Patent Grant
12112936
The present invention relates generally to charge detection mass spectrometry instruments, and more specifically to apparatuses and methods for conducting pulsed mode operation of such instruments.
Mass Spectrometry provides for the identification of chemical components of a substance by separating gaseous ions of the substance according to ion mass and charge. Various instruments and techniques have been developed for determining the masses of such separated ions, and one such technique is known as charge detection mass spectrometry (CDMS). In CDMS, ion mass is determined as a function of measured ion mass-to-charge ratio, typically referred to as “m/z,” and measured ion charge.
High levels of uncertainty in m/z and charge measurements with early CDMS detectors has led to the development of an electrostatic linear ion trap (ELIT) detector in which ions are made to oscillate back and forth through a charge detection cylinder. Multiple passes of ions through such a charge detection cylinder provides for multiple measurements for each ion, and it has been shown that the uncertainty in charge measurements decreases with n1/2, where n is the number of charge measurements. However, such multiple charge measurements necessarily limit the speed at which ion m/z and charge measurements can be obtained using current ELIT designs. Accordingly, it is desirable to seek improvements in ELIT design and/or operation which increase the rate of ion m/z and charge measurements over those obtainable using current ELIT designs.
The present invention may comprise one or more of the features recited in the attached claims, and/or one or more of the following features and combinations thereof. In one aspect, a charge detection mass spectrometer may comprise an ion source configured to generate ions from a sample, an ion trap configured to receive and store the generated ions therein and to selectively release stored ions therefrom, an electrostatic linear ion trap (ELIT) spaced apart from the ion trap, the ELIT including first and second ion mirrors and a charge detection cylinder positioned therebetween, and means for selectively controlling the ion trap to release at least some of the stored ions therefrom to travel toward and into the ELIT, and for controlling the first and second ion mirrors in a manner which traps in the ELIT at least one of the ions traveling therein and causes the at least one trapped ion to oscillate back and forth between the first and second ion mirrors each time passing through and inducing a corresponding charge on the charge detection cylinder.
In another aspect, a charge detection mass spectrometer may comprise an ion source configured to generate ions from a sample, at least one voltage source configured to produce a plurality of output voltages, an ion trap coupled to a first set of the plurality of output voltages and configured to be responsive a trapping state thereof to receive and store the generated ions therein and to a transmission state thereof to selectively release stored ions therefrom, an electrostatic linear ion trap (ELIT) spaced apart from the ion trap, the ELIT including front and rear ion mirrors and a charge detection cylinder positioned therebetween, the front and rear ion mirrors each coupled to second and third sets respectively of the plurality of output voltages and configured to be responsive to transmission states thereof to transmit ions therethrough and to reflection states thereof to reflect ions entering therein from the charge detection cylinder back into the charge detection cylinder, and processing circuitry for controlling the first set of voltages to the transmission state thereof to cause the ion trap to release at least some of the stored ions therefrom to travel toward and into the ELIT via the front ion mirror, and to thereafter control the third set of voltages, followed by the second set of voltages, to the reflection states thereof to trap at least one of the ions traveling therein and cause the at least one trapped ion to oscillate back and forth between the front and rear ion mirrors each time passing through and inducing a corresponding charge on the charge detection cylinder.
In yet another aspect, a method is provided for operating a charge detection mass spectrometer including an electrostatic linear ion trap (ELIT) having a charge detection cylinder positioned between front and rear ion mirrors and an ion trap spaced apart from the front ion mirror. The method may comprise generating ions from a sample, storing the generated ions in the ion trap, controlling the ion trap to release at least some of the stored ions therefrom and travel toward and into the ELIT via the front ion mirror, after controlling the ion trap to release stored ions, controlling the rear ion mirror to a reflection state in which the rear ion mirror reflects ions entering therein from the charge detection cylinder back through the charge detection cylinder and toward the front ion mirror, and after controlling the rear ion mirror to the reflection state thereof, controlling the front ion mirror to a reflection state in which the front ion mirror reflects ions entering therein from the charge detection cylinder back through the charge detection cylinder and toward the rear ion mirror to trap in the ELIT at least one of the ions released from the ion trap such that the at least one trapped ion oscillates between the front and rear ion mirrors each time passing through and inducing a corresponding charge on the charge detection cylinder.
For the purposes of promoting an understanding of the principles of the invention, 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 an electrostatic linear ion trap (ELIT) array including two or more ELITs or ELIT regions and means for controlling them such that at least two of the ELITs or ELIT regions simultaneously operate to measure a mass-to-charge ratio and a charge of at least one ion captured therein. In this manner, the rate of ion measurement is increased by at a factor of two or more as compared with conventional single ELIT systems, and a corresponding reduction in total ion measurement time is realized. In some embodiments, an example of which will be described in detail below with respect to
Referring to
In the illustrated embodiment, the ELIT array 14 is illustratively provided in the form of a cascaded, i.e., series or end-to-end, arrangement of three ELITs or ELIT regions. Three separate charge detectors CD1, CD2, CD3, are each surrounded by a respective ground cylinder GC1-GC3 and are operatively coupled together by opposing mirror electrodes. A first mirror electrode M1 is operatively positioned between the ion source 12 and one end of the charge detector CD1, a second mirror electrode M2 is operatively positioned between the opposite end of the charge detector CD1 and one end of the charge detector CD2, a third mirror electrode M3 is operatively positioned between the opposite end of the charge detector CD2 and one end of the charge detector CD3, and a fourth mirror electrode is operatively positioned at the opposite end of the charge detector CD3. In the illustrated embodiment, each of the ion mirrors M1-M3 define axially adjacent ion mirror regions R1, R2, and the ion mirror M4 illustratively defines a single ion mirror region R1. Illustratively, the region R2 of the first mirror electrode M1, the charge detector CD1, the region R1 of the second mirror electrode M2 and the spaces between CD1 and the mirror electrodes M1, M2 together define a first ELIT or ELIT region E1 of the ELIT array 14, the region R2 of the second mirror electrode M2, the charge detector CD2, the region R1 of the third mirror electrode M3 and the spaces between CD2 and the mirror electrodes M2, M3 together define a second ELIT or ELIT region E2 of the ELIT array 14, and the region R2 of the third mirror electrode M3, the charge detector CD3, the region R1 of the mirror electrode M4 and the spaces between CD3 and the mirror electrodes M3, M4 together define a third ELIT or ELIT region E3 of the ELIT array 14. It will be understood that in some alternate embodiments, the ELIT array 14 may include fewer cascaded ELITs or ELIT regions, e.g., two cascaded ELITs or ELIT regions, and that in other alternate embodiments the ELIT array 14 may include more cascaded ELITs or ELIT regions, e.g., four or more cascaded ELITs or ELIT regions. The construction and operation of any such alternate ELIT array 14 will generally follow that of the embodiment illustrated in
In the illustrated embodiment, four corresponding voltage sources V1-V4 are electrically connected to the ion mirrors M1-M4 respectively. Each voltage source V1-V4 illustratively 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 to
The voltage sources V1-V4 are illustratively shown electrically connected by a number, P, of signal paths to a conventional processor 16 including a memory 18 having instructions stored therein which, when executed by the processor 16, cause the processor 16 to control the voltage sources V1-V4 to produce desired DC output voltages for selectively establishing electric fields within the regions R1, R2 of the respective ion mirrors M1-M4. P may be any positive integer. In some alternative embodiments, one or more of the voltage sources V1-V4 may be programmable to selectively produce one or more constant output voltages. In other alternative embodiments, one or more of the voltage sources V1-V4 may 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 mirror electrodes M1-M4 in alternate embodiments.
Each charge detector CD1-CD3 is electrically connected to a signal input of a corresponding one of three charge sensitive preamplifiers CP1-CP3, and the signal outputs of each charge preamplifier CP1-CP3 is electrically connected to the processor 16. The charge preamplifiers CP1-CP3 are each illustratively operable in a conventional manner to receive detection signals detected by a respective one of the charge detectors CD1-CD3, to produce charge detection signals corresponding thereto and to supply the charge detection signals to the processor 16. The processor 16 is, in turn, illustratively operable to receive and digitize the charge detection signals produced by each of the charge preamplifiers CP1-CP3, and to store the digitized charge detection signals in the memory 18. The processor 16 is further illustratively coupled to one or more peripheral devices 20 (PD) for providing signal input(s) to the processor 16 and/or to which the processor 16 provides signal output(s). In some embodiments, the peripheral devices 20 include at least one of a conventional display monitor, a printer and/or other output device, and in such embodiments the memory 18 has instructions stored therein which, when executed by the processor 16, cause the processor 16 to control one or more such output peripheral devices 20 to display and/or record analyses of the stored, digitized charge detection signals. In some embodiments, a conventional microchannel plate (MP) detector 22 may be disposed at the ion outlet of the ELIT array 14, i.e., at the ion outlet of the ion mirror M4, and electrically connected to the processor 16. In such embodiments, the microchannel plate detector 22 is operable to supply detection signals to the processor 16 corresponding to detected ions and/or neutrals.
As will be described in greater detail below, the voltage sources V1-V4 are illustratively controlled in a manner which causes ions to be introduced into the ELIT array 14 from the ion source 12, and which selectively captures and confines at least one ion to oscillate within each of three separate ELITs or ELIT regions E1-E3 such that each captured ion(s) repeatedly passes through a respective one of the charge detectors CD1-CD3 in a respective one of the three ELITs or ELIT regions E1-E3. A plurality of charge and oscillation period values are measured at each charge detector CD1-CD3, and the recorded results are processed to determine mass-to-charge ratio and mass values of the ion(s) captured in each of the three ELITs or ELIT regions E1-E3. Depending upon a number of factors including, but not limited to, the dimensions of the three ELITs or ELIT regions E1-E3, the ion oscillation frequency and the resident times of the ions within each of the three ELITs or ELIT regions E1-E3, captured ion(s) oscillate simultaneously within at least two of the three ELITs or ELIT regions E1-E3, and in typical implementations within each of the three of the ELITs or ELIT regions E1-E3, such that ion charge and mass-to-charge ratio measurements can be collected simultaneously from at least two of the three ELITs or ELIT regions E1-E3.
Referring now to
A second mirror electrode 302 of the ion mirror MX is spaced apart from the first mirror electrode 301 and defines a passageway therethrough of diameter P2. A third mirror electrode 303 is spaced apart from the second mirror electrode 302 and likewise defines a passageway therethrough of diameter P2. The second and third mirror electrodes 302, 303 illustratively have equal thickness of D2≥D1. A fourth mirror electrode 304 is spaced apart from the third mirror electrode 303. The fourth mirror electrode 304 defines a passageway therethrough of diameter P2 and illustratively has a thickness D3≈3D2. A plate or grid 30A is illustratively positioned centrally within the passageway of the fourth mirror electrode 304 and defines a central aperture CA therethrough having a diameter P3. In the illustrated embodiment, P3<P1 although in other embodiments P3 may be greater than or equal to P1. A fifth mirror electrode 305 is spaced apart from the fourth mirror electrode 304, and a sixth mirror electrode 306 is spaced apart from the fifth mirror electrode 305. Illustratively, the fifth and sixth mirror electrodes 305, 306 are identical to the third and second mirror electrodes 303, 302 respectively.
For each of the ion mirrors M1-M3, a seventh mirror electrode 307 is formed by the ground cylinder, GCX, disposed about a respective one of the charge detectors CDX. The seventh electrode 307 of the ion mirror M4, on the other hand, may be a stand-alone electrode since the ion mirror M4 is the last in the sequence. In either case, the seventh mirror electrode 307 defines an aperture A2 centrally therethrough which serves as an ion entrance and/or exit to and/or from the ion mirror MX. The aperture A2 is illustratively the mirror image of the aperture A1, and is of a conical shape which decreases linearly between the external and internal faces of GCX from expanded diameter P2 defined at the external face of GCX to the reduced diameter P1 at the internal face of GCX. The seventh mirror electrode 307 illustratively has a thickness of D1. In some embodiments, as illustrated by example in
The mirror electrodes 301-307 are illustratively equally spaced apart from one another by a space S1. Such spaces S1 between the mirror electrodes 301-307 may be voids in some embodiments, i.e., vacuum gaps, and in other embodiments such spaces S1 may be filled with one or more electrically non-conductive, e.g., dielectric, materials. The mirror electrodes 301-307 are axially aligned, i.e., collinear, such that a longitudinal axis 24 passes centrally through each aligned passageway and also centrally through the apertures A1, A2 and CA. In embodiments in which the spaces S1 include 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 electrodes 301-307 and which have diameters of P2 or greater.
In each of the ion mirrors M1-M4, the region R1 is defined between the aperture A1 of the mirror electrode 301 and the central aperture CA defined through the plate or grid 30A. In each of the ion mirrors M1-M3, the adjacent region R2 is defined between the central aperture CA defined through the plate or grid 30A and the aperture A2 of the mirror electrode 307.
Within each ELIT or ELIT region E1-E3, a respective charge detector CD1-CD3, each in the form of an elongated, electrically conductive cylinder, is positioned and spaced apart between corresponding ones of the ion mirrors M1-M4 by a space S2. Illustratively, S2>S1, although in alternate embodiments S2 may be less than or equal to S2. In any case, each charge detection cylinder CD1-CD3 illustratively defines a passageway axially therethrough of diameter P4, and each charge detection cylinder CD1-CD3 is oriented relative to the ion mirrors M1-M4 such that the longitudinal axis 24 extends centrally through the passageway thereof. In the illustrated embodiment, P1<P4<P2, although in other embodiments the diameter of P4 may be less than or equal to P1, or greater than or equal to P2. Each charge detection cylinder CD1-CD3 is illustratively disposed within a field-free region of a respective one of the ground cylinders GC1-GC3, and each ground cylinder GC1-GC3 is positioned between and forms part of respective ones of the ion mirrors M1-M4 as described above. In operation, the ground cylinders GC1-G3 are illustratively controlled to ground potential such that the first and seventh electrodes 301, 307 are at ground potential at all times. In some alternate embodiments, either or both of first and seventh electrodes 301, 307 in one or more of the ion mirrors M1-M4 may be set to any desired DC reference potential, and in other alternate embodiments either or both of first and seventh electrodes 301, 307 in one or more of the ion mirrors M1-M4 may be electrically connected to a switchable DC or other time-varying voltage source.
As briefly described above, the voltage sources V1-V4 are illustratively controlled in a manner which causes ions to be introduced into the ELIT array 14 from the ion source 12, and which causes at least one ion to be selectively captured and confined to oscillate within each of three separate ELITs or ELIT regions E1-E3 such that each captured ion(s) repeatedly passes through a respective one of the charge detectors CD1-CD3 in a respective one of the three ELITs or ELIT regions E1-E3. Charge and oscillation period values are measured at each charge detector CD1-CD3 each time a respective oscillating ion(s) passes therethrough. The measurements are recorded and the recorded results are processed to determine mass-to-charge ratio and mass values of the ion(s) captured in each of the three ELITs or ELIT regions E1-E3.
Within each ELIT or ELIT region E1-E3 of the ELIT array 14, at least one ion is captured and made to oscillate between opposed regions of the respective ion mirrors M1-M4 by controlling the voltage sources V1-V4 to selectively establish ion transmission and ion reflection electric fields within the regions R1, R2 of the ion mirrors M1-M4. In this regard, each voltage source VX is illustratively configured in one embodiment to produce seven DC voltages DC1-DC7, and to supply each of the voltages DC1-DC7 to a respective one of the mirror electrodes 301-307 of the respective ion mirror MX. In some embodiments in which one or more of the mirror electrodes 301-307 is to be held at ground potential at all times, the one or more such mirror electrodes 301-307 may alternatively be electrically connected to the ground reference of the voltage supply VX and the corresponding one or more voltage outputs DC1-DC7 may be omitted. Alternatively or additionally, in embodiments in which any two or more of the mirror electrodes 301-307 are to be controlled to the same non-zero DC values, any such two or more mirror electrodes 301-307 may be electrically connected to a single one of the voltage outputs DC1-DC7 and superfluous ones of the output voltages DC1-DC7 may be omitted.
As illustrated by example in
Referring now to
With reference to
Following step 102, the process 100 advances to step 104 where the processor 16 is operable to pause and determine when to advance to step 106. In one embodiment of step 102, the ELIT array 14 is illustratively controlled in a “random trapping mode” in which the ion mirrors M1-M4 are held in their transmission modes for a selected time period during which one or more ions generated by the ion source 12 will be expected to enter and travel through the ELIT array 14. As one non-limiting example, the selected time period which the processor 16 spends at step 104 before moving on to step 106 when operating in the random trapping mode is on the order of 1-3 millisecond (ms) depending upon the axial length of the ELIT array 14 and of the velocity of ions entering the ELIT array 14, although it will be understood that such selected time period may, in other embodiments, be greater than 3 ms or less than 1 ms. Until the selected time period has elapsed, the process 100 follows the NO branch of step 104 and loops back to the beginning of step 104. After passage of the selected time period, the process 100 follows the YES branch of step 104 and advances to step 106. In some alternate embodiments of step 104, such as in embodiments which include the microchannel plate detector 22, the processor 16 may be configured to advance to step 106 only after one or more ions has been detected by the detector 22, with or without a further additional delay period, so as to ensure that ions are being transmitted through the ELIT array 14 before advancing to step 106. In other alternate embodiments, the ELIT array 14 may illustratively be controlled by the processor 16 in a “trigger trapping mode” in which the ion mirrors M1-M4 are held in their ion transmission modes until at least one ion is detected at the charge detector CD3. Until such detection, the process 100 follows the NO branch of step 104 and loops back to the beginning of step 104. Detection by the processor 16 of at least one ion at the charge detector CD3 is indicative of the at least one ion passing through the charge detector CD3 toward the ion mirror M4 and serves as a trigger event which causes the processor 16 to follow the YES branch of step 104 and advance to step 106 of the process 100.
Following the YES branch of step 104 and with reference to
Following step 106, the process 100 advances to step 108 where the processor 16 is operable to pause and determine when to advance to step 110. In embodiments of step 108 in which the ELIT array 14 is controlled by the processor 16 in random trapping mode, the ion mirrors M1-M3 are held at step 108 in their transmission modes for a selected time period during which one or more ions may enter the ELIT or ELIT region E3. As one non-limiting example, the selected time period which the processor 16 spends at step 108 before moving on to step 110 when operating in the random trapping mode is on the order of 0.1 millisecond (ms), although it will be understood that such selected time period may, in other embodiments, be greater than 0.1 ms or less than 0.1 ms. Until the selected time period has elapsed, the process 100 follows the NO branch of step 108 and loops back to the beginning of step 108. After passage of the selected time period, the process 100 follows the YES branch of step 108 and advances to step 110. In alternate embodiments of step 108 in which the ELIT array 14 is controlled by the processor 16 in trigger trapping mode, the ion mirrors M1-M3 are held in their ion transmission modes until at least one ion is detected at the charge detector CD3. Until such detection, the process 100 follows the NO branch of step 108 and loops back to the beginning of step 108. Detection by the processor 16 of at least one ion at the charge detector CD3 ensures that at least one ion is moving through the charge detector CD3 and serves as a trigger event which causes the processor 16 to follow the YES branch of step 108 and advance to step 110 of the process 100.
Following the YES branch of step 108 and with reference to
The ion reflection electric field R31 operates, as described above, to reflect the one or more ions entering the region R1 of M3 back toward the ion mirror M2 (and through the charge detector CD2) as described above with respect to
Following steps 110 and 112, the process 100 advances to step 114 where the processor 16 is operable to pause and determine when to advance to step 116. In embodiments of step 114 in which the ELIT array 14 is controlled by the processor 16 in random trapping mode, the ion mirrors M1-M2 are held at step 114 in their transmission modes for a selected time period during which one or more ions may enter the ELIT or ELIT region E2. As one non-limiting example, the selected time period which the processor 16 spends at step 114 before moving on to step 116 when operating in the random trapping mode is on the order of 0.1 millisecond (ms), although it will be understood that such selected time period may, in other embodiments, be greater than 0.1 ms or less than 0.1 ms. Until the selected time period has elapsed, the process 100 follows the NO branch of step 114 and loops back to the beginning of step 108. After passage of the selected time period, the process 100 follows the YES branch of step 114 and advances to step 116. In alternate embodiments of step 114 in which the ELIT array 14 is controlled by the processor 16 in trigger trapping mode, the ion mirrors M1-M2 are held in their ion transmission modes until at least one ion is detected at the charge detector CD2. Until such detection, the process 100 follows the NO branch of step 114 and loops back to the beginning of step 114. Detection by the processor 16 of at least one ion at the charge detector CD2 ensures that at least one ion is moving through the charge detector CD2 and serves as a trigger event which causes the processor 16 to follow the YES branch of step 114 and advance to step 116 of the process 100.
The ion reflection electric field R21 operates, as described above, to reflect the one or more ions entering the region R1 of M2 back toward the ion mirror M1 (and through the charge detector CD1) as described above with respect to
Following the YES branch of step 114 and as the at least one ion in the ELIT or ELIT region E3 continues to oscillate back and forth through the charge detection cylinder CD3 between the ion mirrors M3 and M4, the process 100 advances to step 116. With reference to
Following steps 116 and 118, the process 100 advances to step 120 where the processor 16 is operable to pause and determine when to advance to step 122. In embodiments of step 120 in which the ELIT array 14 is controlled by the processor 16 in random trapping mode, the ion mirror M1 is held at step 120 in its transmission mode of operation for a selected time period during which one or more ions may enter the ELIT or ELIT region E1. As one non-limiting example, the selected time period which the processor 16 spends at step 120 before moving on to step 122 when operating in the random trapping mode is on the order of 0.1 millisecond (ms), although it will be understood that such selected time period may, in other embodiments, be greater than 0.1 ms or less than 0.1 ms. Until the selected time period has elapsed, the process 100 follows the NO branch of step 120 and loops back to the beginning of step 120. After passage of the selected time period, the process 100 follows the YES branch of step 120 and advances to step 122. In alternate embodiments of step 120 in which the ELIT array 14 is controlled by the processor 16 in trigger trapping mode, the ion mirror M1 is held in its ion transmission mode of operation until at least one ion is detected at the charge detector CD1. Until such detection, the process 100 follows the NO branch of step 120 and loops back to the beginning of step 120. Detection by the processor 16 of at least one ion at the charge detector CD1 ensures that at least one ion is moving through the charge detector CD1 and serves as a trigger event which causes the processor 16 to follow the YES branch of step 120 and advance to step 122 of the process 100.
Following the YES branch of step 120, and as at least one ion in the ELIT or ELIT region E3 continues to oscillate back and forth through the charge detection cylinder CD3 between the ion mirrors M3 and M4 and also as at least another ion in the ELIT or ELIT region E2 simultaneously continues to oscillate back and forth through the charge detection cylinder CD2 between the ion mirrors M2 and M3 the process 100 advances to step 122. With reference to
Following steps 122 and 124, the process 100 advances to step 126 where the processor 16 is operable to pause and determine when to advance to step 128. In one embodiment, the processor 16 is configured, i.e. programmed, to allow the ions to oscillate back and forth simultaneously through each of the ELITs or ELIT regions E1-E3 for a selected time period, i.e., a total ion cycle measurement time, during which ion detection events, i.e., by each of the charge detectors CD1-CD3, are recorded by the processor 16. As one non-limiting example, the selected time period which the processor 16 spends at step 126 before moving on to step 128 is on the order of 100-300 millisecond (ms), although it will be understood that such selected time period may, in other embodiments, be greater than 300 ms or less than 100 ms. Until the selected time period has elapsed, the process 100 follows the NO branch of step 126 and loops back to the beginning of step 126. After passage of the selected time period, the process 100 follows the YES branch of step 126 and advances to steps 128 and 140. In some alternate embodiments of the process 100, the voltage sources V1-V4 may illustratively be controlled by the processor 16 at step 126 to allow the ion(s) to oscillate back in forth through the charge detectors CD1-CD3 a selected number of times, i.e., a total number of measurement cycles, during which ion detection events, i.e., by each of the charge detectors CD1-CD3, are recorded by the processor 16. Until the processor counts the selected number ion detection events of one or more of the charge detectors CD1-CD3, the process 100 follows the NO branch of step 126 and loops back to the beginning of step 126. Detection by the processor 16 of the selected number of ion detection events serves as a trigger event which causes the processor 16 to follow the YES branch of step 126 and advance to steps 128 and 140 of the process 100.
Following the YES branch of step 126, the processor 16 is operable at step 128 to control the voltage sources V1-V4 to set the output voltages DC1-DC7 of each in a manner which changes or switches the operation of all of the ion mirrors M1-M4 from the ion reflection mode of operation to the ion transmission mode of operation in which the ion mirrors M1-M4 each operate to allow passage of ions therethrough. Illustratively, the voltage sources V1-V4 are illustratively controlled at step 128 of the process 100 to produce the voltages DC1-DC7 according to the all-pass transmission mode as illustrated in Table I above, which re-establishes the ion trajectory 50 illustrated in
Following step 128, the processor 16 is operable at step 130 to pause for a selected time period to allow the ions contained within the ELIT array 14 to be transmitted out of the ELIT array 14. As one non-limiting example, the selected time period which the processor 12 spends at step 130 before looping back to step 102 to restart the process 100 is on the order of 1-3 milliseconds (ms), although it will be understood that such selected time period may, in other embodiments, be greater than 3 ms or less than 1 ms. Until the selected time period has elapsed, the process 100 follows the NO branch of step 130 and loops back to the beginning of step 130. After passage of the selected time period, the process 100 follows the YES branch of step 130 and loops back to step 102 to restart the process 100.
Also following the YES branch of step 126, the process 100 additionally advances to step 140 to analyze the data collected during steps 112, 118 and 124 of the process 100 just described. In the illustrated embodiment, the data analysis step 140 illustratively includes step 142 in which the processor 16 is operable to compute Fourier transforms of the recorded sets of stored charge detection signals provided by each of the charge preamplifiers CP1-CP3. The processor 16 is illustratively operable to execute step 142 using any conventional digital Fourier transform (DFT) technique such as for example, but not limited to, a conventional Fast Fourier Transform (FFT) algorithm. In any case, the processor 16 is operable at step 142 to compute three Fourier Transforms, FT1, FT2 and FT3, wherein FT1 is the Fourier Transform of the recorded set of charge detection signals provided by the first charge preamplifier CP1, thus corresponding to the charge detection events detected by the charge detection cylinder CD1 of the ELIT or ELIT region E1, FT2 is the Fourier Transform of the recorded set of charge detection signals provided by the first charge preamplifier CP2, thus corresponding to the charge detection events detected by the charge detection cylinder CD2 of the ELIT or ELIT region E2 and FT3 is the Fourier Transform of the recorded set of charge detection signals provided by the first charge preamplifier CP3, thus corresponding to the charge detection events detected by the charge detection cylinder CD3 of the ELIT or ELIT region E3.
Following step 142, the process 100 advances to step 144 where the processor 16 is operable to compute three sets of ion mass-to-charge ratio values (m/Z1, m/z2 and m/z3), ion charge values (z1, z2 and z3) and ion mass values (m1, m2 and m3), each as a function of a respective one of the computed Fourier Transform values FT1, FT2, FT3). Thereafter at step 146 the processor 16 is operable to store the computed results in the memory 18 and/or to control one or more of the peripheral devices 20 to 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 in any of the ELITs or ELIT regions E1-E3 is 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 ELIT or ELIT region, and the fundamental frequency ff is determined directly from the respective computed Fourier Transform. Thus, ff1 is the fundamental frequency of FT1, ff2 is the fundamental frequency of FT2 and ff3 is the fundamental frequency of FT3. Typically, C is determined using conventional ion trajectory simulations. In any case, the value of the ion charge, z, is proportional to the magnitude FTMAG of the FT, taking into account the number of ion oscillation cycles. Ion mass, m, is then calculated as a product of m/z and z. Thus, with respect to the recorded set of charge detection signals provided by the first charge preamplifier CP1, the processor 16 is operable at step 144 to compute m/z1=C/ff12, z1=F(FTMAG1) and m1=(m/z1)(z1). With respect to the recorded set of charge detection signals provided by the second charge preamplifier CP2, the processor 16 is similarly operable at step 144 to compute m/z2=C/ff22, z2=F(FTMAG2) and m2=(m/z2)(z2), and with respect to the recorded set of charge detection signals provided by the third charge preamplifier CP3, the processor 16 is likewise operable at step 144 to compute m/z3=C/ff32, z3=F(FTMAG3) and m3=(m/z3)(z3).
Referring now to
Focusing on the ion source 12, it will be understood that the source 12 of ions entering the ELIT 10 may be or include, in the form of one or more of the ion source stages IS1-ISQ, any conventional source 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 ion charge states, and the like. It will be understood that the ion source 12 may 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 instrument 70, it will be understood that the instrument 70 may 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) 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 ion charge states, and the like. It will be understood that the ion processing instrument 70 may 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 includes one or more mass spectrometers, any one or more such mass spectrometers may be implemented in any of the forms described above with respect to
As one specific implementation of the ion separation instrument 60 illustrated in
As another specific implementation of the ion separation instrument 60 illustrated in
As yet another specific implementation of the ion separation instrument 60 illustrated in
As still another specific implementation of the ion separation instrument 60 illustrated in
Referring now to
MS/MS, e.g., using only the ion separation instrument 82, is a well-established approach where precursor ions of a particular molecular weight are selected by the first mass spectrometer 84 (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 stage 86. The fragment ions are then analyzed by the second mass spectrometer 86 (MS2). Only the m/z values of the precursor and fragment ions are measured in both MS1 and 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 instrument 82 to the CDMS 10, 200, 300 illustrated and described herein, it is possible to select a narrow range of m/z values and then use the CDMS 10, 200, 300 to determine the masses of the m/z selected precursor ions. The mass spectrometers 84, 88 may 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 MS1 can be fragmented in the ion dissociation stage 86, and the resulting fragment ions can then be analyzed by MS2 (where only the m/z ratio is measured) and/or by the CDMS instrument 10, 200, 300 (where the m/z ratio and charge are measured simultaneously). Low mass fragments can thus be analyzed by conventional MS while high mass fragments (where the charge states are not resolved) are analyzed by CDMS.
Referring now to
The ELIT 204 is illustratively identical to the ELIT 202 just described with ion mirrors M3, M4 corresponding to the ion mirrors M1, M2 of the ELIT 202, with the voltage sources V3, V4 corresponding to the voltage sources V1, V2 of the ELIT 202 and with inlet/outlet apertures AI2/AO2 defining a longitudinal axis 242 extending through the ELIT 204 and illustratively bisecting the apertures AI2, AO2. A charge amplifier CP2 is electrically coupled to the charge detection cylinder CD2 of the ELIT 204, and is illustratively identical in structure and function to the charge preamplifier CP2 illustrated in
The ELIT 206 is likewise illustratively identical to the ELIT 202 just described with ion mirrors M5, M6 corresponding to the ion mirrors M1, M2 of the ELIT 202, with the voltage sources V5, V6 corresponding to the voltage sources V1, V2 of the ELIT 202 and with inlet/outlet apertures AI3/AO3 defining a longitudinal axis 243 extending through the ELIT 206 and illustratively bisecting the apertures AI3, AO3. A charge amplifier CP3 is electrically coupled to the charge detection cylinder CD3 of the ELIT 206, and is illustratively identical in structure and function to the charge preamplifier CP3 illustrated in
The voltage sources V1-V6, as well as the charge preamplifier CP1-CP3, are operatively coupled to a processor 210 including a memory 212 as described with respect to
In the embodiment illustrated in
The ion steering array 208 illustratively includes 3 sets of four electrically conductive pads P1-P4, P5-P8 and P9-P12 arranged on each of two spaced-apart planar substrates such that each of the electrically conductive pads P1-P12 on one of the planar substrates is aligned with and faces a respective one of the electrically conductive pads on the other substrate. In the embodiment illustrated in
Referring now to
Referring specifically to
The opposed pad pairs P31, P32 and P41, P42 are upstream of the opposed pad pairs P11, P12 and P21, P22, and the opposed pad pairs P11, P12 and P21, P22 are conversely downstream of the opposed pad pairs P41, P42 and P31, P32. In this regard, the “unaltered direction of ion travel” through the channel 225, as this term is used herein, is “upstream,” and generally parallel with the direction A of ions exiting the ion source 12. Transverse edges 220C, 222C of the substrates 220, 222 are aligned, as are opposite transverse edges 220D, 222D, and the “altered direction of ion travel” through the channel 225, as this term is used herein, is from the aligned edges 220C, 222C toward the aligned edges 220D, 222D, and generally perpendicular to both such aligned edges 220C, 222C and 220D, 222D.
In the embodiment illustrated in
Referring now to
Referring now specifically to
Referring again to
With reference to
With reference to
With reference to
At the same time or following control of the ELIT 202 as just described, and with the ion(s) oscillating within the ELIT 202 back and forth between the ion mirrors M1, M2, the processor 210 is operable to control VST to switch the voltages applied to pads P2 and P4 back to VREF, to switch the voltages applied to pads P5-P8 from —XV to VREF and to switch the voltages applied to pads P9-P12 from VREF to —XV, as also illustrated in
With reference now to
Following the operating state illustrated in
At the same time or following control of the ELIT 204 as just described with respect to
In any case, the processor 210 is operable at some point thereafter to control V6 to produce voltages which cause the ion mirror M6 to switch from the ion transmission mode of operation to the ion reflection mode of operation so as to reflect ions back toward M5. The timing of this switch of M6 illustratively depends on whether the operation of the ELIT 206 is being controlled by the processor 210 in random trapping mode or in trigger trapping mode as described with respect to
As also illustrated in
After the ions have oscillated back and forth within each of the ELITs 202, 204 and 206 for a total ion cycle measurement time or a total number of measurement cycles, e.g., as described above with respect to step 126 of the process 100 illustrated in
Depending upon a number of factors including, but not limited to, the dimensions of the ELITS 202, 204, 206, the frequency or frequencies of oscillation of ions through each ELIT 202, 204, 206 and the total number of measurement cycles/total ion cycle measurement time in each ELIT 202, 204, 206, ions may simultaneously oscillate back and forth within at least two of the ELITs 202, 204 and 206, and ion charge/timing measurements taken from respective ones of the charge preamplifiers CP1, CP2 and CP3 may therefore be simultaneously collected and stored by the processor 210. In the embodiment illustrated in
Referring now to
The ion mass detection system 300 is identical in some respects to the ion mass detection system 200 in that the ion mass detection system 300 includes an ion source 12 operatively coupled to an ion steering array 208, the structures and operation of which are as described above. The instructions store in the memory 306 further illustratively include instructions which, when executed by the processor 304, cause the processor 304 to control the ion steering array voltage source VST as described below.
In the embodiment illustrated in
An ion trap voltage source VIT is operatively coupled between the processor 304 and each of the ion traps IT1-IT3. The voltage source VIT is illustratively configured to produce suitable DC and AC, e.g., RF, voltages for separately and individually controlling operation of each of the ion traps IT1-IT3 in a conventional manner.
The processor 304 is illustratively configured, e.g. programmed, to control the ion steering array voltage source VST to sequentially steer one or more ions exiting the ion aperture IA of the ion source 12, as described with respect to
As the ion traps IT1-IT3 are being filled with ions, the processor 304 is configured, i.e., programmed, to control V1 and V2 to produce suitable DC voltages which control the ion mirrors M1 and M2 of the ELIT E1-E2 to operate in their ion transmission operating modes so that any ions contained therein exit via the ion outlet apertures AO1-AO3 respectively. When, via control of the ion steering array 208 and the ion traps IT1-IT3 as just described, at least one ion is trapped within each of the ion traps IT1-IT3, the processor 304 is configured, i.e., programmed, to control V2 to produce suitable DC voltages which control the ion mirrors M2 of the ELITs E1-E3 to operate in their ion reflection operating modes. Thereafter, the processor 304 is configured to control the ion trap voltage source VIT to produce suitable voltages which cause the ion outlets TO1-TO3 of the respective ion traps IT1-IT3 to simultaneously open to direct at least one ion trapped therein into a respective one of the ELITs E1-E3 via a respective ion inlet aperture AI1-AI3 of a respective ion mirror M1. When the processor 304 determines that at least one ion has entered each ELIT E1-E3, e.g., after passage of some time period following simultaneous opening of the ion traps IT1-IT3 or following charge detection by each of the charge preamplifiers CP1-CP3, the processor 304 is operable to control the voltage source V1 to produce suitable DC voltages which control the ion mirrors M1 of the ELTs E1-E3 to operate in their ion reflection operating modes, thereby trapping at least one ion within each of the ELITs E1-E3.
With the ion mirrors M1 and M2 of each ELIT E1-E3 operating in the ion reflection operating mode, the at least one ion in each ELIT E1-E3 simultaneously oscillates back and forth between M1 and M2, each time passing through a respective one of the charge detection cylinders CD1-CD3. Corresponding charges induced on the charge detection cylinders CD1-CD3 are detected by the respective charge preamplifiers CP1-CP3, and the charge detection signals produced by the charge preamplifiers CP1-CP3 are stored by the processor 304 in the memory 306 and subsequently processed by the processor 304, e.g., as described with respect step 140 of the process 100 illustrated in
Although the embodiments of the ion mass detection systems 200 and 300 are illustrated in
Referring now to
As briefly described above, the instrument 400 illustrated in
In some embodiments in which the ion source 404 is positioned outside of the differentially pumped source region 408 and is operable to generate and supply ions to the source region 408 as described above, the source region 408 may illustratively include an ion processing interface 410 configured to efficiently transmit ions with a broad mass distribution to the ion inlet of the ion trap 418. In some such embodiments, the interface 410 may illustratively include a drift tube 412 having an open end positioned adjacent to or spaced apart from the ion outlet end of the capillary 406, and having an opposite end coupled to one end of a funnel region 414 which tapers from the end of the drift tube 412 to a reduced cross-section ion outlet. An ion carpet 416 may be operatively coupled to the ion outlet of the funnel region 414, and may define an ion passageway therethrough coupled to the ion inlet of the ion trap 418. At least one output V2 of the voltage source 450 is electrically coupled to the interface 410 and supplies a number, K, of DC and/or time-varying voltage signals to the interface 401 to control operation thereof, where K may be any positive integer. A central, longitudinal axis A of the instrument 400 illustratively passes centrally through the various ion inlets and outlets just described and further described below. In embodiments which include it, the interface 410 illustratively defines a virtual jet disrupter therein configured to disrupt the gas jet generated by gas flow through the capillary 406 and into the differentially pumped region 408, to thermalize the ions and to focus the ions into the ion trap 418. Further details relating to the structure and operation of an embodiment of the interface 410 are illustrated and described in co-pending International Patent Application Nos. PCT/US2019/013274, filed Jan. 11, 2019, and PCT/US2019/035379, filed Jun. 4, 2019, both entitled HYBRID ION FUNNEL-ION CARPET (FUNPET) ATMOSPHERIC PRESSURE INTERFACE FOR CHARGE DETECTION MASS SPECTROMETRY, the disclosures of which are expressly incorporated herein by reference in their entireties.
In some alternate embodiments, the source region 408 may not include the interface 410. In other alternate embodiments, the ion source 404 may be provided in the form of one or more other conventional ion sources, one or more of which may be positioned outside of the source region 408 and/or one or more of which may be positioned inside of the source region 408. In some such embodiments, the source region 408 may include the interface 410, and in other such embodiments the interface 410 may be omitted.
The ion inlet of the ion trap 418 is illustratively defined by a central aperture formed through an electrically conductive plate, grid or the like 420 that is electrically connected to an output V3 of the voltage source 450. An ion outlet of the ion trap 418 is spaced apart along the central axis A from the ion inlet, and is likewise illustratively defined by a central aperture formed through an electrically conductive plate, grid or the like 422 that is electrically connected to another output V5 of the voltage source 450. Another pump P2 is operatively coupled to the ion trap 418 and is illustratively operable to pump the ion trap 418 to a lower pressure, e.g., higher vacuum, than that of the source region 408, such that the ion trap 418 defines a second differentially pumped region. In some embodiments, P2 is configured and operable to control the ion trap 418 to a pressure of 10-100 mbar, although in other embodiments P2 may control the ion trap 418 to pressures outside of this range. In some embodiments, a gas source GS may be operatively coupled to the ion trap 418, and in such embodiments may be operable to supply a buffer or other gas to the interior of the ion trap 418. In some such embodiments, the gas is selected such that ion collisions therewith cause a reduction in ion energy. In one embodiment, the ion trap 418 is configured a conventional hexapole ion trap, although in alternate embodiments the ion trap may 418 may have other conventional configurations, e.g., quadrupole, octupole, etc. In any case, the ion trap 418 will typically include a number of elongated, electrically conductive rods surrounding the axis A to which an output V4 of the voltage source 450 is operatively coupled. Illustratively, the output V4 is coupled to the rods in a manner which causes each opposed set or pair of the rods to be out of phase with the other opposed pairs, and the output voltage V4 is illustratively a time-varying, e.g., radio frequency, voltage. In some embodiments, V4 may further include one or more DC voltages.
Operation of the ion trap 418 is conventional in that the voltages V3 and V5 are controllable DC voltages which are controlled to allow ions to enter the trap 418 via the ion inlet, to cause ions to be trapped therein, and to release the ions from the ion outlet. For example, the voltage V3 is illustratively controlled to a DC potential which sets the ion energy. The gas source GS, in embodiments which include it, supplies a background gas with which ions entering the ion trap 418 collide to thermalize excess kinetic energy picked up by the ions from the gas flow from the source region 408 into the ion trap 418. The time-varying voltage V4 operates to confine the ions in the radial direction, and the voltage V5 is controlled to trap ions within the ion trap 418 and to eject ions from the ion trap 418. For example, to transmit ions through the ion trap 418, V5 is typically controlled to a potential that is less than that of V4, whereas to collect and store, i.e., trap, ions, the potential B5 is illustratively raised to a potential at which ions are no longer transmitted through the ion outlet of the ion trap 418.
In some embodiments, as briefly described above, the instrument 400 may include a mass-to-charge ratio filter 424 having an ion inlet illustratively coupled to, or integral with, the ion outlet of the ion trap 418. An ion outlet is spaced apart along the central axis A from the ion inlet of the filter 424, and is illustratively defined by a central aperture formed through an electrically conductive plate, grid or the like 426 that is electrically connected to yet another output V7 of the voltage source 450. Another pump P3 is operatively coupled to the filter 424 and is illustratively operable to pump the filter 424 to a lower pressure, e.g., higher vacuum, than that of the ion trap 418, such that the filter 424 defines a third differentially pumped region. In some embodiments, the gas source GS may be operatively coupled to the filter 424.
The mass-to-charge ratio filter 424 is illustratively provided in the form of a conventional quadrupole mass-to-charge filter, although in alternate embodiments the filter 424 may be provided in the form of a hexapole, octupole or other conventional configuration. In any case, the mass-to-charge ratio filter 424 will typically include a number of elongated, electrically conductive rods surrounding the axis A to which an output V6 of the voltage source 450 is operatively coupled. Illustratively, the output V6 is coupled to the rods in a manner which causes each opposed set or pair of the rods to be out of phase with the other opposed pairs, and the output voltage V6 is illustratively a time-varying, e.g., radio frequency, voltage. In some embodiments, V6 may further include one or more DC voltages.
In some embodiments, the voltage V7 is set to be sufficiently lower than that of the voltage V5 to cause ions to be transmitted through the filter 424. In other embodiments, the voltage V7 may be switched similarly to that of V5 so as to operate the filter 424 as a second ion trap. In the any case, in embodiments in which the voltage V6 is time-varying only, e.g., RF only, the mass-to-charge ratio filter 424 illustratively operates as a high-pass filter, allowing passage through the filter 424 only of ions above a selected mass-to-charge ratio value. The selected mass-to-charge ratio value is illustratively a function of the magnitude of the time-varying voltage V6. In such embodiments, the mass-to-charge ratio filter 424 thus operates as a high mass-to-charge ratio filter to preselect, i.e., pass, only ions having mass-to-charge ratios above a selectable mass-to-charge ratio threshold. In some alternate embodiments, the voltage V6 includes time-varying and DC components, the mass-to-charge ratio filter 424 illustratively operates as a band-pass filter, allowing passage through the filter 424 only of ions within a selected range of mass-to-charge ratios. The selected range of mass-to-charge ratios is illustratively a function of the magnitudes of the time-varying and DC components. In such embodiments, the mass-to-charge ratio filter 424 thus operates as a mass-to-charge ratio band filter to preselect, i.e., pass, only ions having mass-to-charge ratios within a selectable range of ion mass-to-charge ratios.
In some alternate embodiments, the mass-to-charge ratio filter 424 may be positioned upstream of the ion trap 418. In such embodiments, the filter 424 may be controlled in any of the modes just described to pass into the ion trap 418 only ions having mass-to-charge ratios within a specified range of mass-to-charge ratios. In some such embodiments, mass-to-charge ratio filters 424 may be positioned upstream and downstream of the ion trap 418. In such embodiments, the mass-to-charge ratio filter 424 upstream of the ion trap 418 may illustratively be controlled to pass only ions having mass-to-charge ratios within a selected range of mass-to-charge ratios, and the mass-to-charge ratio filter 424 downstream of the ion trap 418 may be controlled to pass only ions having mass-to-charge ratios within a subset of the selected range of mass-to-charge ratios. Alternatively, the two mass-to-charge ratio filters 424 may be controlled to pass only ions having mass-to-charge ratios within the same range of mass-to-charge ratios. In this latter embodiment, the upstream mass-to-charge ratio filter 424 may be controlled to pass into the ion trap 418 only ions having mass-to-charge ratios within a selected range of mass-to-charge ratios, and the mass-to-charge ratio filter 424 downstream of the ion trap 418 may be used to allow ions exiting the ion trap 418 to separate in time as they pass therethrough on their way to the detector 434.
In some alternate embodiments, a conventional drift tube may be substituted for, i.e., in place of, the mass-to-charge ratio filter 424. In some such embodiments, the axial passageway defined through the drift tube may have a constant cross-sectional area. In some such embodiments, the drift tube may be configured and controlled with one or more voltages produced by the voltage source 450 to radially focus ions traveling axially therethrough. In other embodiments, at least a portion of the drift tube adjacent to an ion outlet end thereof may be funnel-shaped, i.e., with decreasing cross-sectional area of the axial passageway in the direction of the ion outlet. In some such embodiments, at least the funnel section is configured and controlled with one or more voltages produced by the voltage source 450 to radially focus ions traveling axially therethrough, and in other embodiments the entire drift tube may be configured and controlled with one or more voltages produced by the voltage source 450 to radially focus ions traveling axially therethrough. In some such embodiments, the plate or grid 426 may be replaced with a conventional ion carpet defining a central aperture therethrough, wherein the ion carpet is configured and controlled with one or more voltages produced by the voltage source 450 to further focus ions into and through the aperture to the next stage of the instrument 400.
The instrument 400 further includes a fourth differentially pumped region 428 having an ion inlet coupled to, or integral with, the ion outlet of the mass-to-charge ratio filter 424. A fourth pump P4 is operatively coupled to the region 428, and is configured to pump the region 428 to a pressure that is less than that of the filter 424. In the illustrated embodiment, the fourth differentially pumped region 428 includes an ion lens and deflectors 430, followed by a conventional energy analyzer 432 electrically connected to a voltage output V8 of the voltage source 450. In one embodiment, the energy analyzer 432 is a dual hemispherical deflection energy analyzer (HDA) configured to transmit a narrow band of ion energies centered around a nominal ion energy of 130 eV/z. In alternate embodiments, the energy analyzer 432 may be implemented in other conventional forms and/or be configured to transmit ion energies centered around other ion energy values.
The instrument 400 further includes the ion mass and charge detector 434 which, in the illustrated embodiment, is provided in the form of a single-stage electrostatic linear ion trap (ELIT). The ELIT configuration is generally a single stage of the ELIT 14 illustrated in
An input of a conventional charge sensitive preamplifier 442 is electrically connected to the charge detection cylinder 440, and an output of the preamplifier 442 is electrically coupled to an input of a conventional processor 444. The processor 444 illustratively includes or is coupled to a memory 446 in which is stored instructions executable by the processor 444 to control operation of the instrument 444 as will be described below. In some embodiments, the processor 444 is operatively coupled to one or more peripheral devices PD 448 via a number, P, of signal paths, wherein P may be any positive integer. In some embodiments, the processor 444 may also be electrically connected to the voltage source 450 via a number, M, of signal paths, wherein M may be any positive integer. In such embodiments, the processor 444 may be programmed to control operation of the voltage source 450. In alternate embodiments, the voltage source 450 may itself be programmable and/or may be manually controlled. In any case, the charge sensitive preamplifier 442, processor 444, memory 446 and peripheral device(s) 448 are illustratively all as described above with respect to
A voltage output V9 of the voltage source 450 is electrically connected to the ion mirror 436, and another voltage output V10 of the voltage source 450 is electrically connected to the ion mirror 438. It will be understood that the voltages V9 and V10 each illustratively include a number of different switchable voltages for controlling operation of respective ones of the ion mirrors 436, 438 as illustrated by example in
Referring now to
The ion source 404 is responsive to the voltage V1 produced by the voltage source 450 to generate ions. In some embodiments, the processor 444 is operable to execute instructions stored in the memory 446 to control the voltage V1 to cause the ion source 404 to generate ions. In alternate embodiments, the voltage source 450 may itself be so programmed, or the voltage source 450 may be manually controlled to produce V1. In any case, the generated ions pass through the source region 408 and into the ion trap 418. In embodiments in which the source region 408 includes the interface 410, the voltage source 450 is operable to produce the one or more voltages V2 for controlling the interface 410 to pass ions therethrough as briefly described above. In any case, the voltage V3 produced by the voltage source 450 controls the ion inlet of the ion trap 418 to set the energies of ions entering from the source region 408 to a target energy, e.g., approximately 130 eV/z. Initially, as indicated in
The pulsed operation of the instrument 400 starts with the voltage(s) V5 switching to the transmission state for a pulse width duration of tW, after which the voltage(s) V5 is/are again switched back to the trapping state. The pulse width duration tW is selectable, i.e., adjustable, and during this time ions stored in the ion trap 418 are released or ejected therefrom and into the region 424 and travel toward the ELIT 434 in response to an electric field established by the voltages V5 and V7. In embodiments in which the region 424 includes a mass-to-charge ratio filter, only ions having mass-to-charge ratio values selected for passage by the voltage(s) V6 pass through the region 424 and into the region 428. Ions having energies in a narrow band of energies about the transmission energy of the energy analyzer 432 pass through the region 428 and into the ion mirror 436 of the ELIT 434, and ions having energies outside of this narrow band are deflected away from the ion inlet of the ELIT 434.
Upon expiration of a delay time tai following transition of the voltage(s) V5 to the ion transmission state to release ions from the ion trap 418, the voltages V10 on the rear ion mirror or end cap 438 are switched from the transmission state to the trapping or reflection state. Ions thereafter entering the rear ion mirror or end cap 438 from the charge detection cylinder 440 are thus reversed in direction by the ion reflection electric field established therein and are accelerated by the ion reflection electric field back through the charge detection cylinder 440 toward the front ion mirror or end cap 436, as described in detail above with respect to
The pulsed mode operation of the CDMS instrument 400 provides for improved detection efficiency by accumulating and storing ions in the ion trap 418, and then controllably releasing the ions from the trap 418 such that their arrival at the ELIT 434 is synchronized with the opening and closing (i.e., transmission mode and reflection mode respectively) of the ion mirrors 436, 438.
There is a substantial distance D1 (e.g., 0.86 m) between the ion outlet of the ion trap 418 and the front end of the charge detection cylinder 440, as illustrated in
m/zMAX=2eE[tD2/d12] (1).
In Equation 1, e is the elementary charge, E is the ion energy, and d1 is as described above and shown in
m/zMIN=2eE[tD2/(d1+2d2+d3)2] (2).
In Equation 2, d2 is the length of the charge detection cylinder 440 and d3 is the distance between the ion inlet/outlet of the respective ion mirrors 436, 438 and the corresponding end of the charge detection cylinder 440. The 2d2 in equation (2) results because the ion travels both back and forth through the charge detection cylinder 440 and d3 results from the time spent in the end cap. In some embodiments of the ELIT 434, d2=d3 so that the time spent by an ion traveling through the charge detection cylinder 440 is equal to the time spent travelling through each end cap 436, 438). In such embodiments, equation (2) reduces to the following:
m/zMIN=2eE[tD2/(d1+3d2)2] (3).
The ratio of the maximum to minimum m/z that can be trapped is thus given by:
m/zMAX/m/zMIN=(d1+3d2)2/d12 (4).
Thus the range of m/z values that can be trapped is independent of the ion energy and the delay time tD. Longer delay times cause the m/z window to shift to larger m/z values but the relative width of the m/z window remains the same. The ratio of the maximum to minimum m/z values for the CDMS instrument 400 in which d2=d3, as described above, is 1.38, so the width of the m/z window that can be trapped with a single delay time tD is m/zMIN to 1.38×m/zMIN. For example, if the delay time tD is set so that 25 kDa is the minimum m/z value that can be trapped, ions with m/z values up to 34.5 kDa can be trapped at the same time.
Truncated hepatitis B virus (HBV) capsid protein (Cp149) was assembled in 300 mM sodium chloride for 24 hours, dialyzed into 100 mM ammonium acetate (Sigma Aldrich, 99.999% trace metal basis) and stored for at least a week before use (to give assembly errors time to self-correct). The initial concentration of the capsid protein was 1 mg/mL. Assembly yields predominantly the icosahedral T=4 capsid (around 32 nm in diameter) composed of 120 capsid protein dimers along with a smaller amount (around 5% in this case) of the icosahedral T=3 capsid with 90 protein dimers. The pseudo critical concentration for HBV assembly in 300 mM NaCl is 3.7 μM and so the final capsid concentration is around 0.22 μM. Samples of the stock solution were purified by size exclusion chromatography (SEC) with a 6 kDa cutoff. Aliquots of the purified solution were then diluted with 100 mM ammonium acetate to the required concentration which ranged from 0.05 μg/mL to 100 μg/mL.
Pyruvate kinase (PK) was prepared at 10 mg/ml in ammonium acetate. Aliquots of the stock solution were purified by SEC with a 6 kDa cutoff. The purified solution was then diluted to 2 mg/mL with 100 mM ammonium acetate.
It should be noted that the number of analytes contained in an electrospray droplet could influence the detection efficiency. An estimate of the average number of capsids present in a droplet can illustratively be obtained from the concentration and droplet size. The average size of the primary electrospray droplets can, in turn, be estimated from the electrospray conditions. For an estimated droplet size of 70 nm, the average number of capsids per droplet is around 0.025 (i.e., 1 in 40 droplets contain a capsid) at the concentration of the HBV stock solution (1 mg/mL).
The intensity gain depends on the trapping efficiency, the pulse width tw and the delay times tai and tD2 (all depicted in
With the high sensitivity afforded by pulsed mode CDMS it is relatively easy to simultaneously inject many ions into the ELIT. However, while it is feasible to analyze multiple ion trapping events and determine m/z values and charges for a few simultaneously trapped ions, ion-ion interactions within the ELIT 434 can cause trajectory and energy fluctuations which degrade the m/z resolving power. Because the trapping of multiple ions with similar m/z values can lead to errors in the data analysis, the measurements depicted in the attached figures were restricted to samples where, on average, one ion is trapped per trapping event. The distribution of trapped ions is a Poisson distribution and when the average trapping efficiency is around 1.0, roughly a third of the trapping events are empty, another third contain a single ion, and the remaining third contain two or more ions. For a sample concentration of 10 μg/mL the number of trapped ions in pulsed mode is much larger than one per event on average and the sample must be diluted for the measurements depicted in the attached figures to be performed.
As noted above, assembly of the HBV capsid protein leads to a small amount of the smaller T=3 capsid in addition to the T=4. The average m/z for the T=4 ions is 28,700 Da and the average m/z for the T=3 ions is 25,500 Da. The ratio of these m/z values is 1.13 which falls within the range that can be trapped simultaneously. In this regard,
If the m/z distribution is broader than the m/zMIN to 1.38×m/zMIN window described above, the total delay time tD can be adjusted to trap different portions of the distribution.
In the illustrated embodiment of the instrument 400 just described, the ion mass and charge detector 434 is provided in the form of a single-stage electrostatic linear ion trap (ELIT), although it will be understood that in other embodiments the ion mass and charge detector 434 may alternatively be provided in the form of a multi-stage ELIT, e.g., the ELIT 14 as described herein with respect to
It will be understood that the dimensions of the various components of any of the ELITs and/or arrays 14, 205, 302, 434 illustrated in the attached figures and described above may illustratively be selected to establish a desired duty cycle of ion oscillation therein and/or within each ELIT or ELIT region E1-E3, corresponding to a ratio of time spent by the ion(s) in the respective charge detection cylinder(s) CD1-CD3 and a total time spent by the ion(s) traversing the combination of the corresponding ion mirrors and the respective charge detection cylinder(s) CD1-CD3 during one complete oscillation cycle. For example, a duty cycle of approximately 50% may be desirable in one or more of the ELITs or ELIT regions for the purpose of reducing noise in fundamental frequency magnitude determinations resulting from harmonic frequency components of the measure signals. Details relating to such dimensional considerations for achieving a desired duty cycle, e.g., such as 50%, are illustrated and described in co-pending International Patent Application No. PCT/US2019/013251, filed Jan. 11, 2019 and entitled ELECTROSTATIC LINEAR ION TRAP DESIGN FOR CHARGE DETECTION MASS SPECTROSCOPY, the disclosure of which is expressly incorporated herein by reference in its entirety.
It will be further understood that one or more charge calibration or resetting apparatuses may be used with the charge detection cylinder(s) of any one or more of the ELITs and/or arrays 14, 205, 302, 434 and/or in any one or more of the region(s) E1-E3 of the ELIT or ELIT array. An example of one such charge calibration or resetting apparatus is illustrated and described in co-pending International Patent Application Nos. PCT/US2019/013284, filed Jan. 11, 2019, and PCT/US2019/035381, filed Jun. 4, 2019, both entitled APPARATUS AND METHOD FOR CALIBRATING OR RESETTING A CHARGE DETECTOR, the disclosures of which are 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 any one or more of the ELITs and/or arrays 14, 205, 302, 434 and/or with one or more region(s) E1-E3 of such ELITs and/or ELIT array, e.g., for trigger trapping or other charge detection events. Examples of some such charge detection optimization apparatuses and techniques are illustrated and described in co-pending International Patent Application No. PCT/US2019/013280, filed Jan. 11, 2019 and entitled APPARATUS AND METHOD FOR CAPTURING IONS IN AN ELECTROSTATIC LINEAR ION TRAP, the disclosure of which is expressly incorporated herein by reference in its entirety.
It will be further still understood that one or more ion source optimization apparatuses and/or techniques may be used with one or more embodiments of the ion source 12 illustrated and described herein, some examples of which are illustrated and described in co-pending International Patent Application Nos. PCT/US2019/013274, filed Jan. 11, 2019, and PCT/US2019/035379, filed Jun. 4, 2019, both entitled HYBRID ION FUNNEL-ION CARPET (FUNPET) ATMOSPHERIC PRESSURE INTERFACE FOR CHARGE DETECTION MASS SPECTROMETRY, the disclosures of which are expressly incorporated herein by reference in their entireties.
It will be still further understood that any of ion mass detection systems 10, 60, 80, 200, 300, 400 illustrated and described herein may be implemented in accordance with real-time analysis and/or real-time control techniques, some examples of which are illustrated and described in co-pending International Patent Application No. PCT/US2019/013277, filed Jan. 11, 2019 and entitled CHARGE DETECTION MASS SPECTROMETRY WITH REAL TIME ANALYSIS AND SIGNAL OPTIMIZATION, the disclosure of which is expressly incorporated herein by reference in its entirety.
It will be further understood that any of the ion mass detection systems 10, 60, 80, 200, 300, 400 illustrated and described herein may be configured to supply multiple ions to any one or more of the ELITs and/or arrays 14, 205, 302, 434 illustrated and described herein such that one or more of such ELITs and/or ELIT arrays is operable to measure mass and charge of multiple ions at a time, some examples of which are illustrated and described in co-pending International Patent Application No. PCT/US2019/013285, filed Jan. 11, 2019 and entitled APPARATUS AND METHOD FOR SIMULTANEOUSLY ANALYZING MULTIPLE IONS WITH AN ELECTROSTATIC LINEAR ION TRAP, the disclosure of which is expressly incorporated herein by reference in its entirety.
It will be still further understood that in one or more of the ion mass detection systems 10, 60, 80, 200, 300, 400 illustrated and described herein, at least one ELIT may alternatively be provided in the form of an orbitrap, some examples of which are illustrated and described in co-pending International Patent Application No. PCT/US2019/013278, filed Jan. 11, 2019 and entitled ORBITRAP FOR SINGLE PARTICLE MASS SPECTROMETRY, the disclosure of which is expressly incorporated herein by reference in its entirety.
It will be further understood that the CDMS instrument 400 may additionally be included as an embodiment of the ion mass detection system illustrated in
While the invention 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 the invention are desired to be protected.
This patent application is a U.S. national stage entry of PCT Application No. PCT/US2020/052009, filed Sep. 22, 2020, which claims the benefit of and priority to U.S. Provisional Patent Application No. 62/905,921, filed Sep. 25, 2019, the disclosures of which are expressly incorporated herein by reference in their entireties.
This invention was made with government support under GM131100 awarded by the National Institutes of Health. The government has certain rights in the invention.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2020/052009 | 9/22/2020 | WO |
| Publishing Document | Publishing Date | Country | Kind |
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| WO2021/061650 | 4/1/2021 | WO | A |
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| Number | Date | Country | |
|---|---|---|---|
| 20220344145 A1 | Oct 2022 | US |
| Number | Date | Country | |
|---|---|---|---|
| 62905921 | Sep 2019 | US |
