Patent Grant
11862448
The present disclosure relates generally to charge detection instruments, and more specifically to apparatuses and methods for calibrating 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, spurious, extraneous and/or other charges picked up on the charge detector can present challenges to distinguishing valid and detectable charges from charge detector noise, and this effect becomes even more pronounced as charge signal levels approach the noise floor of the charge detector. Accordingly, it is desirable to seek improvements in ELIT design and/or operation which extend the range of valid, detectable charge measurements over those obtainable using current ELIT designs.
The present disclosure 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 a first aspect, a charge detection mass spectrometer (CDMS) may comprise an ion source configured to generate ions from a sample, a mass spectrometer configured to separate the generated ions as a function of ion mass-to-charge ratio, an electrostatic linear ion trap (ELIT) having a charge detection cylinder disposed between first and second ion mirrors, wherein ions exiting the mass spectrometer are supplied to the ELIT, a charge generator for generating free charges, a field free region between the charge generator and the charge detection cylinder, and a processor configured to control operation of the first and second ion mirrors to trap at least one ion from the source of ions therein, and to thereafter cause the trapped at least one ion to oscillate back and forth between the first and second ion mirrors each time passing through the charge detection cylinder and inducing at least one corresponding charge thereon, and wherein the processor is configured to control the charge generator, with no ions in the charge detection cylinder, to generate a target number of free charges and cause the target number of free charges to travel across the field-free region and into contact with the charge detection cylinder to deposit the target number of free charges thereon and thereby calibrate or reset the charge detection cylinder to a corresponding target charge level.
In a second aspect, an instrument for separating ions may comprise an ion source configured to generate ions from a sample, a first mass spectrometer configured to separate the generated ions as a function of mass-to-charge ratio, an ion dissociation stage positioned to receive ions exiting the first mass spectrometer and configured to dissociate ions exiting the first mass spectrometer, a second mass spectrometer configured to separate dissociated ions exiting the ion dissociation stage as a function of mass-to-charge ratio, and a charge detection mass spectrometer (CDMS) coupled in parallel with and to the ion dissociation stage such that the CDMS can receive ions exiting either of the first mass spectrometer and the ion dissociation stage, the CDMS comprising (i) at least one ion separation instrument configured to separate ions as a function of at least one molecular characteristic, (ii) an electrostatic linear ion trap (ELIT) having a charge detection cylinder disposed between first and second ion mirrors, wherein ions exiting the at least one ion separation instrument are supplied to the ELIT, (iii) a charge generator for generating free charges, (iv) a field free region between the charge generator and the charge detection cylinder, and (v) a processor configured to control the charge generator to generate a target number of free charges and cause the target number of free charges to travel across the field-free region and into contact with the charge detection cylinder to deposit the target number of free charges thereon and thereby calibrate or reset the charge detection cylinder to a corresponding target charge level, wherein masses of precursor ions exiting the first mass spectrometer are measured using the CDMS, mass-to-charge ratios of dissociated ions of precursor ions having mass values below a threshold mass are measured using the second mass spectrometer, and mass-to-charge ratios and charge values of dissociated ions of precursor ions having mass values at or above the threshold mass are measured using the CDMS.
In a third aspect, a method is provided for resetting or calibrating a charge detector of a charge detection mass spectrometer (CDMS), the charge detector including an electrostatic linear ion trap (ELIT) having a charge detection cylinder disposed between first and second ion mirrors. The method may comprise controlling, with a processor, a charge generator to generate a target number of free charges, and accelerating the generated target number of free charges across a field-free region defined between the charge generator and the charge detection cylinder and into contact with the charge detection cylinder to deposit the target number of free charges thereon and thereby calibrate or reset the charge detection cylinder to a corresponding target charge level.
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 an electrostatic linear ion trap (ELIT) including an apparatus for calibrating or resetting the charge detector thereof, and to means and methods for controlling both. In one embodiment, an example of which will be described in detail below with respect to
Referring to
In the illustrated embodiment, the ELIT 14 illustratively includes a charge detector CD surrounded by a ground chamber or cylinder GC and operatively coupled to opposing ion mirrors M1, M2 respectively positioned at opposite ends thereof. The ion mirror M1 is operatively positioned between the ion source 12 and one end of the charge detector CD, and ion mirror M2 is operatively positioned at the opposite end of the charge detector CD. Each ion mirror M1, M2 defines a respective ion mirror region R1, R2 therein. The regions R1, R2 of the ion mirrors M1, M2, the charge detector CD, and the spaces between the charge detector CD and the ion mirrors M1, M2 together define a longitudinal axis 22 centrally therethrough which illustratively represents an ideal ion travel path through the ELIT 14 and between the ion mirrors M1, M2 as will be described in greater detail below.
In the illustrated embodiment, voltage sources V1, V2 are electrically connected to the ion mirrors M1, M2 respectively. Each voltage source V1, V2 illustratively includes one or more switchable DC voltage sources which may be controlled or programmed to selectively produce a number, N, 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, V2 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, V2 to produce desired DC output voltages for selectively establishing ion transmission and ion reflection electric fields, TEF, REF respectively, within the regions R1, R2 of the respective ion mirrors M1, M2. P may be any positive integer. In some alternate embodiments, either or both of the voltage sources V1, V2 may be programmable to selectively produce one or more constant output voltages. In other alternative embodiments, either or both of the voltage sources V1, V2 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 mirrors M1, M2 in alternate embodiments.
The charge detector CD is illustratively provided in the form of an electrically conductive cylinder which is electrically connected to a signal input of a charge sensitive preamplifier (or charge sensitive amplifier) CP, and the signal output of the charge preamplifier CP is electrically connected to the processor 16. The charge preamplifier CP is illustratively operable in a conventional manner to receive a charge signal (CH) corresponding to a charge induced on the charge detection cylinder CD by an ion passing therethrough, to produce a charge detection signal (CHD) corresponding thereto and to supply the charge detection signal CHD to the processor 16. In some embodiments, the charge preamplifier CP may include conventional feedback components, e.g., one or more resistors and/or other conventional feedback circuitry, coupled between the output and at least one of the inputs thereof. In some alternate embodiments, the charge preamplifier CP may not include any resistive feedback components, and in still other alternate embodiments the charge preamplifier CP may not include any feedback components at all. In any case, the processor 16 is, in turn, illustratively operable to receive and digitize charge detection signals CHD produced by the charge preamplifier CP, and to store the digitized charge detection signals CHD 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.
The voltage sources V1, V2 are illustratively controlled in a manner, as described in detail below, which selectively traps an ion entering the ELIT 14 and causes the trapped ion to oscillate back and forth between the ion mirrors M1, M2 such that it repeatedly passes through the charge detection cylinder CD. A plurality of charge and oscillation period values are measured at the charge detection cylinder CD, and the recorded results are processed to determine mass-to-charge ratio, charge and mass values of the ion trapped in the ELIT 14.
Referring now to
A second mirror electrode 302 of each ion mirror M1, M2 is spaced apart from the first mirror electrode 301 by a space having width W2. The second mirror electrode 302, like the mirror electrode 301, has thickness W1 and defines a passageway centrally therethrough of diameter P2. A third mirror electrode 303 of each ion mirror M1, M2 is likewise spaced apart from the second mirror electrode 302 by a space of width W2. The third mirror electrode 302 has thickness W1 and defines a passageway centrally therethrough of width P1.
A fourth mirror electrode 304 is spaced apart from the third mirror electrode 303 by a space of width W2. The fourth mirror electrode 304 illustratively has a thickness of W1 and is formed by a respective end of the ground cylinder, GC disposed about the charge detector CD. The fourth mirror electrode 304 defines an aperture A2 centrally therethrough which is illustratively conical in shape and increases linearly between the internal and external faces of the ground cylinder GC from a diameter P3 defined at the internal face of the ground cylinder GC to the diameter P1 at 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 electrodes 301-304 may be voids in some embodiments, i.e., vacuum gaps, and in other embodiments such spaces may be filled with one or more electrically non-conductive, e.g., dielectric, materials. The mirror electrodes 301-304 and the endcaps 32 are axially aligned, i.e., collinear, such that a longitudinal axis 22 passes centrally through each aligned passageway and also centrally through the apertures A1, A2. In embodiments in which the spaces between the mirror electrodes 301-304 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 301-304 and which illustratively have diameters of P2 or greater. Illustratively, P1>P3>P2, although in other embodiments other relative diameter arrangements are possible.
A region R1 is defined between the apertures A1, A2 of the ion mirror M1, and another region R2 is likewise defined between the apertures A1, A2 of the ion mirror M2. The regions R1, R2 are 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, M2 by a space of width W3. In on embodiment, W1>W3>W2, and P1>P3>P2, although in alternate embodiments other relative width arrangements are possible. In any case, the longitudinal axis 22 illustratively extends centrally through the passageway defined through the charge detection cylinder CD, such that the longitudinal axis 22 extends centrally through the combination of the passageways defined by the regions R1, R2 of the ion mirrors M1, M2 and the passageway defined through the charge detection cylinder CD. In operation, the ground cylinder GC is illustratively controlled to ground potential such that the fourth mirror electrode 304 of each ion mirror M1, M2 is at ground potential at all times. In some alternate embodiments, the fourth mirror electrode 304 of either or both of the ion mirrors M1, M2 may be set to any desired DC reference potential, or to a switchable DC or other time-varying voltage source.
In the embodiment illustrated in
Each ion mirror M1, M2 is illustratively controllable and switchable, by selective application of the voltages D1-D4, between an ion transmission mode (
As illustrated by example in
Example sets of output voltages D1-D4 produced by the voltage sources V1, V2 respectively to control a respective one of the ion mirrors M1, M2 to the ion transmission and reflection modes described above are shown in TABLE I below. It will be understood that the following values of D1-D4 are provided only by way of example, and that other values of one or more of D1-D4 may alternatively be used.
While the ion mirrors M1, M2 and the charge detection cylinder CD are illustrated in
The voltage sources V1, V2 are illustratively controlled in a manner which selectively establishes ion transmission and ion reflection electric fields in the region R1 of the ion mirror M1 and in the region R2 of the ion mirror M2 in a manner which allows ions to enter the ELIT 14 from the ion source 12, and which causes an ion to be selectively trapped within the ELIT 14 such that the trapped ion repeatedly passes through the charge detector CD as it oscillates within the ELIT 14 between the ion mirrors M1 and M2. A charge induced on the charge detector CD each time an ion passes therethrough is detected by the charge preamplifier CP, and a corresponding charge detection signal (CHD) is produced by the charge preamplifier CP. The magnitude and timing of timing of the charge detection signal (CHD) produced by the charge preamplifier CP is recorded by the processor 16 for each charge detection event as this term is defined herein. Each charge detection event record illustratively includes an ion charge value, corresponding to a magnitude of the detected charge, and an oscillation period value, corresponding to the elapsed time between charge detection events, and each charge detection event record is stored by the processor 16 in the memory 18. The collection of charge detection events resulting from oscillation of an ion back and forth through the charge detector CD a selected number of times or for a selected time period, i.e., a making up an ion measurement event as this term is defined herein, are then processed to determine charge, mass-to-charge ratio and mass values of the ion.
In one embodiment, the ion measurement event data are processed by computing, with the processor 16, a Fourier Transform of the recorded collection of charge detection events. The processor 16 is illustratively 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 processor 16 is 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 processor 16 is illustratively 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 an ion oscillating back and forth through the charge detector CD of an ELIT between opposing ion mirrors M1, M2 thereof is inversely proportional to the square of the fundamental frequency ff of the oscillating ion 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, and the fundamental frequency ff is determined directly from the computed Fourier Transform. The value of the ion charge, z, is proportional to the magnitude FTMAG of the fundamental frequency ff, 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 16 is 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 source 12, 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.
Referring again to
In one embodiment, the charge generator CG is configured to be responsive to a control signal C produced by the processor 16 to generate free charges 28 which pass through the charge outlet 26 of the one or more charge outlet passages 24 into the space 36 defined between the inner surface of the ground chamber or cylinder GC and the outer surface of the electrically conductive charge detection cylinder CD. In the illustrated embodiment, the charges 28 produced by the charge generator are positive charges, although the charge generator CG may in alternate embodiments be configured to produce negative charges or to selectively produce positive or negative charges.
In one embodiment, the charge generator CG is configured, or controllable using conventional control circuitry and/or conventional control techniques, to be responsive to activation of the control signal C produced by the control circuit 16 to generate and supply to the space 36 within the ELIT 14 a predictable number of free charges 28, within any desired tolerance level, per unit of time. The unit of time may have any desired duration. In such embodiments, the total number of charges 28 supplied by the charge generator CG to the space 36 within the ELIT 14 in response to a single activation of the control signal C is thus controllable as a function of the number of charges 28 produced by the charge generator CG per unit time and a duration, i.e., pulse width, of the active portion of the control signal C. In alternate embodiments, the charge generator CG may be configured to produce a programmable number of charges 28 per unit time. In still other embodiments, the charge detector CG may be configured such that the number of charges 28 produced thereby in response to the control signal C is constant and predictable, or programmable, within any desired tolerance level, regardless and independently of the duration of the control signal C. In such embodiments, the number of charges 28 supplied by the charge generator CG to the space 36 within the ELIT 14 in response to any single activation of the control signal C is thus constant and predictable, and the total number of charges 28 that may be supplied by the charge generator CG to the space 36 within the ELIT 14 is controllable as a function of the total number of charges 28 produced with each single activation of the control signal C and the total number of activations of the control signal C produced by the processor 16.
The charge generator CG may be provided in the form of any conventional charge generator. As one example, the charge generator CG may be or include a conventional filament responsive to a voltage or current applied thereto to generate and produce the free charges 28. As another example, the charge generator CG may be or include an electrically conductive mesh or grid responsive to a voltage or current applied thereto to generate and produce the free charges 28. As yet another example, the charge generator CG may be or include a particle charge generator configured to produce the free charges in the form of charged particles from a sample source. Examples of such particle charge generators may include, but are not limited to, an electrospray ionization (ESI) source, a matrix-assisted Laser Desorption Ionization (MALDI) source, or the like. In any case, the charge generator CG is operable to generate and supply charges to the space 36 within the ELIT 14 via the charge outlet(s) of the one or more charge outlet passages extending into, and/or fluidly coupled to, the space 36.
With no charge induced on the charge detector CD by a charged particle passing therethrough or by one or more free charges 28 produced by the charge generator GC, the charge detection cylinder CD illustratively operates at or near a reference charge level CHREF. As the charge detection cylinder CD is not powered or grounded, the reference charge level CHREF is typically tens of charges (i.e., elementary charges “e”) or less, although in some applications the reference charge level CHREF may be more than tens of charges.
As described above, the charge generator CG is responsive to control signals C produced by the processor 16 or other control signal generating circuitry to generate charges 28 of desired polarity which then pass into the space 36 between the inner surface of the ground cylinder GC and the outer surface of the charge detection cylinder CD. As the ground cylinder GC is generally maintained at ground potential and the charge detection cylinder CD typically operates at or near ground potential, the space 36 is substantially a field-free region. In some embodiments, the one or more charge outlet passages 24 and/or the body of the charge generator CG illustratively include(s) one or more regions in which an electric field of suitable direction is established by the voltage source VCG (or by some other source(s)) for the purpose of accelerating the generated charges 28 into the field free region 36 so that the accelerated charges 28 then travel through the field free region 36 toward and into contact with the outer surface of the charge detection cylinder CD. When such charges 28 contact the outer surface of the charge detection cylinder CD, they impart their respective charges onto the charge detection cylinder CD. In this regard, the generation of charges 28 by the charge generator GC, and travel of the generated charges through the field free region 36 toward and into contact with the outer surface of the charge detection cylinder to thereby impart their charges onto the charge detection cylinder defines a “charge injection” process via which the generated charges 28 calibrate or reset the charge detection cylinder CD and/or the charge sensitive preamplifier CP in some embodiments thereof. Such injected charges may illustratively be removed from the charge detection cylinder CD by applying an equal amount of opposite charge, and may therefore illustratively be used to calibrate and/or reset the charge detection cylinder in some applications and/or to calibrate or reset the charge preamplifier in other applications.
The “charge injection” process just described is different from a “charge induction” process in which charge may be induced on the charge detection cylinder CD by establishing a voltage difference between the charge detection cylinder CD and a voltage reference, e.g., ground potential. One illustrative technique for inducing charge on the charge detection cylinder CD without physically coupling one or more wires and/or one or more electronic devices to the charge detection cylinder CD is to configure the charge generator GC such that the voltage source VCG establishes a potential of desired polarity on the at least one charge outlet passage 24. Establishing a DC potential on the at least one charge outlet passage 24 without generating charges 28 will generally create an electric field between the at least one charge outlet passage 24 and the charge detection cylinder CD, thus inducing a DC voltage and, in turn, a charge on the charge detection cylinder CD. The magnitude of the induced charge will generally be dependent upon the strength of the established electric field and thus upon the magnitude of the voltage applied by the voltage source VCG to the at least one charge outlet passage 24. Such induced charges may illustratively be removed or modified by applying a different voltage, e.g., ground or other potential, to the charge detection cylinder CD, and may therefore be used to compensate for switching voltages applied to the ion mirror(s) M1 and/or M2, and for calibrating the charge preamplifier CP in some embodiments thereof. In alternate embodiments of the charge generator CG described above in which the charge generator CG is operable to generate free charges, the charge generator CG may thus be configured to operate as a charge induction antenna. In such embodiments, the voltage source VCG is controlled, illustratively by the processor 16, to produce a DC voltage, a voltage pulse or a series of voltage pulses, or a voltage waveform which is/are applied to the charge outlet passage(s) 24 to create or establish one or more corresponding electric fields between the charge outlet passage(s) 24 generally (and in some embodiments the charge outlet(s) 26 specifically) and the charge detection cylinder CD to thereby induce a corresponding charge or charges on the charge detection cylinder. In such embodiments, the charge outlet passage(s) 24 may, but need not, include one or more charge outlets 26 in fluid communication with the space 36. In some embodiments, for example, in which the charge generator CG is configured strictly for charge induction, the charge outlet passage(s) 24 may be or include one or more electrically conductive rods, probes, filaments or the like which does/do not include any outlets for dispensing or otherwise producing free charges. In other embodiments in which the charge generator CG is configured to operate as a charge induction device and a charge injection device, the charge outlet passage(s) 24 will illustratively include one or more charge outlets 24 as described above for dispensing or otherwise producing free charges 28.
Thus, in some embodiments, the charge generator CG is illustratively configured to operate strictly as a charge injection device in which the charge generator CG is responsive to control signals C to generate charges 28 of suitable polarity and to accelerate the generated charges 28 out of the at least one charge outlet 26 of the at least one charge outlet passage 24 and into the field free region 36 such that the generated charges 28 travel through the field free region 36 toward and into contact with the external surface of the charge detection cylinder CD to impart their charges on the charge detection cylinder CD. In alternate embodiments, the charge generator CG may illustratively be configured to operate strictly as a charge induction device in which the charge generator CG is responsive to control signals C to apply at least one voltage of suitable magnitude and polarity to establish a corresponding electric field within the region 36 between the at least one charge outlet passage 24 and the charge detection cylinder CD to induce a DC voltage, and thus a charge, on the charge detection cylinder CD. In other alternate embodiments, the charge generator CD may illustratively be configured to operate both (e.g., simultaneously or separately) as a charge injection device and as a charge induction device in which the charge generator CG is responsive to control signals C produced by the processor 16 to generate charges 28 of suitable polarity and/or to apply one or more voltages of suitable magnitude and polarity to establish an electric field within the region 36 between the at least one charge outlet passage 24 and the charge detection cylinder CD to (i) induce a DC voltage, and thus a charge, on the charge detection cylinder CD, and (ii) to also accelerate the generated charges 28, under the influence of the established electric field within the region 36, toward and into contact with the external surface of the charge detection cylinder CD to impart their charges on the charge detection cylinder CD. The charge generator CG may thus be configured and operable strictly as a charge injector, strictly as a charge inducer or as a combination charge injector and charge inducer.
In embodiments in which the charge generator CG is configured and operable as a charge injector to produce a controlled number of charges 28 which then travel to, or are transported to, and in contact with the outer surface of the charge detection cylinder CD, such charges illustratively impart a target charge level, CHT, on the charge detection cylinder CD. In one embodiment, the number and polarity of the generated charges 28 may be selected to impart a target charge level CHT that is greater than CHREF, e.g., to achieve a constant target charge level CHT which is above CHREF and any noise induced thereon, and in other embodiments the number and polarity of the generated charges 28 may be selected to impart a target charge level CHT that is less than CHREF, e.g., to achieve a target charge level CHT at or near a zero charge level. In embodiments in which the charge generator CG is configured and operable as a charge inducer to controllably establish an electric field which induces a DC voltage or potential on the charge detection cylinder CD, such DC voltage or potential illustratively induces the target charge level CHT of suitable magnitude and polarity on the charge detection cylinder CD. In embodiments in which the charge generator CG is configured and operable as a combination charge injector and charge inducer, the net charge induced and imparted on the charge detection cylinder is the target charge CHT of suitable magnitude and polarity.
The reference charge level CHREF on the charge detection cylinder CD is subject to one or more potentially significant sources of charge noise which may introduce uncertainty in charge detection events as a result of uncertainty in the reference charge level at any point in time. Referring to
Such charge noise 50, from any source, is undesirable as it can produce false charge detection events and/or can require setting a charge detection threshold higher than desired. As an example of the former case, the plot of
In the embodiment of the ELIT 14 illustrated in
In alternate embodiments, the target number and polarity of the generated charges 28 may be selected to neutralize at least one or the combination of the reference charge level CHREF and any charge noise present on the charge detection cylinder CD so as to induce a resulting target charge level CHT on the charge detection cylinder CD which is less than CHREF, e.g., to achieve a target charge level CHT or near a zero charge level. Such a result may illustratively be accomplished by controlling the charge generator CG to first inject positive charges and to then inject negative charges, or to alternatively induce a suitable charge on the charge detection cylinder CD by controlling the voltage source VCG to apply one or more corresponding voltages to the charge generator CG. In some embodiments in which an amount of charge noise 50 at the input charge sensitive preamplifier CP is specifically targeted (e.g., in embodiments in which the charge sensitive preamplifier does not include any feedback components as described above), the target charge level CHT may be a charge magnitude and/or polarity which, when deposited or imparted on the charge detection cylinder CD, acts to clear such charge noise 50 therefrom and thus from the input of the charge preamplifier so as to reset the charge sensitive preamplifier CP to predictable operating conditions.
In any case, the target number of charges 28 generated by the charge generator CG and transported to, and in contact with, the outer surface of the charge detection cylinder CD and/or the charge induced on the charge detection cylinder CD by the operation of the charge generator CG, operate to set the charge detection cylinder CD to a substantially predictable and repeatable target charge level CHT, as illustrated by example in
Referring now to
When the ELIT 14 has been operating in the state illustrate in
Referring now to
Referring now to
Referring now to
With both of the ion mirrors M1, M2 controlled to the ion reflection operating mode (R), the ion is made to oscillate back and forth between the regions R1 and R2 of the respective ion mirrors M1, M2 by the ion reflection electric fields established therein, as described above and as illustrated by the ion trajectory 66 depicted in
The charge cylinder calibration or reset technique described with respect to
Referring now to
At still a further subsequent time T4, the ion 70 still traveling in the direction A has just exited the charge detection cylinder CD and is poised to enter the region R2 of the ion mirror M2 as illustrated in
At a subsequent time T7, the ion reflection electric field (R) established in the region R2 of the ion mirror M2 has trapped and reversed the direction of the ion 70 so that it is now traveling in the opposite direction B toward the entrance of the charge detection cylinder CD adjacent to the ion mirror M2 as illustrated in
The following examples are provided to illustrate three specific applications; one in which the charge generator CG is controlled to selectively produce free charges 28 as part of a charge injection process to deposit or impart a respective net charge on the charge detection cylinder CD, one in which the charge generator CG is controlled as part of a charge induction process to selectively induce a charge on the charge detection cylinder, and one in which the charge generator CG is controlled as part of a charge preamplifier calibration process to selectively induce a high frequency charge on the charge detection signal during normal operation of the ELIT in which mass and charge of a charged particle is measured thereby, to process the detected high frequency charges and to use the information provided thereby to compensate for any drift in gain of the charge preamplifier over time. It will be understood that such applications are provided only by way of example, and should not be understood to limit the concepts described herein in any way.
The first example application is specifically targeted at embodiments in which the charge sensitive preamplifier does not include any feedback components, or at least in which the charge sensitive preamplifier does not include any feedback components operable to bleed or otherwise dissipate or remove charges that may build up or otherwise accumulate on the charge detection cylinder CD as charges are induced thereon by trapped ions passing therethrough. In such embodiments, charge that builds up or accumulates on the charge detection cylinder raises the base charge level at the input of the charge sensitive preamplifier, thus causing the output of the charge preamplifier to drift upwardly and, eventually, to the level of the supply voltage of the charge sensitive preamplifier. In such embodiments, the charge generator CG is configured to operate in charge injection mode, and the processor 16 is operable to control the charge generator CG to generate free charges 28 of appropriate polarity and quantity which, when deposited or imparted on the charge detection cylinder CD, counteracts the accumulated or built up charge thereby resetting the charge level of the charge detection cylinder CD and the input of the charge sensitive preamplifier to the reference charge level CHREF or other selectable charge level.
The second example application is specifically targeted at embodiments in which the charge generator is configured to operate in charge induction mode to counteract or at least reduce charges induced on the charge detection cylinder CD by electric field transients produced when switching either or both of the ion mirrors M1, M2 between ion transmission and ion reflection modes as described above. Generally, each time the voltage source V1 and/or V2 is controlled by the processor 16 to modify the respective voltages applied to the ion mirror M1 and/or the ion mirror M2 to switch from an ion transmission electric field TEF to an ion reflection electric field REF or vice versa, the switching from one electric field to the other creates an electric field transient which induces a corresponding transient charge on the charge detection cylinder CD. This transient charge, at least in some instances, saturates the output of the charge sensitive preamplifier for some period of time, and in other instances causes the charge sensitive preamplifier to produce one or more pulses detectable by the processor 16. In either instance, such outputs produced by the charge sensitive preamplifier do not correspond to charges induced on the charge detection cylinder CD by a trapped ion passing therethrough, and following any such switching of either ion mirror M1, M2 or simultaneously of both ion mirrors M1, M2 charge detection data collection by the processor 16 is conventionally paused or delayed for a period of time to allow the transient charge induced on the charge detection cylinder CD to dissipate. In this regard, the processor 16 is operable in this second example to control the charge generator CG and/or the voltage source VCG to produce a counter-pulse each time one or both of the ion mirrors M1, M2 is/are switched between ion transmission and reflection modes, wherein such counter-pulse induces a charge on the charge detection cylinder CD equal or approximately equal and opposite to the transient charge induced on the charge detection cylinder CD by the switching of the ion mirror(s) M1 and/or M2 so as to counteract or at least reduce the net transient charge induced on the charge detection cylinder by such switching of the ion mirror(s) M1 and/or M2. Illustratively, the shape, duration and/or magnitude of the voltage counter-pulse produced by the voltage source VCG is controlled to create an electric field between the charge generator CG and the charge detection cylinder CD having a corresponding shape, duration and/or magnitude to induce a charge on the charge detection cylinder which is equal and opposite to the transient charge induced on the charge detection cylinder CD by the switching of the ion mirror(s) M1, M2. Such counter-pulsing by the voltage source VCG illustratively avoids saturating the charge preamplifier CP and, in any case, provides for the processing of charge detection data following switching of the ion mirror(s) M1 and/or M2 much sooner than in conventional ELIT and/or CDMS instruments.
It will be understood that the transient charge induced on the charge detection cylinder CD by the switching of the ion mirror M1 may be different from that induced by the switching of the ion mirror M2, either of which may be different from that induced when simultaneously switching both ion mirrors M1, M2, and that any such transient charges induced on the charge detection cylinder CD when switching either or both ion mirrors M1, M2 from transmission mode to reflection mode may be different than when switching from reflection mode to transient mode. The processor 16 may thus be programmed in this example application to control the shape, duration and/or magnitude of the voltage counter-pulse produced by the voltage source VCG differently, depending upon how and which of the ion mirrors M1, M2 (or both) are being switched, to selectively create an appropriate electric field between the charge generator CG and the charge detection cylinder CD which has a corresponding shape, duration and/or magnitude to induce a charge on the charge detection cylinder which is equal and opposite to any such transient charge being induced on the charge detection cylinder CD by such switching of the ion mirror(s) M1 and/or M2.
The third example application is specifically targeted at embodiments in which the charge sensitive preamplifier may be susceptible to drift in gain over time, e.g., due to one or any combination of, but not limited to, amplifier operating temperature, amplifier operating temperature gradients, and signal history. In such embodiments, the charge generator CG is illustratively controlled to selectively induce high frequency charges on the charge detection cylinder CD during normal operation of the ELIT 14 in which mass and charge of charged particles are measured thereby as described herein, to process the detected high frequency charges and to use information provided thereby to compensate for any drift in gain of the charge sensitive preamplifier CP over time. In this regard, the simplified flowchart of
In this regard, the process 200 begins at step 202 where the processor 16 is operable to set a counter, j, equal to 1 or some other starting value. Thereafter at step 204 the processor 16 is operable to control the voltage source VCG and/or the charge generator CG to produce a high frequency voltage of suitable constant or stable magnitude to create a corresponding high-frequency electric field between the outlet 26, e.g., in the form of an antenna or other suitable structure, of the charge generator CG and the charge detection cylinder CD which induces a corresponding high frequency charge on the charge detection cylinder CD. The term “high frequency,” as used in this embodiment, should be understood to mean a frequency that is at least high enough so that the resulting portion of the frequency domain charge detection signal CHD during normal operation of the ELIT 14 is distinguishable from the portion of CHD resulting from detection of charge induced by a charged particle, i.e., an ion, passing through the charge detection cylinder. In this regard, the “high frequency” should at least be higher than the highest oscillation frequency of any ion oscillating back and forth in the ELIT 14 as described above. The high frequency voltage produced by VCG and/or CG may take any shape, e.g., square, sinusoidal, triangular, etc., and have any desired duty cycle. In one example embodiment, which should not be considered limiting in any way, the high frequency voltage produced at the antenna 26 is a square wave which, in the frequency domain, includes only the fundamental frequency and odd harmonics.
Following step 204, the process 200 advances to step 206 where the processor 16 is operable to measure the charge, CI, induced on the charge detector CD by the high frequency signal produced at the antenna 26 by processing the corresponding charge detection signal CHD produced by the charge sensitive preamplifier CP. Thereafter at step 208, the processor 16 is operable to convert the time-domain charge detection signal CHD to a frequency domain charge detection signal, CIF, e.g., using any conventional signal conversion technique such a discrete Fourier transform (DFT), fast Fourier transform (FFT) or other conventional technique. Thereafter at step 210, the processor 16 is operable to determine the peak magnitude, PM, of the fundamental frequency of the charge detection signal CIF. Thereafter at step 212, the processor 16 is operable to compare the counter value, j, to a target value, N. Generally, N will be the sample size of a data set containing multiple, sequentially measured values of PM, and will define the size of a moving average window used to track the drift of the charge sensitive preamplifier CP. In this regard, N may have any positive value. Generally, lower values of N will produce a more responsive but less smooth moving average, and higher values of N will conversely produce a less responsive but more smooth moving average. Typically, N will be selected based on the application. In one example application, which should not be considered limiting in any way, N is 100, although in other applications N may be less than 100, several hundred, 1000 or several thousand.
If, at step 212, the processor 16 determines that j is less than or equal to N, the process 200 advances to step 214 where the processor 16 is operable to add PM(j) to an N-sample data set stored in the memory 18. Thereafter at step 216, the processor is operable to increment the counter, j, and to then loop back to step 206. If, at step 212, the processor 216 instead determines that j is greater than N, the process 200 advances to step 218 where the processor 16 is operable to determine an average, AV, of the N-sample data set value PM1-N. In one embodiment, the processor 16 is illustratively operable at step 218 to compute AV as an algebraic average of PM1-N, although in alternate embodiments the processor 16 may be operable at step 218 to compute AV using one or more other conventional averaging techniques or processes.
Steps 202-218 of the process 200 are illustratively executed prior to operation of the instrument 10 to measure a spectrum of masses and charges of ions generated from a sample as described herein. In this regard, the purpose of steps 202-218 is to build an N-sample data set of peak magnitude values PM and to establish a baseline gain or gain factor, AV, of the charge sensitive preamplifier CP prior to normal operation of the ELIT 14 to measure ion mass and charge as described herein. It will be understood, however, that in other embodiments steps 202-218 may be re-executed at any time, e.g., randomly, periodically or selectively, to reestablish the baseline gain or gain factor.
Following step 218, the processor 16 is illustratively operable to begin a CDMS analysis of a sample by the instrument 10 as described herein, e.g., by controlling the voltage sources V1 and V2 to measure masses and charges of ions generated from a sample with the ELIT 14. Thereafter at step 222, as such operation of the instrument 10 and ELIT 14 is taking place, and as the charge generator CG is continually controlled to induce the high frequency charge HFC on the charge detection cylinder CD, the processor 16 is operable, for each charge detection signal CHD produced by the charge sensitive preamplifier in response to a charge induced on the charge detection cylinder CD by a charged particle passing therethrough, to (a) determine PM, e.g., in accordance with steps 206-210 or other conventional process for determining PM, (b) add PM to the N-sample data set and delete the oldest PM value so as to advance the N-sample data set “window” by one data point, (c) determine a new average, NAV, of the now updated N-sample data set, e.g., in accordance with step 218 or other conventional averaging techniques, (d) determine a charge sensitive preamplifier gain calibration factor, GCF, as a function of AV and NAV, and (e) modify the portion of the charge detection signal CHD produced by the charge sensitive preamplifier in response to a charge induced on the charge detection cylinder CD by a charged particle passing therethrough as a function of GCF to compensate for any drift in gain of the charge sensitive preamplifier CP.
It will be understood that any of several conventional techniques may be used by the processor 16 at step 222(d) to determine GCF. In one embodiment, for example, GCF may be the ratio GCF=NAV/AV or GCF=AV/NAV. In other embodiments, AV may be normalized, e.g., to a value of 1 or some other value, and NAV may be similarly normalized as a function of the normalized AV to produce GCF in the form of a normalized multiplier. Other techniques will occur to those skilled in the art, and it will be understood that any such other techniques are intended to fall within the scope of this disclosure. In any case, the processor 16 is illustratively operable at step 222(e) to modify the portion of the charge detection signal CHD produced by the charge sensitive preamplifier in response to a charge induced on the charge detection cylinder CD by a charged particle passing therethrough to compensate for any drift in gain of the charge sensitive preamplifier CP by multiplying the peak magnitude of this portion of the charge detection signal CH by GCF. Those skilled in the art will recognize other techniques for executing step 222(e) to include in GCF other factors that may affect the gain of CP, to include one or more weighting values to boost or attenuate the gain of CP based on one or more factors, or the like.
Referring now to
Referring to
Referring now to
Referring now to
Focusing on the ion source 12, it will be understood that the source 12 of ions entering the ELIT 14 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 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. 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 herein.
Turning now to the ion processing instrument 110, it will be understood that the instrument 110 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 or shifting ion charge states, and the like. It will be understood that the ion processing instrument 110 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 herein.
As one specific implementation of the ion separation instrument 100 illustrated in
As another specific implementation of the ion separation instrument 100 illustrated in
As yet another specific implementation of the ion separation instrument 100 illustrated in
As still another specific implementation of the ion separation instrument 100 illustrated in
Referring now to
MS/MS, e.g., using only the ion separation instrument 130, is a well-established approach where precursor ions of a particular molecular weight are selected by the first mass spectrometer 132 (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 134. The fragment ions are then analyzed by the second mass spectrometer 136 (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 130 to the CDMS 10, it is possible to select a narrow range of m/z values and then use the CDMS 10 to determine the masses of the m/z selected precursor ions. The mass spectrometers 132, 136 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 134, 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 (where the m/z ratio and charge 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 CDMS 10.
It will be understood that the dimensions of the various components of the ELIT 14 and the magnitudes of the electric fields established therein, as implemented in any of the systems 10, 100, 120 illustrated in the attached figures and described above, may illustratively be selected so as to establish a desired duty cycle of ion oscillation within the ELIT 14, corresponding to a ratio of time spent by an ion in the charge detection cylinder CD and a total time spent by the ion traversing the combination of the ion mirrors M1, M2 and the charge detection cylinder CD during one complete oscillation cycle. For example, a duty cycle of 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 ELIT 14 in any of the systems 10, 100, 120, 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 co-pending 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 still further understood that the charge detection cylinder calibration or reset apparatus and techniques illustrated in the attached figures and described herein may be used in each of two or more ELITs and/or in each of two or more ELIT regions in applications which include at least one ELIT array having two or more ELITs or having two or more ELIT regions. Examples of some such ELITs and/or ELIT arrays are illustrated and described in 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 source 12 as part of or in combination with any of the systems 10, 100, 120 illustrated 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 still further understood that any of the systems 10, 100, 120 illustrated 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 co-pending 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.
It will be still further understood that in any of the systems 10, 100, 120 illustrated in the attached figures and described herein, the ELIT 14 may be replaced with an orbitrap, and that the charge detection cylinder calibration or reset apparatus and techniques illustrated in the attached figures and described herein may be used with such an orbitrap. An example of one such orbitrap is illustrated and described in U.S. Patent Application Ser. No. 62/769,952, filed Nov. 20, 2018 and in co-pending International Patent Application No. PCT/US2019/013278, filed Jan. 11, 2019, both entitled ORBITRAP FOR SINGLE PARTICLE MASS SPECTROMETRY, the disclosures of which are both expressly incorporated herein by reference in their entireties.
It will be yet further understood that one or more ion inlet trajectory control apparatuses and/or techniques may be used with the ELIT 14 of any of the systems 10, 100, 120 illustrated in the attached figures and described herein to provide for simultaneous measurements of multiple individual ions within the ELIT 14. Examples of some such ion inlet trajectory control apparatuses and/or techniques are illustrated and described in U.S. Patent Application Ser. No. 62/774,703, filed Dec. 3, 2018 and in co-pending International Patent Application No. PCT/US2019/013285, filed Jan. 11, 2019, both entitled APPARATUS AND METHOD FOR SIMULTANEOUSLY ANALYZING MULTIPLE IONS WITH AN ELECTROSTATIC LINEAR ION TRAP, 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 ELIT 14 illustrated 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. As another example, while the concepts, structures and/or techniques of this disclosure have been described as being implemented in an electrostatic linear ion trap (ELIT), it will be understood that such concepts, structures and/or techniques are not intended to be limited to ELITs or variants thereof, but rather are intended to be applicable to any conventional charge detector or charge detection apparatus. Accordingly, any conventional charge detector or charge detection apparatus implementing the concepts, structures and/or techniques illustrated in the attached figures and described herein are intended to fall within the scope of this disclosure.
This is a continuation of U.S. patent application Ser. No. 17/468,841, filed Sep. 8, 2021, which is a divisional application of U.S. patent application Ser. No. 17/058,553, filed Nov. 4, 2020 and now U.S. Pat. No. 11,177,122, which is a U.S. national stage entry of PCT Application No. PCT/US2019/035381, filed Jun. 4, 2019, which claims the benefit of and priority to U.S. Provisional Patent Application Ser. No. 62/680,272, filed Jun. 4, 2018, and is a continuation-in-part of International Patent Application No. PCT/US2019/013284, filed Jan. 11, 2019, the disclosures of which are all-incorporated herein by reference in their entireties.
This invention was made with government support under CHE1531823 awarded by the National Science Foundation. The United States Government has certain rights in the invention.
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| Number | Date | Country | |
|---|---|---|---|
| 20230154736 A1 | May 2023 | US |
| Number | Date | Country | |
|---|---|---|---|
| 62680272 | Jun 2018 | US |
| Number | Date | Country | |
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| Parent | 17058553 | US | |
| Child | 17468841 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 17468841 | Sep 2021 | US |
| Child | 18149743 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/US2019/013284 | Jan 2019 | US |
| Child | 17058553 | US |
