in the ion dissociation stage206. The fragment ions are then analyzed by the second mass spectrometer208(MS2). Only the m/z values of the precursor and fragment ions are measured in both MS1and MS2. For high mass ions, the charge states are not resolved and so it is not possible to select precursor ions with a specific molecular weight based on the m/z value alone. However, by coupling the instrument220to the CDMS100as illustrated inFIG.12B, it is possible to select a narrow range of m/z values and then use the CDMS100to determine the masses of the m/z selected precursor ions. The mass spectrometers204,208may be, for example, one or any combination of a magnetic sector mass spectrometer, time-of-flight mass spectrometer or quadrupole mass spectrometer, although in alternate embodiments other mass spectrometer types may be used. In any case, the m/z selected precursor ions with known masses exiting MS1can be fragmented in the ion dissociation stage206, and the resulting fragment ions can then be analyzed by MS2(where only the m/z ratio is measured) and/or by the CDMS instrument100(where the m/z ratios and charges of multiple ions are measured simultaneously). Low mass fragments, i.e., dissociated ions of precursor ions having mass values below a threshold mass value, e.g., 10,000 Da (or other mass value), can thus be analyzed by conventional MS, using MS2, while high mass fragments (where the charge states are not resolved), i.e., dissociated ions of precursor ions having mass values at or above the threshold mass value, can be analyzed by the CDMS100.

It will be understood that the dimensions of the various components of the ELIT14and the magnitudes of the electric fields established therein, as implemented in any of the systems10,100,200,210illustrated in the attached figures and described above, may illustratively be selected as to establish a desired duty cycle of ion oscillation within the ELIT14, corresponding to a ratio of time spent by the ion(s) in the charge detection cylinder CD and a total time spent by the ion(s) traversing the combination of the ion mirrors M1, M2and the charge detection cylinder CD during one complete oscillation cycle. For example, a duty cycle of approximately 50% may be desirable for the purpose of reducing noise in fundamental frequency magnitude determinations resulting from harmonic frequency components of the measured signals. Details relating to such dimensional and operational considerations for achieving a desired duty cycle, e.g., such as 50%, are illustrated and described in U.S. Patent Application Ser. No. 62/616,860, filed Jan. 12, 2018, U.S. Patent Application Ser. No. 62/680,343, filed Jun. 4, 2018 and International Patent Application No. PCT/US2019/013251, filed Jan. 11, 2019, all entitled ELECTROSTATIC LINEAR ION TRAP DESIGN FOR CHARGE DETECTION MASS SPECTROMETRY, the disclosures of which are all expressly incorporated herein by reference in their entireties.

It will be further understood that one or more charge detection optimization techniques may be used with the ELIT14in any of the systems10,100,200,210illustrated in the attached figures and described herein e.g., for trigger trapping or other charge detection events. Examples of some such charge detection optimization techniques are illustrated and described in U.S. Patent Application Ser. No. 62/680,296, filed Jun. 4, 2018 and in International Patent Application No. PCT/US2019/013280, filed Jan. 11, 2019, both entitled APPARATUS AND METHOD FOR CAPTURING IONS IN AN ELECTROSTATIC LINEAR ION TRAP, the disclosures of which are both expressly incorporated herein by reference in their entireties.

It will be further understood that one or more charge calibration or resetting apparatuses may be used with the charge detection cylinder CD of the ELIT14in any of the systems10,100,200,210illustrated in the attached figures and described herein. An example of one such charge calibration or resetting apparatus is illustrated and described in U.S. Patent Application Ser. No. 62/680,272, filed Jun. 4, 2018 and in International Patent Application No. PCT/US2019/013284, filed Jan. 11, 2019, both entitled APPARATUS AND METHOD FOR CALIBRATING OR RESETTING A CHARGE DETECTOR, the disclosures of which are both expressly incorporated herein by reference in their entireties.

It will be still further understood that the ELIT14illustrated in the attached figures and described herein, as part of any of the systems10,100,200,210also illustrated in the attached figures and described herein, may alternatively be provided in the form of at least one ELIT array having two or more ELITs or ELIT regions and/or in any single ELIT including two or more ELIT regions, and that the concepts described herein are directly applicable to systems including one or more such ELITs and/or ELIT arrays. Examples of some such ELITs and/or ELIT arrays are illustrated and described in U.S. Patent Application Ser. No. 62/680,315, filed Jun. 4, 2018 and in co-pending International Patent Application No. PCT/US2019/013283, filed Jan. 11, 2019, both entitled ION TRAP ARRAY FOR HIGH THROUGHPUT CHARGE DETECTION MASS SPECTROMETRY, the disclosures of which are both expressly incorporated herein by reference in their entireties.

It will be further understood that one or more ion source optimization apparatuses and/or techniques may be used with one or more embodiments of the ion source12illustrated and described herein as part of or in combination with any of the systems10,150,180,200,220illustrated in the attached figures and described herein, some examples of which are illustrated and described in U.S. Patent Application Ser. No. 62/680,223, filed Jun. 4, 2018 and entitled HYBRID ION FUNNEL-ION CARPET (FUNPET) ATMOSPHERIC PRESSURE INTERFACE FOR CHARGE DETECTION MASS SPECTROMETRY, and in co-pending International Patent Application No. PCT/US2019/013274, filed Jan. 11, 2019 and entitled INTERFACE FOR TRANSPORTING IONS FROM AN ATMOSPHERIC PRESSURE ENVIRONMENT TO A LOW PRESSURE ENVIRONMENT, the disclosures of which are both expressly incorporated herein by reference in their entireties.

It will be further understood that any of the systems10,100,200,210illustrated in the attached figures and described herein may be implemented in or as part of systems configured to operate in accordance with real-time analysis and/or real-time control techniques, some examples of which are illustrated and described in U.S. Patent Application Ser. No. 62/680,245, filed Jun. 4, 2018 and International Patent Application No. PCT/US2019/013277, filed Jan. 11, 2019, both entitled CHARGE DETECTION MASS SPECTROMETRY WITH REAL TIME ANALYSIS AND SIGNAL OPTIMIZATION, the disclosures of which are both expressly incorporated herein by reference in their entireties.

While this disclosure has been illustrated and described in detail in the foregoing drawings and description, the same is to be considered as illustrative and not restrictive in character, it being understood that only illustrative embodiments thereof have been shown and described and that all changes and modifications that come within the spirit of this disclosure are desired to be protected. For example, it will be understood that the ELIT14illustrated in the attached figures and described herein is provided only by way of example, and that the concepts, structures and techniques described above may be implemented directly in ELITs of various alternate designs. Any such alternate ELIT design may, for example, include any one or combination of two or more ELIT regions, more, fewer and/or differently-shaped ion mirror electrodes, more or fewer voltage sources, more or fewer DC or time-varying signals produced by one or more of the voltage sources, one or more ion mirrors defining additional electric field regions, or the like.