Patent Publication Number: US-11646191-B2

Title: Instrument, including an electrostatic linear ion trap, for separating ions

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of U.S. patent application Ser. No. 16/960,170, filed Jul. 6, 2020, which is a U.S. national stage entry of PCT Application No. PCT/US2019/013251, filed Jan. 11, 2019, which claims the benefit of and priority to U.S. Provisional Patent Application Ser. No. 62/616,860, filed Jan. 12, 2018 and to U.S. Provisional Patent Application Ser. No. 62/680,343, filed Jun. 4, 2018, the disclosures of which are incorporated herein by reference in their entireties. 
    
    
     GOVERNMENT RIGHTS 
     This invention was made with government support under CHE1531823 and 0832651 awarded by the National Science Foundation. The United States Government has certain rights in the invention. 
    
    
     FIELD OF THE DISCLOSURE 
     The present disclosure relates generally to charge detection mass spectrometry instruments, and more specifically to performing mass and charge measurements with such instruments. 
     BACKGROUND 
     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 n 1/2 , where n is the number of measurements. However, in the continued quest for greater measurement resolution, the ELIT remains limited by uncertainties in both m/z measurements and charge measurements. Accordingly, it is desirable to seek improvements in ELIT design and/or operation which further reduce measurement uncertainties for either or both of ion charge and mass-to-charge ratio (m/z). 
     SUMMARY 
     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, an electrostatic linear ion trap may comprise a first ion mirror defining a first axial passageway therethrough, a second ion mirror defining a second axial passageway therethrough, a charge detection cylinder defining a third axial passageway therethrough, the charge detection cylinder positioned between the first and second ion mirrors such that the first, second and third axial passageways are in-line with each other, and at least one voltage source coupled to the first and second ion mirrors, the at least one voltage source configured to establish electric fields in each of the first and second ion mirrors configured to reflect an ion entering a respective one of the first and second axial passageways from the third axial passageway of the charge detection cylinder back through the third axial passageway of the charge detection cylinder and toward the other of the first and second axial passageways such the ion oscillates back and forth through the charge detection cylinder between the first and second ion mirrors with a duty cycle, corresponding to a ratio of time spent by the ion in the third axial passageway of the charge detection cylinder and total time spent traversing a combination of the first and second ion mirrors and the charge detection cylinder during one complete oscillation cycle, of approximately 50%. 
     In a second aspect, an electrostatic linear ion trap may comprise a first ion mirror defining a first axial passageway therethrough, a second ion mirror identical to the first ion mirror and defining a second axial passageway therethrough identical to the first axial passageway defined through the first ion mirror, a charge detection cylinder defining a third axial passageway therethrough, the charge detection cylinder positioned between the first and second ion mirrors such that the first, second and third axial passageways are in-line with each other, and at least one voltage source coupled to the first and second ion mirrors, the at least one voltage source configured to establish electric fields in each of the first and second ion mirrors configured to reflect an ion entering a respective one of the first and second axial passageways from the third axial passageway of the charge detection cylinder back through the third axial passageway of the charge detection cylinder and into the other of the first and second axial passageways such the ion oscillates back and forth through the charge detection cylinder between the first and second ion mirrors with a time spent by the ion passing each time through the charge detection cylinder approximately equal to a sum of time spent by the ion travelling from a stopped position within one of the first and second ion passageways into a respective end of the charge detection cylinder and time spent by the ion traveling from an opposite respective end of the charge detection cylinder to a stopped position within the other of the first and second ion passageways. 
     In a third aspect, a method is provided for operating an electrostatic linear ion trap having first and second ion mirrors separated by a charge detection cylinder, wherein each of the first and second ion mirrors and the charge detection cylinder axially aligned with one another. The method may comprise establishing a first electric field in the first ion mirror, the first electric field configured and oriented to stop in the first ion mirror an ion exiting a first end of the charge detection cylinder proximate to the first ion mirror and traveling into the first ion mirror, and to accelerate the stopped ion in the first ion mirror back into the first end of the charge detection cylinder, and establishing a second electric field in the second ion mirror, the second electric field configured and oriented to stop in the second ion mirror an ion exiting a second end of the charge detection cylinder, opposite the first end thereof, proximate to the second ion mirror and traveling into the second ion mirror, and to accelerate the stopped ion in the second ion mirror back into the second end of the charge detection cylinder, such that the at least one ion oscillates through the charge detection cylinder back and forth between the first and second ion mirrors under the influence of the first and second electric fields, wherein the first and second electric fields are established such that time spent by the at least one ion passing through the charge detection cylinder during each oscillation cycle is approximately equal to a sum of time spent in each of the first and second ion mirrors. 
     In a fourth aspect, a method is provided for operating an electrostatic linear ion trap having first and second ion mirrors separated by a charge detection cylinder, wherein each of the first and second ion mirrors and the charge detection cylinder axially aligned with one another. The method may comprise establishing a first electric field in the first ion mirror, the first electric field configured and oriented to stop in the first ion mirror an ion exiting a first end of the charge detection cylinder proximate to the first ion mirror and traveling into the first ion mirror, and to accelerate the stopped ion in the first ion mirror back into the first end of the charge detection cylinder, and establishing a second electric field in the second ion mirror, the second electric field configured and oriented to stop in the second ion mirror an ion exiting a second end of the charge detection cylinder, opposite the first end thereof, proximate to the second ion mirror and traveling into the second ion mirror, and to accelerate the stopped ion in the second ion mirror back into the second end of the charge detection cylinder, such that the at least one ion oscillates through the charge detection cylinder back and forth between the first and second ion mirrors under the influence of the first and second electric fields, wherein the first and second electric fields are established such that the ion oscillates back and forth through the charge detection cylinder between the first and second ion mirrors with a duty cycle, corresponding to a ratio of time spent by the ion in the third axial passageway of the charge detection cylinder and total time spent traversing a combination of the first and second ion mirrors and the charge detection cylinder during one complete oscillation cycle, of approximately 50% 
     In a fifth aspect, a system for separating ions may comprise an ion source configured to generate ions from a sample, at least one ion separation instrument configured to separate the generated ions as a function of at least one molecular characteristic, and the electrostatic linear ion trap as described in any of the first through fourth aspects, wherein one of the first and second ion mirrors defines an aperture configured to allow passage of at least one ion exiting the at least one ion separation instrument into the one of the first and second ion mirrors for oscillation thereof back and forth through the charge detection cylinder between the first and second ion mirrors. 
     In a sixth aspect, a system 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), including the electrostatic linear ion trap as described in any of the first through fourth aspects, coupled in parallel with and to the ion dissociation stage such that the CDMS can receive ions exiting either of the first mass spectrometer and the ion dissociation stage, wherein masses of precursor ions exiting the first mass spectrometer are measured using 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. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG.  1    is a simplified block diagram of an embodiment of an electrostatic linear ion trap (ELIT) illustrating dimensional information. 
         FIG.  2    is a simplified block diagram of the ELIT of  FIG.  1    shown with an ion source and control and measurement components coupled thereto to form an embodiment of a charge detection mass spectrometer (CDMS). 
         FIG.  3    is a simplified flowchart illustrating an embodiment of a process for controlling operation of the ELIT of  FIGS.  1  and  2    to determine ion mass and charge information. 
         FIG.  4 A  is a plot of a normalized time-domain detection signal resulting from the ELIT of  FIGS.  1  and  2    operating with approximately a 50% duty cycle. 
         FIG.  4 B  is a plot of relative FFT magnitude vs. oscillation frequency illustrating an FFT of the detection signal of  FIG.  4 A . 
         FIG.  5    is a plot of simulated ion charge measurement uncertainty as a function of duty cycle for the ELIT illustrated in  FIGS.  1  and  2   . 
         FIG.  6 A  is a simplified block diagram of an embodiment of an ion separation instrument including the ELIT illustrated in  FIGS.  1 - 2    and operating as described herein, showing example ion processing instruments which may form part of the ion source upstream of the ELIT and/or which may be disposed downstream of the ELIT to further process ion(s) exiting the ELIT. 
         FIG.  6 B  is a simplified block diagram of another embodiment of an ion separation instrument including the ELIT illustrated in  FIGS.  1 - 2    and operating as described herein, showing an example implementation which combines conventional ion processing instruments with the CDMS or ELIT illustrated and described herein. 
     
    
    
     DESCRIPTION OF THE ILLUSTRATIVE EMBODIMENTS 
     For the purposes of promoting an understanding of the principles of the 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. 
     Referring to  FIG.  1   , a simplified block diagram is shown of an embodiment of an electrostatic linear ion trap (ELIT)  10 . In the illustrated embodiment, the ELIT  10  includes a pair of ion mirrors M 1 , M 2  with a charge detector CD positioned therebetween. As will be described in greater detail below, ions introduced into the ELIT  10  are made to oscillate between the ion mirrors M 1 , M 2 , each time passing through the charge detector CD. A plurality of charge and oscillation period values are measured at the charge detector CD, and the recorded results are processed to determine ion mass-to-charge ratio and ion mass values. 
     In the illustrated embodiment, the ion mirror M 1  includes three spaced-apart, electrically conductive mirror electrodes ME 1 -ME 3  with a plate or cover PL 1  over the exposed face of the electrode ME 1 . The plate or cover PL 1  defines an aperture A 1  centrally therethrough which serves as an ion entrance to the ELIT  10 . The spaces S 1 , S 2  between the electrodes ME 1 , ME 2  and ME 2 , ME 3  respectively may be voids in some embodiments, and in other embodiments the spaces S 1 , S 2  may be filled with one or more electrically non-conductive, e.g., dielectric, materials. The mirror electrodes ME 1 -ME 3  are each illustratively of thickness D 1  and define a cylindrical passageway therethrough of diameter P 1 . The mirror electrodes ME 1 -ME 3  are axially aligned such that a longitudinal axis C passes centrally through each aligned cylindrical passageway and also centrally through the aperture A 1 . In embodiments in which the spaces S 1 , S 2  include one or more electrically non-conductive materials, such materials will likewise define respective passageways therethrough which are axially aligned with the cylindrical passageways defined through the mirror electrodes ME 1 -ME 3  and which have diameters of P 1  or greater. In any case, the spaces S 1 , S 2  each illustratively define a length d 1  between opposing faces of the respective mirror electrodes ME 1 -ME 3  such that the axial length, AL 1 , of the ion mirror M 1  is AL 1 =3D 1 +2d 1 . The ion entrance A 1  defined through the plate or cover PL 1  illustratively has a diameter P 2 . 
     Another ion mirror M 2  includes mirror electrodes ME 4 , ME 5  and ME 6  substantially identical in arrangement, construction and dimensions to the mirror electrodes ME 1 , ME 2  and ME 3  respectively of the ion mirror M 1  as described above, and is spaced apart from the ion mirror M 1  such that the distal face of the mirror electrode ME 3  faces the distal face of the mirror electrode ME 4 . A plate or cover PL 2  is disposed over the exposed face of the electrode ME 6  of the ion mirror M 2 , and the plate or cover PL 2  defines an aperture A 2  centrally therethrough, also illustratively of diameter P 2 , which serves as an ion exit from the ELIT  10 . The longitudinal axis C extends centrally through the passageways defined by the mirror electrodes ME 4 -ME 6  and spaces S 1 , S 2  of the mirror electrode M 2  as illustrated in  FIG.  1   . 
     A charge detector CD in the form of an electrically conductive cylinder of length D 3  is positioned between the spaced apart ion mirrors M 1 , M 2 . The charge detection cylinder CD illustratively defines a cylindrical passageway axially therethrough of diameter P 3 , and the charge detection cylinder CD is oriented relative to the ion mirrors M 1 , M 2  such that the longitudinal axis C extending centrally through the passageways defined through the ion mirrors M 1 , M 2  also extends centrally through the passageway defined through the charge detection cylinder CD. In some embodiments, as illustrated by example in  FIG.  1   , the charge detection cylinder CD is disposed within a field-free region FFR of a ground cylinder GC positioned between the ion mirrors M 1 , M 2 . A ground electrode GE 1  of thickness D 2  is defined at one end of the ground cylinder GC, and an external face of the ground electrode GE 1  is illustratively spaced apart from the exposed face of the mirror electrode ME 3  of the ion mirror M 1  by a space S 3  of length d 1  (e.g., equal to the lengths of each of the spaces S 1 , S 2 ). In alternate embodiments, the space S 3  may have a length greater or lesser than d 1 . In any case, the ground electrode GE 1  illustratively defines a conical aperture A 3  therethrough which decreases linearly between the external and internal faces thereof from the same diameter P 1  of the passageway defined through the mirror electrodes ME 1 -ME 6  at the external face of GE 1  to a reduced diameter P 4  at the internal face of GE 1 . Another ground electrode GE 2  also of thickness D 2  is defined at an opposite end of the ground cylinder GC, and an external face of the ground electrode GE 2  is illustratively spaced apart from the exposed face of the mirror electrode ME 4  of the ion mirror M 2  by a space S 3  of length d 1 . In alternate embodiments, the space S 3  may have a length greater or lesser than the length d 1 . In any case, the ground electrode GE 2  also illustratively defines a conical aperture A 4  therethrough which decreases linearly between the external and internal faces thereof from the same diameter P 1  of the passageway defined through the mirror electrodes ME 1 -ME 6  to the diameter P 4  such that the ground electrodes GE 1  and GE 2  are identically configured. The internal or inner faces of the ground electrodes GE 1  and GE 2  are illustratively spaced apart from one another by a distance D 4  which defines the length of the field free region FFR. In the illustrated embodiment, the charge detection cylinder CD is centered axially within the field free region FFR such that the opposite ends of the charge detection cylinder CD are each spaced apart from an inner face of a respective one of the ground electrodes GE 1 , GE 2  by a distance d 2 . 
     The total axial length, TL, of the ELIT  10 , not including the end plates or covers PL 1 , PL 2 , is TL=6D 1 +2D 2 +D 3 +6d 1 +2d 2 . In one specific example embodiment, the various dimensional parameters described above may have the numerical values set forth in the following TABLE I, although it will be understood that such numerical values are provided only by way of example and should not be considered limiting in any way. 
     
       
         
           
               
               
               
             
               
                   
                 TABLE I 
               
               
                   
                   
               
               
                   
                   
                 Numerical 
               
               
                   
                 Dimensional 
                 Value  
               
               
                   
                 Parameter 
                 (millimeters) 
               
               
                   
                   
               
             
            
               
                   
                 D1 
                  4.57 
               
               
                   
                 D2 
                  3.81 
               
               
                   
                 D3 
                 50.04 
               
               
                   
                 D4 
                 50.8  
               
               
                   
                 d1 
                  0.127 
               
               
                   
                 d2 
                  0.38 
               
               
                   
                 P1 
                 13.97 
               
               
                   
                 P2 
                 3.0 
               
               
                   
                 P3 
                  6.35 
               
               
                   
                 P4 
                 3.3 
               
               
                   
                   
               
            
           
         
       
     
     Although the mirror electrodes ME 1 -ME 6  of the ion mirrors M 1 , M 2  are illustrated in  FIGS.  1  and  2    and described above as defining cylindrical passageways therethrough of diameter P 1 , it will be understood that in alternate embodiments one or more of the mirror electrodes ME 1 -ME 6  may define non-cylindrical passageways therethrough such that the variable P 1  for such one or more mirror electrodes represents a cross-sectional area and profile that is not circular. Likewise, although the charge detection cylinder CD is illustrated in  FIGS.  1  and  2    and described above as defining a cylindrical passageway therethrough of diameter P 3 , it will be understood that in alternate embodiments the passageway defined through the charge detection cylinder CD may be non-cylindrical such that the variable P 3  in such embodiments represents a cross-sectional area and profile that is not circular. In still other embodiments, regardless of the shape of the cross-sectional profiles, the cross-sectional areas of the passageways defined through the mirror electrodes ME 1 -ME 3  may be different from those of the passageways defined through the mirror electrodes ME 4 -ME 6 . 
     Referring now to  FIG.  2   , the ELIT  10  of  FIG.  1    is shown along with an ion source  25  and electrical control and measurement components coupled thereto to form an embodiment of a charge detection mass spectrometer (CDMS)  40 . In the illustrated embodiment, three voltage sources, V 1 , V 2  and V 3 , are electrically connected to the mirror electrodes ME 1 , ME 2 , ME 3  respectively of the ion mirror M 1 , and three voltage sources V 4 , V 5 , V 6  are electrically connected to the mirror electrodes ME 4 , ME 5 , ME 6  of the ion mirror M 2 . In some alternate embodiments, one or more of the mirror electrodes ME 1 , ME 2 , ME 3  of the ion mirror M 1  may share a voltage source with (a) corresponding one(s) of the mirror electrodes ME 4 , ME 5 , ME 6  of the ion mirror M 2 . In any case, each voltage source V 1 -V 6  is illustratively a switchable DC voltage source which may be programmed or controlled to selectively switch between programmable or controllable DC voltage levels. In the illustrated embodiment, the voltage sources V 1 -V 6  are shown electrically connected to a conventional processor  12  including a memory  14  having instructions stored therein which, when executed by the processor  12 , cause the processor  12  to control the voltage sources V 1 -V 6  to selectively produce desired DC output voltages VO 1 -VO 6  respectively. In some alternative embodiments, one or more of the voltage sources V 1 -V 6  may be programmable to selectively produce desired output voltages. In other alternative embodiments, one or more of the voltage sources V 1 -V 6  may be configured to produce a time-varying output voltage of any desired shape. It will be understood that more or fewer voltage sources may be electrically connected to the mirror electrodes M 1 , M 2  in alternate embodiments. In any case, the ground chamber GC is illustratively grounded such that the ground electrodes GE 1 , GE 2  are both at ground potential. In some alternate embodiments, either or both of the ground electrodes GE 1 , GE 2  may be set to any desired DC reference potential, and in other alternate embodiments either or both of the ground electrodes GE 1 , GE 2  may be electrically connected to a switchable DC or time-varying voltage source. 
     The charge detection cylinder CD is electrically connected to a signal input of a conventional charge pre-amplifier  16  (CP) having a signal output electrically connected to the processor  12 . As an ion within the ELIT  10  oscillates back and forth between the ion mirrors M 1 , M 2  as briefly described above, it passes each time through the charge detection cylinder CD where it induces at least a portion of its charge onto the charge detection cylinder CD. The charge pre-amplifier  16  is illustratively responsive to each such induced charge detected at its input to produce a corresponding amplified charge detection signal which is provided as an input to the processor  12 . The processor  12  is illustratively operable to receive and digitize such charge detection signals produced by the charge pre-amplifier  16 , and to store the digitized charge detection signals in the memory  14 . The processor  12  is further illustratively coupled to one or more peripheral devices  18  for providing signal input(s) to the processor  12  and/or to which the processor  12  provides signal output(s). In some embodiments, the peripheral devices  18  include at least one of a conventional display monitor, a printer and/or other output device, and the memory  14  has instructions stored therein which, when executed by the processor  12 , cause the processor  12  to control one or more such output peripheral devices  18  to display and/or record analyses of the stored, digitized charge detection signals. In some embodiments, a conventional microchannel plate detector  20  may be disposed at the ion outlet of the ELIT  10  and electrically connected to the processor  12  as shown by dashed-line representation in  FIG.  2   , and in such embodiments the microchannel plate detector  20  is operable to supply detection signals to the processor  12  corresponding to detected ions and/or neutrals. 
     As further illustrated in  FIG.  2   , an ion source  25  is coupled to the ion inlet of the ELIT  10 , and the ion source  25  is configured to supply ions  30  to the ELIT  10  through the ion inlet A 1  of the plate or cover PL 1 . In one example embodiment, the ion source  25  illustratively includes a source of ions  25   1  operatively coupled to a mass spectrometer  25   2 . In this example embodiment, the source of ions  25   1  is illustratively configured and operable in a conventional manner to generate and supply ions to the mass spectrometer  25   2 , and the mass spectrometer  25   2  is configured and operable in a conventional manner to separate ions as a function of ion mass-to-charge ratio such that ions  30  supplied to the ELIT  10  are those exiting the mass spectrometer  25   2 . Conventionally, CDMS is a single-particle measurement technique in which charge and mass-to-charge ratio values are measured for individual charged particles, i.e., individual ions, and in which such measurements for multiple ions are then collected and used to produce mass and charge spectral information for the sample from which the ions are generated. In the CDMS  40  illustrated in  FIG.  2    operating as such a single-particle measurement instrument, the ELIT  10  is illustratively controlled, as described in further detail below, in a manner which favors trapping therein of individual ions exiting the mass spectrometer  25   2 . Charges induced on the charge detection cylinder CD, as the trapped ion oscillates in the ELIT  10  between the ion mirrors M 1 , M 2 , are detected by the charge preamplifier CP, and the corresponding charge detection signals produced by the charge preamplifier CP are processed by the processor  12  to determine the ion&#39;s charge and mass-to-charge ratio from which the ion&#39;s mass can then be computed. 
     In the example embodiment illustrated in  FIG.  2    in which the ion source  25  includes a source of ions  25   1  coupled to an ion inlet of a mass spectrometer  25   2 , the mass spectrometer  25   2  may be of any conventional design including, for example, but not limited to a time-of-flight (TOF) mass spectrometer, a reflectron mass spectrometer, a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer, a quadrupole mass spectrometer, a multi-quadrupole mass spectrometer, a sector mass spectrometer, such as a magnetic sector mass spectrometer, or the like. The source of ions  25   1  may illustratively be or include any conventional ion source for supplying ions to the mass spectrometer  25   2  including for example, but not limited to, one or any combination of at least one ion generating device such as an electrospray ionization source, a matrix-assisted laser desorption ionization (MALDI) source or the like. In some embodiments, the ion source  25  may further illustratively include other ion processing instruments or stages prior to, i.e., upstream of, the source of ions  25   1 , between the source of ions  25   1  and the mass spectrometer  25   2  and/or between the mass spectrometer  25   2  and the ELIT  10 . Examples of such other ion processing instruments or stages may include, but are not limited to, one or any combination of one or more molecular separation instruments configured to separate ions over time as a function of at least one molecular characteristic, such as an ion mobility spectrometer, another mass spectrometer, a liquid or gas chromatograph, or the like, one or more instruments for collecting and/or storing ions (e.g., one or more quadrupole, hexapole and/or other ion traps), one or more instruments for filtering ions (e.g., according to one or more molecular characteristics such as ion mass, charge, ion mass-to-charge, ion mobility, ion retention time and the like), one or more instruments for fragmenting or otherwise dissociating ions, one or more instruments for normalizing or shifting ion charge states, and the like. In any case, as briefly described above and as illustrated by example in  FIG.  2   , an ion  30  introduced into the ELIT  10  from the ion source  25  is made to oscillate between the ion mirrors M 1 , M 2 , each time passing through the charge detector CD, and the resulting charges induced by the ion  30  on the charge detection cylinder CD are detected by the charge preamplifier  16 . The corresponding charge detection signals produced by the charge preamplifier CP are then processed by the processor  12  to determine ion mass-to-charge ratio and ion mass values. As will be described in greater detail below, the ion  30  is trapped within the ELIT  10  and made to oscillate between the ion mirrors M 1 , M 2  thereof by selectively controlling the voltage sources V 1 -V 6  to establish electric fields within and between the mirror electrodes ME 1 -ME 3  of each ion mirror M 1 , M 2  for selectively transmitting ions therethrough and for selectively reflecting ions therefrom back toward the opposite ion mirror M 1 , M 2 . 
     Referring now to  FIG.  3   , a simplified flowchart is shown illustrating an embodiment of a process  100  for controlling the voltage sources V 1 -V 6  to trap an ion  30  supplied by the ion source  25  within the ELIT  10  and to cause the trapped ion  30  to oscillate back and forth between the ion mirrors M 1 , M 2 , and for processing recorded charge detection signals to determine ion charge, ion mass-to-charge ratio and ion mass values. In the illustrated embodiment, the process  100  is illustratively stored in the memory  14  in the form of instructions which, when executed by the processor  12 , cause the processor  12  to perform the stated functions. In alternate embodiments in which one or more of the voltage sources V 1 -V 6  is/are programmable independently of the processor  12 , one or more aspects of the process  100  may be executed in whole or in part by the one or more of the programmable voltage sources V 1 -V 6 . For purposes of this disclosure, however, the process  100  will be described as being executed solely by the processor  12 . The process  100  will further be described as operating on a positively charged ion  30 , although it will be understood that the process  100  may alternatively operate on a negatively charged ion. 
     With reference to  FIGS.  2  and  3   , the process  100  begins at step  102  where the processor  12  is operable to control one or more of the voltage sources V 1 -V 6  to set the voltages VO 1 -VO 6  in a manner which causes each of the ion mirrors M 1  and M 2  to operate in a “transmission mode” in which each of the ion mirrors M 1 , M 2  operates to pass ions therethrough. Such control of the ion mirrors M 1  and M 2  to their respective transmission modes causes the ion  30  supplied by the ion source  25  to pass completely through the ELIT  10  as at least partially depicted in  FIG.  2   . Illustratively, the output voltages VO 1 -VO 3  produced by the voltage sources V 1 -V 3  respectively are controlled by the processor  12  at step  102  to establish a net “transmission” electric field E N1  in the ion mirror M 1  which focusses the ion  30  passing into the ion mirror M 1  toward the longitudinal axis C extending centrally through the ELIT  10 . As a result of this focusing effect of the ion transmission electric field E N1 , the ion  30  exiting M 1  attains a narrow trajectory through the charge detector CD, i.e., close to the longitudinal axis C, and into the ion mirror M 2 . The output voltages VO 4 -VO 6  produced by the voltage sources V 4 -V 6  respectively are likewise illustratively controlled at step  102  to establish a net “transmission” electric field E N2  in the ion mirror M 2 , identical or similar to the ion transmission electric field E N1 , which focuses the ion  30  toward the longitudinal axis C such that the ion  30  passes through the ion mirror M 2  and then through the exit aperture A 2  defined in the plate PL 2 . 
     Following step  102 , the process  100  advances to step  104  where the processor  12  is operable to pause and determine when to advance to step  106 . In one embodiment, the processor  12  is operable at step  104  to pause for a predefined or programmable time period to allow ions exiting the ion source  25  to enter and pass through the ELIT  10 . As one non-limiting example, the selected time period which the processor  12  spends at step  104  before moving on to step  106  is on the order of 1 millisecond (ms), although it will be understood that such selected time period may, in other embodiments, be greater than 1 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  20 , the processor  12  may be operable to control the voltage sources V 1 -V 6  to hold the ion mirrors M 1 , M 2  in their transmission modes until at least one ion  30  is detected at the microchannel plate detector  20 . Until such detection, the process  100  follows the NO branch of step  104  and loops back to the beginning of step  104 . 
     Following the YES branch of step  104 , the processor  12  is operable at step  106  to control the voltage sources V 4 -V 6  to set the output voltages VO 4 -VO 6  in a manner which changes or switches the operation of the ion mirror M 2  from transmission mode of operation to a “reflection mode” of operation in which the ion mirror M 2  operates to “reflect” an ion contained therein back toward the ion mirror M 1  (and through the charge detector CD) by first decelerating and stopping the ion, and then accelerating the ion back in the opposite direction while focusing the ion toward the longitudinal axis C such that the ion passes in a narrow trajectory about the longitudinal axis C from the ion mirror M 2  back toward the ion mirror M 1 . Illustratively, the output voltages VO 4 -VO 6  produced by the voltage sources V 4 -V 6  respectively are controlled by the processor  12  at step  106  to establish a net “reflection” electric field E N3  in the ion mirror M 2  oriented to reflect the ion  30  entering therein from the charge detector CD back toward the ion mirror M 1  (and through the charge detector CD) as illustrated by example in  FIG.  2   . Illustratively, the output voltages VO 1 -VO 3  produced by the voltage sources V 1 -V 3  respectively are unchanged at step  106  so that the ion mirror M 1  remains in its transmission mode to allow one or more additional ions  30  to enter into the ion mirror M 1  from the mass spectrometer  25  or other ion source. In such embodiments, the process  100  advances from step  106  to step  108  where the processor  12  is operable to pause and determine when to advance to step  110 . 
     In one embodiment of step  108 , the ELIT  10  is illustratively controlled in a “random trapping mode” in which the ion mirror M 2  is held in the reflection mode and the ion mirror M 1  is held in the transmission mode for a selected time period as one or more ions  30  enter the ion mirror M 1  from the ion source  25 . As one non-limiting example, the selected time period which the processor  12  spends at step  108  before moving on to step  110  is on the order of 1 millisecond (ms), although it will be understood that such selected time period may, in other embodiments, be greater than 1 ms or less than 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 some alternate embodiments of step  108 , the ELIT  10  may illustratively be controlled by the processor  12  in a first version of a “trigger trapping mode” in which the ion mirror M 1  is held in the transmission mode and the ion mirror M 2  is held in the reflection mode until an ion  30  is detected by the charge detector CD. 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  12  of the ion by the charge detector CD serves as a trigger event which causes the processor  12  to follow the YES branch of step  108  and advance to step  110  of the process  100 . In this version of the trigger trapping mode, the detected ion serving as the trigger event may be an ion entering the ELIT  10  from the ion source  25  and passing through the charge detection cylinder CD toward the ion mirror M 2 , or an ion reflected by the ion mirror M 2  and passing back through the charge detection cylinder CD toward the ion mirror M 1 . 
     In a second version of the “trigger trapping mode,” steps  104  and  106  may be omitted, and detection by the processor  12  of an ion by the charge detector CD at step  108  again serves as a trigger event which causes the processor  12  to follow the YES branch of step  108  and advance to step  110 . In this version of the trigger trapping mode, the ion mirrors M 1 , M 2  are both in transmission mode such that the detected ion serving as the trigger event may only be an ion entering the ELIT  10  from the ion source  25  and passing through the charge detection cylinder CD toward the ion mirror M 2 . 
     Following the YES branch of step  108  in any of the trapping modes described above, the processor  12  is operable at step  110  to control the voltage sources V 1 -V 3  to set the output voltages VO 1 -VO 3  in a manner which changes or switches the operation of the ion mirror M 1  from transmission mode of operation to the reflection mode of operation in which the ion mirror M 1  operates to reflect an ion contained therein back toward the ion mirror M 2  (and through the charge detector CD). Illustratively, the output voltages VO 1 -VO 1  produced by the voltage sources V 1 -V 3  respectively are controlled by the processor  12  at step  110  to establish a net “reflection” electric field E N4  in the ion mirror M 1 , which is identical or similar to the ion reflection electric field E N3  established within the ion mirror M 2 , and which is oriented to reflect the ion  30  entering therein from the charge detector CD back toward the ion mirror M 2  (and through the charge detector CD) as illustrated by example in  FIG.  2   . The output voltages VO 4 -VO 6  produced by the voltage sources V 4 -V 6  are unchanged at step  110  so that the net electric field E N3  remains in the ion mirror M 2  so as to maintain the ion mirror M 2  in the reflection mode of operation. At step  110 , the ion  30  is trapped within the ELIT  10 , and with both of the ion mirrors M 1  and M 2  operating in the reflection modes the ion  30  traversing the length of the ELIT  10  is reflected by each of the respective ion reflection electric fields E N3  and E N4  in a manner which enables the ion  30  to oscillate back and forth between the ion mirrors M 1  and M 2 , each time passing through the charge detector CD along a narrow trajectory about the central longitudinal axis C of the ELIT  10 . 
     Following step  110 , the process  100  advances to step  112  where, as the ion is oscillating within the ELIT  10  back and forth between the ion mirrors M 1 , M 2  during a “detection phase,” detection by the charge preamplifier CP of the charge induced on the charge detector CD by each passage of the ion therethrough (hereinafter referred to as a “charge detection event”) is recorded, i.e., stored in the memory  14 , by the processor  12 . Illustratively, the detection information recorded at step  112  includes amplitude and timing information, i.e., the amplitudes of each charge detection signal as well as the time of each charge detection signal relative to a reference time and/or relative to a time of a previous charge detection signal. 
     Following step  112 , the process  100  advances to step  114  where the processor  12  is operable to pause and determine when to advance to step  114 . In one embodiment, the processor  12  is configured, i.e. programmed, to allow the ion(s) to oscillate through the ELIT  10  back and forth between the ion mirrors M 1 , M 2  during the detection phase for a selected time period during which charge detection events are recorded by the processor  12 . As one non-limiting example, the selected time period which the processor  12  spends in the detection phase at step  114  before moving on to step  116  is on the order of 100 millisecond (ms), although it will be understood that such selected time period may, in other embodiments, be greater than 100 ms or less than 100 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  114 . After passage of the selected time period, the process  100  follows the YES branch of step  114  and advances to step  116 . In some alternate embodiments of step  114 , the ELIT  10  may illustratively be controlled by the processor  12  to allow the ion(s) to oscillate back in forth through the charge detector CD during the detection phase a selected number of times during which charge detection events are recorded by the processor  12 . Until the processor counts the selected number charge detection events, the process  100  follows the NO branch of step  114  and loops back to the beginning of step  114 . Detection by the processor  12  of the selected number of charge detection events serves as a trigger event which causes the processor  12  to follow the YES branch of step  114  and advance to step  116  of the process  100 . 
     Following the YES branch of step  114 , the processor  12  is operable at step  116  to control the voltage sources V 1 -V 6  to set the output voltages VO 1 -VO 6  in a manner which changes or switches the operation of both of the ion mirrors M 1  and M 2  from reflection mode of operation to the transmission mode of operation in which the ion mirrors M 1 , M 2  each operate to allow passage of ions therethrough. Illustratively, the output voltages VO 1 -VO 6  produced by the voltage sources V 1 -V 6  respectively are controlled by the processor  12  at step  116  to re-establish net electric fields E N1  and E N2  in the ion mirrors M 1 , M 2  as described above and as illustrated in  FIG.  2   . Thereafter at step  118 , the processor  12  is programed to pause for a selected time period to allow the ions contained within the ELIT  10  to exit. As one non-limiting example, the selected time period which the processor  12  spends at step  118  before looping back to step  102  to restart the process  100  is on the order of 1 millisecond (ms), although it will be understood that such selected time period may, in other embodiments, be greater than 1 ms or less than 1 ms. Until the selected time period has elapsed, the process  100  follows the NO branch of step  118  and loops back to the beginning of step  118 . After passage of the selected time period, the process  100  follows the YES branch of step  118  and loops back to step  102  to restart the process  100 . 
     As described above, each detection by the charge preamplifier CP of a charge induced on the charge detector CD by passage of an ion therethrough is referred to as a “charge detection event.” As the ion oscillates back and forth between the ion mirrors M 1 , M 2 , multiple charge detection events are recorded. The total number of oscillations allowed before the process  100  advances from step  114  to step  116 , or the total time allowed between step  110  and advancement of the process  100  from step  114 , is referred to an ion trapping event. By either definition, the ion  30  oscillates back and forth between the ion mirrors M 1 , M 2  for a “total trapping time” of an ion trapping event during which multiple charge detection events are recorded. 
     Following another YES branch of step  114 , the process  100  additionally advances to step  120  to analyze the data collected during the ion trapping event just described. In the illustrated embodiment, the data analysis step  120  illustratively includes step  122  where the processor  12  is operable to compute a Fourier transform of the collected set of stored charge detection signals recorded during the ion trapping event. The processor  12  is illustratively operable to execute step  122  using any conventional digital Fourier transform (DFT) technique such as for example, but not limited to, a conventional Fast Fourier Transform (FFT) algorithm. Following step  122 , the process  100  advances to step  124  where the processor  12  is operable to compute values of ion mass-to-charge ratio (m/z) and ion charge (z), each as a function of the computed FFT, and thereafter at step  126  the processor  12  is operable to store the computed results in the memory  14  and/or to control one or more of the peripheral devices  18  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  30  oscillating in an ELIT is inversely proportional to the square of the fundamental frequency ff of the oscillating ion  30  according to the equation:
 
 m/z=C/ff   2 ,
 
where C is a constant that is a function of the ion energy and also a function of the dimensions of the ELIT. Typically, C is determined using conventional ion trajectory simulations. In any case, the value of the ion charge, z, is proportional to the magnitude of the fundamental frequency of the FFT, taking into account the number of ion oscillation cycles. Ion mass, m, is then calculated as a product of m/z and z. 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.
 
     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  25 , and ion mass-to-charge, ion charge and ion mass values are determined/computed for each such ion trapping event at step  120  of the process  100 . 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. 
     Generally, uncertainty in the determination of ion mass with an ELIT depends on the uncertainties in the m/z and z measurements. In the process  100  just described, the measured m/z values are inversely proportional to the square of the fundamental frequency, ff, and the measured charge values are proportional to the magnitude of the FFT fundamental frequency. It has been determined through simulation and experimentation that because the measured charge values are proportional to the magnitude of the fundamental frequency, ff, of the oscillating charge detection signal, uncertainty in the charge measurements can be reduced by increasing the signal-to-noise ratio of the fundamental frequency ff of the oscillating charge detection signal relative to one or more harmonics of the oscillating charge detection signal. 
     The oscillating charge detection signal just described is substantially a square-wave signal having a duty cycle, DC, defined as a ratio of the time spent by the ion  30  in the charge detection cylinder CD and the time spent by the ion  30  traversing the entire ELIT during one oscillation cycle. In particular, and referring again to  FIG.  1   , the duty cycle, DC, is the ratio of the time spent by the ion  30  in the zone Z 3  and the time spent by the ion  30  traversing the sum of the zones Z 1  through Z 3  during one oscillation cycle. The length DZ 1  and DZ 2  of each of the zones Z 1  and Z 2  is the same and is given by DZ 1 =DZ 2 =3D 1 +D 2 +3d 1 +d 2 , and the length of the zone Z 3  is D 3 . The time spent by an ion  30  traversing the distance DZ 1  of Z 1  as the ion is reflected by M 1  toward M 2  is T DZ11 , the time spent by the ion  30  passing through the distance D 3  following reflection by M 1  through DZ 1  is T Z31 , and the time spent by the ion  30  traversing the distance DZ 2  of Z 2  after emerging from the charge detector CD is T DZ21 . Similarly, the time spent by the ion  30  traversing the distance DZ 2  of Z 2  as the ion is reflected by M 2  back toward M 1  is T DZ22 , the time spent by the ion  30  passing through the distance D 3  following reflection by M 2  through DZ 2  is T Z32 , and the time spent by the ion  30  traversing the distance DZ 1  of Z 1  after emerging from the charge detector CD is T DZ12 . The duty cycle for the ELIT  10  illustrated in  FIG.  1    is thus DC=(T Z31 +T Z32 )/(T DZ11 +T Z31 +T DZ21 +T DZ22 +T Z32 +T DZ12 ) 
     Referring to  FIGS.  4 A and  4 B , it is generally understood in the signal waveform analysis art that square-wave signals having a 50% duty cycle produce only odd-valued signal harmonics. Applying this relationship to the control of the ELIT  10  illustrated in  FIG.  2   , the output voltages VO 1 -VO 6  of the voltage sources V 1 -V 6  are illustratively controlled, taking into account the dimensions of the ELIT  10  illustrated in  FIG.  1   , to establish the ion reflection electric fields, i.e., the electric field E N3  of the ion mirror M 2  operating in reflection mode and the electric field E N4  also operating in reflection mode, in a manner which results in an oscillating charge detection signal having a duty cycle of approximately 50%. Because a 50% duty cycle square wave does not have any even-numbered harmonic frequency components, fewer harmonic frequency components will thus be included in the FFT computed by the processor  12  at step  114  as compared to that of an oscillating charge detection signal having a duty cycle other than 50%. Fewer such harmonic frequency components will yield a higher magnitude fundamental frequency peak and, since the ion charge value computed by the processor  12  at step  120  is proportional to the magnitude of the fundamental frequency ff, uncertainty in the ion charge measurement value will accordingly be reduced due to the increases signal-to-noise ratio of the fundamental frequency peak relative to the harmonics. Operating the ELIT  10  with an oscillating charge detection signal having a duty cycle at or near 50% so as to include fewer harmonic frequency components, i.e., to specifically exclude even-numbered harmonics, further illustratively reduces effects of ion kinetic energy spread on the fundamental frequency so as to also reduce uncertainty in the ion mass-to-charge measurement values. 
     In order to achieve a 50% duty cycle, the time spent by an ion  30  traversing the distance DZ 1 +Z 3 +DZ 2  must be equal to the time spent by the ion  30  traversing the distance DZ 2 +Z 3 +DZ 2  in the opposite direction. The duty cycle equation set forth in the previous paragraph thus simplifies to DC=T Z3 /(T DZ1 +T Z3 +T DZ2 ), where T Z3  is the time spent by the ion  30  traversing D 3  in either direction, T DZ1  is the time spent by the ion  30  travelling through each of DZ 1  and DZ 2  toward the other and T DZ2  is the time spent by the ion  30  traveling into each of DZ 1  and DZ 2  prior to being reflected, i.e., prior to changing directions under the influence of the net electric fields E N4  and E N3  respectively. Moreover, the requirement DC=½ results in T Z3 =T DZ1 +T DZ2 , such that, during each single-direction pass through the ELIT  10 , the time spent by the ion  30  passing each through the charge detection cylinder CD should be approximately equal to the sum of the time spent reflecting the ion  30  from a stopped state in one of the ion mirrors M 1 , M 2  to the respective end or entrance of the charge detection cylinder CD and the time spent by the ion exiting the opposite end of the charge detection cylinder CD and traveling toward and into the other ion mirror M 1 , M 2  to a stopped state. 
     Referring now to  FIG.  5   , a plot is shown of simulated charge measurement error RMSD(e) vs. duty cycle in which the duty cycle, DC, of the ELIT  10  having the example dimensions illustrated in the above TABLE I was varied between 30 and 70%. As the plot illustrates, uncertainty in the ion charge measurement of an oscillating charge detection signal has a minimum value at a duty cycle of approximately 50%. 
     Referring again to  FIGS.  2  and  3   , the processor  12  is illustratively operable at steps  102 ,  106 ,  110  and  116  to control the output voltages VO 1 -VO 6  produced by the voltage sources V 1 -V 6  in a manner which establishes the net electric fields E N1 -E N4  described above, taking into account the dimensions of the ELIT  10 , particularly, but not exclusively, the axial lengths DZ 1 , DZ 2  and Z 3  and the cross-sectional areas, e.g., radial diameters, P 1  and P 3 , that results in approximately a 50% duty cycle of the oscillating charge detection signal. Using the example dimensions of the ELIT  10  illustrated in TABLE I above, one example set of output voltages VO 1 -VO 6  produced by the voltage sources V 1 -V 6  respectively at each of the four steps  102 ,  106 ,  110  and  116  is shown in TABLE II below. It will be understood that the following values of VO 1 -VO 6  are provided only by way of example, and that other values of VO 1 , VO 2 , VO 3 , VO 4 , VO 5  and/or VO 6  at one or more of the steps  102 ,  106 ,  110 ,  116  may alternatively be used. 
     
       
         
           
               
               
               
             
               
                   
                 TABLE II 
               
               
                   
                   
               
               
                   
                 Step of  
                 Output Voltages  
               
               
                   
                 Process 100 
                 (volts DC) 
               
               
                   
                   
               
             
            
               
                   
                 102 
                 VO1 = VO6 = 0  
               
               
                   
                   
                 VO2 = VO5 = 135 
               
               
                   
                   
                 VO3 = VO4 = 95  
               
               
                   
                 106 
                 VO1 = 0  
               
               
                   
                   
                 VO2 = VO5 = 135 
               
               
                   
                   
                 VO3 = 95  
               
               
                   
                   
                 VO4 = 125 
               
               
                   
                   
                 VO6 = 190 
               
               
                   
                 110 
                 VO1 = VO6 = 190 
               
               
                   
                   
                 VO2 = VO5 = 135 
               
               
                   
                   
                 VO3 = VO4 = 125 
               
               
                   
                 116 
                 VO1 = VO6 = 0  
               
               
                   
                   
                 VO2 = VO5 = 135 
               
               
                   
                   
                 VO3 = VO4 = 95  
               
               
                   
                   
               
            
           
         
       
     
     Referring now to  FIG.  6 A , a simplified block diagram is shown of an embodiment of an ion, i.e., charged particle, separation instrument  200  which may include the ELIT  10  configured and operable as described herein, which may include the CDMS  40  configured and operable as described herein, which may include any number of ion processing instruments forming part of the ion source  25  upstream of the ELIT  10  and/or which may include any number of ion processing instruments disposed downstream of the ELIT  10  to further process ions exiting the ELIT  10 . In this regard, the ion source  25  is illustrated in  FIG.  6 A  as including a number, Q, of ion source stages IS 1 -IS Q  which may be or form part of the ion source  25  described in one form above with respect to  FIG.  2   , where Q may be any positive integer. Alternatively or additionally, an ion processing instrument  210  is illustrated in  FIG.  6 A  as being coupled to the ion outlet of the ELIT  10 , wherein the ion processing instrument  210  may include any number of ion processing stages OS 1 -OS R , where R may be any positive integer. 
     Focusing on the ion source  25 , it will be understood that the source  25  of ions entering the ELIT  10  may be or include, in the form of one or more of the ion source stages IS 1 -IS Q , 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  25  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 above with respect to  FIG.  2   . 
     Turning now to the ion processing instrument  210 , it will be understood that the instrument  210  may be or include, in the form of one or more of the ion processing stages OS 1 -OS R , 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 or guides), 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  210  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  FIG.  2   . 
     As one specific implementation of the ion separation instrument  200  illustrated in  FIG.  6 A , which should not be considered to be limiting in any way, the ion source  25  illustratively includes 3 stages, and the ion processing instrument  210  is omitted. In this example implementation, the ion source stage IS 1  is a conventional source of ions, e.g., electrospray, MALDI or the like, the ion source stage IS 2  is a conventional ion filter, e.g., a quadrupole or hexapole ion guide, and the ion source stage IS 3  is a mass spectrometer of any of the types described above. In this embodiment, the ion source stage IS 2  is controlled in a conventional manner to preselect ions having desired molecular characteristics for analysis by the downstream mass spectrometer, and to pass only such preselected ions to the mass spectrometer, wherein the ions analyzed by the ELIT  10  will be the preselected ions separated by the mass spectrometer according to mass or mass-to-charge ratio. The preselected ions exiting the ion filter may, for example, be ions having a specified ion mass or mass-to-charge ratio, ions having ion masses or ion mass-to-charge ratios above and/or below a specified ion mass or ion mass-to-charge ratio, ions having ion masses or ion mass-to-charge ratios within a specified range of ion mass or ion mass-to-charge ratio, or the like. In some alternate implementations of this example, the ion source stage IS 2  may be the mass spectrometer and the ion source stage IS 3  may be the ion filter, and the ion filter may be otherwise operable as just described to preselect ions exiting the mass spectrometer which have desired molecular characteristics for analysis by the downstream ELIT  10 . In other alternate implementations of this example, the ion source stage IS 2  may be the ion filter, and the ion source stage IS 3  may include a mass spectrometer followed by another ion filter, wherein the ion filters each operate as just described. 
     As another specific implementation of the ion separation instrument  200  illustrated in  FIG.  6 A , which should not be considered to be limiting in any way, the ion source  25  illustratively includes 2 stages, and the ion processing instrument  210  is again omitted. In this example implementation, the ion source stage IS 1  is a conventional source of ions, e.g., electrospray, MALDI or the like, the ion source stage IS 2  is a conventional mass spectrometer of any of the types described above. This is the CDMS implementation described above with respect to  FIG.  2    in which the ELIT  10  is operable to analyze ions exiting the mass spectrometer. 
     As yet another specific implementation of the ion separation instrument  200  illustrated in  FIG.  6 A , which should not be considered to be limiting in any way, the ion source  25  illustratively includes 2 stages, and the ion processing instrument  210  is omitted. In this example implementation, the ion source stage IS 1  is a conventional source of ions, e.g., electrospray, MALDI or the like, and the ion processing stage OS 2  is a conventional single or multiple-stage ion mobility spectrometer. In this implementation, the ion mobility spectrometer is operable to separate ions, generated by the ion source stage IS 1 , over time according to one or more functions of ion mobility, and the ELIT  10  is operable to analyze ions exiting the ion mobility spectrometer. In an alternate implementation of this example, the ion source  25  may include only a single stage IS 1  in the form of a conventional source of ions, and the ion processing instrument  210  may include a conventional single or multiple-stage ion mobility spectrometer as a sole stage OS 1  (or as stage OS 1  of a multiple-stage instrument  210 ). In this alternate implementation, the ELIT  10  is operable to analyze ions generated by the ion source stage IS 1 , and the ion mobility spectrometer OS 1  is operable to separate ions exiting the ELIT  10  over time according to one or more functions of ion mobility. As another alternate implementation of this example, single or multiple-stage ion mobility spectrometers may follow both the ion source stage IS 1  and the ELIT  10 . In this alternate implementation, the ion mobility spectrometer following the ion source stage IS 1  is operable to separate ions, generated by the ion source stage IS 1 , over time according to one or more functions of ion mobility, the ELIT  10  is operable to analyze ions exiting the ion source stage ion mobility spectrometer, and the ion mobility spectrometer of the ion processing stage OS 1  following the ELIT  10  is operable to separate ions exiting the ELIT  10  over time according to one or more functions of ion mobility. In any implementations of the embodiment described in this paragraph, additional variants may include a mass spectrometer operatively positioned upstream and/or downstream of the single or multiple-stage ion mobility spectrometer in the ion source  25  and/or in the ion processing instrument  210 . 
     As still another specific implementation of the ion separation instrument  200  illustrated in  FIG.  6 A , which should not be considered to be limiting in any way, the ion source  25  illustratively includes 2 stages, and the ion processing instrument  210  is omitted. In this example implementation, the ion source stage IS 1  is a conventional liquid chromatograph, e.g., HPLC or the like configured to separate molecules in solution according to molecule retention time, and the ion source stage IS 2  is a conventional source of ions, e.g., electrospray or the like. In this implementation, the liquid chromatograph is operable to separate molecular components in solution, the ion source stage IS 2  is operable to generate ions from the solution flow exiting the liquid chromatograph, and the ELIT  10  is operable to analyze ions generated by the ion source stage IS 2 . In an alternate implementation of this example, the ion source stage IS 1  may instead be a conventional size-exclusion chromatograph (SEC) operable to separate molecules in solution by size. In another alternate implementation, the ion source stage IS 1  may include a conventional liquid chromatograph followed by a conventional SEC or vice versa. In this implementation, ions are generated by the ion source stage IS 2  from a twice separated solution; once according to molecule retention time followed by a second according to molecule size, or vice versa. In any implementations of the embodiment described in this paragraph, additional variants may include a mass spectrometer operatively positioned between the ion source stage IS 2  and the ELIT  10 . 
     Referring now to  FIG.  6 B , a simplified block diagram is shown of another embodiment of an ion separation instrument  220  which illustratively includes a multi-stage mass spectrometer instrument  230  and which also includes the charge detection mass spectrometer (CDMS)  40 , illustrated in  FIG.  2    and described herein and implemented in the embodiment of  FIG.  6 B  as a high-mass ion analysis component. In the illustrated embodiment, the multi-stage mass spectrometer instrument  230  includes an ion source (IS)  25 , as illustrated and described herein, followed by and coupled to a first conventional mass spectrometer (MS 1 )  232 , followed by and coupled to a conventional ion dissociation stage (ID)  234  operable to dissociate ions exiting the mass spectrometer  232 , e.g., by one or more of collision-induced dissociation (CID), surface-induced dissociation (SID), electron capture dissociation (ECD) and/or photo-induced dissociation (PID) or the like, followed by an coupled to a second conventional mass spectrometer (MS 2 )  236 , followed by a conventional ion detector (D)  238 , e.g., such as a microchannel plate detector or other conventional ion detector. The CDMS  40  is coupled in parallel with and to the ion dissociation stage  234  such that the CDMS  40  may selectively receive ions from the mass spectrometer  236  and/or from the ion dissociation stage  232 . 
     MS/MS, e.g., using only the ion separation instrument  230 , is a well-established approach where precursor ions of a particular molecular weight are selected by the first mass spectrometer  232  (MS 1 ) 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  234 . The fragment ions are then analyzed by the second mass spectrometer  236  (MS 2 ). Only the m/z values of the precursor and fragment ions are measured in both MS 1  and MS 2 . 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  230  to the CDMS  40  illustrated and described herein, it is possible to select a narrow range of m/z values using MS 1  and then use the CDMS  40  to determine the masses of the m/z selected precursor ions. The mass spectrometers  232 ,  236  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, non-limiting examples of which are described hereinabove. In any case, the m/z selected precursor ions with known masses exiting MS 1  can be fragmented in the ion dissociation stage  234 , and the resulting fragment ions can then be analyzed by MS 2  (where only the m/z ratio is measured) and/or by the CDMS instrument  40  (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 MS 2 , 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. 
     It will be understood that one or more charge detection optimization techniques may be used with the ELIT  10  alone and/or in any of the systems  40 ,  200 ,  220  illustrated in the attached figures and described herein, e.g., for trigger trapping and/or other charge detection events. Examples of some such charge detection optimization techniques are illustrated and described in co-pending U.S. Patent Application Ser. No. 62/680,296, filed Jun. 4, 2018 and in co-pending International Patent Application No. PCT/US2019/13284, filed Jan. 11, 2019, both entitled APPARATUS AND METHOD FOR CAPTURING IONS IN AN ELECTROSTATIC LINEAR ION TRAP, the disclosures of which are both expressly incorporated herein by reference in their entireties. 
     It will be further understood that one or more charge calibration or resetting apparatuses may be used with the charge detection cylinder CD of the ELIT  10  alone and/or in any of the systems  40 ,  200 ,  220  illustrated in the attached figures and described herein. An example of one such charge calibration or resetting apparatus is illustrated and described in co-pending U.S. Patent Application Ser. No. 62/680,272, filed Jun. 4, 2018 and in co-pending International Patent Application No. PCT/US2019/13284, filed Jan. 11, 2019, both entitled APPARATUS AND METHOD FOR CALIBRATING OR RESETTING A CHARGE DETECTOR, the disclosures of which are both expressly incorporated herein by reference in their entireties. 
     It will be still further understood that the design concepts for achieving a desired duty cycle within the ELIT  10  alone and/or in any of the systems  40 ,  200 ,  220  illustrated in the attached figures and described herein may be implemented in an ELIT array including two or more ELITs and/or in any ELIT including two or more ELIT regions. Examples of some such ELITs and/or ELIT arrays are illustrated and described in co-pending U.S. Patent Application Ser. No. 62/680,315, filed Jun. 4, 2018 and in co-pending International Patent Application No. PCT/US2019/13283, 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  25  illustrated and described herein in combination with the ELIT  10  along and/or in any of the systems  40 ,  200 ,  220  illustrated in the attached figures and described herein, some examples of which are illustrated and described in co-pending 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/US2019/13274, 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 the charge detection mass spectrometer  40 , the ion separation instrument  200 , the ion separation instrument  230  and/or the ELIT  10  illustrated in the attached figures 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 U.S. Patent Application Ser. No. 62/680,245, filed Jun. 4, 2018 and co-pending International Patent Application No. PCT/US2019/13277, 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 yet further understood that one or more ion inlet trajectory control apparatuses and/or techniques may be used with the ELIT  10  alone and/or in any of the systems  40 ,  200 ,  220  illustrated in the attached figures and described herein to provide for simultaneous measurements of multiple individual ions within the ELIT  10 . Examples of some such ion inlet trajectory control apparatuses and/or techniques are illustrated and described in co-pending U.S. Patent Application Ser. No. 62/774,703, filed Dec. 3, 2018 and in co-pending International Patent Application No. PCT/US2019/13285, 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, while the ELIT  10  illustrated in the attached figures has been described herein as being designed and operated with an oscillating charge detection signal having a duty cycle of approximately 50% for the purpose of reducing noise in fundamental frequency magnitude determinations resulting from harmonic frequency components of the signal, this disclosure also contemplates alternatively or additionally employing other structures and/or techniques for reducing the effects of harmonic frequency components on such fundamental frequency magnitude determinations. Examples of such other structures and/or techniques may include, but are not limited to, one or more harmonic component filtering structures and/or techniques, one or more wave-shaping structures and/or techniques, one or more multi-phase operating structures and/or techniques, and the like. As another example, although the ion mirrors M 1  and M 2  are illustrated in the attached figures and described herein as each including an aligned arrangement of three spaced-apart mirror electrodes, it will be understood that such embodiments are provided only by way of example and should not be considered limiting in any way. Alternate embodiments in which either or both of the ion mirrors M 1 , M 2  include more or fewer mirror electrodes are intended to fall within the scope of this disclosure. As yet another example, it will be understood that the steps of the process  100  illustrated in the attached figures and described herein are also provided only by way of example and should not be considered limiting in any way. Alternate techniques for operating the ELIT  10  described herein to capture the measurements and data described herein are intended to fall within the scope of this disclosure, and it will be recognized that any such alternate techniques will be a mechanical step for one skilled in the art using the concepts described herein as a template. As still another example, it will be understood that the ELIT  10  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.