WO2025158320A1

WO2025158320A1 - Rapid environmental equilibration of detection components in mass spectrometers

Info

Publication number: WO2025158320A1
Application number: PCT/IB2025/050714
Authority: WO
Inventors: Adam Curtis CAREW; Robert NIECKARZ
Original assignee: DH Technologies Development Pte Ltd
Current assignee: DH Technologies Development Pte Ltd
Priority date: 2024-01-26
Filing date: 2025-01-23
Publication date: 2025-07-31
Anticipated expiration: 2026-07-26
Also published as: WO2025158321A1

Abstract

In various aspects, provided are methods of stabilizing the gain of an optical ion detector including a microchannel plate (MCP) and a scintillator in communication with the MCP such that electrons generated by the MCP in response to incidence of ultraviolet photons thereon are received by the scintillator to generate photons, which include configuring the MCP for generating a plurality of electrons in response to incidence of ultraviolet photons on the MCP, exposing the MCP to a beam of ultraviolet photons to generate a plurality of electrons for irradiating an input surface of the scintillator and thereby causing degassing of at least a portion of one or more molecules adsorbed on the scintillator's input surface, and maintaining such irradiation over a temporal period until the optical ion detector exhibits a substantially stable gain profile.

Description

RAPID ENVIRONMENTAL EQUILIBRATION OF DETECTION COMPONENTS IN MASS SPECTROMETERS

Technical Field

The present disclosure relates generally to systems and methods for performing mass spectrometry, and more particularly to workflows for use in mass spectrometry for achieving a stable ion detection signal.

Background

The present disclosure provides systems and methods for performing mass spectrometry, and particularly such systems and methods for stabilizing an ion detector for acquisition of mass and abundance data.

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

In mass spectrometry systems, a variety of detectors can be utilized for generating ion detection signals. In particular, the use of optical ion detectors is becoming more prevalent. It is generally desired that such detectors exhibit a stable gain over the time period in which ion detection signals are acquired.

Summary

In various aspects, provided are methods of stabilizing the gain of an optical ion detector, where the optical ion detector includes a microchannel plate (MCP) and a scintillator in communication with the MCP such that electrons generated by the MCP are received by the scintillator to generate photons. Typically, and in various embodiments, the optical ion detector includes one or more photomultiplier tubes (PMTs) that can receive the photons generated by the scintillator and generate electrical pulses in response to the detection of the photons.

In various embodiments of the methods of stabilizing the gain of an optical ion detector, the methods comprise: (i) applying a bias voltage to the MCP, (ii) directing a plurality of photons having a wavelength in the ultraviolet portion of the electromagnetic spectrum onto the MCP thereby causing the MCP to generate electrons thereby irradiating an input surface of the scintillator and thereby causing degassing of at least a portion of molecules adsorbed on the input surface of the scintillator, and (iii) monitoring a gain of the optical ion detector during exposure of the MCP to the plurality of photons, and (iv) maintaining the direction of the plurality of photons onto the MCP over a temporal period until the optical ion detector exhibits a substantially stable gain profile.

In various aspects, provided are methods conditioning a mass spectrometer for ion detection and use, wherein the mass spectrometer comprises an optical ion detector, the optical ion detector comprising at least one microchannel plate (MCP) for generating electrons in response to photons having a wavelength in the ultraviolet portion of the electromagnetic spectrum incident thereon, and at least one scintillator in communication with the MCP for receiving electrons generated by the MCP and generating photons in response to the electrons being incident on an input surface of at least one of the scintillators. Typically, and in various embodiments, the optical ion detector includes one or more photomultiplier tubes (PMTs) that can receive the photons generated by the scintillator and generate electrical pulses in response to the detection of the photons.

In various embodiments of the methods of conditioning a mass spectrometer for ion detection and use, the methods comprise: (i) stabilizing the gain of the optical ion detector using any of the embodiments of stabilizing the gain of an optical ion detector provided herein (such as, e.g., (a) applying a bias voltage to the MCP, (b) directing a plurality of photons having a wavelength in the ultraviolet portion of the electromagnetic spectrum onto the MCP thereby causing the MCP to generate electrons thereby irradiating an input surface of the scintillator and thereby causing degassing of at least a portion of molecules adsorbed on the input surface of the scintillator, and (c) monitoring a gain of the optical ion detector during exposure of the MCP to the plurality of photons, and (d) maintaining the direction of the plurality of photons onto the MCP over a temporal period until the optical ion detector exhibits a substantially stable gain profile), (ii) after the optical ion detector exhibits a substantially stable gain profile, directing a reference ion beam containing a reference ion having a reference ion mass onto the detector and monitoring a mass spectrum produced thereby, and (iii) wherein after a conditioning period after the optical ion detector exhibits a substantially stable gain profile, said mass spectrum no longer substantially exhibits a mass shift in the reference ion mass arising from the step of the stabilizing the gain of the ion optical detector.

In various embodiments of the various aspects, the methods include configuring the MCP for generating a plurality of electrons in response to incidence of ultraviolet (UV) wavelength photons on the MCP, exposing the MCP to a plurality of photons having a wavelength in the ultraviolet portion of the electromagnetic spectrum (also referred to as the so as an ultraviolet photon beam herein) to generate a plurality of electrons that irradiates an input surface of the scintillator and thereby causing degassing of at least a portion of one or more molecules adsorbed on the scintillator’s input surface, and monitoring a gain of the optical ion detector during exposure of the MCP to the ultraviolet photon beam over a temporal period until the optical ion detector exhibits a substantially stable gain profile.

In various embodiments of the various aspects, photons of the ultraviolet photon beam have a wavelength in a range between about 150 nm to about 400 nm, and/or in a range between about 250 nm to about 350 nm. In various embodiments, the surface power density of the ultraviolet photon beam is at least 2.5 milliwatts (mW) per square centimeter (cm²) at an input surface of the MCP, and/or is at least 2.5 mW/cm² at an input surface of the MCP

A wide variety of light sources can be used to provide the ultraviolet photon beam, including, but not limited to, UV lamps, UV light emitting diodes (UV LEDs), UV lasers, etc. It is to be understood that a wide variety of optical elements, e.g., mirrors, prisms, lenses, etc., can be used to direct and/or condition (e.g. focus, defocus, collimate, etc.) the UV light irradiating the MCP. For example, in various embodiments, the UV light source comprises a UV LED and collimation lens. In addition, such light sources, can be employed in various embodiments to generate a substantially constant UV photon flux for provision of a reference photon beam.

In various aspects, provided are methods of stabilizing the gain of an optical ion detector, the optical ion detector including a scintillator in optical communication with one or more photon detectors (such as, e.g., photomultiplier tubes (PMTs)) that can receive the photons generated by the scintillator and generate electrical pulses in response to the detection of the photons, where the UV photon beam is directed onto the input surface of the scintillator to cause the degassing of at least a portion of the gases adsorbed on the scintillator’s input surface. In various embodiments these methods comprise (i) directing a plurality of photons having a wavelength in the ultraviolet portion of the electromagnetic spectrum onto an input surface of the scintillator and thereby causing degassing of at least a portion of molecules adsorbed on the input surface of the scintillator, (ii) monitoring a gain of the optical ion detector during exposure of the input surface of the scintillator to the plurality of photons, and (iii) maintaining the direction of the plurality of photons onto the input surface of the scintillator over a temporal period until the optical ion detector exhibits a substantially stable gain profile. Without being held to theory, if the incident UV light photon has an appropriate wavelength then it can deposit sufficient energy to the molecule to overcoming the binding energy of the adsorbed molecule to the surface. The desorbed molecule then enters the gas phase and ultimately will get pumped away by the vacuum system or adsorbed onto other parts of the vacuum system.

In various embodiments of the various aspects, the bias voltage is applied to the MCP is in a range of between about 600V to about 1200 V; and/or a range between about 900V to about 1100 V.

In various embodiments of the various aspects, the bias voltage applied to the MCP is selected such that the plurality of the electrons generated by the MCP provides an electron flux that is non-damaging to the MCP and/or the scintillator. In various embodiments, the bias voltage is selected such that: (i) the electron flux does not exceed about 3x10⁸ electrons/(second mm²), (ii) the electron flux from the MCP is within about 10% of a maximum permissible electron flux for irradiating the input surface of the scintillator, (iii) the voltage difference between the MCP and the input surface of the scintillator is in the range between about 1.5 kV to about 10 kV, and/or (iv) combinations thereof.

In various embodiments of the various aspects, the optical ion detector is positioned in a low-pressure chamber, e.g., in a chamber that is maintained at a pressure in a range of about IxlO'⁸ Torr to about IxlO'⁴ Torr; and in various embodiments in a range of about IxlO'⁸ Torr to about IxlO'⁶ Torr.

In various embodiments of the various aspects, the temporal period over which the UV photon beam is directed onto the MCP (or input surface of the scintillator) is predetermined. For example, a predefined temporal period can be selected based on previously-obtained data regarding the time required for conditioning of the optical ion detector. In various embodiments of the various aspects, the temporal period over which the UV photon beam is directed onto the MCP (or input surface of the scintillator) is dynamically determined. For example, the gain exhibited by the optical ion detector in response to incidence of the UV photon beam on the optical ion detector is monitored in real-time and direction of the UV photon beam on the optical ion detector maintained until the observed gain exhibits a target substantial stability, e.g., remains stable within an acceptable variation over a time period commensurate with an anticipated data acquisition period. In various embodiments, a controller receiving data from the optical ion detector and operably coupled to the UV light source can terminate the UV photon irradiation process, e.g., via transmission of a control signal to the ion source, upon the observed gain exhibiting a target substantial stability.

In various embodiments of the various aspects, a substantially stable gain profile of the optical ion detector can be characterized by one or more of: (i) the detector generating a plurality of ion detection pulses having a characteristic pulse height and/or duration, i.e., pulse height and/or duration that remains substantially constant over a target time period, e.g., over a time period corresponding to a typical data acquisition time period, (ii) the detector generating a plurality of ion detection pulses exhibiting a substantially linear relationship between their pulse height and an intensity of reference beam incident on the optical ion detector, and (iii) the optical ion detector exhibiting a substantially constant gain during a data acquisition period. In various embodiments, the optical ion detector exhibiting a substantially constant gain during a data acquisition period comprises the measured ion current changing less than about 5% over about a 5 minute period.

The term “a reference beam” as used herein refers to a beam of photons or an ion beam having a known and/or uniform intensity, e.g., an intensity that remains substantially constant over a target period, such as a period during which conditioning of the optical ion detector is performed.

In various embodiments of the various aspects, the bias voltage applied to the MCP and/or the intensity of the ion beam utilized for conditioning the optical ion detector can be selected such that a stable gain of the optical ion detector can be achieved over a temporal period less than about 120 minutes. In various embodiments, e.g., a stable gain of the optical ion detector can be achieved during a temporal period less than about 60 minutes. In various embodiments, e.g., a stable gain of the optical ion detector can be achieved during a temporal period less than about 45 minutes. In various embodiments, e.g., a stable gain of the optical ion detector can be achieved during a temporal period less than about 20 minutes. In various embodiments, e.g., a stable gain of the optical ion detector can be achieved during a temporal period less than about 15 minutes.

In various embodiments of the various aspects, the adsorbed molecules that are degassed from the scintillator via impact of the MCP generated electrons on the scintillator’s input surface can be atmospheric gas molecules, for example, one or more of oxygen (O2), nitrogen (N2), and water vapor (H2O).

In various aspects, provided are methods for stabilizing an optical ion detector for use in mass spectrometry, where the ion detector includes at least one microchannel plate (MCP) for generating electrons in response to ultraviolet wavelength photons incident thereon, at least one scintillator in communication with the MCP for receiving electrons generated by the MCP on an input surface of at least one of the at least one scintillators and thereby generating photons in response to the electrons incident on its input surface. In various embodiments, the methods include applying a bias voltage to the MCP, and directing the ultraviolet photon beam onto the MCP, while the ion detector is exposed to a low-pressure environment, e.g., an ambient pressure in a range of about 1x1 O'⁸ Torr to about 1x1 O'⁴ Torr, to generate a plurality of electrons, where the electrons received by the scintillator via its input surface can cause degassing of at least a portion of one or more molecules adsorbed on the input surface of the scintillator. In various embodiments, the beam of ultraviolet photons can be directed to the MCP for a predefined temporal period so as to configure the optical ion detector for stable operation.

In various embodiments of the various aspects, the temporal period required for stabilizing the gain of the optical ion detector can be determined based on previous measurements of the variation of the gain of the optical ion detector in response to incidence of a reference beam on the optical ion detector. For example, such measurements can be utilized to identify the time required for the output of the optical ion detector, e.g., measured as ion counts per second, to reach a substantially stable condition, e.g., when the temporal variation of the optical ion detector’s output in response to exposure to the reference beam is less than a threshold, e.g., less than about 5%. Various criteria can be employed to assess whether the optical ion detector has achieved a substantially stable operational status. In various embodiments of the various aspects, such substantially stable operational status can be based on the optical ion detector exhibiting a substantially constant gain, e.g., as evidenced by substantially uniform height and/or duration of optical ion detector’s output pulses in response to the reference beam intensity.

In various embodiments of various aspects, such substantially stable operational status can be based on the detector generating a plurality of ion detection pulses exhibiting a substantially linear relationship between their pulse height and an intensity of a reference beam incident on the optical ion detector. For example, in various embodiments the stability of the optical ion detector’s operation can be assessed by varying the intensity of a beam of ultraviolet photons, i.e., a plurality of photons having a wavelength in the ultraviolet portion of the electromagnetic spectrum, incident on the optical ion detector and determining whether the relationship between the gain provided by the optical ion detector and the intensity of the incident photon beam is substantially linear.

Further understanding of various aspects and embodiments of the present teachings can be obtained by reference to the following detailed description in conjunction with the associated drawings, which are described briefly below.

Brief Description of the Drawings

FIG. 1 schematically depicts two processes that can be employed for desorption (aka degassing) of molecules adsorbed on a surface of a scintillator utilized in an optical ion detector employed in a mass spectrometry system,

FIG. 2A is a flow chart depicting various steps in a method according to an aspect and embodiment for stabilizing the gain of an optical ion detector employed in a mass spectrometry system,

FIG. 2B is a flow chart depicting various steps in a method according to an aspect and embodiment for conditioning a mass spectrometer for ion detection and use,

FIG. 3A is a schematic view of an optical ion detector that can be stabilized in accordance with various aspects and embodiments of the present teachings, FIG. 3B schematically depicts a side window in the housing of the optical ion detector for introduction of externally generated photons onto the input surface of the scintillator,

FIG. 4 schematically depicts a mass spectrometer in which an optical ion detector is incorporated whose gain can be stabilized and/or conditioned for ion detection and use in accordance with various aspects and embodiments of the present teachings,

FIG. 5 shows an example of ion detection data generated by an optical ion detector in response to incidence of the UV photon beam on the MCP of the optical ion detector,

FIG. 6 shows data for stabilizing the gain of an ion optical detector by irradiating the MCP with an ion beam, where Panel A shows an example of ion detection data generated by an optical ion detector in response to incidence of an ion beam on the MCP, and Panel B shows the a significant mass shift in a reference ion mass that can occur after use of an ion beam to stabilize the gain, and

FIG. 7 shows data for stabilizing the gain of an ion optical detector by irradiating the MCP with UV photon beam, where Panel A shows an example of ion detection data generated by an optical ion detector in response to incidence of the UV photon beam on the MCP, and Panel B shows the substantial absence of a mass shift in a reference ion mass after use of UV photon beam to stabilize the gain.

Detailed Description

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

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

As used herein the term “and/or” includes any and all combinations of one or more of the associated listed items.

The term “optical ion detector,” as used herein, refers to a detector for detecting ions via generation of photons in response to incidence of ions on the detector. For example, ions incident on the detector can cause generation of electrons, which in turn are incident on a scintillator to generate photons, which can be detected, for example, by a photomultiplier tube (PMT), to generate electrical signals.

The gain of an optical ion detector refers to a ratio of the output electrical charge to input ion charge, where the gain is typically tuned to be in the range of IxlO⁴ to IxlO⁶. This allows the detector to generate a detectable electrical signal that is quantifiable and proportional to the input ion beam flux. It is to be understood that in the context of generating an optical ion detector output signal by irradiation of the MCP and/or scintillator with an ultraviolet photon beam, this description of gain applies mutatis mutandis and, for the purposes of determining if the optical ion detector exhibits a substantially stable gain profile, does not necessarily require an absolute quantitation of gain, but rather, a relative determination is sufficient.

In various embodiments of the various aspects, the gain of the optical ion detector, and its temporal stability, can be assessed using parameters associated with the output signal of the optical ion detector, such as one or more of: (i) the height and/or the width of the ion detection pulses generated by the optical ion detector, (ii) the relationship between the signal intensity, e.g., characterized by the pulse heights, as a function of the intensity of a reference beam incident on the detector, and (iii) the optical ion detector exhibiting a substantially constant gain during a data acquisition period.

The term “reference beam” as used herein refers to a beam of photons or an ion beam having a known and/or uniform intensity, e.g., an intensity that remains substantially constant over a target period, such as a period during which conditioning of the optical ion detector is performed. The term “reference ion beam” is used herein to refer to a reference beam comprised of ions, and the term “reference photon beam” is used herein to refer to a reference beam comprised of a plurality of photons.

The present disclosure is generally based in part on several unexpected discoveries, that an unstable gain exhibited by certain optical ion detectors that employ scintillators as a component of the ion detection system can be due, at least in part, to the outgassing of molecules (such as, e.g. atmospheric gas molecules) adsorbed onto one or more detection surfaces, e.g., the surface of a scintillator, and that UV light incident on a MCP can produce sufficient MCP electron generation to desorb molecules adsorbed on the scintillator input surface, even though the UV photon detection efficiency of a typical MCP is very low, for example ~1% for 150 nm wavelength photons and this detection efficiency generally rapidly decreases as photon wavelength increases.

Specifically and without being bound to any particular theory, gas molecules can be readily adsorbed on a scintillator’s input surface when the optical ion detector is exposed to pressures above that typically found in the low pressure environment of a chamber of the mass spectrometer in which the detector is positioned and operated. Subsequent exposure of the optical ion detector to a low pressure environment can cause desorption, i.e. outgassing, of the adsorbed molecules, which can in turn adversely affect ion detection signals generated by the detector. This desorption process however, can be very, very slow; negatively impacting mass spectrometer operation for days.

More specifically and without being bound to any particular theory, when an optical ion detector is exposed to common atmospheric gas molecules, such as oxygen (O2), nitrogen (N2) and water vapor (H2O), at atmospheric pressure, these gas molecules can be adsorbed onto metallic surfaces of the optical ion detector’s components with a significant binding energy. As a result, when the optical ion detector is exposed to a vacuum environment, e.g., during operation of a mass spectrometer utilizing the optical ion detector, the adsorbed gases can be released from such surfaces at very slow rates. In optical ion detectors in which light-generating components, such as scintillators, are employed, the release of the adsorbed gases could adversely affect the amount of light that is generated, as well as its temporal properties, which in turn adversely affects the operation of the optical ion detector and mass spectrometric data reliability.

In various aspects and embodiments, methods and/or workflows for performing mass spectrometry are provided, which include stabilizing the gain of the optical ion detector of the mass spectrometer to achieve environmental equilibration, i.e. gain stability, of the optical ion detector before mass spectrometric measurements and experimental data collection are initiated.

In various embodiments, the present methods of stabilizing the gain of the optical ion detector, when the optical ion detector is exposed to a vacuum environment, promote accelerated desorption of adsorbed molecules (such as, for example, atmospheric gases) such that a new equilibrium distribution of molecules on metal surfaces of the optical ion detector is established. As discussed in more detail below, such gain stabilization of the optical ion detector can allow for stable and reproducible performance of the optical ion detector. In particular, in various embodiments, such stabilization of the optical ion detector gain can increase linear dynamic range and provide resolution enhancements.

In various aspects and embodiments, methods and/or workflows for performing mass spectrometry that help achieve rapid removal of adsorbed molecules from a scintillator of an optical ion detector, which can in turn allow the scintillator to reach an equilibrium state suitable for stable operation of the optical ion detector. More specifically, in various embodiments, such removal of adsorbed molecules and stabilization of the optical ion detector gain can be achieved by maximizing the number of electrons that can safely irradiate an input surface of the scintillator. By way of example, in an optical ion detector that includes a microchannel plate (MCP) for generating electrons in response to incident ions and a scintillator that receives the electrons and generates photons, a DC bias voltage applied to the MCP can be increased as much as safely possible (e.g., in various embodiments, by about +50 V, by about +100 V, by about +150 V, by about +200 V, by about +250 V, and/or by about +300 V relative to a value utilized during normal operation of the optical ion detector) and the surface power density of UV photon beam incident on the MCP can be maximized without damaging the optical ion detector. In various embodiments, the bias voltage applied to photomultiplier tubes in an optical detector, can be lowered, e.g., to prevent ageing of the photomultiplier tubes that detect the photons generated by the scintillator. While in this state, the ion detection signals can be monitored until a substantially stable operation of the optical ion detector is achieved, and the stabilizing of an optical ion detector gain can be performed for a predetermined temporal period.

FIG. 1 schematically depicts processes for causing the degassing of molecules adsorbed on the input surface of the scintillator. In the process depicted in Panel A, a plurality of electrons emitted by an MCP of the optical ion detector can impinge on the input surface of the scintillator to impart energy to the adsorbed molecules to cause their degassing, as shown schematically in Panel C. In the process depicted in Panel B, UV photons directed to the input surface of the scintillator can deposit sufficient energy into at least a portion of the molecules adsorbed on the scintillator’s input surface to cause those molecule to desorb and enter gas phase (see, Panel C).

Referring to FIG. 2A, schematically depicted is a flow chart providing various steps of a method for stabilizing the gain of an optical ion detector that is suitable for use in mass spectrometry, where the optical ion detector includes at least one microchannel plate (MCP) for generating electrons in response to ions incident thereon in data acquisition operation and at least one scintillator for generating photons in response to the incidence of the electrons generated by the MCP on the scintillator’s input surface. In various embodiments, the method includes applying a bias voltage to the MCP (20) and directing a UV photon beam onto the MCP to generate a plurality of electrons (22). In various embodiments, the bias voltage applied to the MCP is in a range between about 600V to about 1200V, and/or in a range between about 900V to about 1100V.

The incidence of the electrons generated by the MCP on the input surface of the scintillator can cause degassing of at least a portion of molecules adsorbed on an input surface of the scintillator. Without being limited to any particular theory, the electrons incident on the scintillator can cause degassing of one or more adsorbed molecules on the input surface of the scintillator by providing energy to the adsorbed molecules so that they can overcome the binding energy associated with their adsorption on the scintillator’s input surface. A gain of the optical ion detector is monitored (24) and the exposure of the MCP to the UV photon beam maintained for a temporal period until the monitored gain exhibits a substantially stable gain profile (26). That is, it is believed without being held to theory, that a substantially stable gain profile can be achieved after sufficient degassing of the adsorbed gas molecules such that the optical ion detector can be operated in a stable fashion, i.e. any further degassing does not materially impact the temporal gain profile during data acquisition.

In various embodiments of the various aspects, such a temporal period is determined dynamically by monitoring the output signal of the optical ion detector, or alternatively, a predefined temporal period, e.g., based on previously-obtained data, may be employed.

In the various embodiments of the various aspects, a variety of criteria can be used and/or data monitored to determine if the optical ion detector is exhibiting a substantially stable gain profile. For example, a substantially stable temporal gain profile of the optical ion detector can be characterized by one or more of the optical ion detector: (i) generating a plurality of ion detection pulses having a characteristic pulse height that remains substantially constant over a target time period, e.g., over a time period corresponding to a typical data acquisition time period, (ii) generating a plurality of ion detection pulses having a characteristic pulse duration that remains substantially constant over a target time period, e.g., over a time period corresponding to a typical data acquisition time period, (iii) generating a plurality of ion detection pulses exhibiting a substantially linear relationship between their pulse height and an intensity of reference UV photon beam incident on the optical ion detector, and (iv) exhibiting a substantially constant gain during a data acquisition period, e.g., the measured ion current changing less than about 5% over about a 5 minute period. It is to be understood however, that any other suitable criteria for assessing the stability of the gain of the optical ion detector can also be employed instead of or in addition to one or more of the criteria set forth herein.

In various aspects, the desorption of at least a portion of the molecules adsorbed on an input surface of the scintillator can be achieved via directing a beam of UV photons onto the input surface of the scintillator itself to deposit sufficient energy into the adsorbed molecules so as to overcome their binding energy with the underlying surface, thereby causing the molecules to desorb from the surface. By way of example, in various embodiments, photons in the ultraviolet (UV) portion of the electromagnetic spectrum, e.g., photons with a wavelength less than about 400 nm, can be used to cause degassing of the gas molecules from the scintillator’s input surface. The desorbed molecules entering the gas phase can be removed be removed from the system, (e.g., by a vacuum system, condensation device (e.g. a cold finger, adsorbed onto a high surface material such as molecular sieve, etc.)), and/or deposited elsewhere in the system.

Various embodiments and aspects of the present methods employing a UV photon beam provide additional unexpected benefits when compared to methods of conditioning an optical ion detector that employ exposing the MCP to an ion beam, to in turn generate electrons that impinge on an input surface of a scintillator to desorb adsorbed molecules. In methods employing an ion beam, even after a stable gain profile is achieved for the optical ion detector, the mass spectrometer exhibits a shift in the observed mass of reference ions. Such mass shifts are often large (-100 ppm) in the context of the accuracy and reproducibility required for many mass spectrometric analyses. Although such mass shifts decrease over time, this conditioning time, the time between when the optical ion detector exhibits a substantially stable gain profile and when the mass shift has abated such that the mass spectrometer is ready for data acquisition, is typically long on the time scale of many hours.

In contrast it was unexpectedly discovered that various embodiments and aspects of the present methods can provide substantially reduced conditioning times, that is in various embodiment mass shifts less than about 10 ppm immediately after the optical ion detector has exhibited a substantially stable gain profile. In general, a mass shift of less than about 5 ppm, and often less than about 2 ppm, is desired if not required for many mass spectrometric work flows and analysis protocols.

In various embodiments, a mass shift of less than about 10 ppm is provided in less than about 12 hours, 1 hour, 10 minutes, and/or 1 minute. In various embodiments, a mass shift of less than about 8 ppm is provided in less than about 12 hours, 1 hour, 10 minutes, and/or 1 minute. In various embodiments, a mass shift of less than about 5 ppm is provided in less than about 12 hours, 1 hour, 10 minutes, and/or 1 minute. In various embodiments, a mass shift of less than about 2 ppm is provided in less than about 12 hours, 1 hour, 10 minutes, and/or 1 minute. In various embodiments, a mass shift of less than about 2 ppm is provided in less than about 12 hours, 1 hour, 10 minutes, and/or 1 minute. For example, the data presented in the context of FIG. 7, discussed in more detail below, shows a mass shift of about? ppm substantially immediately after the optical ion detector exhibited a substantially stable gain profile.

Without being held to theory, is it believed that the mass shifts observed with ion beam methods are due to ion optic contamination that allows for certain optics and elements to acquire charges, which later discharges, arising from use of the ion beam strong enough to generate sufficient electrons from the MCP to desorb molecules adsorbed on the scintillator input surface. It has been observed that mass shifts due to use of such an ion beam can requires days to dissipate to levels below 10 ppm.

It is to be understood that other factors also contribute to mass shifts, such as for example, thermal drift (i.e. temperature changes), power supply voltage drift (e.g., in particular for those power supplies connected to ion filtering elements), and power supply temperature changes (typically heating). It is further to be understood that reduction and/or substantial elimination of mass shift effects in the present aspects and embodiments provide herein, is with respect to those produced by methods to stabilize the gain of an ion optical detector.

Accordingly, in various aspects and embodiments provided are methods for conditioning a mass spectrometer for ion detection and use, the methods comprising: (i) stabilizing the gain of the optical ion detector using any of the embodiments herein of stabilizing the gain of an optical ion detector using a UV photon beam, and then (ii) after the optical ion detector exhibits a substantially stable gain profile, directing a reference ion beam containing a reference ion having a reference ion mass onto the detector and (iii) monitoring a mass spectrum produced thereby over a conditioning period, (iv) wherein after the conditioning period, said mass spectrum no longer substantially exhibits a mass shift in the reference ion mass arising from the step of stabilizing the gain of the ion optical detector.

Referring to FIG. 2B, schematically depicted is a flow chart providing various steps of a method for conditioning a mass spectrometer for ion detection and use, where the mass spectrometer includes and optical ion detector comprising at least one microchannel plate (MCP) for generating electrons in response to ions incident thereon in data acquisition operation and at least one scintillator for generating photons in response to the incidence of the electrons generated by the MCP on the scintillator’s input surface. In various embodiments, the method includes applying a bias voltage to the MCP (30) and directing a UV photon beam onto the MCP to generate a plurality of electrons (32). In various embodiments, the bias voltage applied to the MCP is in a range between about 600V to about 1200V, and/or in a range between about 900V to about 1100V. A gain of the optical ion detector is monitored (34) and the exposure of the MCP to the UV photon beam maintained for a temporal period until the monitored gain exhibits a substantially stable gain profile (36). After a substantially stable gain profile is achieved, a reference ion beam containing at least one reference ion mass is directed onto the optical ion detector (38) and the mass spectrum produced thereby monitored over a conditioning period (40) where the conditioning period is the time period by which the mass spectrum no longer substantially exhibits a mass shift in the reference ion mass (40) arising from the step of stabilizing the gain of the ion optical detector.

It is to be understood that, in the various aspects and embodiments herein, any step of monitoring does not require constant monitoring, but includes, and is not limited to, constant, periodic, predetermined time points, dynamically determined intervals (e.g. based on previous monitored data, previous instrument behavior, theory), sporadic, and random monitoring. In general, any monitoring protocol sufficient to determine the achieving of the desired operation state (e.g. gains stability, sufficient mass shift reduction) can be used. It is also to be understood that such monitoring can be performed automatically, with the use of artificial intelligence, manually, or combinations thereof.

FIG. 3A schematically depicts a multi-channel optical ion detector 100 according to various embodiments of an optical ion detector and illustrates various aspects and embodiments, of directing a UV photon beam onto the MCP or onto an input surface of the scintillator. FIG. 3A, illustrates only four ion detection channels for simplicity and ease of discussion (herein referred to as ion channels 1, 2, 3, and 4) but it is to be understood that the present teachings are applicable to any number of ion channels. The optical ion detector 100 includes a microchannel plate (MCP) 102 that generates electrons 103 in response to incidence of a UV photon beam (i.e. a plurality of photons having a wavelength in the ultraviolet portion of the electromagnetic spectrum) 104 on the MCP. A DC voltage source 105a operating under control of a controller 107 can apply a bias DC voltage to the MCP 102 to facilitate the generation of electrons in response to the UV photon beam striking the MCP. The optical ion detector includes a scintillator 106 that receives the electrons generated by the MCP in response to its exposure to the ion beam. While in this embodiment a single scintillator is shared among the four channels of the optical ion detector, it is to be understood that the present teachings are not limited to this schematically depicted arrangement, e.g., each channel could have its own dedicated scintillator. The scintillator generates photons in response to the incidence of electrons on an input surface 106a. In this embodiment, each of the ion detection channels (1, 2, 3, and 4) includes a photomultiplier tube (PMT), i.e., PMTs 107a, 107b, 107c, 107d, which generates an electronic signal in response to the detection of the photons. In various embodiments, the ion detection channels (1, 2, 3, and 4) can be optically isolated from one another by a plurality of partitions 109a, 109b, and 109c.

Generally, during the operation of a mass spectrometer, the optical ion detector is exposed to a vacuum environment, which in absence of conditioning of the optical ion detector, can lead to the release of gases, such as atmospheric gas molecules previously adsorbed onto the input surface of the scintillator, which can in turn cause a degradation of signals generated by the detector.

For conditioning of the optical ion detector 100 prior to the initiation of mass spectrometric measurements, the controller 107 can cause the DC voltage source 105a to apply a bias voltage to the MCP 102. In various embodiments, the bias voltage can be set to optimize the generation of electrons by the MCP without causing damage to the MCP or the scintillator. By way of example, in various embodiments, the DC bias voltage applied to the MCP can be in a range of about 900 V to about 1100 V. Instead or in addition, in various embodiments, the intensity of the UV photon beam, more precisely and specifically the surface power density of the UV photons at an input surface of the MCP (or input surface of the scintillator when the UV photon beam is directly applied thereto), employed can be chosen to maximize the generation of electrons by the MCP, without damaging the MCP or the scintillator. By way of example, and without limitation, the UV photon beam can be at least 2.5 milliwatts (mW) per square centimeter (cm²), or 4.0 mW/cm² at an input surface of the MCP (or input surface of the scintillator when the UV photon beam is directly applied thereto).

In various embodiments, the bias voltage(s) applied to the photomultiplier tubes can be lowered to prevent aging of the photomultiplier tubes by the detector photons generated by the

Y1 scintillator. By way of example, the controller 107 can control a DC voltage source 105b that applies bias voltage(s) to the PMT’s to set those bias voltages at a desired value.

In various embodiments, the bias voltage is selected such that the voltage difference between the MCP and the input surface of the scintillator is in the range between about 1.5 kV to about 10 kV. By way of example, the controller 107 can control a DC voltage source 105c that applies bias voltage to the scintillator and/or a DC voltage source 105b that applies bias voltage to the MCP to set the voltage difference at a desired value.

The incidence of a higher flux of electrons on the input surface of the scintillator can advantageously reduce the time required for stabilizing the optical ion detector by accelerating the degassing of molecules, such as atmospheric gases, adsorbed on the input surface of the scintillator. However, if the electron flux is too high, it may damage the MCP, the scintillator and/or cause ageing of the photomultiplier tubes. Accordingly, in various embodiments, the intensity of the reference ion beam and/or the bias voltage applied to the MCP can be selected to ensure fast stabilization of the optical ion detector, while ensuring that various components of the optical ion detector, including the scintillator and the photomultiplier tubes, will not be damaged. In various embodiments, fast stabilization of the ion optical detector comprises stabilizing the gain of the optical ion detector within a temporal period less than about 120 minutes, less than about 60 minutes, less than about 45 minutes, less than about 20 minutes, and /or less than about 15 minutes.

In various embodiments, the gain of the optical ion detector is monitored during the conditioning of the detector until a stable gain is achieved. In some embodiments, such monitoring of the optical ion detector’s gain can be performed automatically, e.g., by monitoring the intensity of a reference mass peak.

Referring again to FIG. 3A, in various aspects and embodiments, rather than relying on the emission of electrons from the MCP and their incidence on the input surface of the scintillator for degassing the adsorbed molecules, a UV photon beam 110 can be directed onto the input surface of the scintillator to cause degassing of at least a portion of the molecules adsorbed on the scintillator’s input surface. In various embodiments, the wavelength of the incident photons is in the ultraviolet range of the electromagnetic spectrum, e.g., a wavelength equal to or less than about 400 nm, so that the incident photons can impart sufficient energy to the adsorbed molecules to cause their desorption from the scintillator’s input surface and their entry into the gas phase. In various embodiments, one or more pumps can remove the gas-phase molecules from the optical ion detector.

By way of further illustration, FIG. 3B schematically depicts that in various embodiments a side window 112 provided in the housing of the optical ion detector can be utilized for introducing the UV photon beam 110 into the optical ion detector so that the photons are incident on the input surface of the scintillator.

The various methods and workflow discussed herein for conditioning an optical ion detector can be employed in connection with the use of a variety of different mass spectrometric systems for performing a variety of mass spectrometric measurements.

By way of example, and without limitation, FIG. 4 schematically depicts a mass spectrometric system 400 in which an optical ion detector 420 is incorporated, which can be conditioned in one or more of the manners disclosed herein. More specifically, the mass spectrometric system 400 includes an ion source 403 for receiving a sample and ionizing one or more target analytes of interest within the sample. The ion source can include any suitable ion source, including, for example, ion sources that provide ions through electrospray ionization (ESI), matrix-assisted laser desorption ionization (MALDI), ion bombardment, application of electrostatic fields (e.g., field ionization and field desorption), chemical ionization, etc.

The ions generated by the ion source 403 are received by an ion guide QJet, which includes a set of rods 401 arranged in a quadrupole configuration, two of which 401a/401b are visible in the figure and employs a combination of gas dynamics and radio frequency fields to cause focusing of the ions. The ions exiting the QJet ion guide are focused by an ion lens IQ0 into an ion guide Q0, which includes a set of quadrupole rods 404, two of which 404a/404b are visible in the figure, to which RF voltages can be applied for causing radial confinement of the ions and generate an ion beam that is in turn received by an ion mass filter QI. The ion guides QJet, Q0, and the mass filter QI are disposed in differentially-pumped chambers that are maintained at progressively lower pressures.

An ion lens IQ1 focuses the ions exiting the Q0 ion guide into the mass filter QI. The mass filter QI includes a stubby lens 406 formed by a set of quadrupole rods (two of which 406a/406b are visible in the figure) to which RF voltages can be applied to cause focusing of the ions. The mass filter QI further includes a set of quadrupole rods 410, two of which 410a/410b are visible in the figure, to which a combination of RF and DC voltages can be applied to allow the selection of one or more precursor ions having m/z ratios within a target m/z range for transmission to a downstream ion dissociation device Q2, e.g., a collision cell, in this example via an ion lens IQ2. Although in this embodiment a collision cell is employed as the ion dissociation device, in other embodiments, other types of ion dissociation devices, such as those that employ EAD, e.g., electron capture dissociation, can be used.

A controller 405 can be employed to configure the mass filter QI to allow, during each measurement cycle, the passage of precursor ions corresponding to a target analyte and its associated internal standard.

As discussed in more detail below, the mass filter QI can be configured to allow passage of a target analyte ion and an internal standard ion associated with the target analyte.

More specifically, a DC voltage source 426 and an RF voltage source 428 operating under control of the controller 405 can apply RF and DC voltages to the mass filter QI in a manner known in the art and as informed by the present teachings to configure the bandpass window of the mass filter. By way of example, and without limitation, the RF voltage applied to the rods of the QI mass filter can have a frequency in a range of about 200 kHz to about 12 MHz and a peak-to-peak amplitude (V_pp) in a range of about 100 volts to about 10 kilovolts (kV).

The ions passing through mass filter QI are received by a collision cell Q2 in which the ions undergo dissociation to generate a plurality of product ions. The product ions are in turn received by a downstream time-of-flight (TOF) mass analyzer 418, which generates ion detection data in response to the detection of the product ions. More specifically, in this embodiment, the TOF mass analyzer 418 includes the optical ion detector 420, which detects ions received by the TOF mass analyzer and generates ion detection data in response to the detection of those ions. The optical ion detector and other components of the TOF mass analyzer 418 are positioned in a low-pressure chamber, e.g., a chamber typically maintained at a pressure in a range of about 1x10'⁸ Torr to about 1x1 O'⁶ Torr. As such, the optical ion detector 420 requires stabilization prior to the acquisition of ion detection data. Further, a data processing module 425 receives the ion detection data generated by the optical ion detector and processes the ion detection data to generate a mass spectrum of the detected ions. By way of example, in various embodiments, after the gain of the optical ion detector has been substantially stabilize, the conditioning a mass spectrometer for ion detection and use can be achieved by introducing a reference sample into the ion source to generate a reference ion beam having one mor more reference ion masses. In various embodiments, mass filter QI may be employed to select ions having m/z ratios within a particular range for being incident on the optical ion detector, that is, e.g. QI is used to select one or more reference ion masses from the reference ion beam. In various embodiments, the collision cell Q2 may be employed to generate a reference ion mass. However, it is to be understood that a wide variety of approaches know to the art can be used to generate and/or select a reference ion mass. The ion detection data generated by the optical ion detector in response to the incidence of ions in the reference ion beam on the MCP (i.e. the mass spectrum) can then be monitored until the one or more reference ion masses no longer substantially exhibit a mass shift.

For example, the data processing module can process the ion detection data to generate a mass spectrum of the incident ions. The intensity of one or more reference mass peaks within the mass spectrum can be monitored as a way of assessing if a mass shift is present and the degree of this shift. Once any mass shift is no longer exhibited that arises from the method used to stabilize the gain of the ion optical detector, the data processing module can transmit a signal to the controller and/or user interface indicating that the conditioning period has been achieved and the mass spectrometer is ready for use.

The following example is provided for further elucidation of various aspects of the present teachings, and is not presented to provide necessarily an optimal way of practicing the present teachings and/or optimal results that may be obtained.

Example

The data of FIGs. 5 to 7 was obtained on a 4-channel optical ion detector having a configuration similar to that shown in FIG. 3A. The mass spectrometer was qTOF instrument similar to that depicted in FIG. 4. The data in FIGs. 5 and 7 shows data for a method of stabilizing the gain of an optical ion detector using a UV photon beam according to various embodiments of the present teachings, while FIG. 6 shows data for a method of stabilizing the gain of an optical ion detector using an ion beam. In each case a bias voltage of approximately 1200 V was applied to the MCP. The data of FIG. 7 was obtained using a 255 nm LED with a 5 cm focal length collimation lens, operated at 1 mW optical output to apply a UV photon beam with an estimated surface power density of 0.08 mW/cm² at the MCP input surface. Simultaneously with the UV beam, an attenuated (using a 1% ion transmission control (ITC) parameter) ion beam, to provide a reference ion beam (with reference ion mass of 832.5 Da), was directed to the detector in order to track the mass drift in the system during the conditioning process. The data of FIG. 5, was substantially as for FIG. 7, but without use of a reference ion beam. The data of FIG. 6, was obtained using a MCP voltage of about 1100 V, directing the mass spectrometer’s full ion beam (i.e. with a 100% ITC parameter) onto the detector in order to produce a similar effect, with corresponding increased mass drift.

FIG. 5 shows the temporal variation of an output signal generated by an optical ion detector utilized in a TOF mass analyzer in response to the incidence of a UV photon beam on the MCP of the ion optical detector. The depicted signal is the sum total of all ions in the mass spectrum (TIC). The data shows that the ion detection signal, in response to incidence of a substantially constant flux of UV photons on the optical ion detector, increases exponentially until it reaches a plateau that remains substantially constant over time. In other words, in this example, the data indicates that in response to irradiation by the UV photon beam, the optical ion detector reaches a substantially stable gain profile in an exponential fashion.

In some cases, such data regarding the behavior of the optical ion detector in response to UV irradiation, can be utilized to predict the temporal period required for stabilizing the gain of a particular optical ion detector utilized in a particular mass spectrometer. Alternatively, as noted above, in various embodiments, dynamic monitoring of an optical ion detector can be employed, e.g., in a manner discussed above, to select and/or determine when the temporal period has been reached.

FIGs. 6 and 7 show data for the mass shift observed in mass spectra of the mass spectrometer of this example, after the optical ion detector exhibits substantially stable gain. Panel A in each of FIGs. 6 and 7 show the temporal variation of an output signal generated by an optical ion detector utilized in a TOF mass analyzer in response to the incidence of an ion beam (in the case of FIG 6) and UV photon beam (in the case of FIG 7) on the MCP of the ion optical detector. The depicted signal in Panels A of FIGs. 6 and 7 is the sum total of all ions in the mass spectrum (TIC). As can be seen in Panels A of FIGs. 6 and 7 both approaches to achieving a substantially stable gain profile of the optical ion detector exhibit an exponential increase that reaches a plateau in about 40 minutes.

However, Panels B in FIGs. 6 and 7 show a distinct difference in the shift observed in a reference mass (here 832.5 Da) after the optical ion detector gain has been substantially stabilized. The relative mass shift can be observed by comparing the reference ion mass position at the beginning of the stabilization process, traces 602, 702, in FIGs. 6 and 7 respectively, to that at the end of the process, traces 604, 704, in FIGs. 6 and 7 respectively. A substantial mass shift can be seen in FIG. 6, Panel B, of approximately +40 ppm, after stabilization while the mass shift in FIG. 7, Panel B is only about 7 ppm after stabilization. In addition, it is believed the mass shift of about 7 ppm seen in FIG. 7, Panel B, is primarily due to other factors (e.g. thermal drift) and not the ion optical detector stabilization method. The “pedestal” 706 seen in FIG. 7, Panel B, are counts being generated by UV photons which generate a sufficiently large pulse of electrons from the MCP to generate a detectable visible photon (or photons) at the scintillator output. Since there is no preferred arrival time for the UV photons, they appear as a uniform “noise” level in the spectrum.

It should be noted that significant reliance should not be placed in the absolute position of the reference mass position in Panels B of FIGs. 6 and 7, as precise mass calibration was not performed, but rather reliance can be placed in the relative change in position of the reference ion mass. Lastly, the difference in peak height in the beginning, traces 602, 702, compared to the respective end mass spectra, traces 604, 704, is immaterial for the present purposes as the peaks in FIG. 7, Panel B, have been normalized (and thus will show as equal in height), while those in FIG. 6, Panel B, have not been normalized.

Although some aspects have been described in the context of an apparatus, it is clear that these aspects also represent a description of the corresponding method, where a block or device corresponds to a method step or a feature of a method step. Analogously, aspects described in the context of a method step also represent description of a corresponding block or item or feature of a corresponding apparatus. Some or all of the method steps may be executed by (or using) a hardware apparatus, like for example, a processor, a microprocessor, a programmable computer or an electronic circuit. In some embodiments, some one or more of the most important method steps may be executed by such an apparatus. Depending on certain implementation requirements, embodiments of the invention can be implemented in hardware and/or in software. The implementation can be performed using a non- transitory storage medium such as a digital storage medium, for example a floppy disc, a DVD, a Blu-Ray, a CD, a ROM, a PROM, and EPROM, an EEPROM or a FLASH memory, having electronically readable control signals stored thereon, which cooperate (or are capable of cooperating) with a programmable computer system such that the respective method is performed. Therefore, the digital storage medium may be computer readable.

While various embodiments have been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive; embodiments of the present disclosure are not limited to the disclosed embodiments. Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing embodiments of the present disclosure, from a study of the drawings, the disclosure, and the appended claims.

In the claims, the word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality. A single processor or other processing unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measured cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

Claims

What is claimed is:

1. A method for stabilizing a gain of an optical ion detector for use in mass spectrometry, wherein the optical ion detector comprises a microchannel plate (MCP) and a scintillator in communication with the MCP such that electrons generated by the MCP in response to incidence of ions thereon are received by the scintillator to generate photons, the method comprising: applying a bias voltage to the MCP, directing a plurality of photons having a wavelength in the ultraviolet portion of the electromagnetic spectrum onto the MCP thereby causing the MCP to generate electrons thereby irradiating an input surface of the scintillator and thereby causing degassing of at least a portion of molecules adsorbed on the input surface of the scintillator, monitoring a gain of the optical ion detector during exposure of the MCP to the plurality of photons, and maintaining the direction of the plurality of photons onto the MCP over a temporal period until the optical ion detector exhibits a substantially stable gain profile.

2. The method of Claim 1, wherein said photons have a wavelength in a range between about 150 nm to about 400 nm.

3. The method of Claim 2, wherein the plurality of photons have a wavelength in a range between about 250 nm to about 350 nm.

4. The method of any one of Claims 1-3, wherein the plurality of photons provide a surface power density of at least 2.5 milliwatts (mW) per square centimeter (cm²) at an input surface of the MCP.

5. The method of Claim 4, wherein the plurality of photons provide a surface power density of at least 4.0 mW/cm² at an input surface of the MCP.

6. The method of Claim 1, wherein the step of monitoring a gain of the optical ion detector comprises substantially continuous monitoring of the gain.

7. The method of Claim 6, wherein the bias voltage applied to the MCP is in a range between about 600V to about 1200 V.

8. The method of Claim 7, wherein the bias voltage applied to the MCP is in a range between about 900V to about 1100 V.

9. The method of any one of Claims 2-8, wherein the bias voltage is selected such that the voltage difference between the MCP and the input surface of the scintillator is in the range between about 1.5 kV to about 10 kV.

10. The method of any one of Claims 2-9, wherein the bias voltage is selected such that the plurality of the electrons provides an electron flux that is within about 10% of a maximum permissible electron flux for irradiating the input surface of the scintillator.

11. The method of any one of Claims 2-10, wherein the bias voltage applied to the MCP is selected such that the substantially stable gain profile of the optical ion detector is achieved during a temporal period less than about 20 minutes.

12. The method of Claim 1, wherein said molecules adsorbed on the scintillator’s input surface comprise one or more of oxygen (O2), nitrogen (N2), and water vapor (H2O).

13. The method of Claim 1, wherein the optical ion detector comprises at least one photomultiplier tube (PMT), and the method further comprises detecting photons generated by the scintillator by the least one photomultiplier tube (PMT) to generate one or more ion detection pulses.

14. The method of Claim 1, wherein said substantially stable gain profile for the optical ion detector is characterized by the optical ion detector generating a plurality of ion detection pulses having a substantially uniform pulse duration.

15. The method of Claim 1, wherein said substantially stable gain profile for the optical ion detector is characterized by the detector generating a plurality of ion detection pulses exhibiting a substantially linear relationship between their pulse height and an intensity of a reference input beam incident on the optical ion detector.

16. The method of Claim 15, wherein the reference input beam is an ion beam or a photon beam.

17. The method of Claim 1, wherein said substantially stable gain profile for the optical ion detector is characterized by the optical ion detector exhibiting a substantially constant gain during a data acquisition period.

18. The method of Claim 1, wherein said substantially stable gain profile for the optical ion detector is characterized by one or more of: (a) the optical ion detector generating a plurality of ion detection pulses having a substantially uniform pulse duration, (b) the detector generating a plurality of ion detection pulses exhibiting a substantially linear relationship between their pulse height and an intensity of a reference input beam incident on the optical ion detector, and (c) the optical ion detector exhibiting a substantially constant gain during a data acquisition period.

19. The method of Claim 1, wherein the optical ion detector is positioned in a low-pressure chamber.

20. The method of Claim 19, wherein the low-pressure chamber is maintained at a pressure in a range of about IxlO'⁸ Torr to about IxlO'⁴ Torr.

21. The method of Claim 20, wherein the low-pressure chamber is maintained at a pressure in a range of about IxlO'⁸ Torr to about IxlO'⁶ Torr.

22. The method of any one of Claims 1-21, wherein the monitoring a gain of the optical ion detector is selected from the group consisting of substantially continuous monitoring, periodic monitoring, and sporadic monitoring.

23. A method for conditioning a mass spectrometer for ion detection and use, wherein the mass spectrometer comprises an optical ion detector, the optical ion detector comprising at least one microchannel plate (MCP) for generating electrons in response to photons having a wavelength in the ultraviolet portion of the electromagnetic spectrum incident thereon, and at least one scintillator in communication with the MCP for receiving electrons generated by the MCP and generating photons in response to the electrons being incident on an input surface of at least one of the scintillators, the method comprising: stabilizing a gain of the optical ion detector using the methods of any one of

Claims 1-22, after the optical ion detector exhibits a substantially stable gain profile, directing a reference ion beam containing a reference ion having a reference ion mass onto the optical ion detector, and monitoring a mass spectrum produced by directing the reference ion beam onto the optical ion detector over a conditioning period, wherein after the conditioning period said mass spectrum no longer substantially exhibits a mass shift in the reference ion mass arising from the step of the stabilizing the gain.

24. The method of Claim 23, wherein said conditioning period is less than about 1 minute.

25. The method of any one of Claims 22-24, wherein said mass spectrum no longer substantially exhibits a mass shift in the reference ion mass when said mass shift is less than about 5 ppm.

26. The method of any one of Claims 22-24, wherein said mass spectrum no longer substantially exhibits a mass shift in the reference ion mass when said mass shift is less than about 2 ppm.

27. A method for stabilizing a gain of an optical ion detector for use in mass spectrometry, wherein the optical ion detector comprises a scintillator in optical communication with one or more photon detectors (such as, e.g., photomultiplier tubes (PMTs)) that can receive the photons generated by the scintillator and generate electrical pulses in response to the detection of the photons, the method comprising: directing a plurality of photons having a wavelength in the ultraviolet portion of the electromagnetic spectrum onto an input surface of the scintillator and thereby causing degassing of at least a portion of molecules adsorbed on the input surface of the scintillator, monitoring a gain of the optical ion detector during exposure of the input surface of the scintillator to the plurality of photons, and maintaining the direction of the plurality of photons onto the input surface of the scintillator over a temporal period until the optical ion detector exhibits a substantially stable gain profile.