Automatic positioning of electrospray ionization emitter

Abstract

To provide a position control system that implements automatic positioning of an electrospray ionization emitter.SOLUTION: A position control system may obtain image data representative of one or more images that depict an inlet of a mass spectrometer and an emitter positioned near the inlet, and adjust, based on the image data, a position of the emitter relative to the inlet to an optimum position that is at or near a reference position relative to the inlet.SELECTED DRAWING: Figure 4

Description

Technical Field

[0001] (Related Application) This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 470,649, filed on June 2, 2023, the entire content of which is incorporated herein by reference.

[0002] The present invention relates to the automatic positioning of an electrospray ionization emitter.

Background Art

[0003] A mass spectrometer is a sensitive instrument that can be used to detect, identify, and / or quantify molecules based on their mass-to-charge ratio (m / z). A mass spectrometer generally includes an ion source for generating ions from the components contained in a sample, a mass analyzer for separating the ions based on their m / z, and an ion detector for detecting the separated ions. The mass spectrometer can be connected to a computer-based software platform that constructs a mass spectrum showing the relative abundance of each of the detected ions as a function of m / z using data from the ion detector. The m / z of ions can be used to detect and quantify molecules in both simple and complex mixtures.

[0004] Ion sources can generate ions from analytes in many different ways. In conventional electrospray ionization (ESI), a liquid sample flows through a small-diameter capillary emitter positioned in front of the mass spectrometer inlet. A high voltage is applied to the liquid sample in the emitter to generate an electrospray, resulting in the formation of analyte ions. The analyte ions entering the mass spectrometer inlet are then analyzed by mass spectrometry to generate a mass spectrum of the analyte ions. In conventional ESI, the liquid sample has a flow rate in the range of about 1 microliter per minute (μL) (1 μL / min) to about 1 milliliter per minute (mL) (1 mL / min). In nanospray ionization (NSI), the liquid sample flows through the emitter at a nanoscale flow rate in the range of about 10 - 50 nanoliters per minute (nL) / min (10 - 50 nL / min) to about 1000 - 1500 nL / min. The lower flow rate of NSI produces smaller aerosol droplets, which makes NSI more efficient than conventional ESI when ionizing analytes. As a result, NSI results in a significant increase in sensitivity, as demonstrated by the signal response of the mass spectrometer.

[0005] However, the sensitivity, efficiency, stability, and reproducibility of the ESI method vary depending on factors such as, among others, solvent conditions, mobile phase composition, flow rate, analyte chemistry, electrospray voltage and current, sheath (or nebulizing) gas flow rate, ambient pressure, temperature, and the geometry of the inlet, particularly the position of the emitter relative to the mass spectrometer inlet. This is especially true for NSI, where the optimal spatial position of the emitter depends on the spray mode and is on the order of a fraction of a millimeter wide in all directions. For example, a deviation of just 100 micrometers (μm) in the emitter position from the optimal position can result in a 20% decrease in signal intensity and a decrease in signal stability. Furthermore, inconsistent emitter positioning across different instrument configurations can make it difficult to accurately reproduce experiments. SUMMARY OF THE INVENTION

[0006] The following description presents a simplified overview of one or more aspects of the methods and systems described herein in order to provide a basic understanding of such aspects. This overview is not an extensive overview of all contemplated aspects, nor is it intended to identify key or critical elements of all aspects or to delineate the scope of any or all aspects. Its sole purpose is to present some concepts of one or more aspects of the methods and systems described herein in a simplified form as a prelude to the more detailed description presented below.

[0007] In some examples, the system includes one or more processors and a memory storing executable instructions that, when executed by the one or more processors, cause the computing device to obtain image data representing one or more images depicting an inlet of a mass spectrometer and an emitter positioned near the inlet, and based on the image data, adjust the position of the emitter relative to the inlet to a reference position relative to the inlet or an optimal position near it, including performing a process.

[0008] In some examples, a non - transitory computer - readable medium stores instructions that, when executed, direct at least one processor of a computing device for mass spectrometry to obtain image data representing one or more images depicting an inlet of a mass spectrometer and an emitter positioned near the inlet, and based on the image data, adjust the position of the emitter relative to the inlet to a reference position relative to the inlet or an optimal position near it, including performing a process.

[0009] In some examples, the system includes an automatic positioning system configured to hold an ionization emitter near the inlet of a mass spectrometer and adjust the position of the ionization emitter relative to the inlet of the mass spectrometer, an imaging system configured to capture images of the ionization emitter and the inlet of the mass spectrometer, and a position control system that obtains, from the imaging system, image data representing one or more images depicting the inlet of the mass spectrometer and the ionization emitter positioned near the inlet, and based on the image data, instructs the automatic positioning system to adjust the position of the ionization emitter relative to the inlet of the mass spectrometer to a reference position relative to the inlet or an optimal position near it.

Brief Description of the Drawings

[0010] The accompanying drawings illustrate various embodiments and are part of this specification. The illustrated embodiments are merely examples and do not limit the scope of the present disclosure. Throughout the drawings, the same or similar reference numerals indicate the same or similar elements.

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DETAILED DESCRIPTION OF THE INVENTION

[0011] As described herein, a position control system can automatically identify the optimal position of an ionization emitter. In some use cases, the position control system can obtain a set of mass spectra by instructing an auto-positioning system to sequentially position the ionization emitter at multiple positions relative to the inlet of a mass spectrometer (e.g., the inlet of a mass analyzer). The position control system can instruct the mass spectrometer to obtain the mass spectrum of the ions introduced into the inlet while the ionization emitter is positioned at each of the multiple positions. The ions introduced into the inlet include the ions emitted from the ionization emitter. The position control system can generate an ion intensity map representing the detected intensity of the ions introduced into the inlet of the mass spectrometer as a function of the position of the ionization emitter based on the set of mass spectra. Based on the ion intensity map, the position control system can identify the optimal position of the ionization emitter. The position control system can also position the ionization emitter at the optimal position. Next, experimental analysis can be performed using the ionization emitter at the optimal position.

[0012] In other examples, the position control system can acquire image data representing one or more images depicting an ionization emitter positioned at and near the inlet of a mass spectrometer. Based on the image data, the position control system can adjust the position of the ionization emitter relative to the inlet. In this way, the position control system can position the ionization emitter at or near a reference position relative to the inlet. Next, an experimental analysis can be performed using the ionization emitter at the reference position.

[0013] The systems and methods described herein provide various benefits that may include one or more advantages over conventional systems and ion sources. For example, in some conventional systems, the position of the emitter is fixed at a single position and cannot be adjusted, while other conventional systems require manual emitter adjustment using, for example, a micrometer. As a result, conventional systems will have poor reproducibility of method performance for each emitter, for each piece of equipment, and for each user, with sub-optimal sensitivity. In contrast, the systems and methods described herein fully automate the emitter positioning process. Additionally, the systems and methods described herein can be configured to adjust the position of the emitter to optimize one or more characteristics of the detected signal, such as, for example, signal intensity, signal-to-noise ratio, and signal stability. In other examples, the systems and methods described herein can be configured to adjust the position of the emitter to or near a reference position. As a result, the systems and methods described herein improve sensitivity and / or reproducibility even across different emitters, different equipment, and different users. Further, the systems and methods described herein can be performed more quickly compared to the manual adjustment of conventional systems. Additionally, in some examples, the systems and methods described herein can be performed using only the solvent systems and flow conditions commonly used during column equilibration and / or column washing without injecting the analyte into the mobile phase. Further, the systems and methods described herein can be used with many different solvent systems having various mobile phase compositions and do not require knowledge of the specific solvent system used during the experiment. In some examples, the emitter can be automatically positioned without acquiring a mass spectrum and without requiring ions or solvent.

[0014] Reference is now made to the figures to describe various embodiments in more detail. The systems and methods described herein can provide one or more of the advantages described above, and / or various additional and / or alternative advantages made apparent herein.

[0015] The systems and methods described herein may be implemented in conjunction with a mass spectrometer. FIG. 1 shows the functional components of an exemplary mass spectrometer 100. As shown in the figure, the mass spectrometer 100 includes an ion source 102, a mass analyzer 104, and a controller 106. The mass spectrometer 100 may further include any additional or alternative components (not shown) that may be adapted to a particular implementation form (e.g., ion optics, filters, automatic sample collection devices, etc.).

[0016] The ion source 102 is configured to generate an ion stream 108 from a sample by electrospray ionization (ESI) and deliver the ions to the mass analyzer 104. Exemplary ion sources are described in more detail below with reference to FIG. 2.

[0017] The mass analyzer 104 is configured to receive the ion stream 108 and separate the ions according to the m / z of each ion. The mass analyzer 104 may be implemented by any suitable mass analyzer such as a quadrupole mass filter, an ion trap (e.g., a three-dimensional quadrupole ion trap, a cylindrical ion trap, a linear quadrupole ion trap, a toroidal ion trap, etc.), a time-of-flight (TOF) mass analyzer, an electrostatic trap mass analyzer (e.g., an Orbitrap mass analyzer, an orbital electrostatic trap such as a Kingdon trap), a Fourier transform ion cyclotron resonance (FT-ICR) mass analyzer, a sector mass analyzer, etc.

[0018] An ion detector (not shown) is configured to detect ions at each of a variety of different m / z and generate an electrical signal representative of the ion intensity accordingly. This electrical signal is transmitted to the controller 106 for processing such as constructing a mass spectrum of the sample. For example, the mass analyzer 104 can direct a beam of separated ions to the ion detector, which is configured to detect the ions in the beam and generate or provide data that the controller 106 can use to construct a mass spectrum of the sample. The ion detector can be implemented by any suitable detection device, including but not limited to an electron multiplier tube, a Faraday cup, etc.

[0019] The controller 106 can be communicatively coupled to the mass spectrometer 100 and configured to control the operation of the mass spectrometer. For example, the controller 106 can be configured to control the operation of various hardware components included in the ion source 102 and / or the mass analyzer 104. By way of illustration, the controller 106 can control the high voltage applied to the emitter in the ion source 102, control the acquisition time of the mass analyzer 104, control the oscillating voltage power supply and / or the DC power supply to supply an RF voltage and / or a DC voltage to the mass analyzer 104, adjust the values of the RF voltage and the DC voltage to select an effective m / z (including a mass tolerance window) for analysis, and adjust the sensitivity of the ion detector (e.g., by adjusting the detector gain).

[0020] The controller 106 can also include, and / or provide, a user interface configured to enable interaction between a user of the mass spectrometer 100 and the controller 106. The user can interact with the controller 106 via the user interface by tactile, visual, auditory, and / or other sensory communication. For example, the user interface can include a display device (e.g., a liquid crystal display (LCD) display screen, a touch screen, etc.) for displaying information (e.g., mass spectra, notifications, etc.) to the user. The user interface can also include an input device (e.g., a keyboard, a mouse, a touch screen device, etc.) that enables the user to provide input to the controller 106. In other examples, the display device and / or the input device can be separate from the controller 106 but communicatively coupled to the controller 106. For example, the display device and the input device can be included in a computer (e.g., a desktop computer, a laptop computer, etc.) communicatively connected to the controller 106 via a wired connection (e.g., by one or more cables) and / or a wireless connection.

[0021] The controller 106 can include any suitable hardware (e.g., a processor, circuitry, etc.) and / or software to be useful in a particular implementation. FIG. 1 shows the controller 106 being included within the mass spectrometer 100, and alternatively, the controller 106 can be implemented completely or partially separately from the mass spectrometer 100 by a computing device, etc., communicatively coupled to the mass spectrometer 100 via a wired connection (e.g., a cable) and / or a network (e.g., a local area network, a wireless network (e.g., Wi-Fi), a wide area network, the Internet, a cellular data network, etc.).

[0022] In some embodiments, mass spectrometer 100 may be implemented by a tandem mass spectrometer, which may be a time tandem or a space tandem type. For example, a space tandem mass spectrometer may include, in addition to mass analyzer 104, one or more collision cells and one or more additional mass analyzers (not shown in FIG. 1). As used herein, the term "collision cell" is intended to encompass any structure configured to generate product ions via a controlled dissociation process and is not limited to devices used for collision-activated dissociation. For example, the collision cell may be configured to fragment ions using collision induced dissociation (CID), electron transfer dissociation (ETD), electron capture dissociation (ECD), photo induced dissociation (PID), surface induced dissociation (SID), etc. The collision cell may be positioned upstream from the mass filter, and the mass filter separates the fragmented ions based on the mass-to-charge ratio of the ions. In some embodiments, mass analyzer 104 may include a combination of multiple mass filters and / or collision cells, such as a triple quadrupole mass analyzer, where the collision cell is inserted into the ion path between independently operable mass filters. transfer dissociation, ETD), electron capture dissociation, ECD), photo induced dissociation (PID), surface induced dissociation (SID), etc. to fragment the ions. The collision cell may be positioned upstream from the mass filter, and the mass filter separates the fragmented ions based on the mass-to-charge ratio of the ions. In some embodiments, mass analyzer 104 may include a combination of multiple mass filters and / or collision cells, such as a triple quadrupole mass analyzer, where the collision cell is inserted into the ion path between independently operable mass filters.

[0023] In some embodiments, the mass spectrometer 100 can be coupled to a separation system within a composite system configured to separate the components of a sample analyzed by the mass spectrometer 100. In performing the analysis by the combined system, the separation system is configured to receive the sample to be analyzed and separate specific components within the sample. In some examples, the separation system can also detect the relative abundance of the separated components, such as by generating a chromatogram representing the components within the sample. The separation system can be implemented by any device configured to separate the components contained in the sample, such as a liquid chromatograph (LC) (e.g., a high-performance liquid chromatograph (HPLC)), a gas chromatograph (GC), an ion chromatograph, a capillary electrophoresis system, etc. The components separated by the separation system are delivered to the mass spectrometer 100 for mass spectrometry by the mass spectrometer 100. The components separated by the separation system are delivered to the mass spectrometer 100 for mass spectrometry by the mass spectrometer 100.

[0024] FIG. 2 shows a functional diagram of an exemplary implementation of an interface between the ion source 102 and the mass analyzer 104. FIG. 2 is merely exemplary, and the ion source 102 and the mass analyzer 104 may have other suitable configurations. As shown, the ion source 102 includes an automatic positioning system 202, a high voltage source 204, and a high voltage line 206. The ion source 102 may also include additional or alternative components not shown in FIG. 2 that may be useful in a particular implementation, such as a source housing (e.g., containing the components of the ion source 102 and / or attached to the mass analyzer 104), a camera, an adapter, a lock, mounting components, a gas supply line, etc.

[0025] The automatic positioning system 202 is configured to hold the emitter 208 having the tip 210 at a controlled distance (e.g., about 0.1 - 3 cm) from the inlet 212 to the mass spectrometer 104. The inlet 212 is shown adjacent to the mass spectrometer 104 for illustrative purposes only. It will be appreciated that various other components such as ion optics, ion guides, ion traps, ion mobility separators, filters, and / or collision cells can be positioned between the inlet 212 and the mass spectrometer 104. The inlet 212 can have any suitable configuration such as an orifice or a capillary (e.g., an ion transfer tube such as a circular bore ion transfer tube (ITT), or a high capacity transfer tube (HCTT) such as a letterbox inlet). In an alternative example, the inlet 212 is a field asymmetric ion mobility spectrometry (FAIMS) inlet orifice, and the FAIMS electrodes are positioned immediately before the inlet to the mass spectrometer. When the emitter 208 is attached to the automatic positioning system 202, the automatic positioning system 202 can automatically adjust the position of the emitter 208 relative to the inlet 212 (e.g., the position of the tip 210) in response to a control signal received from the position control system 214. The operation of the position control system 214 and the feedback control of the automatic positioning system 202 are described in more detail below. The automatic positioning system 202 can include any suitable mechanical and / or electrical components (e.g., actuators, gears, motors, shafts, cranks, slides, stages, etc.) configured to adjust the position of the emitter 208 translationally and / or rotationally in any of 1 - 6 degrees of freedom. In some examples, the emitter 208 is attached to a movable carriage of the automatic positioning system 202, and the movable carriage can be moved by a precision motion system, an XYZ robot, an XYZ manipulator, one or more linear translation stages, one or more rotational stages, one or more piezoelectric actuators, and / or any combination of the above.

[0026] The emitter 208 may be a needle or capillary configured for electrospray ionization. The emitter 208 may be formed from, for example, glass, stainless steel, borosilicate, or any other suitable material, and may be coated with an outer coating such as a polyimide or other polymer coating. In some examples, the emitter 208 is configured for NSI low flow rates (e.g., from about 10 - 50 nL / min up to a maximum of about 1000 - 1500 nL / min). In other examples, the emitter 208 is configured for capillary flow rates (e.g., from about 1 μL / min up to a maximum of about 10 - 20 μL / min), micro flow rates (e.g., from about 10 μL / min up to a maximum of about 100 μL / min), or conventional ESI analysis flow rates (e.g., greater than about 50 μL / min). The emitter 208 may be included within an emitter cartridge, which holds the emitter 208 and includes a mounting unit (e.g., a mounting arm that can be coupled to the movable carriage of the auto - positioning system 202) for attachment to the auto - positioning system 202, an adapter for connecting or integrating the emitter 208 to a separation system (e.g., an LC or GC analysis column), on - board non - volatile memory (which can store position data and / or other data that can be used for positioning the emitter 208), and / or any other suitable components, but is not limited thereto. In some examples where the emitter cartridge includes on - board memory, the emitter cartridge may be communicatively coupled to the controller 106 and / or the position control system 214, such as by a wired or wireless connection.

[0027] The mobile phase system 218 provides a liquid solution that flows through the emitter 208. The liquid solution can include a solvent and, if a sample is injected into the liquid solution, that sample. The mobile phase system 218 may include, for example, a mobile phase pump, a syringe pump, a separation system (e.g., an LC or GC system), a container, or any other suitable source or combination of sources of the mobile phase. When the ion source 102 is used for NSI, the mobile phase flows through the emitter 208 at a nanoscale flow rate in the range of from about 10 nL / min up to a maximum of about 1000 or 1500 nL / min.

[0028] The voltage source 204 is configured to apply a DC spray voltage (e.g., about 2 to 6 kilovolts (kV) for ESI or about 0.7 to 3.5 kV for NSI) to the emitter 208 or the mobile phase via a high voltage line 206 (e.g., an electrical cable or other wiring or electrical connection). The spray voltage generates a strong electric field at the tip 210 of the emitter 208. Alternatively, an electric field may be generated by applying a high voltage to the mass spectrometer inlet 212 with the emitter 208 grounded. As ions are emitted from the tip 210, the electric field induces ion movement within the mobile phase, resulting in electrohydrodynamic collapse of the mobile phase, generation of charged droplets, and formation of a spray plume 216 that moves toward the inlet 212 of the mass spectrometer 104. As the spray plume 216 moves toward the inlet 212, the solvent evaporates from the charged droplets, gradually increasing the charge intensity on the surface of the droplets until the droplets split into one or more charged gas-phase ions. The charged gas-phase ions are then introduced into the inlet 212 of the mass spectrometer 104 by the electric field, the vacuum at the inlet, and, if present, the application of sheath gas at the emitter.

[0029] In some examples, the emitter 208 is inserted into a nozzle 220 and a sheath gas such as nitrogen gas (N2) flows coaxially around the emitter 208 within the nozzle 220. As the mobile phase exits the tip 210, the sheath gas exits the distal end of the nozzle 220 and flows around the spray plume 216, thereby controlling the position, shape, and direction of the spray plume 216 and reducing mass stratification. The sheath gas flow rate can be adjusted to achieve the desired position and shape of the spray plume 216. The sheath gas can also reduce the surface tension barrier and initiate spray plume 216 formation. In a further example, a heated auxiliary gas can be used to assist in desolvation of the charged droplets within the spray plume 216. However, at low flow rates (e.g., nanoflow), good sensitivity can be obtained without sheath gas and / or auxiliary gas.

[0030] In some examples, as shown in FIG. 2, emitter 208 is inclined with respect to the longitudinal axis of inlet 212. Any suitable angle can be used (e.g., 45°, 30°, 22.5°, 15°, etc.). In other examples, emitter 208 is not inclined with respect to the longitudinal axis of inlet 212, but is positioned such that the longitudinal axis of emitter 208 and the longitudinal axis of inlet 212 are substantially parallel.

[0031] When the sample is injected into the mobile phase, the electrospray ionization process generates gas-phase analyte ions from the analyte molecules contained in the sample and introduces those analyte ions into mass spectrometer 104. The electrospray ionization process also generates some solvent ions and introduces those solvent ions into inlet 212 of mass spectrometer 104, and when the sample is injected into the mobile phase, introduces those solvent ions together with the analyte ions. Solvent ions include ion species derived from non-analyte solvent molecules (e.g., molecules present in the mobile phase such as solvent molecules, mobile phase additives or modifier molecules, and mobile phase contaminants or impurity molecules, but not limited thereto), ion species added to non-analyte solvent molecules, and / or ion species derived from solvent clusters (e.g., clusters of two or more non-analyte solvent molecules). The electrospray ionization process also generates ambient ions, incorporates the ambient ions into the charged droplets, and introduces the ambient ions, together with the solvent ions and, when the sample is injected into the mobile phase, together with the analyte ions, into inlet 212 of mass spectrometer 104. Ambient ions are derived from ambient molecules. Ambient molecules are vapor species that are not present in the mobile phase but are present in the environment around the tip 210 of emitter 208. Ambient molecules can be ionized through a charge transfer reaction with spray plume 216. One common group of ambient molecules is polysiloxanes, which can be derived from sources such as deodorants, fragrances, floor waxes, and / or room sprays.

[0032] The mass analyzer 104 receives ions in the spray plume 216 entering the inlet 212 and performs mass spectrometry on the analyte ions. As described above, the controller 106 can process the received signals and construct a mass spectrum of the ions introduced into the inlet 212 based on the signals detected by the ion detector in the mass analyzer 104. The position control system 214 receives data representing the mass spectrum generated by the controller 106 (the "mass spectrum data 222"), uses the mass spectrum data 222 to determine the optimal position of the emitter 208 relative to the inlet 212, and can control the automatic positioning system 202 to adjust the position of the emitter 208 relative to the inlet 212. FIG. 2 shows that the position control system 214 is separate from the controller 106, but in some examples, the position control system 214 is implemented, in whole or in part, by the controller 106 and / or the automatic positioning system 202.

[0033] If the quality of the detected signals, such as signal intensity, signal-to-noise ratio, and signal stability, is a priority for the user, the emitter 208 should be positioned relative to the inlet 212 such that the signal detected from the analyte ions is optimized. However, analyte ions are not easily used for optimizing the position of the emitter 208 when the chromatographic column is coupled to the emitter 208. Analyte molecules cannot be easily injected into the mobile phase due to the interaction between the analyte molecules and the stationary phase in the column, and this interaction makes it difficult to obtain a steady-state response for position optimization. An injection port for injecting analyte molecules may be added downstream of the column but upstream of the emitter. However, the injection port would require modifying the existing system with new hardware. Considering these problems associated with analyte ions, the position control system 214 optimizes the emitter position based on proxy ions.

[0034] A proxy ion is a non-analyte ion that is expected or assumed to behave in space in the same manner as an analyte ion would behave in the same space under the same conditions. The analyte ions are generated at the tip 210 of the emitter 208 and travel toward the inlet 212 within the spray chamber 216 when the sample is injected into the mobile phase. Thus, non-analyte ions that are generated at the tip 210 and travel toward the inlet 212 within the spray chamber 216 are assumed to behave in the same manner as the analyte ions and are therefore referred to herein as proxy ions. Proxy ions generally include solvent ions that are also generated at the tip 210 and may also include ambient ions that are generated at or near the tip 210 and travel toward the inlet within the spray chamber 216. On the other hand, some ambient ions are not generated at or near the tip 210 and / or do not travel the same path as the proxy ions toward the inlet 212. Such ambient ions do not accurately mimic the behavior of the analyte ions and are therefore referred to herein as contaminant ions. As described below, in some examples, the position control system 214 assumes that the influence of contaminant ions is minimal and therefore treats all ions, including both solvent ions and contaminant ions, that are introduced into the inlet 212 and mass analyzed as proxy ions. In other examples, the position control system 214 classifies certain detected ions as contaminant ions and excludes the contaminant ions when optimizing the position of the emitter 208. In the examples below, the position of the emitter 208 can be optimized using only the mobile phase without injecting the sample into the mobile phase and without the need for any additional hardware.

[0035] If reproducibility of emitter position across different emitters, instruments, and / or facilities is a priority for the user, the position control system 214 optimizes the emitter position without the need to generate or analyze any ions. Instead, the position control system 214 optimizes the emitter position based on images of the emitter and the inlet captured by one or more cameras included in the ion source 102.

[0036] FIG. 3 shows an exemplary functional diagram of the position control system 214. The position control system 214 may be implemented separately from the mass spectrometer 100. In some examples, the position control system 214 is implemented, in whole or in part, by the mass spectrometer 100 (e.g., by the controller 106, by the automatic positioning system 202, or by any other component of the mass spectrometer 100) and / or by the emitter cartridge.

[0037] The position control system 214 can include, but is not limited to, a storage facility 302 and a processing facility 304 that are selectively and communicatively coupled to each other. The facilities 302 and 304 can each include or be implemented by hardware and / or software components (e.g., a processor, a memory, a communication interface, instructions stored in the memory for execution by the processor, etc.). In some examples, the facilities 302 and 304 can be distributed among multiple devices and / or multiple locations to be useful for a particular implementation.

[0038] The storage facility 302 maintains (e.g., stores) executable data used by the processing facility 304 to perform any of the operations described herein. For example, the storage facility 302 can store instructions 306 that can be executed by the processing facility 304 to perform any of the operations described herein. The instructions 306 can be implemented by any suitable application, software, code, and / or other executable data instance.

[0039] The memory device 302 can also maintain any data acquired, received, generated, managed, used, and / or transmitted by the processing device 304. For example, the memory device 302 can maintain mass spectrometry data 222 and / or optimization algorithm data. The optimization algorithm data can include one or more optimization algorithms maintained by the processing device 304 to optimize the signals acquired by the mass spectrometer 100 and to position the emitter 208 relative to the inlet 212, and thereby used by, or associated with, the same. The memory device 302 may also be coupled within a cartridge assembly unit that contains the emitter 208 and optionally other elements such as a chromatography column.

[0040] The processing device 304 can be configured to perform the various processing operations described herein (e.g., execute instructions 306 stored in the memory device 302). It will be recognized that the operations and examples described herein are merely illustrative of the many different types of operations that can be performed by the processing device 304. In the description herein, any reference to an operation performed by the position control system 214 can be understood to be performed by the processing device 304 of the position control system 214. Further, in the description herein, any operation performed by the position control system 214 can be understood to include the position control system 214 instructing or commanding another system or device to perform the operation.

[0041] In some examples, the position control system 214 is configured to automatically adjust the ion source 102 to optimize the quality of the signal (the "MS signal") detected by the mass spectrometer 100 for a selected m / z, m / z range, or one or more target analytes. As used herein, "selected m / z" may be a specific m / z with or without a mass tolerance window (e.g., ±0.5 m / z), or a specific narrow m / z range (e.g., 30 - 120, or 200 - 220 m / z). The quality of the MS signal may be indicated by the value of one or more performance indices of the MS signal, such as intensity, spray current, signal-to-noise ratio ("SNR"), relative standard deviation (relative standard deviation, "RSD"), system robustness, and / or any other suitable performance metric representing the quality of the MS signal. The RSD of the detected signal represents the stability of the detected signal (e.g., the amount of variability in the MS signal), although signal stability may also be represented by other performance metrics.

[0042] As described above, the quality of the MS signal may depend on certain user-configurable parameters, such as the position of the emitter tip 210 relative to the inlet 212, the spray voltage applied to the emitter 208, the sheath gas flow rate (in implementations using sheath gas), the flow rate of the mobile phase flowing through the emitter 208, the composition of the solvent in the mobile phase, and / or the electrospray mode (e.g., spindle, multi-spindle, cone jet, multi-jet, etc.). In an NSI ion source, the optimal position of the emitter tip 210 can be on the order of a fraction of a millimeter wide on all sides. The quality of the MS signal may also depend on other factors that are not easily controlled by the user, such as ambient conditions (e.g., temperature, ambient air flow, humidity, pressure, etc.), instrument characteristics (e.g., inlet geometry, etc.). Thus, the position control system 214 can perform various operations to automatically adjust the ion source 102 to improve or optimize a performance metric (e.g., intensity, SNR, and / or RSD), as described below.

[0043] As used herein, "optimize" and variations thereof mean to seek the best, desired, or satisfactory solution from a set of possible solutions, but the best solution need not necessarily be obtained if, for example, the optimization process ends before finding the best solution (e.g., based on meeting a stopping criterion), if there are multiple solutions that meet a predefined criterion, or if the selected optimization technique cannot converge to the best solution. Similarly, as used herein, an "optimal" parameter means a solution obtained as a result of performing an optimization process, and thus may not necessarily be the absolute extreme value of the parameter (e.g., the absolute maximum or minimum value), but still adjusts the parameter to effect an improvement and / or meet one or more criteria.

[0044] In some examples, the position control system 214 can adjust the ion source 102 to optimize the performance index of the MS signal by controlling the automatic positioning system 202 to adjust the position of the emitter 208 relative to the inlet 212 based on the mass spectral data 222 acquired by the mass spectrometer 100. The position of the emitter 208 refers to the position of the tip 210 relative to the inlet 212 (e.g., the center point of the inlet 212 at the front portion (emitter side) of the inlet 212). The position control system 214 can determine the 3D coordinates of the optimal position of the emitter 208 relative to the inlet 212 (or 2D coordinates or 1D coordinates, respectively, if the emitter 208 is adjustable along two axes or only one axis). The optimal position of the emitter 208 refers to the spatial position of the emitter 208 relative to the inlet 212 where the performance index of the detected MS signal has an optimal value (e.g., a maximum intensity value or a maximum SNR) and / or meets one or more criteria (e.g., exceeds a threshold intensity level or a threshold SNR). In some scenarios, it will be recognized that there may be multiple optimal positions for the emitter 208, such as when multiple different emitter positions generate MS signals whose performance indices meet the threshold conditions, or when different performance indices have different optimal emitter positions.

[0045] The position of the emitter 208 may be determined based on the emitter 208 (e.g., the emitter tip 210 or a marker on the emitter 208), the emitter cartridge, or the movable carriage of the automatic positioning system 202. For example, when the emitter 208 is attached to the automatic positioning system 202, the exact position of the emitter tip 210 relative to the inlet 212 may not be known because such positions can vary across different users, facilities, and emitters. Thus, the position of the emitter 208 relative to the inlet 212 (e.g., the position of the emitter tip 210) can be determined based on the position (e.g., 3D coordinates) of the movable carriage of the automatic positioning system 202 to which the emitter 208 is attached, since the position of the emitter 208 is fixed relative to the movable carriage.

[0046] In some examples, the position control system 214 uses robotics or kinematics to track the position of the movable carriage. Alternatively, the position of the emitter 208 is tracked by using a depth sensor (e.g., a time-of-flight sensor, an infrared sensor, etc.), an interferometer, or computer vision. For example, the ion source 102 may include a camera configured to capture an image of the emitter 208 and determine the position of the emitter tip 210 based on the captured image. In some examples, the emitter 208 (or the emitter cartridge) may include a marker (e.g., a reflective sticker or other fiducial) that is recognized by image recognition and can be used to determine the position of the emitter 208. If the position of the camera relative to the inlet 212 is not fixed or is not known, the position of the emitter 208 relative to the inlet 212 can be determined based on image recognition of both the emitter 208 and the inlet 212. In yet further examples, the position of the emitter 208 may be determined by an optical lever.

[0047] In the following example, the signal strength is the performance index, and the position control system 214 determines the optimal position of the emitter 208 by generating an ion intensity map and identifying the optimal position of the emitter 208 based on the ion intensity map. The ion intensity map is a set of data that represents the detected intensity of one or more (or all) of the ions introduced into the inlet 212 of the mass spectrometer 104 as a function of the spatial position of the emitter 208 relative to the inlet 212. Exemplary ion intensity maps and methods for generating ion intensity maps are described in more detail below. The ion intensity map is a type of ion signal quality map. It will be recognized that the following examples can be appropriately modified to optimize the emitter position based on different performance indices of the detected signal, such as SNR or signal stability (e.g., RSD). In these examples, the position control system 214 can generate different ion signal quality maps (e.g., in some cases, an SNR map or an RSD map) and identify the optimal emitter position based on the ion signal quality map.

[0048] FIG. 4 shows a flowchart of an exemplary method 400 for optimizing the position of the emitter 208 relative to the inlet 212. FIG. 4 shows exemplary operations according to one embodiment, but other embodiments can omit, add, reorder, and / or modify any of the operations shown in FIG. 4. Each operation of method 400 can be performed in any suitable manner.

[0049] In operation 402, the position control system 214 obtains a set of mass spectra. The set of mass spectra is a set of mass spectral data that can be used to generate an ion intensity map. The position control system 214 instructs the automatic positioning system 202 to sequentially position the emitter 208 at a plurality of positions within a search region located near the inlet 212, and while the emitter 208 is positioned at each of the plurality of positions, the mass spectrometer 100 is instructed to obtain the mass spectrum of the ions introduced into the inlet 212 of the mass analyzer 104, whereby a set of mass spectra can be obtained. The set of mass spectra includes each mass spectrum obtained at each emitter position. The ions introduced into the inlet 212 include ions emitted from the emitter 208 (e.g., solvent ions) and, optionally, ambient ions present in the environment near the emitter 208 and / or the inlet 212.

[0050] The mass spectrum can be obtained by any suitable method. In some examples, the mass spectrum is obtained by full MS acquisition (e.g., MS acquisition over a wide m / z range such as 30 - 1000 m / z, 400 - 1000 m / z, etc.). MS acquisition can be acceptable for faster instruments such as time-of-flight and ion trap type (e.g., orbitrap type) mass analyzers. In other examples, the mass spectrum is obtained by an MS / MS acquisition method such as a selected ion monitoring (SIM) acquisition method with a wide separation window. For example, SIM acquisition can cover a narrower m / z range where proxy ions are expected and / or contaminant ions are not expected or not expected to be detected at high abundance. SIM acquisition can be acceptable for slower instruments such as triple quadrupole mass analyzers. In some examples, the mass spectrum is obtained using SIM acquisition over an m / z range of about 30 - about 400 m / z, over an m / z range of about 30 m / z - about 350 m / z, over an m / z range of about 30 - about 300 m / z, or over an m / z range of about 30 m / z - about 250 m / z. It will be recognized that other acquisition techniques such as full MS / MS acquisition or MSn acquisition (where n is greater than 2) can be used. In other examples, targeted MS / MS acquisition (e.g., selected reaction monitoring (SRM) acquisition, multiple reaction monitoring (MRM) acquisition, or parallel reaction monitoring (PRM) acquisition) may be performed to obtain data regarding one or more known solvent system ions.

[0051] In some examples, operation 402 begins with emitter 208 being positioned at a default home, based on the particular instrument being used (e.g., a particular mass spectrometer, ion source, or emitter cartridge). Alternatively, the default home position is based on particular experimental conditions (e.g., a particular one or more target analytes, selected m / z, solvent conditions, sheath gas flow rate, and / or spray voltage). The default home position can be determined empirically, such as by performing method 400. In some examples, the emitter cartridge can include on-board non-volatile memory that can be read by position control system 214 to position emitter 208 at an initial position and store data representing a default home position (coordinates) that can be used. Alternatively, position control system 214 may obtain data representing the default home position from a remote computing system.

[0052] In some examples, the sampled search region is a two-dimensional (2D) search region positioned in front of inlet 212. The search region is defined by a first axis and a second axis orthogonal to the first axis, but remains at a fixed position along a third axis orthogonal to the first and second axes.

[0053] Figures 5A and 5B show an exemplary configuration of the 2D search region relative to inlet 212 of mass spectrometer 104. Figure 5A shows a front view of inlet 212, and Figure 5B shows a side view of inlet 212 and emitter 208 positioned in front of inlet 212. Legend L is arbitrarily oriented such that the Z-axis extends along the longitudinal axis 502 of inlet 212 (shown by the "T" in Figure 5A and the dashed-dotted line in Figure 5B), the X-axis extends horizontally (left to right in Figure 5A), and the Y-axis extends vertically (up and down in Figures 5A and 5B). Emitter 208 is tilted with respect to the longitudinal axis 502 of inlet 212 within the Y-Z plane.

[0054] As shown in FIGS. 5A and 5B, a search region 504 (indicated by the dashed lines in FIG. 5A and the dashed rectangle in FIG. 5B) is positioned in front of the inlet 212. The search region 504 is in a plane extending along the Z-axis (first axis) and the Y-axis (second axis). In the examples of FIGS. 5A and 5B, the search region 504 is parallel to the axis 502 of the inlet 212 (e.g., parallel to the Z-axis (third axis)). The search region 504 can have any suitable dimensions that can be useful for a particular implementation. In some examples, the search region 504 has a length (along the Z-axis) and / or height (along the Y-axis) of about 0.5 millimeters (mm) to about 5.0 mm along the Z-axis and / or Y-axis. In further examples, the search region 504 has a length and / or height of about 1.0 millimeter (mm) to about 3.0 mm. In still further examples, the search region 504 has a length and / or height of about 1.5 mm to about 2.5 mm.

[0055] FIGS. 6A and 6B show another exemplary configuration of the search region 504. FIGS. 6A and 6B are similar to FIGS. 5A and 5B, but in FIGS. 6A and 6B, the search region 504 (indicated by the dashed rectangle in FIG. 6A and the dashed line in FIG. 6B) is in a plane extending along the X-axis (first axis) and the Y-axis (second axis). In the examples of FIGS. 6A and 6B, the search region 504 is orthogonal to the axis 502 of the inlet 212 (e.g., orthogonal to the Z-axis (third axis)). The emitter 208 is not inclined with respect to the longitudinal axis 502 of the inlet 212.

[0056] The search region 504 can have any other suitable orientation, shape, and size that can be useful for a particular implementation. For example, the search region 504 can be orthogonal to the axis of the emitter 208 regardless of the position or orientation of the emitter 208. In other examples, the search region 504 is one-dimensional (1D) such that the emitter 208 is sequentially positioned at multiple positions along only one direction. In further examples, the search region 504 is three-dimensional (3D) such that the emitter 208 is sequentially positioned at multiple positions in 3D space. Further, the search region 504 can have any other shape, such as circular, elliptical, triangular, irregular, etc., that can be useful for a particular implementation.

[0057] As described above, in operation 402, the position control system 214 instructs the automatic positioning system 202 to sequentially position the emitter 208 at a plurality of positions within the search region 504. To make method 400 robust to noise and / or to speed up the process, the step size between adjacent positions or consecutive positions can be fixed, selected from a schedule, adaptively determined, and / or dynamically modified during method 400. Any suitable step size can be used. As described above, the detected signal can be overly sensitive to deviations of a fraction of 1 millimeter (e.g., just 100 μm, or less than 100 μm) of the emitter 208 from the optimal position. In some examples, the automatic positioning system 202 uses a step size of about 1 μm to about 50 μm, about 1 μm to about 25 μm, about 1 μm to about 10 μm, or about 2 μm to about 5 μm to sequentially position the emitter 208 at each of a plurality of positions within the search region 504.

[0058] In some examples, the position control system 214 can speed up the process of sampling the search region 504 by taking step sizes that are two times, three times, or more. For example, using a step size of 2 μm, the position control system 214 samples the search region 504 by positioning the emitter 208 at a plurality of positions that are 4 μm (a two - times step size) apart along both the first axis and the second axis, thereby sampling the search region in a checkerboard pattern. In some examples, the position control system 214 can estimate the signal value of a skipped position by interpolation or the like based on the signal values of one or more adjacent sampled positions. It will be recognized that any suitable sampling pattern can be used.

[0059] While a set of mass spectra is being acquired, the search region 504 remains at a position fixed relative to the inlet 212 along a third axis that is orthogonal to the first and second axes (the "third axis position"). In the examples of FIGS. 5A and 5B, the emitter 208 is tilted in the Y-Z plane relative to the axis 502 of the inlet 212. Thus, the search region 504 remains at a fixed position along the X axis (the third axis), while the emitter 208 is sequentially positioned at a plurality of positions within the Y-Z plane. In the examples of FIGS. 6A and 6B, the emitter 208 is not tilted relative to the axis 502 of the inlet 212, the search region 504 remains at a fixed position along the Z axis (the third axis), while the emitter 208 is sequentially positioned at a plurality of positions within the X-Y plane.

[0060] The position control system 214 can determine the third axis position in any suitable manner. In some examples, the third axis position is the default position of the particular instrument being used (e.g., a particular mass spectrometer, ion source, or emitter cartridge). In other examples, the third axis position is the default position for particular experimental conditions (e.g., a particular one or more target analytes, selected m / z, solvent conditions, sheath gas flow rate, and / or spray voltage). In some examples, the emitter cartridge can include on-board non-volatile memory that can store data representing the third axis position, which can be read and used by the position control system 214 to position the emitter 208 at the third axis position prior to performing operation 402. Alternatively, the position control system 214 may obtain data representing the third axis position from a remote computing system. In some examples, the third axis position is indicated by the default home position described above.

[0061] In other examples, the third axis position is determined by executing an optimization routine. FIG. 7 shows an exemplary method 700 for determining an optimal third axis position. Method 700 may be executed before executing method 400. FIG. 7 shows exemplary operations according to one embodiment, although other embodiments may omit, add, reorder, and / or modify any of the operations shown in FIG. 7. Each operation of method 700 can be executed in any suitable way. Method 700 is executed before executing method 400.

[0062] In operation 702, the position control system 214 instructs the automatic positioning system 202 to sequentially position the emitter 208 at a plurality of positions along the third axis, and while the emitter 208 is positioned at each of the plurality of positions along the third axis, obtains a third axis set of mass spectra by obtaining the mass spectrum of the ions introduced into the inlet 212. The ions introduced into the inlet 212 include ions emitted from the emitter 208 (e.g., solvent ions) and, optionally, ambient ions present in the environment near the emitter 208 and / or the inlet 212. The position control system 214 obtains a third axis set of mass spectra while maintaining the emitter 208 at a fixed position along the first and second axes. The fixed positions along the first and second axes can be determined in any suitable way, such as manually or based on default positions. The most reasonable emitter positions along the first and second axes enable the determination of the optimal position along the third axis.

[0063] In the examples of FIGS. 5A and 5B, the emitter 208 is positioned at a plurality of positions along the X axis (third axis) while remaining at a fixed position along the Z axis (first axis) and the Y axis (second axis). In the examples of FIGS. 6A and 6B, the emitter 208 is positioned at a plurality of positions along the Z axis (third axis) while remaining at a fixed position along the X axis (first axis) and the Y axis (second axis).

[0064] In operation 704, the position control system 214 identifies an optimal position along a third axis for the ionization emitter based on a third axis set of the mass spectrum. For example, the position control system 214 can identify the optimal position along the third axis as the position that resulted in an optimal signal (e.g., the strongest signal). The position control system 214 can assign the optimal position as the third axis position.

[0065] In operation 706, the position control system 214 instructs the auto-positioning system 202 to move the emitter 208 to the third axis position. The position control system 214 can then initiate method 400 to identify optimal emitter positions along the first and second axes.

[0066] Referring again to FIG. 4, in operation 404, the position control system 214 generates an ion intensity map based on a set of mass spectra. The ion intensity map includes a set of data representing the detected intensity of one or more of the ions introduced into the inlet 212 of the mass spectrometer 100 as a function of the position of the emitter 208. Examples of ion intensity maps and methods of generating ion intensity maps are described in more detail below.

[0067] In operation 406, the position control system 214 identifies an optimal position for the ionization emitter based on the ion intensity map. For example, the position control system 214 may select any position within the search region where the signal of the ion intensity map has an optimal value as the optimal position. For example, the optimal position may be a position within the search region where the ion intensity map has the highest intensity value.

[0068] In operation 408, the position control system 214 positions the emitter 208 at the optimal position (e.g., instructs the automatic positioning system 202 to position the emitter 208 at the optimal position). Next, an analysis experiment can be performed with the emitter 208 in the optimal position. In some examples, the position control system 214 automatically positions the emitter 208 at the optimal position upon completion or termination of method 400. In other examples, the position control system 214 can provide information indicating the optimal position, or multiple optimal positions if there are two or more, for display on a graphical user interface associated with the position control system 214. The user may then provide user input to permit repositioning of the emitter 208 to the optimal position and / or to select an optimal position from among multiple optimal positions. In response to receiving the user input, the position control system 214 can then move the emitter 208 to the optimal position approved or selected by the user input (e.g., can instruct the automatic positioning system 202 to move it).

[0069] In some examples, upon ending method 400, the position control system 214 stores data representing the optimal emitter position in the on-board memory of the emitter cartridge and / or in the storage facility of the mass spectrometer 100 and / or the position control system 214. Additionally or alternatively, the position control system 214 may transmit data representing the optimal emitter position to a remote computing system, which may use the data alone or in combination with data received from other optimizations to establish a default home position for a particular instrument and / or experimental conditions.

[0070] In some examples, method 400 is executed in response to receiving user input. For example, before performing an analytical experiment to analyze one or more analytes, the user may select an emitter position optimization button presented on a graphical user interface associated with the mass spectrometer. In response to the user selection of the emitter position optimization button, the position control system 214 can initiate the execution of method 400 and / or method 700. In other examples, the user can select an emitter position optimization button on the graphical user interface during the execution of the analysis to recalibrate the emitter position. In some examples, the user can recalibrate the emitter position during a column equilibration step (e.g., while the LC column is being equilibrated with the mobile phase) or during a column wash step.

[0071] Next, various examples of a method of generating an ion intensity map, and identifying an optimal emitter position based on the ion intensity map (operation 404) will be described.

[0072] In some examples, the ion intensity map is a total ion map. The total ion map represents or indicates the total signal (e.g., total intensity or total ion current) of all ions detected at each emitter position. The total ion map can be generated by summing the detected intensity signals of all ions represented for each respective mass spectrum for each of a plurality of positions within the search region. In embodiments using a total ion map, it is assumed that most or all of the ions entering the inlet 212 are proxy ions and the presence of contaminant ions can be ignored.

[0073] FIG. 8 shows a graph 800 depicting an exemplary total ion map that can be generated from a set of mass spectra obtained by sampling the search region 504 of FIGS. 6A and 6B. As shown in graph 800, the total ion map shows the total (e.g., sum) intensity at each (X,Y) coordinate position of emitter 208. As indicated by legend 802, darker positions in graph 800 indicate higher intensity levels and lighter positions indicate lower intensity levels. As seen in graph 800, the emitter position having the highest total intensity level is at the (X,Y) coordinate position of approximately (950, 700). Thus, position control system 214 can identify the position (950, 700) as the optimal emitter position and move emitter 208 to the identified optimal emitter position. The total ion map (and any other ion intensity map described herein) includes the underlying data that can be used to generate the graph 800 shown in FIG. 8 (or any other graphical depiction of the ion intensity map herein), and it will be recognized that position control system 214 does not need to generate a graph or other graphical depiction of the total ion map (or any other ion intensity map) to perform any of the methods described herein, including methods 400 and 700.

[0074] In other examples, the ion intensity maps referred to in operations 404 and 406 are extracted ion maps. An extracted ion map represents intensity (e.g., total intensity) as a function of emitter position for only a selected subset of ions. In these examples, signals from various ions are filtered such that an ion intensity map is generated, and thus the optimal position is determined based largely or entirely on the signals corresponding to the proxy ions.

[0075] The extracted ion map can be configured and generated in a variety of different ways. In some examples, the extracted ion map includes a set of data representing the total intensity of the set of strongest signals for each mass spectrum as a function of the emitter position. In these examples, it is assumed that contaminant ions generally have lower signal levels than proxy ions, and thus, by using only the signals from the set of most abundant ions detected at each emitter position to generate the extracted ion map, the contaminant ion signal levels can be largely or completely excluded. In some implementations, the extracted ion map is generated by summing the intensity signals of the strongest signals (e.g., the N strongest signals, where N is an integer in the range of 3 to 20, 5 to 15, or any other suitable number) for each mass spectrum. Proxy ions are assumed to generate the highest intensity signals, but there may be scenarios where signals generated by contaminant ions are also included in the set of strongest signals. However, the contaminant ion signals are negligible compared to the proxy ion signals, and the total intensity of the strongest signals is assumed to give a reasonably accurate representation of the behavior of the analyte ions.

[0076] In other examples, the extracted ion map represents the total intensity of the signals of a set of ions having m / z values below the m / z threshold as a function of the emitter position. In these examples, contaminant ions are generally assumed to have m / z values greater than the m / z threshold. In many cases, contaminant ions such as polysiloxanes have m / z values greater than about 300 m / z. In some examples, the m / z threshold is a value between about 250 m / z and 400 m / z. In other examples, the m / z threshold is a value between about 275 m / z and 375 m / z. In other examples, the m / z threshold is a value between about 300 m / z and 350 m / z. The m / z threshold can be any other value and can be set based on knowledge of the particular environment in which the experiment is being conducted (e.g., based on the m / z of contaminant ions known to be present) and / or based on knowledge of the particular solvent system. By generating an ion intensity map based only on signals having m / z values below the m / z threshold, most of the signals from contaminant ions can be excluded when generating the ion intensity map.

[0077] In other examples, the extracted ion map represents the signal intensity as a function of the emitter position for one or more selected sets of ions (e.g., one or more selected m / z). For example, the selected ions may be proxy ions (e.g., solvent ions) known to be derived from the mobile phase. Thus, the position control system 214 can optimize the emitter position based on the analysis of one or a few specific proxy ions.

[0078] In other examples, to filter contaminant ions from the extracted ion map, the extracted ion map is generated based on the classification of one or more ions. For example, the extracted ion map may represent the total intensity of all signals of a set of ions that do not include ions classified as contaminant ions. In these examples, the position control system 214 can execute a classification process to classify one or more detected ions as contaminant ions and generate an extracted ion map based only on the signals of ions not classified as contaminant ions. For example, the position control system 214 may generate an extracted ion map by summing the intensity values of all ions not classified as contaminant ions for each emitter position. In other examples, the extracted ion map may represent the total intensity of all signals of a set of ions that include only ions classified as proxy ions. In these examples, the position control system 214 can execute a classification process to classify one or more detected ions as proxy ions and generate an extracted ion map based only on the signals of the proxy ions. For example, the position control system 214 may generate an extracted ion map by summing the intensity values of all proxy ion signals for each emitter position.

[0079] In some examples, the position control system 214 executes a classification process for all detected ions. In other examples, the position control system 214 executes a classification process for only a subset of the detected ions. For example, the position control system 214 may execute a classification process for only the set of most abundant ions (e.g., based on the total intensity of each ion across all emitter positions), all ions having intensity values at any emitter position above a threshold intensity value, or all ions having m / z values within a threshold m / z range (e.g., less than an m / z threshold, greater than an m / z threshold, within a target m / z range (e.g., 30 - 300 m / z), etc.).

[0080] Next, an exemplary classification process will be described. FIG. 9 shows a flowchart of an exemplary classification process 900. FIG. 9 shows exemplary operations according to one embodiment, but other embodiments may omit, add, reorder, and / or modify any of the operations shown in FIG. 9. Each operation of classification process 900 can be performed in any suitable manner. In some examples, classification process 900 performs operation 404 of method 400.

[0081] In operation 902, the position control system 214 generates an extracted ion map for each selected ion (e.g., each selected m / z) among the set of selected ions based on the set of mass spectra obtained in operation 402 of method 400. The set of selected ions can include all ions detected in the set of mass spectra, or a subset of one or more detected ions (e.g., a set of the N most abundant ions, a set of ions within a defined m / z range, specific known contaminant ions, etc.). Each extracted ion map represents intensity as a function of the emitter position for the corresponding selected ion. The position control system 214 can generate an extracted ion map for each selected ion by extracting intensity values only for the selected ions from the set of mass spectra.

[0082] FIG. 10 shows a graph 1000 depicting an exemplary extracted ion map for a selected ion (m / z 371) corresponding to a general polysiloxane contaminant ion. The extracted ion map depicted by graph 1000 can be generated from a set of mass spectra obtained by sampling the search region 504 of FIGS. 6A and 6B. As shown in graph 1000, the extracted ion map shows the intensity values of the selected ion at each (X,Y) coordinate position of emitter 208. As indicated by legend 1002, darker positions indicate higher intensity levels and lighter positions indicate lower intensity levels. As can be seen, due to the fact that the selected ion corresponds to a contaminant ion and not to a proxy ion originating from emitter 208, there is no distinct optimal position for emitter 208.

[0083] Returning again to FIG. 9, in operation 904, position control system 214 classifies each selected ion based on its corresponding extracted ion map and a reference ion map. In some examples, the reference ion map is an ion intensity map representing the detected intensity values of one or more proxy ions (e.g., for a reference m / z or in a reference m / z range such as 30 - 300 m / z) or analyte ions. The reference ion map excludes the intensity values of contaminant ions. Thus, the reference ion map shows the intensity pattern that would be expected to be achieved by proxy ions. In some examples, the reference ion map is generated based on a reference set of mass spectra obtained prior to the set of mass spectra from which the extracted ion map is generated. The reference set of mass spectra and / or the reference ion map for the reference m / z or reference m / z range may be generated by a manufacturer and / or accessed by position control system 214 from a remote computing system. The reference set of mass spectra may be obtained in an environment substantially free of ambient molecules that generate contaminant ions. Additionally or alternatively, the reference set of mass spectra may be generated by removing any signals corresponding to known contaminant ions from the reference set of mass spectra.

[0084] FIG. 11 shows a graph 1100 depicting an exemplary reference ion map. The reference ion map depicted by the graph 1100 can be generated from a reference set of mass spectra obtained by sampling a search region near the inlet to a mass spectrometer. As shown in graph 1100, the reference ion map shows intensity values at each (X, Y) coordinate position of emitter 208. As indicated by legend 1102, darker positions indicate higher intensity levels and lighter positions indicate lower intensity levels. As can be seen in graph 1100, the optimal position of emitter 208 should occur at or near the (X, Y) coordinate position of (1100, 650).

[0085] In some examples, the position control system 214 may perform a calibration step to align the reference ion map with the extracted ion map for the selected ion map, since the reference ion map may be generated using different instrument settings and may have an offset in coordinate space. The calibration may be performed in any suitable manner, such as based on pattern recognition using the extracted ion map, another extracted ion map obtained from a set of mass spectra, and / or based on a default home position for the set of mass spectra.

[0086] The position control system 214 may classify the selected ions using classification rules based on the corresponding extracted ion map and the reference ion map. The classification rules specify which classification criteria are applied and how the classification criteria are applied. The classification criteria are based on classification parameters that indicate or represent the similarity between the extracted ion map and the reference ion map. Exemplary classification parameters include, but are not limited to, the cross-correlation coefficient, the matrix norm to mean ratio, the difference (distance) at the optimal position along the first axis (e.g., the Z-axis), the difference (distance) at the optimal position along the second axis (e.g., the Y-axis), the total difference (distance) at the optimal position (e.g., the total distance based on both the first axis difference component and the second axis difference component), the result of linear discriminant analysis, and the result of principal component analysis. The values of the classification parameters can be determined using one or more statistical comparison techniques such as cross-correlation, optimal position difference, linear discriminant analysis, and principal component analysis. Additionally or alternatively, one or more classification criteria may be based on a comparison performed using a trained machine learning model (e.g., a trained neural network), a random forest algorithm, and / or a support vector machine.

[0087] The classification criteria are satisfied when each classification parameter determined by the position control system 214 meets a predetermined condition (e.g., a minimum value, a maximum value, or another value) of the classification parameter. For example, the cross-correlation criterion may be satisfied when the cross-correlation coefficient is greater than a minimum cross-correlation threshold, the matrix norm to mean ratio criterion may be satisfied when the matrix norm to mean ratio is greater than a minimum matrix norm to mean ratio threshold, and the Z-axis difference, Y-axis difference, and / or total difference criteria may be satisfied when the calculated difference is less than a maximum distance threshold.

[0088] As described above, the classification rules specify which classification criteria are applicable and how those classification criteria are applied to classify the selected ions. The set of classification criteria can include any combination of classification criteria so as to be suitable for a particular implementation. In some examples, the set of classification criteria includes at least a cross-correlation criterion and a matrix norm-to-average ratio criterion. The set of classification criteria can be applied in any suitable manner.

[0089] For example, the position control system 214 can classify the selected ions as contaminant ions in response to a determination that the threshold number of applied classification criteria (e.g., 1, 2, 3, 1 / 2, greater than 1 / 2, etc.) is not satisfied. For example, assume that the classification rules apply a cross-correlation criterion, a matrix norm-to-average ratio criterion, a Z-axis difference criterion, and a Y-axis difference criterion, and that all classification criteria must be satisfied or the selected ions are classified as contaminant ions. If the position control system 214 determines that any one of the classification criteria is not satisfied (e.g., the matrix norm-to-average ratio criterion is less than the minimum matrix norm-to-average threshold), the position control system 214 classifies the selected ions as contaminant ions. On the other hand, if the position control system 214 determines that all of the classification criteria are satisfied, the position control system 214 does not classify the selected ions as contaminant ions.

[0090] As another example, assume that the classification rules specify that the threshold number of classification criteria that must be satisfied is two (or 1 / 2), and the position control system 214 determines that less than two (e.g., one or zero) classification criteria are satisfied. In this case, the position control system 214 classifies the selected ions as contaminant ions. On the other hand, if the position control system 214 determines that any two or more classification criteria are satisfied, the position control system 214 does not classify the selected ions as contaminant ions.

[0091] In the above example, the position control system 214 classifies ions into either contaminant ions or non - contaminant ions. Such classification can be used when the extracted ion map excludes ions classified as contaminant ions. In other examples, the position control system 214 may, additionally or alternatively, classify ions as proxy ions. Such classification can be useful when the extracted ion map is based only on ions classified as proxy ions. In some examples, the position control system 214 classifies selected ions as proxy ions in response to a determination that a threshold number (e.g., 1, 2, 3, 1 / 2, greater than 1 / 2, all, etc.) of applied classification criteria are met.

[0092] In some examples, ions not classified as contaminant ions are thus classified as proxy ions, or ions not classified as proxy ions are thus classified as contaminant ions. In other examples, the classification rules may allow for some gray area where some ions are not clearly classified as either contaminant ions or proxy ions. For example, a cross - correlation coefficient greater than a first threshold may indicate a proxy ion, a cross - correlation coefficient less than a second threshold may indicate a contaminant ion, and a cross - correlation coefficient between the first threshold and the second threshold may indicate an unclassified ion (e.g., a gray - area ion). Such unclassified ions can be used to generate an extracted ion map that excludes only contaminant ions, but not to generate an extracted ion map based only on proxy ions.

[0093] The classification rules and / or any specific parameters of each classification criterion may be set or selected manually by the user, set by default (e.g., established by the manufacturer), or set automatically based on various factors such as instrument type, experimental conditions, and / or environmental conditions.

[0094] In some examples, the position control system 214 presents ion classifications to the user (e.g., via a graphical user interface) and / or presents ion intensity maps extracted for one or more ions, and may receive user input (e.g., user input to classify or reclassify one or more selected ions) indicating which ions should be included when generating the ion intensity map. In a further example, the position control system 214 does not classify the selected ions, but instead presents a similarity score (e.g., a value of one or more classification parameters) determined based on a comparison of the ion map extracted for the selected ions and a reference ion map, and receives user input to classify the selected ions.

[0095] Referring again to FIG. 9, in operation 906, the position control system generates an ion intensity map (e.g., an extracted ion map) based on the classification of each selected ion of a set of mass spectra and a set of selected ions. For example, the position control system 214 may generate an extracted ion map based only on ions not classified as contaminant ions or based only on ions classified as proxy ions.

[0096] Once one or more ions have been classified and an ion intensity map has been generated based on the classification of the set of mass spectra and the one or more selected ions (operation 906), the position control system 214 performs operation 406 of method 400 to identify an optimal position of the emitter 208 based on the ion intensity map generated in operation 906.

[0097] Using the classification rules described above (e.g., based on a comparison of the extracted ion map (m / z 371) of FIG. 10 and the reference ion map of FIG. 11), the position control system 214 may classify the selected ion (m / z 371) as a contaminant ion. Thus, the position control system 214 may exclude the extracted ion map of FIG. 10 when generating an ion intensity map used to optimize the position of the emitter 208.

[0098] FIG. 12 shows a graph 1200 depicting an exemplary extracted ion map for another selected ion (m / z 136). The extracted ion map depicted by graph 1200 can be generated from a set of mass spectra obtained by sampling the search region 504 of FIGS. 6A and 6B. As shown in graph 1200, the extracted ion map shows the intensity values of m / z 136 at each (X,Y) coordinate position of emitter 208. As indicated by legend 1202, darker positions indicate higher intensity levels and lighter positions indicate lower intensity levels. Using the classification rules described above (e.g., based on a comparison of the extracted ion map (m / z 136) of FIG. 12 with the reference ion map of FIG. 11), position control system 214 does not classify the selected ion (m / z 136) as a contaminant and / or classifies the selected ion as a proxy ion. Thus, position control system 214 includes the extracted ion map of FIG. 12 when generating an ion intensity map used to optimize the position of emitter 208.

[0099] In the above example of ion classification, the reference ion map is generated based on a reference set of mass spectra. In other examples, the reference ion map is an ion map generated from a set of mass spectra. For example, the reference ion map may be a total ion map representing the signals of all ions detected for an experiment. Alternatively, the reference ion map may be an extracted ion map representing the signals of a subset of detected ions (e.g., all ions having an m / z less than a threshold amount such as 300 m / z). Position control system 214 can classify a selected ion based on the extracted ion map and the reference ion map for the selected ion in any of the ways described above. This classification allows position control system 214 to identify signals that do not behave like the overall signal pattern observed and classify the ions that generate such abnormal signals as contaminant ions.

[0100] In the ion intensity maps shown in FIGS. 11 and 12, the signal intensity has a local (e.g., circular) cloud distribution that can occur when sheath gas is not used. When sheath gas is used, due to the ion transport function of the sheath gas, the signal intensity can have a substantially linear or elongated cloud distribution. This fact can be utilized to classify ions that do not have a similar pattern. For example, the position control system 214 can identify the linear cloud pattern in the total ion map (reference ion map) and classify any ion having an extracted ion map without a similar linear cloud pattern as a contaminant ion.

[0101] FIG. 13 shows a graph 1300 depicting an exemplary total ion map having a linear cloud distribution. The total ion map depicted by graph 1300 can be generated from a set of mass spectra obtained by sampling the search region 504 of FIGS. 5A and 5B. As shown in graph 1300, the total ion map shows the total intensity values at each (Z, Y) coordinate position of the emitter 208. As indicated by the legend 1302, darker positions indicate higher intensity levels and lighter positions indicate lower intensity levels. As seen in graph 1300, the region of highest intensity forms a substantially linear cloud distribution as marked by a dashed line 1304 centered on the linear cloud.

[0102] Utilizing the linear cloud distribution resulting from the use of sheath gas as shown in FIG. 13, a rapid emitter position optimization process can be performed without mapping the entire search region. Next, an exemplary rapid optimization process will be described with reference to FIGS. 14 and 15.

[0103] FIG. 14 shows a flowchart of an exemplary method 1400 for performing a rapid optimization process. FIG. 14 shows exemplary operations according to one embodiment, although other embodiments may omit, add, reorder, and / or modify any of the operations shown in FIG. 14. Each operation of method 1400 can be performed in any suitable manner. FIG. 15 shows a side view of an exemplary configuration of emitter 208 positioned in front of inlet 212 of mass spectrometer 104. Legend L indicates that the Z-axis extends along longitudinal axis 1502 of inlet 212 (shown by the dashed line in FIG. 15), the Y-axis extends vertically within the page (from top to bottom in FIG. 15), is orthogonal to the Z-axis, the X-axis extends out of the page, and is arbitrarily oriented so as to be orthogonal to the Y-axis and the Z-axis. Emitter 208 is inclined with respect to longitudinal axis 1502 in the Y-Z plane.

[0104] Referring now to FIG. 14, in operation 1402, position control system 214 identifies a third axis position of emitter 208 relative to inlet 212. As described above, the third axis position is a fixed position relative to inlet 212 along a third axis (e.g., the X-axis) that is orthogonal to the first axis (e.g., the Z-axis) and the second axis (e.g., the Y-axis). Position control system 214 can perform operation 1402 in any of the ways described herein, based on a default third axis position or by performing method 700 described above, for example.

[0105] In operation 1404, position control system 214 identifies a search path. The search path is a virtual line within a search plane (e.g., the Y-Z plane) defined by the first and second axes and includes the third axis position that corresponds to or indicates the distribution of optimal emitter positions while the emitter remains at the third axis position. Here, operation 1404 will be described with reference to FIG. 15.

[0106] To identify the search path, the position control system 214 may obtain a set of mass spectrometry data by sampling along each of a set of scan lines 1504-1 to 1504-4 in the search plane 1506 (e.g., horizontal and / or vertical lines in the Y-Z plane). The position control system 214 sequentially positions the emitter 208 at each of a plurality of positions along the scan line 1504 and samples along each scan line 1504 by obtaining a mass spectrum while the emitter 208 is positioned at each of the plurality of positions along the scan line 1504. The position control system 214 accesses instrument configuration data indicating the instrument configuration (e.g., the orientation angle of the emitter 208 relative to the inlet 212, sheath gas settings (e.g., flow rate), sweep gas settings, FAIMS voltage, FAIMS gas settings, etc.) and can use the instrument configuration data to select two or more scan lines 1504 in the search plane 1506 that are expected to intersect the yet-to-be-identified search path. In some examples, the position control system 214 accesses the instrument configuration data based on the storage facility 302 of the position control system 214, the on-board memory of the emitter cartridge, and / or user input provided by the user. FIG. 15 shows four scan lines 1504, but the position control system 214 can sample along any other suitable number of scan lines 1504, such as 2 to 20, 4 to 15, or 5 to 10. Generally, the number of scan lines 1504 sampled is small to facilitate rapid optimization of the emitter position. Further, while FIG. 15 shows that only horizontal scan lines 1504 are sampled, in other examples, vertical scan lines and / or diagonal scan lines can be sampled in addition to or instead of the horizontal scan lines 1504.

[0107] The position control system 214 can then identify the optimal position 1508 (e.g., optimal positions 1508-1 to 1508-4) (e.g., the position of maximum intensity) for each scan line 1504 based on a set of mass spectra acquired while the emitter 208 is positioned along each scan line 1504. The position control system 214 can perform a regression (e.g., linear regression) to fit the search path 1510 to the optimal position 1508. When sheath gas is used, the search path 1510 generally follows a straight-line path from the emitter 208 to the inlet 212.

[0108] Referring again to FIG. 14, in operation 1406, the position control system 214 acquires a set of mass spectra while the emitter is sequentially positioned at a plurality of positions along the search path. For example, as shown in FIG. 15, the position control system 214 can sequentially position the emitter 208 at a plurality of positions along the search path 1510 and acquire a mass spectrum while the emitter 208 is positioned at each position along the search path 1510.

[0109] In operation 1408, the position control system can identify the optimal emitter position along the search path 1510 based on a set of mass spectra acquired by sampling along the search path 1510. The optimal position can be identified by any suitable method. For example, if signal intensity is the performance metric, the optimal position is the position along the search path 1510 where the detected signal intensity is maximum.

[0110] In operation 1410, the position control system 214 positions the emitter 208 at the optimal position identified in operation 1408. Then, an experiment can be performed with the emitter 208 in the optimal position. In method 1400, the optimal emitter position can be quickly identified without sampling a large search area.

[0111] In the above example, the signal intensity is the performance index, and the position control system 214 determines the optimal position of the emitter 208 based on the ion intensity map. In an alternative example, the performance index is a measure of signal stability (e.g., standard deviation or RSD), and the position control system 214 determines the optimal position of the emitter 208 based on the signal stability map. FIGS. 16A and 16B show graphs 1600A and 1600B depicting exemplary RSD maps, respectively. The RSD map depicted by graph 1600A can be generated from a set of mass spectra obtained by sampling the search region 504 of FIGS. 5A and 5B without using sheath gas, and the RSD map shown by graph 1600B can be generated from a set of mass spectra obtained by sampling the search region 504 of FIGS. 5A and 5B using sheath gas. As shown in graphs 1600A and 1600B, the RSD map shows the RSD values at each (Z, Y) coordinate position of the emitter 208. As indicated by legends 1602A and 1602B, brighter positions indicate lower RSD values (higher signal stability), and darker positions indicate higher RSD values (lower signal stability). Similarly, method 1400 may be performed using a measure of signal stability as the performance index instead of intensity.

[0112] Methods 400 and 1400 have been described above as optimizing the position of emitter 208, but methods 400 and 1400 can also optimize spray voltage, the flow rate of the mobile phase flowing through the emitter and / or the composition of the solvent in the mobile phase (such as in the case of a uniform solvent gradient), sheath gas flow rate, optional FAIMS gas flow rate, and / or other ion source parameters such as electrospray mode. In some examples, position control system 214 can optimize one or more additional parameters along with the emitter position. For example, sampling of the search region (e.g., operation 402) can be performed over a small 4-dimensional, 5-dimensional, or n-dimensional hypercube. As an alternative, position control system 214 can optimize one or more additional parameters independently of the emitter position. This may be performed, for example, after optimization of the emitter position. For example, after identifying the optimal emitter position, position control system 214 can optimize the sheath gas flow rate, FAIMS gas flow rate, mobile phase flow rate, solvent composition, spray voltage, and / or electrospray mode while emitter 208 is positioned at the optimal location.

[0113] In some examples, the position control system 214 can acquire multiple sets of mass spectra, and each set of mass spectra is acquired using a unique configuration of parameters (e.g., mobile phase flow rate, sheath gas flow rate, and spray voltage). For each set of mass spectra, the position control system 214 can execute method 400 or 1400 to identify the optimal emitter position. In this way, the position control system 214 identifies a set of multiple optimal positions for the emitter 208, and each optimal position is configured for a unique set of conditions / parameters. Then, the position control system 214 can automatically select a specific optimal emitter position from the set of optimal positions and move the emitter 208 to the selected optimal emitter position. Alternatively, the position control system 214 can provide information about the specific parameters of each optimal emitter position to the user and receive user input to select the specific optimal emitter position. Then, the position control system 214 can move the emitter 208 to the selected optimal emitter position.

[0114] As described above, the ion source 102 can be connected to a separation system (e.g., an LC system) and operated in an online mode. In the online mode, the composition of the mobile phase can change over time across the eluent gradient (e.g., the LC gradient). As a result, the optimal position of the emitter 208 can also change with the gradient. Other optimal ion source settings, such as the optimal spray voltage and / or the optimal sheath gas flow rate, can also change over time. Therefore, the position control system 214 can be configured to schedule the adjustment of the emitter 208 (e.g., the trajectory of the emitter 208) and / or the adjustment of other ion source settings to settings that are optimal at different positions and different times in the gradient. For this purpose, the position control system 214 can optimize the position of the emitter 208 and / or other ion source settings as described above, for different target analytes, for each selected m / z, and / or for different solvent conditions that can be anticipated during the course of the analysis run. During the analysis run, the position control system 214 can adjust the ion source parameters in real time according to the schedule.

[0115] Instead of scheduling the trajectory of emitter 208 and / or other ion source settings before performing the analysis run, the position control system 214 can optimize the emitter position and / or other ion source settings in real time during the analysis run when the mobile phase is changing. For example, the position control system 214 may detect when the eluate from the LC column changes (e.g., when a particular analyte is detected or when the intensity of the analyte reaches a threshold level), and in response, optimize the emitter position and / or other ion source settings using any of the methods described herein.

[0116] In some examples, methods 400 and 1400 can be used to determine the quality of emitter 208 or to determine whether emitter 208 is damaged. For this purpose, the position control system 214 may obtain data representing the default home position of emitter 208 (the "default optimization data") based on a given set of conditions (e.g., target analyte, solvent conditions, spray voltage, sheath gas flow rate, etc.). The default optimization data may be generated prior to performing methods 400 or 1400 for a particular experiment and may be stored anywhere, such as within a remote computing system, within an emitter cartridge for emitter 208, or within mass spectrometer 100. The default optimization data may be generated at the factory (e.g., before shipping emitter 208 to a customer) for a particular emitter 208. Alternatively, the default optimization data may be generated remotely (e.g., remotely from the position control system 214, mass spectrometer 100, or emitter cartridge) based on the optimization of one or more other emitters, such as based on an aggregation of optimization data collected for multiple different emitters each time a customer optimizes an emitter for an experiment.

[0117] The position control system 214 can execute method 400 or method 1400 to optimize the position of the emitter 208 under the same or similar conditions as the default optimization data. In some examples, before executing method 400 or method 1400, the position control system 214 may initialize the ion source 102 based on the default optimization data by positioning the emitter 208 at the default home position and setting other ion source settings to their default values. The position control system 214 can then execute method 400 or method 1400 to optimize the ion source settings.

[0118] Next, the position control system 214 can compare the obtained optimal ion source settings with the default optimization data. If the optimal position (or optimal spray voltage or sheath gas flow rate) of the emitter 208 is outside the acceptable range of the default optimization data (e.g., the optimal position varies from the expected optimal position by more than a threshold amount, or the signal measured at the optimal position does not meet a threshold criterion (e.g., minimum threshold intensity or SNR level or maximum threshold RSD)), the position control system 214 can determine that the emitter 208 is damaged or incorrectly installed and can perform a mitigation operation. The mitigation operation can include warning the user (e.g., by an audible, visual, or tactile notification or message) that the emitter 208 is not functioning correctly (e.g., damaged or incorrectly installed), executing another optimization method under different conditions, prompting the user to perform manual adjustments to the emitter 208 or other ion source settings or classification rules or criteria, and / or any other suitable operation.

[0119] In some examples, the quality check process described above may be performed for multiple different target analytes. For example, the position control system 214 may determine that the emitter 208 is functioning properly only if the quality check is satisfied for a minimum number of target analytes or over a specific m / z range.

[0120] Various modifications can be made to the examples described above in this specification. For example, the set of mass spectra can be obtained by acquiring two or more mass spectra at each emitter position and generating an ion intensity map based on a plurality of mass spectra (e.g., addition signal, average signal, median signal, etc.) for each emitter position.

[0121] In the example described above, the position control system 214 automatically positions the emitter 208 so as to optimize signal quality such as signal intensity, SNR, or stability (e.g., RSD). In other examples described herein, the position control system 214 automatically positions the emitter 208 so as to optimize the position of the emitter 208 for reproducibility. In these examples, the position control system 214 is configured to position the tip 210 of the emitter 208 at an optimal position relative to the inlet 212, and this position is at or sufficiently close to a reference position relative to the inlet 212, regardless of the type and configuration of the instruments and components used and regardless of the variation in the manufacturing tolerances of the instruments and components used. Next, image-based automatic positioning will be described with reference to FIG. 17.

[0122] FIG. 17 shows a functional diagram of an exemplary configuration 1700 of an interface between an ion source 102 and a mass spectrometer 104. Since the ion source 102 and the mass spectrometer 104 may have other suitable configurations, FIG. 17 is merely illustrative. The various elements shown and described in FIG. 17 have been shown and described with reference to FIG. 2 and will not be described again here.

[0123] The ion source 102 (e.g., the automatic positioning system 202) is attached to the mass spectrometer in a fixed relationship with the inlet 212, and the position of the inlet 212 relative to the ion source attachment part (not shown) can vary for different configurations and designs of the inlet 212. For example, the inlet 212 may have different configurations such as an orifice, a capillary, a FAIMS orifice, a letterbox inlet, a narrow bore inlet, or a slot inlet. In some examples, a sweep cap is placed over the inlet 212. In other examples, the inlet 212 protrudes beyond the sweep cap. Some configurations of the inlet 212 have protrusions, while other configurations do not. As a result of these variations, the position of the tip 210 can vary across different instrument configurations relative to the inlet 212 when the emitter 208 is positioned at the default position (e.g., the default motor position of the automatic positioning system 202). In some examples, it is up to 0.50 mm. In addition, the inlet 212 is generally sealed within the mass spectrometer 104 using an O-ring, and thus, even for the same type of inlet 212, variations in O-ring compression can result in variations in the position of the tip 210 relative to the inlet 212 across different instruments or installations, or over time as the O-ring wears. These variations are a combination of variations due to tolerances in the manufacture of various mechanical components, in addition to variations in multiple components. In the examples described herein, the position of the emitter 208 relative to the inlet 212 refers to the position of the emitter 208 relative to the center of the opening of the inlet 212 on a virtual plane that includes the outermost surface of the inlet 212 (e.g., the end of the inlet 212 closest to the emitter 208), and the plane is substantially orthogonal to the longitudinal axis 1702 of the inlet 212.

[0124] In ion source 102, the distance by which tip 210 protrudes from the distal end of nozzle 220 can vary across different emitters due to variations in manufacturing tolerances. For example, in the case of an electrospray ionization emitter, the protrusion of tip 210 from the distal end of nozzle 220 (denoted as distance d) can range from about 1.0 mm to about 2.5 mm across different emitters. As a result, when emitter 208 is positioned at the default position (e.g., the default motor position of the automatic positioning system 202), the position of tip 210 of emitter 208 relative to inlet 212 can vary across different emitters.

[0125] As a result of variations in ion source 102 and / or inlet 212, the reproducibility of experiments can be affected over time across different instrument types and configurations and / or as components wear. Position control system 214 can compensate for these variations by performing an automatic positioning process based on image data representing an image depicting inlet 212 and emitter 208 positioned near inlet 212.

[0126] As shown in FIG. 17, the ion source 102 includes an imaging system 1704 communicatively coupled to a position control system 214. The imaging system 1704 is configured to capture an image of an interface between the ion source 102 and the mass analyzer 104 (e.g., an image of the inlet 212 and the emitter 208 positioned near the inlet 212). The imaging system 1704 may be implemented by any suitable imaging system and may include software and hardware components. In the example of FIG. 17, since the position control system 214 positions the emitter 208 within a three-dimensional space in front of the inlet 212, the imaging system 1704 includes two cameras 1706 (e.g., camera 1706-1 and camera 1706-2) positioned such that the optical axes of the cameras 1706 are substantially orthogonal to each other (e.g., 90° ± 5°). For example, the first camera 1706-1 may be positioned above or below the emitter 208 with its optical axis extending along a first axis (e.g., the Y axis as in FIGS. 5A - 6B), and the second camera 1706-2 may be positioned laterally to the emitter 208 with its optical axis extending along a second axis (e.g., the X axis as in FIGS. 5A - 6B). The cameras 1706 are configured to capture a visible light image of the scene (including full-color, monochromatic, or non-white light images) and / or an infrared light image. It will be appreciated that the imaging system 1704 may include any other suitable number (e.g., three or more) of cameras. In other implementations, the imaging system 1704 includes one or more three-dimensional (3D) cameras configured to capture a three-dimensional image of the scene.

[0127] In some examples, imaging system 1704 also includes a control unit (not shown) configured to control the operation of camera 1706 (e.g., turn the camera sensor on and off, adjust zoom or focus, set exposure parameters, etc.) and an image processor (not shown) (e.g., software and / or hardware) for processing the captured image, such as performing white balance and / or adjusting gain. Imaging system 1704 outputs the processed image as image data 1708. FIG. 17 shows that position control system 214 and imaging system 1704 are separate, but in other examples, one or more components of imaging system 1704 (e.g., the control unit, image processor, etc.) are wholly or partially included within position control system 214.

[0128] In an image-based automatic positioning process, position control system 214 obtains image data 1708 from imaging system 1704 and adjusts the position of emitter 208 relative to inlet 212 (e.g., the position of tip 210) based on image data 1708. For example, position control system 214 can use image data 1708 to determine the optimal position of emitter 208 and instruct automatic positioning system 202 to move emitter 208 to the optimal position. The optimal position is a position that is at or within a threshold distance of a reference position relative to inlet 212. The reference position may be obtained by position control system 214 (e.g., from on-board memory on the emitter cartridge for emitter 208, from controller 106, or from a remote computing system), or may be determined experimentally, such as by performing method 400 or method 1400 described above.

[0129] In some examples, the image-based automatic positioning process is an iterative optimization process. Next, with reference to FIGS. 17 and 18, an exemplary image-based iterative automatic positioning process will be described. FIG. 18 shows a flowchart of an exemplary method 1800 for performing an image-based iterative automatic positioning process. Although FIG. 18 shows exemplary operations according to one embodiment, other embodiments may omit, add, reorder, and / or modify any of the operations shown in FIG. 18. Each operation of method 1800 can be performed in any suitable manner. The following description of method 1800 is described using the two-camera implementation of imaging system 1704 as described above. However, it will be recognized that method 1800 may alternatively be performed using any other suitable implementation of imaging system 1704.

[0130] Method 1800 begins with emitter 208 being positioned at an initial position. The initial position may be a default home position or a user-defined position. In some examples, the default position is a default motor position stored in the firmware of ion source 102 based on the fixed motor coordinates of the automatic positioning system 202. In some examples, the default home position is a reference position determined experimentally (e.g., by performing method 400 or method 1400). The default home position may be specific to a particular instrument configuration (e.g., inlet type, ion source, emitter type, etc.) and / or experimental conditions (e.g., mobile phase flow rate, sheath gas flow rate, sweep gas, spray voltage, spray mode, etc.). The particular instrument configuration and / or experimental conditions may be determined in any suitable manner, such as based on user input provided by controller 106 or position control system 214, by accessing the instrument configuration stored in controller 106 or ion source 102, and / or based on image recognition (described in more detail below) using the image data 1708 generated by imaging system 1704.

[0131] In operation 1802, the position control system 214 obtains image data 1708 representing an image captured while the emitter 208 is positioned at its current position (e.g., the initial position). The image data 1708 includes data representing one or more images captured by the first camera 1706-1 and one or more images captured by the second camera 1706-2. To obtain the image data 1708, the position control system 214 can instruct the imaging system 1704 to capture one or more images of the scene while the emitter 208 is positioned at its current position.

[0132] In operation 1804, the position control system 214 determines an updated position of the emitter 208 based on the image data 1708. For example, the position control system 214 can determine the motor step direction and / or motor step size of the automatic positioning system 202 and / or determine an updated position (motor coordinates) of the emitter 208 based on the determined steps. The step direction and / or step size and the corresponding updated emitter position can be determined using an emitter positioning algorithm and the image data 1708 of the current emitter position. Any suitable algorithm or model, such as an iterative algorithm, an optimization algorithm, and / or a machine learning model, can be used as the emitter positioning algorithm. In some examples, some randomness can be used in determining the step direction and / or step size. For example, the emitter positioning algorithm can incorporate a random search or a random walk.

[0133] In some examples, the emitter positioning algorithm is configured to compare the image data 1708 to reference image data to determine the proximity of the current position of the emitter to the reference position of the emitter. The reference position of the emitter may be determined from the reference image data, which includes one or more sets of images depicting an emitter positioned at a reference position (e.g., an ideal or optimal position) relative to the inlet. Each set of images of the reference image data may include a first image captured by camera 1706-1 and a second image captured by camera 1706-2. Each set of images of the reference image data may depict a unique configuration of the ion source, the inlet, or a combination of the ion source and the inlet. For example, each set of images of the reference image data may depict an emitter having a unique variation in the protrusion of the tip 210 from the distal end of the nozzle 220. Additionally or alternatively, each set of images of the reference image data may depict a unique type of inlet 212. Thus, the reference image data depicts various different configurations of the emitter positioned at the reference position relative to the inlet. The reference image data may be generated prior to executing method 1800 using configuration 1700 or any other configuration of the ion source and the inlet.

[0134] The emitter positioning algorithm may be configured to compare the image data 1708 to reference image data to determine the direction in which the emitter is currently offset from the reference position ("offset direction"). In some examples, the emitter positioning algorithm is based on the assumption that the emitter tip within each image set is positioned approximately the same position relative to the inlet, regardless of the particular configuration of the ion source and the inlet, and can determine the offset direction based on a plurality of different image sets included in the reference image data. In other examples, the emitter positioning algorithm can select a particular image set (e.g., the image set that best matches the image data 1708, e.g., the image set that best matches the emitter configuration and / or inlet configuration depicted in the image data 1708) and determine the offset direction based on the selected image set.

[0135] Instead of comparing the image data 1708 with the reference image data, the emitter positioning algorithm may be pre-trained based on the reference image data to determine the 3D coordinates of the reference emitter position (e.g., motor coordinates) relative to the entrance. Thus, the emitter positioning algorithm can be configured to determine the offset direction based on the image data 1708 and the coordinates of the reference emitter position.

[0136] Based on the determined offset direction, the emitter positioning algorithm can determine the motor step direction of the automatic positioning system 202. The emitter positioning algorithm can also determine the motor step size and, based on the determined step direction and motor step size, determine the updated position of the emitter 208 (e.g., updated motor coordinates).

[0137] The motor step size can be fixed (e.g., constant throughout method 1800), selected from a schedule, adaptively determined, and / or dynamically modified during method 1800. A large step size can make method 1800 robust to noise, while a smaller step size can prevent method 1800 from overshooting the optimum value. The motor step size can be predefined (e.g., accessed from memory) or determined based on the image data 1708. For example, the emitter positioning algorithm can determine the extent (e.g., distance) by which the emitter is currently offset from the reference position ("offset distance"). The offset distance can be measured, for example, as the number of pixels within the image data 1708. The motor step size can be determined to completely close the offset distance. Alternatively, the motor step size can be selected to close only a portion of the offset distance or otherwise vary based on the offset distance. For example, the motor step size can decrease (linearly or non-linearly (e.g., exponentially)) as the offset distance decreases. In a further example, the motor step size can decrease for each successive iteration of method 1800.

[0138] As described above, the image features used by the emitter positioning algorithm to determine the updated emitter position are identified in the image data 1708 and distinguished from the noise features. The noise features may include, for example, deposits on the surface of the inlet 212 and / or the emitter 208, background or ambient features, and / or any other features captured in the image that are not used to position the emitter 208. The emitter positioning algorithm may use any suitable image recognition and / or image segmentation process to identify the image features. The image features that can be identified in the image data 1708 include, for example, reference points on the inlet 212 and / or the emitter 208.

[0139] The reference points on the emitter 208 are recognizable in the image data 1708 and are consistently positioned at a fixed distance from the tip 210 across different emitters and emitter types, and generally have little or no variation. Thus, even if the distance d from the tip 210 to the nozzle 220 varies across different emitters and emitter types, the variation in the distance from the tip 210 to the reference point is negligible across different emitters and emitter types.

[0140] In some examples, the reference point on the emitter 208 is an inherent attribute of the emitter 208, such as the tip 210 or the distal end of an outer coating on the emitter 208. FIG. 19A shows an exemplary configuration of an emitter 208 where the reference point is the distal end of the outer coating of the emitter 208. As shown, the emitter 208 is formed from a fused silica core 1902 having an internal lumen 1904 through which the mobile phase can flow. The fused silica core 1902 is coated with an outer coating 1906 such as polyimide. The coating 1906 terminates at a fixed distance from the tip 210 (e.g., machined or ground from the fused silica core 1902). The distal end 1908 of the coating 1906 is an edge feature that can be easily detected in the image data 1708 and thus can be used to determine the updated position of the emitter 208. The distal end 1908 of the coating 1906 may be easier to detect than the tip 210, which generally has small dimensions that may be difficult to distinguish from background features.

[0141] In other examples, the reference point on the emitter 208 is a reference marker added to the emitter 208. FIG. 19B shows an exemplary configuration of an emitter 208 where the reference point is a reference marker added to the emitter 208. FIG. 19B is similar to FIG. 19A, except that in FIG. 19B, the emitter 208 includes a reference marker 1910 on the coating 1906. As shown in FIG. 19B, the reference marker 1910 is a colored band on or around the coating 1906. It will be appreciated that the reference marker 1910 may have any suitable color, shape (e.g., dot, cross, etc.), and / or pattern that can be recognized through image recognition or image segmentation techniques.

[0142] In some examples, the emitter positioning algorithm is trained to distinguish image features used to determine an updated emitter position in image data 1708 from noise features. Noise features may include, for example, deposits on the surface of inlet 212 and / or emitter 208, background or ambient features, or any other features captured in the image that are not used to position emitter 208. Training of the emitter positioning algorithm is described in more detail below.

[0143] In operation 1806, the position control system 214 determines whether a stop criterion is met. Exemplary stop criteria are described in more detail below. If the position control system 214 determines that the stop criterion is not met, method 1800 proceeds to operation 1808. In operation 1808, the position control system 214 controls the automatic positioning system 202 to move the emitter 208 to the updated emitter position identified in operation 1804. Next, the process of method 1800 returns to operation 1802 to perform another iteration.

[0144] However, if the position control system 214 determines that the stop criterion is met, the position control system 214 ends method 1800. When method 1800 ends, the emitter 208 remains at its current position (e.g., the updated position identified in operation 1804 of the immediately preceding iteration). Thus, method 1800 can be used by the position control system 214 to iteratively adjust the position of the emitter 208 until the emitter 208 is positioned optimally with respect to the inlet 212 (e.g., within a threshold distance (e.g., 100 μm) of the reference position, or within that range).

[0145] Any suitable stop criterion (or criteria) can be used to serve a particular implementation. In some examples, the stop criterion includes completion of a predetermined number of iterations. For example, the position control system 214 can track the number of iterations performed in method 1800 and end method 1800 when the number of iterations matches a threshold number (e.g., 10).

[0146] In additional or other examples, the stopping criterion includes a minimum threshold step size. In this example, the step size (or maximum step size) can decrease progressively with each iteration. As a result, a particular small step size can be presumed to indicate that the optimal emitter position has been reached. In a modified example, the stopping criterion includes performing a minimum number (e.g., three times) of consecutive steps each having a step size below a minimum threshold step size.

[0147] In another example, the stopping criterion may be based on the probability of the step direction of the next step. For example, the position control system 214 can determine the probabilities of reverse iteration steps and forward iteration steps and compare these probabilities. The step direction probability may be determined in any suitable manner and may not depend on the step size. If the probabilities are approximately equal (e.g., within a set tolerance range or threshold range of each other, such as within a range of 1%, 0.1%, etc., that can be set), the position control system 214 can end the method 1800.

[0148] In yet a further example, the stopping criterion can include a determination that the improvement of the emitter position has stopped. For example, the position control system 214 can determine whether the current emitter position is better than the emitter position of the previous iteration based on the image data 1708 captured during the current iteration. In response to a determination that the current emitter position of the current iteration is not better than the emitter position of the previous iteration, the position control system 214 can end the method 1800. The position control system 214 can compare the image data 1708 from different iterations in any suitable manner, such as by applying one-way analysis of variance, Mann-Whitney U test, Student's t test, and / or any other suitable population-based comparison method.

[0149] In some examples, upon completion of method 1800, the position control system 214 may store data representing the optimal emitter position in the on-board memory of the emitter cartridge and / or the storage facility of the mass spectrometer 100 (the optimal position may be associated with a particular emitter cartridge and / or all emitter cartridges of the same type). Additionally or alternatively, the position control system 214 may transmit data representing the optimal emitter position to a remote computing system, and the remote computing system may use the data alone or in combination with data received from other optimizations to establish a default home position for a particular instrument configuration.

[0150] In a modified example of method 1800, prior to operation 1802, the position control system 214 may determine the instrument interface settings and, based on the determined instrument interface settings, select an appropriate emitter positioning algorithm (e.g., an algorithm trained for the same or similar instrument settings) for positioning the emitter 208. The instrument interface settings may indicate the type and / or configuration (e.g., size, dimensions, geometry, etc.) of the emitter 208 and / or the inlet 212. For example, the instrument settings may indicate dimensions of the emitter 208 such as the distance from the tip 210 to the nozzle 220, or the distance from the tip 210 to a reference marker on the emitter 208.

[0151] In some examples, the position control system 214 determines the instrument settings by accessing stored data indicating the instrument settings. For example, the position control system 214 may obtain data indicating the type of the inlet 212 from the controller 106. Additionally or alternatively, the position control system 214 may obtain the type or configuration of the emitter 208 from the on-board memory of the ion source 102 or the emitter cartridge mounted within the ion source 102.

[0152] In a further example, the position control system 214 may determine the instrument settings based on the image data 1708 captured while the emitter is in its initial (e.g., default) position (or while the emitter is in any other position). The position control system 214 can determine the instrument settings based on the image data 1708 in any suitable way, such as based on image segmentation and recognition of the shape of the emitter 208 and / or the shape of the inlet 212. In some examples, the position control system 214 is configured to classify the instrument settings based on the image data 1708 of the instrument settings and applies the image data 1708 as an input to a trained classification model. In some examples, the trained classification model can be trained to classify the type of inlet (e.g., orifice, capillary, FAIMS orifice, letterbox inlet, narrow bore inlet, slotted inlet, etc.) and / or the type of sweep cap installed at the inlet. The output of the trained classification model may be a classification or, optionally, a confidence score for the classification. In some examples, the position control system 214 can determine the instrument settings based on the output classification only when the confidence score exceeds a threshold level. The trained classification model can be implemented by any suitable machine learning model, including but not limited to a neural network (e.g., convolutional neural network (CNN)) or a decision tree algorithm. In some examples, the classification model is a supervised machine learning model trained using labeled image data depicting various different instrument settings.

[0153] In other examples, the position control system 214 can determine the instrument settings based on image segmentation and recognition of the emitter identification marker and / or the inlet identification marker. In these examples, the emitter identification marker is a reference marker disposed on the emitter 208 and identifies the type and / or configuration (e.g., size, dimensions, geometry, etc.) of the emitter 208. The reference marker can be implemented by, for example, a color-coded marker, a shape-coded marker, a pattern-coded marker (e.g., barcode, QR (registered trademark) code, etc.), and / or any other distinguishable marker. Similarly, the inlet identification marker is a reference marker positioned near the inlet 212 and identifies the type and / or configuration (e.g., size, dimensions, etc.) of the inlet 212. The reference marker can be implemented by, for example, a color-coded marker, a shape-coded marker, a pattern-coded marker, and / or any other distinguishable marker. The information indicated by the emitter identification marker and / or the inlet identification marker can be used in any suitable manner, such as to select an appropriate emitter positioning algorithm from among a plurality of different emitter positioning algorithms.

[0154] The above examples illustrate optimizing the position of the emitter 208 relative to the inlet 212, but the position control system 214 can additionally or alternatively optimize the angle or orientation of the emitter 208 relative to the inlet 212 (e.g., the longitudinal axis 502 of the inlet 212). For example, the automatic positioning system 202 can be configured to rotate the emitter 208 (or the emitter cartridge) about any one or more of the X, Y, and Z axes. The orientation of the emitter 208 relative to the inlet 212 may be adjusted using the methods 400, 1400, and / or 1800 described above. In further modification examples, the principles described herein can be applied to any other type of ESI source, including but not limited to conventional ESI, paper spray ionization, polymer spray ionization, etc.

[0155] As described above, the emitter positioning algorithm can be configured to optimize the position of the emitter 208 relative to the inlet 212 using the image data 1708. In some examples, the emitter positioning algorithm is trained to recognize features within the image data 1708 by any suitable image recognition and / or image segmentation process. The emitter positioning algorithm can be trained in any suitable manner. In some examples, the training data set includes reference image data representing multiple sets of images each depicting a particular configuration of an inlet type (e.g., a FAIMS inlet, an ITT inlet, an HCTT inlet, etc.), and the emitter is positioned at a reference position relative to the inlet within each image. The set of images can include a first image captured by the camera 1706-1 and a second image captured by the camera 1706-2 for each inlet type and emitter configuration. In some examples, the training data set includes different sets of images having the same inlet configuration but different noise levels (e.g., depicting different levels of deposits on the inlet and / or emitter and / or different background features). The emitter positioning algorithm can be trained to recognize features (e.g., the tip 210 of the emitter 208, the distal end 1908 of the coating 1906, the reference marker 1910, the inlet 212) used to position the emitter 208 and / or to ignore noise (e.g., accumulated surface deposits on the inlet 212, accumulated surface deposits on the emitter 208, and / or background features).

[0156] In some examples, a trained emitter positioning algorithm can be used to determine whether emitter 208 has been replaced by comparing previously stored image data 1708 with current image data 1708 (e.g., image data 1708 captured while emitter 208 is positioned at its current location). In response to a determination that the distance d from tip 210 to nozzle 220 has changed by more than a threshold amount (e.g., more than 50 μm, more than 100 μm, or more than 150 μm), position control system 214 may adjust the emitter position coordinates (e.g., motor coordinates for automatic positioning system 202) stored for the currently installed emitter cartridge. In this way, position control system 214 can automatically execute method 1800 when the emitter cartridge is replaced during an experiment. In additional or alternative examples, in response to a determination that the distance d from tip 210 to nozzle 220 has changed by more than a threshold amount, position control system 214 can reset a counter on the emitter cartridge that indicates the usage history or estimated remaining useful life of the emitter (e.g., number of injections, number of power-on hours, current or total amount of solvent exiting the emitter).

[0157] In some examples, position control system 214 may be configured to use image data representing a captured image depicting spray chamber 216 to optimize the position of emitter 208 relative to inlet 212. For example, camera 1706-1 and / or 1706-2, or an additional camera (not shown in FIG. 17), may be configured to capture an image of spray chamber 216 when the mobile phase passes through emitter 208 and is discharged toward inlet 212. The emitter positioning algorithm used by position control system 214 to position emitter 208 may be configured to determine the position of emitter 208 relative to inlet 212 using image data representing the captured image of spray chamber 216 in addition to or instead of image data 1708. For example, position control system 214 can use the image of spray chamber 216 to align spray chamber 216 with inlet 212.

[0158] In some examples, the position control system 214 may be configured to use the image data 1708 to determine the state of the instrument (e.g., emitter 208 and / or inlet 212). For example, the position control system 214 may compare the image data 1708 with reference image data depicting the emitter 208 and / or inlet 212 when the emitter 208 and / or inlet 212 is in an ideal (e.g., new, recently cleaned, good, satisfactory, etc.) state, and based on the comparison, determine whether the inlet 212 is in a good state or a bad state. Any suitable image recognition technique may be used for the comparison. In some examples, the position control system 214 can apply the image data 1708 to a trained machine learning model trained to classify instrument states. Possible instrument state classifications may include, for example, "good" and "bad". Other instrument state classifications may be possible, such as one or more intermediate instrument states (e.g., "moderate"). In a further example, the instrument state may be represented by a numerical value, such as a number between 100% (best state) and 0% (worst state). In some examples, the number can represent the degree of accumulation of deposits on and / or around the emitter 208 and / or inlet 212. Any suitable machine learning model, such as a logistic regression model, a neural network (e.g., CNN), a decision tree model, a naive Bayes model, a k-nearest neighbor (KNN) model, or a support vector machine (SVM), may be used. The machine learning model can be trained in any suitable way, including supervised learning or unsupervised learning. In some examples, the training dataset includes image data depicting the instrument under various different conditions (e.g., different levels of deposit accumulation). In some examples, the training dataset is labeled with a known classification for each depicted instrument state.

[0159] The position control system 214 may be configured to perform a specific operation based on the determined instrument state. In some examples, the position control system 214 may provide an indication of the instrument state. The indication may be provided, for example, at the beginning of the execution of method 400 or method 1800. Additionally or alternatively, the indication may be provided at any time, including during the analysis experiment, in response to a user input that requests a report of the instrument state. In a further example, when the instrument state is determined to be in a particular state (e.g., "bad" or below a threshold level (e.g., 70%)), the position control system 214 may automatically provide a notification of the instrument state by, for example, a display screen communicatively coupled to the position control system 214, may pause the execution of the experiment until a user input for the user to resume the experiment is provided, and / or the position control system 214 may pause the execution of the experiment until it is determined that the inlet state has improved (e.g., changed to "good" or exceeded the threshold level (e.g., exceeded 70%)).

[0160] For the examples described above herein, various modifications can be made. For example, the ion source 102 may be configured to emit ions from the emitter 208 towards the inlet of any other ion manipulation device, such as an ion guide, ion optics, or ion mobility separator. In other modification examples, the systems and methods described above may be used with other electrospray ionization techniques, such as paper spray ionization and polymer spray ionization.

[0161] In certain embodiments, one or more of the processes described herein may be at least partially implemented as instructions embodied in a non-transitory computer-readable medium and executable by one or more computing devices. Generally, a processor (e.g., a microprocessor) receives instructions from a non-transitory computer-readable medium (e.g., memory, etc.) and executes those instructions, thereby performing one or more processes including one or more of the processes described herein. Such instructions may be stored and / or transmitted using any of a variety of known computer-readable media.

[0162] A computer-readable medium (also referred to as a processor-readable medium) includes any non-transitory medium that participates in providing data (e.g., instructions) that can be read by a computer (e.g., by a processor of the computer). Such a medium can take many forms, including but not limited to non-volatile media and / or volatile media. Non-volatile media can include, for example, optical or magnetic disks, and other permanent memories. Volatile media can include, for example, dynamic random access memory (“DRAM”), which typically constitutes main memory. Common forms of computer-readable media include, for example, disks, hard disks, magnetic tapes, any other magnetic media, compact disc read-only memory (“CD-ROM”), digital video disc (“DVD”), any other optical media, random access memory (“RAM”), programmable read-only memory (“PROM”), electrically erasable programmable read-only memory (“EPROM”), FLASH-EEPROM, any other memory chip or cartridge, or any other tangible medium that can be read by a computer.

[0163] Figure 20 shows an exemplary computing device 2000 that can be specifically configured to execute one or more of the processes described herein. As shown in Figure 20, the computing device 2000 may include a communication interface 2002, a processor 2004, a memory device 2006, and an input / output (I / O) module 2008 that are communicatively connected to each other via a communication infrastructure 2010. Although an exemplary computing device 2000 is shown in Figure 20, the components illustrated in Figure 20 are not intended to be limiting. In other embodiments, additional or alternative components may be used. Next, the components of the computing device 2000 shown in Figure 20 will be described in more detail.

[0164] The communication interface 2002 can be configured to communicate with one or more computing devices. Examples of the communication interface 2002 include, but are not limited to, a wired network interface (such as a network interface card), a wireless network interface (such as a wireless network interface card), a modem, an audio / video connection, and any other suitable interface.

[0165] The processor 2004 generally represents any type or form of processing unit that enables data to be processed and / or one or more of the instructions, processes, and / or operations described herein to be interpreted, executed, and / or instructions for their execution to be directed. The processor 2004 can perform operations by executing computer-executable instructions 2012 (such as applications, software, code, and / or other executable data instances) stored in the memory device 2006.

[0166] The memory device 2006 can include one or more data storage media, devices, or configurations, and can employ any type, form, and combination of data storage media and / or devices. For example, the memory device 2006 can include, but is not limited to, any combination of the non-volatile media and / or volatile media described herein. The electronic data including the data described herein can be stored temporarily and / or permanently within the memory device 2006. For example, data representing computer-executable instructions 2012 configured to instruct the processor 2004 to execute any of the operations described herein may be stored within the memory device 2006. In some examples, the data may be arranged in one or more databases existing within the memory device 2006.

[0167] The I / O module 2008 can include one or more I / O modules configured to receive user input and provide user output. One or more I / O modules can be used to receive input for a single virtual experience. The I / O module 2008 can include any hardware, firmware, software, or combination thereof that supports input and output capabilities. For example, the I / O module 2008 can include, but is not limited to, a keyboard or keypad, a touch screen component (e.g., a touch screen display), a receiver (e.g., an RF or infrared receiver), a motion sensor, and / or one or more input buttons, and may include hardware and / or software for capturing user input.

[0168] The I / O module 2008 can include one or more devices for presenting output to the user, including, but not limited to, a graphics engine, a display (e.g., a display screen), one or more output drivers (e.g., a display driver), one or more audio speakers, and one or more audio drivers. In certain embodiments, the I / O module 2008 is configured to provide graphical data to a display for presentation to the user. The graphical data can represent one or more graphical user interfaces and / or any other graphical content, as may be useful in a particular implementation.

[0169] In some examples, any of the systems, computing devices, and / or other components described herein can be implemented by the computing device 2000. For example, the storage facility 302 may be implemented by the storage device 2006, and the processing facility 304 may be implemented by the processor 2004.

[0170] On the other hand, it will be recognized by those skilled in the art that, in the foregoing description, various exemplary embodiments have been described with reference to the accompanying drawings. However, it will be apparent that various modifications and changes may be made thereto without departing from the scope of the invention as set forth in the following claims, and additional embodiments may be implemented. For example, the specific features of one embodiment described herein may be combined with or substituted for the features of another embodiment described herein. Accordingly, the present specification and drawings are to be considered in an illustrative, rather than a limiting, sense.

[0171] The advantages and features of the present disclosure can be further illustrated by the following examples.

[0172] Example 1. A system comprising one or more processors and a memory storing executable instructions, wherein the executable instructions, when executed by the one or more processors, cause the computing device to: obtain a set of mass spectra, wherein obtaining the set of mass spectra comprises instructing an auto-positioning system to sequentially position an ionization emitter at a plurality of positions relative to an inlet of a mass spectrometer, and instructing the mass spectrometer to obtain a mass spectrum of ions introduced into the inlet while the ionization emitter is positioned at each of the plurality of positions, wherein the ions introduced into the inlet include ions emitted from the ionization emitter; generate an ion intensity map representing the detected intensity of ions introduced into the inlet of the mass spectrometer as a function of the position of the ionization emitter, based on the set of mass spectra; and identify an optimal position of the ionization emitter based on the ion intensity map.

[0173] Example 2. The system of Example 1, wherein the ion intensity map includes a total ion map showing the total intensity of ions while the ionization emitter is positioned at each of the plurality of positions for each position of the plurality of positions.

[0174] Example 3. The system of Example 1, wherein the ion intensity map includes an extracted ion map showing the total intensity of a subset of ions while the ionization emitter is positioned at each of the plurality of positions for each position of the plurality of positions.

[0175] Example 4. The system of Example 3, wherein the subset of ions includes a set of ions corresponding to the strongest signals.

[0176] Example 5. The system of Example 3, wherein the subset of ions includes only ions having an m / z value less than an m / z threshold.

[0177] Example 6. The system of Example 5, wherein the m / z threshold is about 300 m / z.

[0178] Example 7. The system described in Example 3, wherein the subset of ions comprises only solvent ions.

[0179] Example 8. The system described in Example 3, wherein the process further comprises classifying selected ions introduced at the inlet as contaminant ions, and the subset of ions excludes ions classified as contaminant ions.

[0180] Example 9. The system described in Example 8, wherein classifying selected ions as contaminant ions comprises generating an extracted ion map for the selected ions based on a set of mass spectra and classifying the selected ions based on the extracted ion map and a reference ion map.

[0181] Example 10. The system described in Example 9, wherein the reference ion map is based on a reference set of mass spectra.

[0182] Example 11. The system described in Example 9, wherein the reference ion map comprises a total ion map generated based on a set of mass spectra.

[0183] Example 12. The system described in Example 9, wherein classifying selected ions based on the extracted ion map and the reference ion map comprises determining at least one of a cross-correlation coefficient and a matrix norm to mean ratio based on the extracted ion map and the reference ion map.

[0184] Example 13. The system described in Example 8, wherein classifying selected ions as contaminant ions comprises flowing sheath gas coaxially around ions emitted from an ionization emitter and determining that an extracted ion map for the selected ions does not have a linear cloud distribution.

[0185] Example 14. The process further includes classifying one or more of the ions introduced at the inlet as proxy ions, and the subset of ions includes only one or more ions classified as proxy ions, the system according to Example 3.

[0186] Example 15. Each mass spectrum of the set of mass spectra is obtained by a selected ion monitoring (SIM) acquisition method, the system according to Example 1.

[0187] Example 16. The SIM acquisition method covers an m / z range of about 30 m / z to about 300 m / z, the system according to Example 15.

[0188] Example 17. The process further includes instructing an automatic positioning system to position the ionization emitter at an optimal position, the system according to Example 1.

[0189] Example 18. The sheath gas flows coaxially around the ions emitted from the ionization emitter, and the plurality of positions relative to the inlet are located along a linear search path, the system according to Example 1.

[0190] Example 19. The process further includes identifying a search path, and identifying the search path includes obtaining an additional set of mass spectrum data by sequentially positioning the emitter at a plurality of positions along each of a plurality of scan lines, obtaining a mass spectrum while the emitter is positioned at each of the plurality of positions, identifying an optimal position along each scan line based on the additional set of mass spectra, and determining the search path based on the optimal positions of each scan line, the system according to Example 18.

[0191] Example 20. A non-transitory computer-readable medium storing instructions that, when executed, cause at least one processor of a computing device for mass spectrometry to obtain a set of mass spectra, the obtaining of the set of mass spectra including instructing an auto-positioning system to sequentially position an ionization emitter at a plurality of positions relative to an inlet of a mass spectrometer, and instructing the mass spectrometer to obtain a mass spectrum of ions introduced into the inlet while the ionization emitter is positioned at each of the plurality of positions, the ions introduced into the inlet including ions emitted from the ionization emitter, generating an ion intensity map representing the detected intensity of ions introduced into the inlet of the mass spectrometer as a function of the position of the ionization emitter based on the set of mass spectra, and identifying an optimal position of the ionization emitter based on the ion intensity map.

[0192] Example 21. The computer-readable medium of Example 20, wherein the ion intensity map includes a total ion map showing the total intensity of ions while the ionization emitter is positioned at each of the plurality of positions for each position of the plurality of positions.

[0193] Example 22. The computer-readable medium of Example 20, wherein the ion intensity map includes an extracted ion map showing the total intensity of a subset of ions while the ionization emitter is positioned at each of the plurality of positions for each position of the plurality of positions.

[0194] Example 23. The computer-readable medium of Example 22, wherein the subset of ions includes a set of ions corresponding to the strongest signals.

[0195] Example 24. The computer-readable medium of Example 22, wherein the subset of ions includes only ions having an m / z value less than an m / z threshold.

[0196] Example 25. The computer-readable medium described in Example 24, wherein the m / z threshold is about 300 m / z.

[0197] Example 26. The computer-readable medium described in Example 22, wherein the subset of ions contains only solvent ions.

[0198] Example 27. The computer-readable medium described in Example 22, wherein the process further includes classifying selected ions introduced at the inlet as contaminant ions, and the subset of ions excludes the ions classified as contaminant ions.

[0199] Example 28. Classifying the selected ions as contaminant ions includes generating an extracted ion map for the selected ions based on a set of mass spectra, and classifying the selected ions based on the extracted ion map and a reference ion map. The computer-readable medium described in Example 27.

[0200] Example 29. The computer-readable medium described in Example 28, wherein the reference ion map is based on a reference set of mass spectra.

[0201] Example 30. The computer-readable medium described in Example 28, wherein the reference ion map includes a total ion map generated based on a set of mass spectra.

[0202] Example 31. Classifying the selected ions based on the extracted ion map and the reference ion map includes determining at least one of a cross-correlation coefficient and a matrix norm to mean ratio based on the extracted ion map and the reference ion map. The computer-readable medium described in Example 28.

[0203] Example 32. Classifying selected ions as contaminant ions includes the sheath gas flowing coaxially around the ions emitted from the ionization emitter and determining that the ion map extracted for the selected ions does not have a linear cloud distribution, the computer-readable medium described in Example 27.

[0204] Example 33. The process further includes classifying one or more of the ions introduced at the inlet as proxy ions, and the subset of ions includes only one or more ions classified as proxy ions, the computer-readable medium described in Example 22.

[0205] Example 34. Each mass spectrum of the set of mass spectra is acquired by a selected ion monitoring (SIM) acquisition method, the computer-readable medium described in Example 20.

[0206] Example 35. The SIM acquisition method covers an m / z range of about 30 m / z to about 300 m / z, the computer-readable medium described in Example 34.

[0207] Example 36. The process further includes instructing an automatic positioning system to position the ionization emitter at an optimal position, the computer-readable medium described in Example 20.

[0208] Example 37. The sheath gas flows coaxially around the ions emitted from the ionization emitter, and the plurality of positions relative to the inlet are located along a linear search path, the computer-readable medium described in Example 20.

[0209] Example 38. The process further includes identifying a search path, and identifying the search path includes obtaining an additional set of mass spectrum data by sequentially positioning an emitter at a plurality of positions along each of a plurality of scan lines, obtaining a mass spectrum while the emitter is positioned at each of the plurality of positions, identifying an optimal position along each scan line based on the additional set of mass spectrum data, and determining a search path based on the optimal position of each scan line. The computer-readable medium according to Example 37.

[0210] Example 39. A system comprising one or more processors and a memory storing executable instructions, which when executed by the one or more processors cause the computing device to obtain a set of mass spectra, and obtaining the set of mass spectra includes instructing an automatic positioning system to sequentially position an ionization emitter at a plurality of positions relative to an inlet of a mass spectrometer, and instructing the mass spectrometer to obtain a mass spectrum of ions introduced into the inlet while the ionization emitter is positioned at each of the plurality of positions, where the ions introduced into the inlet include ions emitted from the ionization emitter, obtaining, generating an ion signal quality map representing a performance index of a signal corresponding to ions introduced into the inlet of the mass spectrometer as a function of the position of the ionization emitter based on the set of mass spectra, and identifying an optimal position of the ionization emitter based on the ion signal quality map.

[0211] Example 40. The system according to Example 39, wherein the performance index includes a signal-to-noise ratio (SNR), and the ion signal quality map includes an SNR map.

[0212] Example 41. The system according to Example 39, wherein the performance index includes a relative standard deviation (RSD), and the ion signal quality map includes an RSD map.

[0213] Example 42. The system of Example 39, wherein the performance index includes a measure of signal stability and the ion signal quality map includes a signal stability map.

[0214] Example 43. The system of Example 39, wherein the process further includes instructing an auto-positioning system to position an ionization emitter at an optimal position.

[0215] Example 44. A system comprising one or more processors and a memory storing executable instructions, wherein the executable instructions, when executed by the one or more processors, cause a computing device to obtain image data representing one or more images depicting an inlet of a mass spectrometer and an emitter positioned near the inlet, and based on the image data, adjust the position of the emitter relative to the inlet to a reference position relative to the inlet or an optimal position near it.

[0216] Example 45. The system of Example 44, wherein the process includes an iterative optimization process including a plurality of iterations, each iteration including obtaining a portion of the image data while the emitter is positioned at a current position, an emitter positioning algorithm, and determining an updated position of the emitter based on the emitter positioning algorithm and the portion of the image data obtained while the emitter is positioned at the current position, and instructing an auto-positioning system to move the emitter to the updated position.

[0217] Example 46. The system of Example 45, wherein each iteration further includes determining whether a stop criterion is met and, in response to determining that the stop criterion is met, ending the iterative optimization process.

[0218] Example 47. Determining that the stop criterion is met includes determining that, based on a portion of the image data captured during the current iteration, the probability of a reverse iteration step and the probability of a forward iteration step are within an acceptable range of each other.

[0219] Example 48. The system of Example 45 further includes determining an instrument interface setting based on image data and selecting an emitter positioning algorithm from a plurality of different emitter positioning algorithms each configured for a particular instrument interface setting based on the determined instrument interface setting.

[0220] Example 49. The emitter is included within an emitter cartridge having on-board memory, and the process further includes storing an optimal position of the emitter within the on-board memory of the emitter cartridge, of the system of Example 44.

[0221] Example 50. Adjusting the position of the emitter includes identifying a reference point on the inlet and on the emitter in the image data and determining an optimal position of the emitter based on the reference points on the inlet and on the emitter, based on an emitter positioning algorithm, of the system of Example 44.

[0222] Example 51. The reference point on the emitter includes a distal end of an outer coating of the emitter, of the system of Example 50.

[0223] Example 52. The reference point on the emitter includes a reference marker on the emitter, of the system of Example 50.

[0224] Example 53. The system of Example 44 further includes an imaging system configured to generate image data.

[0225] Example 54. The imaging system includes a first camera and a second camera, the first camera and the second camera positioned such that an optical axis of the first camera and an optical axis of the second camera are substantially orthogonal, of the system of Example 53.

[0226] Example 55. A non-transitory computer-readable medium storing instructions that, when executed, cause at least one processor of a computing device for mass spectrometry to obtain image data representing one or more images depicting an inlet of a mass spectrometer and an emitter positioned near the inlet, and based on the image data, adjust the position of the emitter relative to the inlet to a reference position relative to the inlet or an optimal position nearby.

[0227] Example 56. The process includes an iterative optimization process including a plurality of iterations, each iteration including obtaining a portion of the image data while the emitter is positioned at a current position, determining an updated position of the emitter based on an emitter positioning algorithm and the portion of the image data obtained while the emitter is positioned at the current position, and instructing an auto-positioning system to move the emitter to the updated position, the computer-readable medium of Example 55.

[0228] Example 57. Each iteration further includes determining whether a stopping criterion is met and, in response to determining that the stopping criterion is met, ending the iterative optimization process, the computer-readable medium of Example 56.

[0229] Example 58. Determining that the stopping criterion is met includes determining that a probability of a reverse iteration step and a probability of a forward iteration step are within an acceptable range of each other based on a portion of the image data captured during the current iteration, the computer-readable medium of Example 57.

[0230] Example 59. The process further includes determining an instrument interface setting based on image data and selecting an emitter positioning algorithm from a plurality of different emitter positioning algorithms each configured for a particular instrument interface setting based on the determined instrument interface setting, the computer-readable medium of Example 56.

[0231] Example 60. The emitter is included within an emitter cartridge having on-board memory, and the process further includes storing an optimal position of the emitter within the on-board memory of the emitter cartridge, the computer-readable medium of Example 55.

[0232] Example 61. Adjusting the position of the emitter includes identifying a reference point on the inlet and on the emitter in the image data and determining an optimal position of the emitter based on the reference points on the inlet and on the emitter, based on an emitter positioning algorithm, the computer-readable medium of Example 55.

[0233] Example 62. The reference point on the emitter includes a distal end of an outer coating of the emitter, the computer-readable medium of Example 61.

[0234] Example 63. The reference point on the emitter includes a reference marker on the emitter, the computer-readable medium of Example 61.

[0235] Example 64. An automatic positioning system configured to hold an ionization emitter near the inlet of a mass spectrometer and adjust the position of the ionization emitter relative to the inlet of the mass spectrometer, an imaging system configured to capture images of the ionization emitter and the inlet of the mass spectrometer, and a position control system that obtains, from the imaging system, image data representing one or more images depicting the inlet of the mass spectrometer and the ionization emitter positioned near the inlet, and based on the image data, instructs the automatic positioning system to adjust the position of the ionization emitter relative to the inlet of the mass spectrometer to a reference position relative to the inlet or an optimal position near it. A system comprising a position control system configured to execute a process including the above.

[0236] Example 65. The system according to Example 64, wherein the imaging system includes a first camera and a second camera, and the optical axes of the first camera and the second camera are substantially orthogonal to each other.

[0237] Example 66. The process includes an iterative optimization process including a plurality of iterations. Each iteration includes obtaining a portion of the image data while the ionization emitter is positioned at the current position, an emitter positioning algorithm, and determining an updated position of the ionization emitter based on the emitter positioning algorithm and the portion of the image data obtained while the ionization emitter is positioned at the current position, and instructing the automatic positioning system to move the ionization emitter to the updated position. The system according to Example 65.

[0238] Example 67. The process further includes determining an instrument interface setting based on the image data, and selecting an emitter positioning algorithm from a plurality of different emitter positioning algorithms each configured for a specific instrument interface setting based on the determined instrument interface setting. The system according to Example 66.

Claims

1. one or more processors; and a memory storing executable instructions that, when executed by the one or more processors, cause the computing device to: acquiring image data representative of one or more images depicting an inlet of a mass spectrometer and an emitter positioned near said inlet; adjusting a position of the emitter relative to the inlet to an optimal position at or near a reference position relative to the inlet based on the image data; A system that causes a process, including

2. The process comprises an iterative optimization process comprising a number of iterations, each iteration comprising: acquiring a portion of the image data while the emitter is positioned at a current location; determining an updated position of the emitter based on an emitter positioning algorithm and the portion of the image data acquired while the emitter was positioned at the current position; and instructing an automated positioning system to move the emitter to the updated position.

3. Each iteration is determining whether a stopping criterion is met; and The system of claim 2 , further comprising: terminating the iterative optimization process in response to determining that the stopping criterion is met.

4. 4. The system of claim 3, wherein determining that the stopping criterion is met includes determining that a probability for a backward iteration step and a probability for a forward iteration step are within a tolerance range of each other based on the portion of image data captured during a current iteration.

5. The process comprises: determining an instrument interface setting based on the image data; and 3. The system of claim 2, further comprising: selecting the emitter location algorithm from among a plurality of different emitter location algorithms each configured for a particular instrument interface setting based on the determined instrument interface setting.

6. the emitter is contained within an emitter cartridge having on-board memory; The system of claim 1 , wherein the process further comprises storing the optimal position of the emitter in the on-board memory of the emitter cartridge.

7. Adjusting the position of the emitter includes: identifying, in the image data, reference points on the entrance and the emitter based on an emitter location algorithm; determining the optimal position of the emitter based on the entrance and the reference point on the emitter; The system of claim 1 , comprising:

8. The system of claim 7 , wherein the reference point on the emitter comprises a distal end of an exterior coating of the emitter.

9. The system of claim 7 , wherein the reference point on the emitter comprises a fiducial marker on the emitter.

10. The system of claim 1 , further comprising an imaging system configured to generate the image data.

11. 11. The system of claim 10, wherein the imaging system comprises a first camera and a second camera positioned such that an optical axis of the first camera and an optical axis of the second camera are substantially orthogonal.

12. A non-transitory computer readable medium storing instructions that, when executed, direct at least one processor of a computing device for mass spectrometry to: acquiring image data representative of one or more images depicting an inlet of a mass spectrometer and an emitter positioned near said inlet; and adjusting a position of the emitter relative to the inlet to an optimal position at or near a nominal position relative to the inlet based on the image data.

13. The process comprises an iterative optimization process comprising a number of iterations, each iteration comprising: acquiring a portion of the image data while the emitter is positioned at a current location; determining an updated position of the emitter based on an emitter positioning algorithm and the portion of the image data acquired while the emitter was positioned at the current position; instructing an automated positioning system to move the emitter to the updated position; The computer readable medium of claim 12 , comprising:

14. Each iteration is determining whether a stopping criterion is met; and terminating the iterative optimization process in response to determining that the stopping criterion is satisfied; and The computer readable medium of claim 13 further comprising:

15. 15. The computer-readable medium of claim 14, wherein determining that the stopping criterion is met comprises determining that a probability for a backward iteration step and a probability for a forward iteration step are within a tolerance range of each other based on the portion of image data captured during a current iteration.

16. The process comprises: determining an instrument interface setting based on the image data; and 14. The computer-readable medium of claim 13, further comprising: selecting the emitter location algorithm from among a plurality of different emitter location algorithms each configured for a particular instrument interface setting based on the determined instrument interface setting.

17. the emitter is contained within an emitter cartridge having on-board memory; the process further includes storing the optimal position of the emitter in the on-board memory of the emitter cartridge.

13. The computer-readable medium of claim 12.

18. Adjusting the position of the emitter includes: identifying, in the image data, reference points on the entrance and the emitter based on an emitter location algorithm; determining the optimal position of the emitter based on the entrance and the reference point on the emitter; The computer readable medium of claim 12 , comprising:

19. an automated positioning system configured to hold an ionization emitter near an inlet of a mass spectrometer and adjust the position of the ionization emitter relative to the inlet of the mass spectrometer; an imaging system configured to capture images of the ionization emitter and the entrance to the mass spectrometer; 1. A position control system configured to execute a process, the process comprising: acquiring image data from the imaging system representative of one or more images depicting the entrance of the mass spectrometer and the ionization emitter positioned near the entrance; and instructing the automatic positioning system to adjust the position of the ionization emitter relative to the entrance of the mass spectrometer to an optimal position at or near a reference position relative to the entrance based on the image data.

20. 20. The system of claim 19, wherein the imaging system comprises a first camera and a second camera, an optical axis of the first camera and an optical axis of the second camera being substantially orthogonal to one another.

21. The process comprises an iterative optimization process comprising a number of iterations, each iteration comprising: acquiring a portion of the image data while the ionization emitter is positioned at a current location; determining an updated position of the ionization emitter based on an emitter positioning algorithm and the portion of the image data acquired while the ionization emitter was positioned at the current position; instructing the automated positioning system to move the ionization emitter to the updated position; The system of claim 20, comprising:

22. The process comprises: determining an instrument interface setting based on the image data; and 22. The system of claim 21, further comprising: selecting the emitter location algorithm from among a plurality of different emitter location algorithms each configured for a particular instrument interface setting based on the determined instrument interface setting.

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