JP2018006050A - Time-of-flight mass spectrometer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To suppress the number of times of measuring a calibrant by reducing a height variation caused by a positional difference on a plate caused by a mechanical error in a movement mechanism configured to move a plate holder in two axis directions.SOLUTION: A metallic plate holder 3 is mounted directly on a flat bottom face plate 1a of a specimen chamber. At a lower side of the bottom face plate 1a, a linear guide 21 extending in an (x) axis direction is disposed and on a movable part 21a of the linear guide 21, a linear guide 22 extending in a (y) axis direction is fixed. On a movable part 22a of the linear guide 22, a magnet 23 is fixed, and the plate holder 3 is attracted by a magnetic force of the magnet 23 while interposing the bottom face plate 1a therebetween. When the magnet 23 is moved in a two-dimensional manner via the linear guides 21, 22 by a motor or the like, the plate holder 3 is also moved in a two-dimensional manner while following that movement. The flat bottom face plate 1a regulates a position of the plate holder 3 in a (z) axis direction, thereby suppressing displacement in a height of a specimen on the plate 3 with movements.SELECTED DRAWING: Figure 2

Description

  The present invention relates to a time-of-flight mass spectrometer, and more particularly, a time-of-flight provided with an ion source that ionizes components in the sample by irradiating the sample with a laser beam, an electron beam, an ion beam, a neutral atomic beam, or the like. The present invention relates to a type mass spectrometer.

  A matrix-assisted laser desorption / ionization (MALDI) method is well known as a technique for irradiating a solid sample with laser light to ionize components in the sample. In a time-of-flight mass spectrometer (hereinafter referred to as “MALDI-TOFMS” in accordance with common practice) equipped with an ion source based on the MALDI method, a sample held on a flat sample plate is generally pulsed. Irradiation with laser light generates ions derived from components contained in the sample. Then, a constant acceleration energy is given to the various ions by an electric field generated by an electrode arranged above the sample and introduced into the flight space, and these ions fly through the flight space of a certain distance and reach the detector. Each flight time is measured. The time of flight of each ion has a predetermined relationship with the mass-to-charge ratio of that ion. Therefore, using this relationship, the measured time of flight is converted into a mass-to-charge ratio, and for example, a mass spectrum indicating the relationship between the mass-to-charge ratio and the ion intensity is created.

  In general MALDI-TOFMS, recesses called wells for spotting a sample to be measured on a sample plate (in some cases, there are no recesses and only the spot positions are shown) are arranged in a matrix. Many samples are formed, and a sample is formed by spotting a liquid sample in each well and drying it. Then, the sample plate is mounted on the plate holder, and the sample in the target well is moved to the laser beam irradiation position by moving the plate holder in two axial directions orthogonal to each other in the horizontal plane, and the mass with respect to the sample is Analysis is carried out (see Patent Document 1).

  5A and 5B are schematic configuration diagrams of a sample plate moving mechanism in a conventional MALDI-TOFMS. FIG. 5A is a front view, FIG. 5B is a side view, and FIG. 5C is a top view. Here, as shown in FIG. 5C, the horizontal plane on which the sample plate 2 is set is the x-axis-y-axis plane, and the flight direction of ions generated by laser light irradiation is the z-axis direction.

  As shown in FIG. 5, a first linear guide 51 extending in the x-axis direction is attached on the bottom plate 1 a of the sample chamber, and on the movable portion 51 a that is linearly movable by the linear guide 51. Further, a second linear guide 52 extending in the y-axis direction is fixed. And the plate holder 3 which can hold | maintain the sample plate 2 is being fixed on the movable part 52a linearly movable by this 2nd linear guide 52. As shown in FIG. The movable portion 51a of the first linear guide 51 and the movable portion 52a of the second linear guide 52 are respectively moved by a driving force such as a motor (not shown), whereby the plate holder 3 is moved to an arbitrary position within a predetermined two-dimensional range. Can be moved to. In addition, the linear guides 51 and 52 can utilize what is disclosed by the nonpatent literature 1, for example.

  In the MALDI-TOFMS described above, the sample surface on the sample plate 2 serves as a flight start point of ions. Therefore, if the height of the surface of the sample plate 2 changes due to various factors, the flight distance changes slightly, which leads to an error in the mass to charge ratio. Therefore, in order to accurately determine the mass-to-charge ratio of ions derived from the target compound, the result of measuring a standard sample (called a calibrant) containing a standard substance with a known theoretical (ie accurate) mass-to-charge ratio. In general, a process called calibration is performed to calibrate the result of measurement of the target sample.

  When there is a non-uniform thickness or warp in one sample plate, the flight distance varies depending on the position in the plane of one sample plate. For this reason, in addition to the sample well for spotting the target sample, a plurality of calibrant wells for spotting the calibrant are provided on the sample plate, and calibration of the measurement result of a certain target sample is performed by the target sample. The measurement is performed using the measurement result of the calibrant formed in the calibrant well closest to the sample well. By such calibration, the mass-to-charge ratio value with respect to the sample component obtained by measuring the target sample is corrected to a value close to the true value (see Patent Document 2).

  If there are many calibrant wells, the time required for calibrant measurement becomes longer and the measurement efficiency decreases. Therefore, it is desirable that calibration can be performed for all target samples in the sample plate using the measurement result of the calibrant formed in one calibrant well in one sample plate. Therefore, improvement of the uniformity of the thickness of the sample plate, prevention of bending, and the like are attempted. However, in fact, factors other than the sample plate have a problem that the height of the sample on one sample plate, that is, the distance between the surface of the sample and the electrode for extracting and accelerating ions varies.

  That is, as described with reference to FIG. 5, the conventional sample plate moving mechanism has a configuration in which a plurality of members are stacked on the bottom plate 1a of the sample chamber. For this reason, the tolerances of the respective members are added, and as a result, the height variation may increase depending on the position on the sample plate 2.

  FIG. 6 shows an actual measurement of the height displacement for each position of the sample well arranged in one direction (x-axis direction) on the sample plate (this position is indicated by the sample number #) in the conventional MALDI-TOFMS. It is an example of a result. From the viewpoint of mass accuracy, it is necessary to suppress the fluctuation to approximately ± 100 ppm, but in this example, it can be seen that there are sample wells that greatly deviate from this. When there is such a large displacement, it is necessary to perform calibration based on the measurement result of the calibrant provided in the vicinity of the sample well, and a plurality of calibrants must be formed on one sample plate. Is essential.

Japanese Patent Laying-Open No. 2015-179017 (paragraph [0003]) JP-A-2015-179630 (paragraphs [0003]-[0004])

"LM Guide", [online], THK Corporation, [Search April 25, 2016], Internet <URL: http://www.thk.com/?q=jp/node/6709>

  The present invention has been made in view of the above problems, and the object of the present invention is to extract and accelerate a sample and ions caused by a moving mechanism capable of moving a sample plate in two axial directions perpendicular to each other. It is an object of the present invention to provide a time-of-flight mass spectrometer that can reduce the number of calibrants formed on a sample plate for calibration by reducing variation in the distance between the electrodes.

The time-of-flight mass spectrometer according to the first aspect of the present invention, which has been made in order to solve the above problems, irradiates a sample held by a sample holding unit with a laser beam or a particle beam to extract ions from the sample. A time-of-flight mass spectrometer that generates and accelerates the generated ions and introduces them into the flight space, and separates and detects the ions according to the mass-to-charge ratio in the flight space,
a) a base plate having a flat front surface;
b) an orthogonal drive unit arranged on the back side of the base plate and capable of moving the movable unit in two mutually perpendicular directions in a plane substantially parallel to the front surface of the base plate;
c) a magnet that is integral with or attached to the movable part, and that pulls the metal sample holder placed on the front surface of the base plate with the base plate in between;
It is characterized by having.

Further, the time-of-flight mass spectrometer according to the second aspect of the present invention, which has been made to solve the above-mentioned problems, irradiates a sample held by a sample holding unit with a laser beam or a particle beam and ions from the sample. A time-of-flight mass spectrometer that accelerates and introduces the generated ions into the flight space and separates and detects the ions according to the mass-to-charge ratio in the flight space,
a) a base plate having a flat front surface;
b) a first drive unit that pushes and / or pulls the side surface of the sample holder placed on the front surface of the base plate in a uniaxial direction in a plane substantially parallel to the front surface of the base plate; ,
c) The side surface of the sample holder placed on the front surface of the base plate is pushed and / or pulled by the first driving unit in a plane substantially parallel to the front surface of the base plate. A second drive that pushes and / or pulls in a direction perpendicular to the direction;
It is characterized by having.

  In the time-of-flight mass spectrometer according to the present invention, ionization methods for ionizing components in a sample are not only MALDI methods but also laser desorption ionization methods (LDI), surface-assisted laser desorption ionization methods (SALDI), secondary Includes ion mass spectrometry (SIMS), desorption ionization on silicon (DIOS), electrospray support / laser desorption ionization (ELDI), fast atom bombardment (FAB), and the like.

  In the time-of-flight mass spectrometer according to the present invention, the sample holder is, for example, a plate holder that holds a sample plate or a flat plate-like table on which a sample is placed.

  In the time-of-flight mass spectrometer according to the present invention, the base plate may be a horizontal surface, a vertical surface, or an oblique surface that is neither of them. For example, when the front surface of the base plate is horizontal, the sample holder is placed directly on the horizontal base plate, and the sample holder slides (or slides) on the upper surface of the base plate.

In order to move the sample holder placed directly on the front surface of the base plate, in the first aspect, the orthogonal drive unit and the magnet arranged on the back side of the base plate are used. The sample holder is moved two-dimensionally without contact. On the other hand, in the second mode, the sample holding part is two-dimensionally operated by applying a force to the side face of the sample holding part by the first and second driving parts arranged on the front surface side of the base plate. Move.
In both the first and second aspects, the front surface of the base plate itself is positioned in the direction perpendicular to the two axes (the thickness direction of the base plate) when the sample holder moves in the biaxial direction. It functions as a kind of guide to regulate. Therefore, if the flatness of the front surface of the base plate is high, fluctuations in the distance between the sample and the ion extraction / acceleration electrode accompanying the movement of the sample holding unit can be suppressed.

  In the time-of-flight mass spectrometer according to the present invention, the base plate can be a bottom plate of a sample chamber in which a sample is accommodated. When an ionization method in which ionization is performed in a vacuum atmosphere is used, the sample chamber can be sealed and the sample chamber is evacuated during mass analysis.

  According to the time-of-flight mass spectrometer according to the present invention, the surface of the sample plate and the ion extraction / acceleration in one sample plate caused by the moving mechanism for moving the sample plate carrying the sample two-dimensionally. The variation in the distance between the electrodes for use can be reduced. Thereby, for example, the number of calibrants prepared on one sample plate can be reduced as compared with the conventional case, and the time required for measuring the calibrant can be shortened to improve the measurement efficiency. Moreover, the trouble of preparing a large number of calibrants can be reduced.

The schematic block diagram of MALDI-TOFMS which is one Example of this invention. It is a schematic block diagram of the movement mechanism of the plate holder in MALDI-TOFMS of a present Example, (a) is a front view, (b) is a side view, (c) is a top view. It is a schematic block diagram of the moving mechanism of the plate holder in MALDI-TOFMS of the other Example of this invention, (a) is a front view, (b) is a side view, (c) is a top view. FIG. 4 is a top view showing a schematic configuration of a modified example of the moving mechanism shown in FIG. 3. It is a schematic block diagram of the movement mechanism of the plate holder in the conventional MALDI-TOFMS, (a) is a front view, (b) is a side view, (c) is a top view. The figure which shows the result of having actually measured the displacement amount of the height for every position of the sample well arranged in one direction on the sample plate in the conventional MALDI-TOFMS.

  Hereinafter, MALDI-TOFMS which is one Example of this invention is demonstrated with reference to an accompanying drawing. FIG. 1 is a schematic configuration diagram of a MALDI-TOFMS of this embodiment. 2A and 2B are schematic configuration diagrams of a plate holder moving mechanism in the MALDI-TOFMS of the present embodiment. Like FIG. 5, FIG. 2A is a front view, FIG. 2B is a side view, and FIG. is there.

  As shown in FIG. 1, a flat plate-shaped metal sample plate 2 is directly placed on a bottom plate 1 a in a sample chamber 1 while being mounted on a metal plate holder 3. Below the sample chamber 1, an XY movement mechanism 20 for moving the plate holder 3 two-dimensionally on the bottom plate 1a is disposed. On the other hand, in the vacuum chamber 10 that communicates with the inside of the sample chamber 1 and is disposed above the sample chamber 1, the extraction electrode 11, the acceleration electrode 12, the reflecting mirror 14, and the flight tube 15 are arranged from the bottom to the top. The detector 16 is arranged. A laser irradiation unit 13 is provided outside the window 10 a formed in the vacuum chamber 10.

  At the time of measurement execution, one sample on the sample plate 2 set at a predetermined laser beam irradiation position is irradiated with a pulsed laser beam emitted from the laser irradiation unit 13 and passed through the window 10a and the reflecting mirror 14, Thereby, the component contained in the sample is ionized. The irradiation position of the laser beam is fixed, and the measurement is performed by irradiating the sample at an arbitrary position on the sample plate 2 by moving the plate holder 3 appropriately by the XY movement mechanism 20. Can do.

  A predetermined voltage is applied to the extraction electrode 11 and the acceleration electrode 12 disposed above the sample plate 2 from a voltage generator (not shown). A predetermined voltage is also applied to the sample plate 2 through the plate holder 3. As described above, ions generated from the sample by irradiation with the laser light are extracted upward from the vicinity of the generation position by the electric field formed between the extraction electrode 11 and the sample, and further formed by the acceleration electrode 12. Acceleration energy is applied by the accelerated electric field. As a result, the ions that have started flying in the upward direction (z-axis direction) fly through the flight space of no electric field and no magnetic field formed in the flight tube 15 and reach the detector 16. Since ions having a smaller mass-to-charge ratio have a higher flight speed in the flight space, the ions having the smaller mass-to-charge ratio reach the detector 16 in order from the various ions that have started flying almost simultaneously. The detector 16 outputs a detection signal corresponding to the amount of incident ions.

  The MALDI-TOFMS of this embodiment is a linear TOFMS that makes ions fly linearly. However, the reflectron TOFMS having a reflectron that reverses the flight trajectory of ions, or the ions repeatedly fly along a circular orbit. Of course, a multi-turn TOFMS may be used.

In the MALDI-TOFMS of the present embodiment, the XY movement mechanism 20 that moves the plate holder 3 corresponding to the sample holder in the present invention in a two-dimensional manner will be described in detail.
As described above, the plate holder 3 is placed on the flat bottom plate 1a corresponding to the base plate in the present invention. This top plate is made of a material that is not attracted to magnetic force, such as non-magnetic stainless steel. The upper surface preferably has not only high flatness but also high smoothness. Therefore, the upper surface of the bottom plate 1a may be subjected to appropriate surface processing or surface treatment.

  As shown in FIGS. 2A and 2B, the XY moving mechanism 20 includes two linear guides 21 and 22 similar to the linear guides 51 and 52 in the conventional apparatus shown in FIG. It is included as an element corresponding to the orthogonal drive unit. That is, a first linear guide 21 extending in the x-axis direction is fixed to a bottom plate of a housing (not shown) of the XY moving mechanism 20, and is placed on the movable portion 21 a of the linear guide 21. The second linear guide 22 extending in the y-axis direction is fixed. A magnet 23 is fixed on the movable portion 22a of the second linear guide 22, and the upper surface of the magnet 23 and the lower surface of the bottom plate 1a are almost in contact with each other or have a minute gap. The movable portions 21a and 22a of the two linear guides 21 and 22 can be moved in the x-axis direction and the y-axis direction by a driving force of a motor or the like (not shown). As a result, the magnet 23 can move two-dimensionally to an arbitrary position within a substantially horizontal plane (x-axis-y-axis plane) below the bottom plate 1a.

  The magnetic force of the magnet 23 reaches the plate holder 3 placed above through the bottom plate 1a. Since the plate holder 3 is attracted to the magnet 23, as described above, when the magnet 23 is moved to an arbitrary position two-dimensionally in a substantially horizontal plane, the plate holder 3 moves two-dimensionally on the bottom plate 1a following the movement. To do. Even when the size of the gap between the upper surface of the magnet 23 and the lower surface of the bottom plate 1a changes to some extent when the magnet 23 moves two-dimensionally, as long as the magnetic force of the magnet 23 reaches the plate holder 3. The plate holder 3 slides or slides on the bottom plate 1a. That is, the entire upper surface of the bottom plate 1a functions as a guide for regulating the position of the lower surface in the z-axis direction when the plate holder 3 moves two-dimensionally. When the holder 3 moves, the displacement in the z-axis direction is very small. Thereby, the displacement of the height of the sample on the sample plate 2 at the laser beam irradiation position is greatly suppressed as compared with the conventional apparatus.

  In the MALDI-TOFMS of the above embodiment, it is natural that the magnet 23 may be an electromagnet instead of a permanent magnet. Further, the sample plate 2 may be moved directly by magnetic force without using the plate holder 3. Further, instead of the plate holder 3 that holds the sample plate 2, a sample stage that is a simple metal plate for placing a sample thereon may be used.

  Next, a plate holder moving mechanism in MALDI-TOFMS according to another embodiment of the present invention will be described. 3A and 3B are schematic configuration diagrams of the moving mechanism. Like FIG. 2, FIG. 3A is a front view, FIG. 3B is a side view, and FIG. 3C is a top view. The same components as those in FIG. 2 are denoted by the same reference numerals.

  In the moving mechanism of the above embodiment, the plate holder 3 is moved in a two-dimensional manner in a non-contact manner using a magnet. However, in this embodiment, two sets of arms arranged so as to sandwich the plate holder 3. Is used to move the plate holder 3 two-dimensionally on the bottom plate 1a. That is, as shown in FIG. 3, the plate holder 3 is sandwiched between the two arms 31a and 31b extending in the y-axis direction and is sandwiched between the two arms 33a and 33b extending in the x-axis direction. The pair of arms 31a and 31b are moved in the x-axis direction by the x-axis direction drive unit 32 while keeping the distance therebetween. On the other hand, the other pair of arms 33a and 33b is moved in the y-axis direction by the y-axis direction drive unit 34 while keeping the distance therebetween. For example, when the pair of arms 31a and 31b move leftward in FIG. 3A, the arm 31b pushes the right side surface of the plate holder 3 so that the plate holder 3 moves leftward on the bottom plate 1a. To slide.

  The two arms 31a, 31b and 33a, 33b are independently moved by the x-axis direction drive unit 32 and the y-axis direction drive unit 34, so that the plate holder 3 is moved to an arbitrary position on the bottom plate 1a. The As in the above embodiment, the entire top surface of the bottom plate 1a functions as a guide for regulating the position of the bottom surface when the plate holder 3 moves two-dimensionally. Therefore, if the flatness of the top surface of the bottom plate 1a is high. The displacement in the z-axis direction during the movement of the plate holder 3 is very small, and the height displacement due to the difference in position on the sample plate 2 can be suppressed.

  In addition, in the example of FIG. 3, the movement of the plate holder 3 was achieved by one of the arms 31a, 31b, 33a, 33b pushing the peripheral surface of the plate holder 3 from the rear, but for example as shown in FIG. The grip-like arms 41 and 43 held by sandwiching the plate holder 3 may be moved by the x-axis direction drive unit 42 and the y-axis direction drive unit 44, respectively. Thus, if the mechanism is such that the plate holder 3 placed on the bottom plate 1a is moved by pushing or pulling from the peripheral surface (side surface), the same effect as in the above embodiment can be obtained. Is clear.

  In any of the above embodiments, the bottom plate 1a is installed horizontally. However, it is obvious that the bottom plate 1a is not necessarily horizontal but may be inclined or vertical. Of course, when the bottom plate 1a is installed vertically in the other embodiments, for example, the plate holder 3 and the bottom plate 1a are attracted by magnetism so that the plate holder 3 does not fall. Just keep it.

  Moreover, although the said Example applies this invention to MALDI-TOFMS, with respect to the sample formed on the sample plate 2 or the sample set | placed on the sample stand, besides a laser beam, it is made into a small diameter. The present invention is applicable to all time-of-flight mass spectrometers equipped with an ion source that irradiates various particle beams such as focused ion beams, electron beams, and neutral atomic beams to ionize components in the sample. Is clear. Examples of such ion sources include LDI, SALDI, SIMS, DIOS, ELDI, and FAB.

  Moreover, the said Example is an example of this invention, and it is clear that even if it changes suitably, amends, and is added within the meaning of this invention, it is included by the claim of this application.

DESCRIPTION OF SYMBOLS 1 ... Sample chamber 1a ... Bottom plate 2 ... Sample plate 3 ... Plate holder 10 ... Vacuum chamber 10a ... Window 11 ... Extraction electrode 12 ... Acceleration electrode 13 ... Laser irradiation part 14 ... Reflector 15 ... Flight tube 16 ... Detector 20 ... XY moving mechanism 21, 22 ... linear guide 21a, 22a ... movable portion 23 ... magnet 31a, 31b, 33a, 33b, 41, 43 ... arm 32, 42 ... x-axis direction drive unit 34, 44 ... y-axis direction drive Part

Claims (3)

The sample held by the sample holder is irradiated with a laser beam or particle beam to generate ions from the sample, the generated ions are accelerated and introduced into the flight space, and the ions are brought into a mass-to-charge ratio in the flight space. A time-of-flight mass spectrometer that detects and separates according to
a) a base plate having a flat front surface;
b) an orthogonal drive unit arranged on the back side of the base plate and capable of moving the movable unit in two mutually perpendicular directions in a plane substantially parallel to the front surface of the base plate;
c) a magnet that is integral with or attached to the movable part, and that pulls the metal sample holder placed on the front surface of the base plate with the base plate in between;
A time-of-flight mass spectrometer. The sample held by the sample holder is irradiated with a laser beam or particle beam to generate ions from the sample, the generated ions are accelerated and introduced into the flight space, and the ions are brought into a mass-to-charge ratio in the flight space. A time-of-flight mass spectrometer that detects and separates according to
a) a base plate having a flat front surface;
b) a first drive unit that pushes and / or pulls the side surface of the sample holder placed on the front surface of the base plate in a uniaxial direction in a plane substantially parallel to the front surface of the base plate; ,
c) The side surface of the sample holder placed on the front surface of the base plate is pushed and / or pulled by the first driving unit in a plane substantially parallel to the front surface of the base plate. A second drive that pushes and / or pulls in a direction perpendicular to the direction;
A time-of-flight mass spectrometer. The time-of-flight mass spectrometer according to claim 1 or 2,
The time-of-flight mass spectrometer is characterized in that the base plate is a bottom plate of a sample chamber in which a sample is accommodated.

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