JP2016028228A - Ionizer, mass spectroscope comprising same, image generation system, image display system, and ionization method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an ionizer which facilitates change of the characteristic frequency of a vibration part of a probe without the necessity of detaching the probe.SOLUTION: An ionizer 100 comprises: a fixation part 16 for fixing a probe 1 to the ionizer 100; liquid supply means 9 for supplying a liquid to an end of the probe 1; an ion extraction electrode 17; electric field generation means (10 and 14) for generating an electric field between the liquid at the end of the probe 1 and the ion extraction electrode 17; and vibration means 2 for applying vibration to the probe 1 so that the states in which the liquid at the end of the probe 1 forms a liquid bridge 4 by contacting with a sample 18 and in which the liquid flies toward the ion extraction electrode 17 due to the electric field are periodically repeated. The ionizer 100 further comprises characteristic frequency change means 20 that changes the characteristic frequency of a vibration part of the probe 1 vibrated by the vibration means 2 in the state in which the probe 1 is fixed to the fixation part 16.SELECTED DRAWING: Figure 1

Description

  The present invention relates to an ionizer that ionizes a substance, a mass spectrometer having the ionizer, an image generation system, an image display system, an ionization method, and the like.

  In recent years, imaging mass spectrometry applying mass spectrometry has been developed as an analysis technique for visualizing the distribution of substances and components existing on the surface of a sample.

  In imaging mass spectrometry, a sample is ionized at an arbitrary measurement point (micro area) on the surface of the sample. Subsequently, mass analysis is performed on the generated ions to obtain a mass spectrum. This is performed at a plurality of measurement points, and a mass spectrum image is formed by associating the obtained mass spectrum with the position information of the measurement points.

  In this case, the spatial resolution of the mass spectrum image is determined by the size of the measurement point when ionizing the sample. Therefore, in order to improve the spatial resolution of the mass spectrum image, a technique for selectively ionizing a sample existing in a minute region is required.

  As such a technique, a method of selectively ionizing using a probe that vibrates a substance existing on a sample surface has been proposed (Patent Document 1 and Patent Document 2).

  In the technique described in Patent Document 1, one end of a probe is fixed to a cantilever, and the cantilever is vibrated to move the tip of the probe so as to reciprocate between the sample and the front of the ion intake portion of the mass spectrometer. . When the tip of the probe comes into contact with the sample, the substance present in the micro area on the sample surface adheres to the probe. Subsequently, the tip portion of the probe to which the substance is attached moves in front of the ion extraction electrode, and the tip portion of the probe is irradiated with voltage or laser light. Thereby, only the substance adhering to the tip of the probe can be selectively ionized.

  The technique described in Patent Document 2 uses a vibrating capillary probe. In Patent Document 2, a liquid bridge is formed between the tip of a probe and a sample surface by supplying a liquid to a partial region of the sample surface through a capillary. By this liquid cross-linking, only the substances existing in the portion in contact with the liquid cross-linking among the substances existing on the sample surface are dissolved in the liquid. Thereafter, the probe vibrates, and the tip of the probe approaches the ion extraction electrode while the liquid forming the liquid bridge is held at the tip of the probe. Then, an electrospray of a liquid is generated by a strong electric field applied between the probe and the ion extraction electrode, and a substance dissolved in the liquid is ionized. The technique described in Patent Document 2 is different from the technique described in Patent Document 1, and it is not necessary to irradiate the substance with laser when ionizing the substance, and softer ionization can be performed.

  Non-patent document 1 is generated by using a device having the same configuration as the device described in patent document 1, and stopping the probe with a substance attached to the tip in the vicinity of the ion intake unit and continuing ionization. It is described that ionic species change over time.

International Publication No. 2007/126141 Specification JP 2013-181840 A

M.M. K. Mandal. , Et. al. , J .; Am. Soc. Mass. Spectrom. , 2011, 22, 1493-1500.

  As described in Non-Patent Document 1, the generated ion species can be changed by changing the time for generating the electrospray. By changing the vibration frequency of the probe in Patent Document 1 or Patent Document 2, the time during which the tip of the probe is approaching the ion extraction electrode can be changed. This suggests that the generated ion species can be changed.

  In the technique described in Patent Document 2, the probe is vibrated at the natural frequency of the probe in order to increase the amplitude of the probe. Therefore, in order to change the vibration frequency of the probe in Patent Document 2, it is necessary to change the natural frequency of the probe.

  However, in Patent Document 2, in order to change the natural frequency of the probe, it was necessary to replace the probe itself. When the probe is replaced, the position on the sample surface where the tip of the probe contacts or approaches changes before and after the probe replacement. Therefore, when the probe is replaced, there is a problem that it takes time and effort to manually change the position of the tip of the probe after replacing the probe.

  Accordingly, an object of the present invention is to provide an ionization apparatus that can easily change the natural frequency of the vibrating portion of the probe without removing the probe.

  An ionization apparatus according to one aspect of the present invention is an ionization apparatus that ionizes the sample included in a region where the probe is brought into proximity or contact with a sample surface and is in contact with or in contact with the probe. A fixing unit fixed to the ionization device, a liquid supply means for supplying a liquid to the end of the probe, an ion extraction electrode, and the liquid adhering to the end of the probe and the ion extraction electrode An electric field generating means for generating an electric field; a state in which the liquid adhering to the end of the probe comes into contact with the sample to form a liquid bridge; and the end of the probe approaches the ion extraction electrode. Vibration means for applying vibration to the probe so as to periodically repeat the state in which the liquid flies toward the ion extraction electrode by the electric field. , The natural frequency of the vibration part of the probe that vibrates by the vibrating means, said probe and having a a natural frequency changing means for changing a state of being fixed to the fixed part.

  According to the present invention, the natural frequency of the vibrating portion of the probe can be easily changed without removing the probe.

It is a schematic diagram which shows the structure of the mass image display system containing the ionization apparatus which concerns on this embodiment. It is the block diagram which shows the structure of the natural frequency change system which concerns on this embodiment, and the flowchart which shows the operation | movement. It is a flowchart which shows the ionization method which concerns on this embodiment. It is the schematic diagram which showed typically the structure of the natural frequency change means which concerns on 1st Embodiment. It is the schematic diagram which showed typically the structure of the natural frequency change means which concerns on 2nd Embodiment. It is the schematic diagram which showed typically the structure of the natural frequency change means which concerns on 3rd Embodiment. It is the schematic diagram which showed typically the structure of the natural frequency change means which concerns on 4th Embodiment. It is the schematic diagram which showed typically the structure of the natural frequency change means which concerns on 5th Embodiment. It is the schematic diagram which showed typically the structure of the natural frequency change means which concerns on 6th Embodiment. It is a flowchart which shows operation | movement of the mitigation system which reduces the fluctuation | variation of the natural frequency which concerns on this embodiment. It is the schematic diagram which showed typically the structure of the natural frequency change means which concerns on 8th Embodiment. It is the schematic diagram which showed typically the structure of the natural frequency change means which concerns on 9th Embodiment.

  DESCRIPTION OF EXEMPLARY EMBODIMENTS Hereinafter, preferred embodiments of the invention will be described with reference to the drawings. In addition, although these embodiment is an example of the best embodiment in this invention, this invention is not limited only to the various structure demonstrated in these embodiment.

(Configuration of ionization apparatus 100)
First, the configuration of an ionization apparatus 100 (hereinafter referred to as “apparatus 100”) common to the embodiments according to the present invention will be described with reference to FIG. FIG. 1 is a schematic diagram illustrating a configuration of a mass image display system including an apparatus 100 according to the present embodiment.

  The apparatus 100 according to the present embodiment includes a probe 1, a vibrating means 2, a sample stage 8, and a liquid supply device 9. In addition, the apparatus 100 according to the present embodiment further includes a conductive flow path 11, an ion take-in unit 7, an electric field generating unit, and a natural frequency changing unit 20 (hereinafter referred to as “changing unit 20”). Have. The electric field generating means includes a voltage applying device 10 and a voltage applying device 14.

  The ion take-in unit 7 includes an ion extraction electrode 17 connected to the voltage application device 14. The ion take-in unit 7 is connected to the mass analyzer 15 so that ions taken from the ion take-in unit 7 can be transferred to the mass analyzer 15.

  The sample 18 is placed and held on the substrate 3. The substrate 3 is placed on the sample stage 8 connected to the sample stage control means 13. The sample stage control means 13 can drive and control the sample stage 8 to move the sample 18 relative to the probe 1. Specifically, the sample stage control means 13 can move the sample 18 in a direction horizontal to the upper surface of the sample stage 8 (XY direction) and a direction perpendicular to the upper surface of the sample stage 8 (Z direction).

  The probe 1 has a flow path (not shown) inside or outside thereof. The liquid supplied from the liquid supply means 9 passes through the flow path (not shown) of the probe 1 and is disposed in a partial region of the surface of the sample 18 held on the substrate 3. The liquid disposed in a partial region on the surface of the sample 18 forms a liquid bridge 4 between the sample 18 and the end of the probe 1. In this specification, “liquid crosslinking” refers to a liquid in a state where the liquid supplied from the probe 1 is in physical contact with at least both the probe 1 and the sample 18. That is, the liquid bridge is formed when the liquid attached to the end of the probe 1 physically contacts the sample 18. The liquid bridge 4 is formed by the surface tension of the liquid.

  As the liquid supplied from the liquid supply means 9, it is preferable to use a liquid that can dissolve the substance contained in the sample 18. When the liquid bridge 4 is formed, the substance on the surface of the sample 18 is dissolved in the liquid forming the liquid bridge 4. The liquid bridge 4 is not formed when the amount of liquid supplied from the probe 1 is insufficient or when the liquid adheres to the opposite side when viewed from the substrate 3 of the probe 1.

  Further, the liquid supplied from the liquid supply means 9 is guided to a flow path (not shown) inside the probe 1 via the conductive flow path 11. At that time, the voltage applying means 10 applies a voltage to the liquid via the conductive channel 11. The type of voltage applied to the liquid is not particularly limited, and may be any of direct voltage, alternating voltage, and pulse voltage. Also, no voltage is applied to the liquid, that is, the voltage applied to the liquid may be zero volts. In this case, a voltage other than zero volts is applied to the ion extraction electrode 17 described later.

  In the present embodiment, a potential different from the potential applied to the ion extraction electrode 17 described later is applied to the liquid passing through the flow path of the probe 1. That is, a potential difference is applied between the ion extraction electrode 17 and the liquid that passes through the flow path of the probe 1 and adheres to the end of the probe. As a result, an electric field is formed between the probe 1 in contact with the liquid and the ion extraction electrode 17. As long as this electric field can be formed, the voltage applied by the voltage applying means 10 may be zero volts.

  As a connection pipe that connects the probe 1, the conductive channel 11, and the liquid supply means 9, for example, a narrow tube that can supply a minute volume of liquid can be used. The thin tube may be made of any of an insulator, a conductor, and a semiconductor. For example, a silica capillary or a metal capillary can be used. Further, the material of the thin tube may be a material whose hardness changes due to heat, and for example, a thermosoftening material, a thermosetting material, or the like can be used.

  The conductive flow path 11 is at least part of the flow path through which the liquid supplied from the liquid supply means 9 is guided to the end of the probe 1 on the opposite side of the liquid supply means 9 through the inside or the outside of the probe 1. Configure. Therefore, you may arrange | position the electroconductive flow path 11 in any position of the said flow path. For example, all or part of the conductive channel 11 may be included in the channel inside the probe 1. Alternatively, the conductive channel 11 may be formed by inserting a conductive object such as a stainless steel wire, a tungsten wire, or a platinum wire into the channel of the probe 1. When the flow path of the probe 1 is arranged outside the probe 1, a flexible thin tube is passed from the liquid supply means 9 to the outside of the probe 1, and the discharge port of the thin tube comes to the end of the probe 1. Should be arranged as follows.

  The vibration unit 2 is a unit that applies vibration to the probe 1. In the probe 1 provided with vibration by the vibration means 2, at least one end of the probe 1 vibrates. Due to this vibration, the distance between the end of the probe 1 and the sample 18 changes periodically.

  The vibration means 2 is not particularly limited as long as the vibration means 2 exhibits vibration having a reproducible constant amplitude when a voltage is applied from the voltage application device 12. For example, a piezoelectric element or a vibration motor can be used as the vibration means 2. Piezoelectric elements, vibration motors, and the like are suitable as the vibration means 2 according to the present embodiment because they can provide high-frequency vibrations and have high durability.

  The position where the vibration means 2 is disposed is not particularly limited as long as it is a position where vibration can be transmitted to the probe 1. Note that the vibration means 2 is not necessarily in contact with the probe 1 while the probe 1 is stationary. However, in that case, it is necessary to contact the probe 1 for vibration transmission at any point in one cycle of vibration of the probe 1. A plurality of vibration means 2 may be opposed to each other so as to sandwich the probe 1 therebetween. Thereby, vibration can be stably given to the probe 1.

  Further, the vibration means 2 may be configured to be attached to the probe 1. When attaching the vibration means 2 to the probe 1, the vibration means 2 may be installed outside the probe 1, or the vibration means 2 may be built in the probe 1. If the vibration means 2 is installed outside the probe, the probe 1 can be made small and light. According to the configuration in which the vibration means 2 is attached to the probe 1, the vibration transmission efficiency of the vibration means 2 with respect to the probe 1 can be improved, so that stable vibration of the probe 1 can be realized. Note that the vibration means 2 may be fixed to a part of the apparatus 100 other than the probe 1.

  In this embodiment, as a method for the vibration means 2 to apply vibration to the probe 1, the vibration means 2 itself vibrates and the probe 1 is vibrated by transmitting the vibration. However, for example, the probe 1 may be made of a piezoelectric element or the like, and the probe 1 may be vibrated by applying a voltage to the probe 1 by the vibration means 2. Alternatively, at least a part of the probe 1 may be formed of a magnetic material, and the probe 1 may be vibrated by applying a magnetic field to the probe 1 by the vibration unit 2.

  When vibration is transmitted to the probe 1 in which the liquid bridge 4 is formed between the sample 18 and the sample 18 by the vibration means 2, the probe 1 vibrates while the liquid that has formed the liquid bridge 4 remains attached to the tip of the probe 1. That is, when the probe 1 vibrates, the state in which the probe 1 and the sample 18 are connected via the liquid and the state in which the probe 1 and the sample 18 are separated can be generated separately.

  In a state where the probe 1 is separated from the sample 18 due to vibration, the liquid that has formed the liquid bridge 4 approaches the ion intake portion 7 having the ion extraction electrode 17. At this time, a voltage different from the voltage applied to the probe 1 by the voltage application device 14 is applied to the ion extraction electrode 17. That is, an electric field is formed between the liquid applied to the end of the probe 1 to which a voltage is applied through the conductive channel 11 and the ion extraction electrode 17. That is, in the apparatus 100 according to the present embodiment, an electric field is generated between the liquid adhering to the end of the probe 1 and the ion extraction electrode 17 by the electric field generating means having the voltage applying device 10 and the voltage applying device 14. Is generated.

  By this electric field, the liquid moves to the side surface of the probe 1 on the side of the ion take-in part 7 to form a Taylor cone 5. In FIG. 1, a Taylor cone 5 is formed on a continuous surface that forms the major axis direction of the probe 1. However, since this position is affected by the electric field between the ion extraction electrode 17 and the liquid, the wettability of the probe 1 with the liquid, etc., the Taylor cone 5 may be formed at a position including other surfaces.

  When the liquid adhering to the end of the probe 1 is sufficiently close to the ion extraction electrode 17, the electric field is increased at the tip of the Taylor cone 5. As a result, electrospray is generated from the liquid, and minute charged droplets 6 are generated. The charged droplet 6 flies toward the ion extraction electrode 17 by an electric field generated between the ion extraction electrode 17 and the liquid. By appropriately setting the magnitude of the electric field, the charged droplet 6 can undergo Rayleigh splitting, and ions of a specific substance in the sample 18 can be generated. The charged droplets 6 and ions are guided to the ion take-in unit 7 according to the flow of the air current and the electric field. At this time, it is preferable that the vibration of the probe 1 includes a movement in a direction approaching the ion capturing portion 7 so that the electric field around the liquid forming the Taylor cone 5 changes with the vibration of the probe 1.

Here, Rayleigh splitting refers to a phenomenon in which the charged droplet 6 reaches the Rayleigh limit, and excessive charges in the charged droplet 6 are released as secondary droplets. While the liquid forms the Taylor cone 5, the electrospray including the charged droplet 6 is generated from the tip of the Taylor cone 5, and while the Rayleigh splitting occurs, the substance included in the charged droplet 6 is gas phase ions. It is known to occur as The threshold voltage Vc at which electrospray is generated is Vc = 0.863 (γd / ε ₀ ) ^0.5 (where γ: surface tension of the liquid, d: distance between the liquid and the ion extraction electrode, ε ₀ : dielectric constant of vacuum) (J. Mass Spectrom. Soc. Jpn., Vol. 58, 139-154, 2010).

  The probe 1 is vibrated by the vibration means 2, and as a result, the portion from the fixed end to the free end of the probe 1 vibrates. When the vibration means 2 is always in contact with the probe 1 while the vibration means 2 is vibrating, the position where the vibration means 2 is in contact is the fixed end of the probe 1. On the other hand, when the vibration means 2 and the probe 1 are separated while the vibration means 2 vibrates, the position where the probe fixing portion 16 is disposed becomes the fixed end of the probe 1. The probe fixing part 16 is a part for fixing at least a part of the probe 1 to the probe device.

  In this specification, the probe vibrating portion 19 (hereinafter referred to as “vibrating portion 19”) refers to a portion of the probe 1 that vibrates substantially. That is, it refers to a portion from the fixed end to the free end of the probe 1 in the entire probe 1. The vibration means 2 is not included in the vibration part 19. The vibration means 2 vibrates the probe 1 in the direction of the arrow in FIG. The vibration of the probe 1 has an amplitude of, for example, about several tens of nm to several hundred μm, and a vibration frequency of, for example, about 10 Hz to 1 MHz.

  The amplitude of the probe 1 is set so that the formation of the liquid bridge 4 and the generation of electrospray occur alternately. When the type of the probe 1, the natural frequency of the vibrating portion 19, and the strength of the electric field generated between the probe 1 and the ion extraction electrode 17 are changed, the amplitude of the probe 1 should be changed as appropriate. Is desirable.

  The apparatus 100 according to the present embodiment is characterized in that ionization of a substance existing in a minute region on the surface of the sample 18 can be performed at high speed. In order to ionize the substance on the surface of the sample 18 at high speed, the probe 1 is preferably vibrated at high speed.

  Another feature of the apparatus 100 according to the present embodiment is that the timing of generation and stop of electrospray can be controlled. Therefore, it is preferable that the timing at which the liquid bridge 4 is formed between the end of the probe 1 and the sample 18 and the timing at which electrospray is generated are clearly separated. Thereby, electrospray is not generated while the liquid bridge 4 is formed, and only charges are supplied to the liquid forming the liquid bridge 4 during this period. Thereafter, when the end of the probe 1 approaches the ion extraction electrode 17 and electrospray is generated, sufficient charge is accumulated in the liquid, so that the electrospray can be generated efficiently. For this purpose, it is preferable to increase the amplitude of the probe 1.

  In order to vibrate the probe 1 at a high speed and with a large amplitude as described above, the natural frequency of the vibration part 19 and the vibration frequency provided by the vibration means 2 are preferably matched. That is, it is preferable that the vibration means 2 applies a vibration having the natural frequency of the vibration portion 19 to the probe 1 to resonate the vibration portion 19.

  In addition, although ionization under atmospheric pressure is described in this specification, the method of changing the natural frequency of the vibration part 19 of the probe 1 according to the present embodiment can be applied to ionization under reduced pressure. Further, the type of liquid used in the present embodiment is not particularly limited, but it is preferable to use a liquid that does not affect the components constituting the flow path. In addition, a substance to be ionized by the apparatus 100 according to the present embodiment is not particularly limited. Since the microregion can be softly ionized at atmospheric pressure by using the apparatus 100 according to the present embodiment, the apparatus 100 according to the present embodiment is suitable for ionization of a biological sample containing macromolecules such as lipids, sugars, and proteins. ing.

(Natural frequency of vibration part 19)
Next, the natural frequency of the vibrating portion 19 of the probe 1 according to this embodiment will be described.

  In general, the natural frequency of a cantilever-like probe having a length L with a weight m added to the tip can be approximated by the following equation (1) if the mass of the probe itself is ignored.

  Here, I is the cross-sectional second moment of the probe, and E is the Young's modulus of the probe. The probe length L is the length from the center of gravity of the entire probe to the fixed end of the probe. In this case, the length L is the length from the position where the weight of mass m is added to the fixed end of the probe. Furthermore, when the probe has a hollow cylindrical shape such as a pipe, the cross-sectional secondary moment I is expressed by the following formula (2).

  Here, D is the outer diameter of the probe, and d is the inner diameter of the probe. Therefore, the natural frequency of the probe can be changed by changing at least one of the four parameters of the probe length L, mass m, probe Young's modulus E, and sectional moment of inertia I.

  The changing means 20 included in the apparatus 100 according to the present embodiment can change the natural frequency of the vibrating portion 19 by changing at least one of these four parameters.

  When changing the natural frequency of the vibrating portion 19, it is preferable that the position of the region where the liquid bridge 4 is formed on the surface of the sample 18 does not change before and after the change. Therefore, it is preferable that the changing unit 20 changes the natural frequency of the vibrating portion 19 without changing the length from the reference point of the apparatus 100 to the tip of the probe 1. Here, the reference point is not particularly limited as long as it is a fixed point on the apparatus 100. For example, a reference point when the sample stage control unit 13 moves or scans the sample stage 8 may be used as the reference point.

  Even when the length from the reference point to the tip of the probe 1 changes when changing the natural frequency, the region where the liquid bridge 4 is formed by controlling the sample stage 8 based on the change amount. The position in the sample 18 can be kept unchanged. For example, the change amount of the position of the liquid bridge 4 before and after the change of the natural frequency is obtained by the computer 22 described later. By driving the sample stage 8 in the opposite direction to the obtained change amount of the position of the liquid bridge 4, without changing the position in the sample 18 of the region where the liquid bridge 4 is formed, The natural frequency of the vibration part 19 can be changed. Alternatively, the coordinates of the position of the liquid bridge 4 may be corrected by the computer 22 based on the obtained change amount of the position of the liquid bridge 4.

  The length of the probe 1 is as long as the liquid bridge 4 is stably formed between the sample 18 on the substrate 3 and the probe 1 and the electrospray 6 is generated when approaching the ion extraction electrode 17. There is no particular limitation. However, if the length of the probe 1 is too short, the amplitude of vibration of the probe 1 becomes small, so that it is difficult to stably generate the liquid bridge 4. If the length of the probe 1 is too long, unintended vibrations in directions other than the direction in which the probe 1 is vibrated by the vibration providing mechanism 2 are likely to occur. Therefore, it is difficult to continuously measure a certain position on the sample 18 on the substrate 3. From the above, the length of the probe 1 is preferably about several hundred μm to several cm, for example.

  The color and pattern of the probe 1 are not particularly limited. A scale may be engraved in the longitudinal direction of the probe 1. By associating the scale with the free end of the probe 1 or the length from the probe fixing portion 16, when the weight or the like is attached to the probe 1, the attachment position of the weight or the like can be clearly grasped. When a plurality of types of scales are engraved on the probe 1, different colors may be assigned to the types of scales.

  Next, a system for changing the natural frequency of the vibration portion 19 according to the present embodiment will be described with reference to FIG. FIG. 2A is a block diagram showing a natural frequency changing system for the vibration portion 19 according to this embodiment.

  As shown in FIG. 2A, the system for changing the natural frequency of the vibration part 19 according to the present embodiment includes an apparatus 100, a mass analyzer 15, a vibration detector 24, a computer 22, and an input of the computer 22. Means 21.

  The vibration detector 24 is a part that detects the vibration of the probe 1 and measures the frequency or amplitude of the vibration of the probe 1. That is, the vibration detector 24 is a frequency measuring means and an amplitude measuring means. Note that the vibration frequency provided by the vibration means 2 and the vibration frequency of the probe 1 do not always coincide with each other. The vibration detector 24 detects the vibration of the probe 1 when the vibration frequency of the vibration means 2 is gradually changed, and the vibration frequency when the amplitude of the probe 1 is maximized is determined as the natural frequency of the vibration portion 19. Get as.

  A high speed camera may be used as the vibration detector 24. In that case, the vibration frequency and amplitude of the probe 1 can be obtained by photographing the vibrating probe 1 with a high-speed camera and analyzing the obtained image. Alternatively, a surface that can reflect light is provided on a part of the probe 1, a laser beam is applied to the surface, and the frequency or amplitude of the probe 1 is measured by an optical lever type detector as the vibration detector 24. good. Alternatively, as the vibration detector 24, a non-contact type laser vibration detector may be used. In that case, the frequency and amplitude of the vibration of the probe 1 can be obtained by measuring and analyzing the time that the probe 1 crosses the laser.

  The computer 22 is connected to the voltage applying means 12 to the vibration means 2, the changing means 20, the vibration detector 24, the input means 21, and the mass analyzer 15. The computer 22 can perform calculations and data analysis based on data obtained by the mass analyzer 15 and the vibration detector 24. In addition, the computer 22 uses the ionizer 100 and the mass analysis unit based on data input from the user via the input unit 21 and data sent from the vibration detector 24, the mass analysis unit 15, the voltage application unit 12, and the like. 15 can be controlled.

  The input means 21 is means for a user to input data and instructions to the computer 22. As the input means 21, for example, a keyboard, a mouse, a touch panel, or the like can be used.

(Operation for changing the natural frequency of the vibration portion 19)
Next, the operation of the system for changing the natural frequency of the vibration portion 19 according to the present embodiment will be described with reference to FIG. FIG. 2B is a flowchart showing the operation of the change system.

  First, the computer 22 sets the frequency f0 (S201).

  Next, information on the frequency f 0 set by the computer 22 is transmitted to the voltage applying unit 12 to the vibrating unit 2. As a result, a voltage is applied to the vibrating means 2 by the voltage applying means 12, and the vibrating means 2 provides the probe 1 with a vibration having the set frequency f0 (S202).

  Subsequently, the vibration detector 24 detects the vibration of the probe 1 and measures the frequency f of the vibration of the probe 1 (S203).

  Next, the vibration detector 24 transmits the detected vibration frequency f of the probe 1 to the computer 22. The computer 22 compares the vibration frequency f of the probe 1 received from the vibration detector 24 with the vibration frequency f0 set by the computer 22 in S202 (S204).

  If the vibration frequency f of the probe 1 does not match the vibration frequency f0 set by the computer 22 in S202, the computer 22 drives the changing means 20 (S205). Thereby, the natural frequency of the vibration part 19 is changed. At this time, the computer 22 sets the drive amount of the changing means 20 based on the expressions (1) and (2) so that the vibration frequency f of the probe 1 approaches the vibration frequency f0 set by the computer 22 in S202. You may control.

  When the vibration frequency f of the probe 1 coincides with the vibration frequency f0 set by the computer 22 in S202, the computer 22 stops driving the changing means 20 (S206). Thereby, the change of the natural frequency of the vibration part 19 is completed (S207).

  When setting the frequency f0 in S201, the user may input an arbitrary frequency f0 using the input means 21. Alternatively, a frequency obtained by increasing or decreasing the natural frequency of the current vibration portion 19 by a predetermined amount may be set as the frequency f0.

  Further, the frequency f0 may be determined by the computer 22 based on the signal intensity of a specific signal acquired by the mass analyzer 15. At this time, mass spectrometry may be performed while changing the vibration frequency of the probe 1, and the vibration frequency of the probe 1 when the signal intensity of the target component becomes maximum may be set as f0.

  As described above, in the present embodiment, the natural frequency of the vibrating portion 19 is changed by driving the changing unit 20.

(Operation to reduce fluctuation of natural frequency of vibration part 19)
Next, the operation of the mitigation system that reduces fluctuations in the natural frequency of the probe 1 will be described with reference to FIG. FIG. 10 is a flowchart showing the operation of the mitigation system. Here, the amplitude of the vibrating portion 19 of the probe 1 refers to an average value of the amplitude measured several times to several thousand times with respect to the vibration of the vibrating portion 19 or an average value of the amplitude measured within a certain time.

  In this specification, “fluctuation of the natural frequency” refers to a phenomenon in which the natural frequency of the vibration portion 19 slightly varies. Even if the natural frequency of the vibration part 19 of the probe 1 is changed and vibration is applied to the constant probe 1 at a constant frequency f, the natural frequency slightly fluctuates and the vibration part 19 continues to resonate. May not be possible. This is considered to be due to the fact that the probe 1 vibrates in an unintended direction depending on the contact state between the vibration means 2 and the probe 1. When fluctuations occur in the natural frequency of the vibration part 19, the vibration part 19 cannot continue to resonate, and the ionization conditions of the sample 18 by the apparatus 100 may vary from measurement point to measurement point. As a result, the reproducibility of measurement by the mass image display system according to the present embodiment may be reduced. Therefore, in the present embodiment, fluctuations in the natural frequency of the vibration portion 19 are reduced by the following mitigation system.

  First, the vibration means 2 applies vibration to the probe 1 at the natural frequency f0 of the vibration portion 19 of the probe 1 (S209). Next, when the fluctuation of the natural frequency of the vibration part 19 is reduced (yes in S210), the amplitude of the probe 1 is measured by the vibration detector 24, and the amplitude value is transmitted to the computer 22 (S211).

  Next, the computer 22 drives the changing means 20, changes the natural frequency from f0 to f0 + Δf, and measures the amplitude of the probe 1 (S212). Subsequently, the computer 22 drives the changing means 20, changes the natural frequency from f0 + Δf to f0−Δf, and measures the amplitude of the probe 1 (S212). Through the series of operations in steps S211 to S213, the original natural frequency f0 and the amplitude of the probe 1 at the frequency obtained by increasing or decreasing the frequency by Δf from f0 can be acquired.

  Next, the computer 22 compares the amplitude measured in each step of S211 to S213 (S215). At this time, the computer 22 calculates a variation in amplitude and a significant difference E when the frequency is f0−Δf, f0, f0 + Δf. If there is no significant difference between the amplitudes (No in S215), the computer 22 drives the changing means 20 to change the frequency to f0 (S217).

  If there is a significant difference between the respective amplitudes (Yes in S215), the computer 22 drives the changing means 20, and newly sets the natural frequency when the amplitude is maximized as f0 (S216). Thereafter, the computer 22 drives the changing means 20 to change the frequency to f0 (S217).

  By repeating S208 to S217 every unit time t seconds, fluctuations in the natural frequency of the vibration portion 19 of the probe 1 can be reduced. In addition, each value of (DELTA) f, t, E is not specifically limited, A user can set arbitrarily. These parameters are set in advance according to the configuration of the apparatus 100 and the type of the probe 1, and the above parameters are automatically input by allowing the user to select the type of the probe 1 and the configuration of the apparatus 100. , Improve user convenience.

  When the sample stage 8 is moved largely, such as when moving the measurement region, the above operation is stopped, and the above operations of S208 to S218 are resumed when the movement of the sample stage 8 is completed. Good to do. Further, the above operation may be started immediately after the vibration of the probe 1 is started, or the above operation may be started when a change in the amplitude of the probe 1 is detected. Further, while the above operation is being performed, if the amplitude of the probe 1 does not change for a certain period of time, the above operation may be stopped, and if the change in amplitude is detected again, the above operation may be resumed. Alternatively, the above operation may be started when the amplitude of the probe 1 becomes equal to or less than a specified value, and the operation may be stopped when the amplitude of the probe 1 exceeds the specified value.

  When the vibration of the probe 1 is modulated or when the sample stage 8 is vibrated in the Z direction, the amplitude of the probe 1 periodically varies. When modulating the vibration of the probe 1, it is preferable to measure the maximum amplitude in one vibration period and apply the above operation. Alternatively, the time for taking the average value of the amplitude of the probe 1 may be set sufficiently longer than the modulation period of the vibration of the probe 1 and the period of vibration of the sample stage 8 in the Z direction.

  In this embodiment, the natural frequency is changed in the order of f0, f0 + Δf, and f0−Δf. However, the order of changing the natural frequency may be arbitrarily changed, and is changed in the order of f0, f0−Δf, and f0 + Δf. May be. Further, the change of the natural frequency is not limited to the above three, and the types of natural frequencies to be changed may be increased, for example, f0, f0 + Δf, f0 + 2Δf, f0-Δf, f0-2Δf, and the like. Thereby, the fluctuation of the natural frequency of the vibration part 19 of the probe 1 can be measured more accurately and reduced more effectively.

  As described above, according to the present embodiment, fluctuations in the natural frequency of the vibration portion 19 of the probe 1 can be reduced.

(Ionization method)
Next, the ionization method according to the present embodiment will be described with reference to FIG. FIG. 3 is a flowchart showing the ionization method according to this embodiment.

  First, the user sets conditions for performing ionization in the apparatus 100 (S301). At this time, the frequency of the probe 1 at the time of ionization, the number of times of ionization for each frequency, the number of measurement points, the position information of the measurement region, and the like are set as conditions. In the present embodiment, it is preferable to set at least two values as the natural frequency of the probe 1 and ionize the sample 18 at two different natural frequencies.

  When the setting of the conditions is completed in S301, the ionization apparatus 100 vibrates the vibration unit 2 and vibrates the probe 1 (S302).

  As described above, in this embodiment, the liquid supply unit 10 arranges the liquid at the end of the probe 1, and the ionization apparatus 100 brings the end of the probe 1 on which the liquid is arranged close to or in contact with the sample 18. Thereby, the liquid bridge 4 is formed between a partial region of the sample 18 and the end of the probe 1 (S303). At this time, the substance contained in the sample 18 is dissolved in the liquid forming the liquid bridge 4.

  Next, the end of the probe 1 is brought close to the ion extraction electrode 17 by vibrating the probe 1. At this time, the probe 1 vibrates in a state where the liquid forming the liquid bridge 4 remains attached to the end of the probe 1. When the end of the probe 1 approaches the ion extraction electrode 17, an electrospray of the liquid is generated by the electric field between the ion extraction electrode 17 generated by the electric field generating means and the liquid at the end of the probe 1 (S304). .

  By the first step (S303) and the second step (S304), it is possible to ionize only the sample 18 in a part of the region where the liquid at the end of the probe 1 is in contact and the liquid bridge 4 is formed. Note that the first step (S303) and the second step (S304) are repeated because the probe 1 vibrates. The ionization is repeated until the predetermined number of times set in S301 is performed (S305).

  Although the number of repetitions of S303 and S304 is specified here by specifying the number of times of ionization, this is not limitative. In other words, the ionization time may be set as the condition set in S301, and the repetition of S303 and S304 may be terminated when a predetermined time has elapsed.

  Next, the computer 22 determines whether or not to change the frequency of the probe 1 (S306). When the frequency is not changed, that is, when the next frequency is not set in the conditions set in S301, the vibration of the probe 1 is stopped (S308).

  When changing the frequency of the probe 1, the natural frequency of the vibration part 19 is changed by the above-described natural frequency changing system, and the frequency of the probe 1 is changed (S305).

  In the present embodiment, the natural frequency of the vibration portion 19 of the probe 1 is changed in this way, and the first step (S303) and the second step (S304) are performed at least twice at different natural frequencies. preferable. At this time, it is preferable to ionize the same region at different natural frequencies, but the present invention is not limited to this. That is, when the sample 18 is ionized, a method of performing ionization at a first frequency in one region and performing ionization at a second frequency in another region is also included in the ionization method according to the present embodiment. .

  Further, the ionization apparatus according to the present embodiment may be an ionization apparatus that changes the natural frequency of the vibration part 19 of the probe 1 and performs ionization at least twice at different natural frequencies.

  Hereinafter, the configuration of the changing unit 20 that changes the natural frequency of the vibrating portion 19 that can be applied to the present invention will be described.

[First Embodiment]
The natural frequency changing means according to the first embodiment will be described with reference to FIG. FIG. 4 is a schematic diagram schematically showing the configuration of the natural frequency changing means according to the first embodiment.

  The changing means 20 according to the present embodiment changes the natural frequency of the vibrating portion 19 by changing the length of the vibrating portion 19. That is, the changing means 20 changes the natural frequency by changing L in the equation (1).

  As shown in FIG. 4, the changing unit 20 according to the present embodiment includes a fixing portion 31, a screw thread 32, a gear 33, a rotation mechanism 34, and a bearing 35.

  The fixing part 31 is a part for fixing the probe 1. That is, when the vibration means 2 arranged so as to come into contact with the probe 1 is arranged on the free end side with respect to the position where the fixing portion 31 is arranged, the vibration means 2 provides vibration to the probe 1. 31 becomes a fixed end and the probe 1 vibrates. That is, the portion of the probe 1 from the free end to the fixed portion 31 is the vibrating portion 19.

  However, when the vibration providing mechanism 2 is always in contact with the probe 1 while the vibration providing mechanism 2 is vibrating, the position where the vibration providing mechanism 2 is in contact is the fixed end of the probe 1. On the other hand, when the vibration means 2 and the probe 1 are separated while the vibration providing mechanism 2 is oscillating, the position where the fixing portion 31 is disposed is the fixed end of the probe 1. Therefore, in this embodiment, the vibration means 2 is disposed so as to intermittently contact the probe 1 while the vibration means 2 is vibrating.

  A screw thread having a shape corresponding to the screw thread 32 is engraved on the fixing part 31, and the fixing part 31 is arranged so that the screw thread of the fixing part 31 meshes with the screw thread 32. Since the screw thread 32 is fixed to the probe 1, the position of the fixing portion 31 can be moved by rotating the probe 1 or the fixing portion 31.

  FIG. 4A shows the changing means 20 according to the present embodiment that moves the position of the fixing portion 31 by rotating the probe 1. In FIG. 4A, the probe 1 is rotated by providing the probe 33 with the gear 33 and rotating the gear 33 by the rotation mechanism 34. Thereby, the fixing | fixed part 31 arrange | positioned so that it may mesh with the screw thread 32 fixed to the probe 1 moves. Since the fixed portion 31 is a fixed end of the vibration portion 19, the length of the vibration portion 19 is changed.

  FIG. 4B shows the changing means 20 according to the present embodiment that moves the position of the fixing portion 31 by rotating the fixing portion 31. In FIG. 4B, the probe 1 is rotated by providing the fixed portion 31 with the gear 33 and rotating the gear 33 with the rotation mechanism 34. Thereby, the fixing | fixed part 31 arrange | positioned so that it may mesh with the screw thread 32 fixed to the probe 1 moves. Since the fixed portion 31 is a fixed end of the vibration portion 19, the length of the vibration portion 19 is changed.

  The fixing unit 31 can be moved by manually rotating the probe 1 or the fixing unit 31, but rotating the fixing unit 31 by an electric rotating mechanism can rotate the fixed unit 31 at high speed and accurately. This is preferable because it is possible.

  As the rotating mechanism 34, for example, a stepping motor or the like can be used. In this case, the natural frequency of the probe 1 is precisely changed by controlling the drive pulse number of the stepping motor by the computer 22 based on the relationship between the length L of the probe 1 and the natural frequency in the equation (1). Can do.

  In the present embodiment, the thread 32 may be created by integral molding with the probe 1 or may be created separately and attached to the probe 1. As a material of the thread 32, for example, a material having a high Young's modulus such as a metal can be used. However, if a material having too high rigidity is used as the material of the thread 32, the fixed end of the probe 1 may be fixed to the joint point on the free end side of the probe 1 and the thread 32. Therefore, in the present embodiment, it is preferable to use a material having a relatively low rigidity as the material of the thread 32.

[Second Embodiment]
The natural frequency changing means according to the second embodiment will be described with reference to FIG. FIG. 5 is a schematic diagram schematically showing the configuration of the natural frequency changing means according to the second embodiment.

  In the present embodiment, the probe 1 has a weight 41. The weight 41 vibrates integrally with the probe 1. That is, the vibration part 19 in this embodiment includes a weight 41. The weight 41 is a weight that can move in the longitudinal direction of the probe 1. The changing means 20 according to the present embodiment changes the natural frequency of the vibrating portion 19 by moving the weight 41 in the longitudinal direction of the probe 1. FIG. 5A shows the changing means 20 according to the present embodiment, which can move the weight 41 attached to the probe 1 in the longitudinal direction of the probe 1.

  In this embodiment, the mass of the probe 1 is sufficiently light compared to the mass of the weight 41. Therefore, the ratio of the mass of the probe 1 to the total mass of the weight 41 and the probe 1 is sufficiently small and can be ignored. Therefore, the movement of the weight 41 in the present embodiment corresponds to the change of the length L in Expression (1).

  That is, when the movable weight 41 attached to the probe 1 is moved to the free end side, L increases and the natural frequency of the probe 1 decreases. At this time, a scale may be provided in the longitudinal direction of the probe 1, and the natural frequency of the vibrating portion 19 when the weight 41 is located at the position of each scale may be associated with each scale. Thereby, the natural frequency of the vibration part 19 can be roughly known without actually measuring the vibration of the probe 1.

  The shape of the weight 41 is not particularly limited. For example, as shown in FIG. 5B, both the probe 1 and the weight 41 may be provided with corresponding threads. Thereby, the position in the probe 1 of the weight 41 can be controlled precisely. In this case, the weight 41 can be moved in the longitudinal direction of the probe by rotating at least one of the probe 1 or the weight 41.

  At this time, it is preferable that a screw hole is formed in the weight 41 and the probe 1 having a thread 46 engraved therein is screwed. Further, when the weight 41 is moved in the longitudinal direction of the probe 1 by rotating the probe 1, it is preferable to provide a guide bar 44 to suppress the rotation of the weight 41 as shown in FIG. A plurality of guide rods 44 having different hardnesses may be prepared, and the guide rods 44 may be exchanged according to the natural frequency of the probe 1.

  The guide bar 44 is arranged so that the rotation of the weight 41 can be suppressed. The guide bar 44 may be disposed so as to be inserted into the weight 41. Or you may arrange | position so that it may press on the weight 41. FIG. Alternatively, the weight 41 may be provided with a groove, and the guide rod 44 may be fitted into the groove. The guide bar 44 does not always need to be in contact with the weight 41, and may be separated from the weight 41 while the probe 1 is vibrating.

  Further, as shown in FIG. 5C, the weight 41 may be moved in the longitudinal direction of the probe 1 by rotating the guide rod 44. In this case, a thread 47 is provided on the guide rod 44, and a thread corresponding to the thread 47 is also provided on the weight 41. Note that the probe 1 and the guide rod 44 may be configured to be rotatable by the same mechanism as in the first embodiment.

  In the present embodiment, the weight 41 can be freely moved from the probe fixing portion 16 of the probe 1 to the free end. However, when the weight 41 is attached to the free end of the probe 1, there is a possibility that the generation of the liquid bridge 4 between the probe 1 and the substrate 3 and the generation of electrospray may be hindered. Therefore, the movable range on the free end side of the weight 41 is preferably set to a position away from the free end by a predetermined distance. If two or more types of weights 41 having different masses are prepared as the movable weights 41 and are exchanged according to the target natural frequency, the mass m of the weights in the equation (1) can also be changed. . Thereby, the variable range of the natural frequency of the vibration part 19 can be expanded.

  The material of the weight 41 is not particularly limited. As a material of the weight 41, metals, rubbers, wood and the like can be used, but it is preferable to use a metal weight 41 from the viewpoint of durability. Moreover, the weight 41 which combined the some material can also be used. For example, the portion of the weight 41 that contacts the probe 1 may be configured using a material having a large coefficient of friction such as rubber. Thereby, it can suppress that the weight 41 moves, while the probe 1 is vibrating.

[Third Embodiment]
The natural frequency changing means according to the third embodiment will be described with reference to FIG. FIG. 6 is a schematic diagram schematically showing the configuration of the natural frequency changing means according to the third embodiment.

  The changing means 20 according to the present embodiment changes the natural frequency of the vibrating portion 19 by attaching a detachable weight 51 to the probe 1. The attached weight 51 vibrates integrally with the probe 1. That is, the vibration part 19 in this embodiment includes a weight 51. In the present embodiment, the mass of the vibrating portion 19 is changed by attaching or detaching the weight 51 or replacing it with another mass. That is, in this embodiment, the natural frequency of the vibration part 19 is changed by changing the mass m in the equation (1).

  If the weight 51 attached to the probe 1 is made heavy, m in Formula (1) becomes large, so that the natural frequency of the vibration part 19 decreases. On the other hand, if the weight 51 attached to the probe 1 is lightened, m in Equation (1) becomes small, so that the natural frequency of the vibrating portion 19 increases. In the present embodiment, a plurality of types of weights 51 having different masses may be prepared as the fixed weights 51. Then, the weight 51 may be exchanged according to the target natural frequency.

  In the present embodiment, since the weight 51 is exchanged each time according to the target natural frequency, it is preferable that the weight 51 be easily attached to and detached from the probe 1. Therefore, in the present embodiment, a weight mounting portion 52 for mounting the weight 51 on the probe 1 is provided.

  The weight mounting part 52 is installed in at least one place of the probe 1. In addition, a plurality of weights 51 can be attached to one weight attachment part 52. The place where the weight 51 and the weight attaching part 52 are attached may be any place of the probe 1. However, when mounted on the free end, the formation of the liquid bridge 4 between the probe 1 and the substrate 3 and the occurrence of electrospray may be hindered, as in the second embodiment. Therefore, it is preferable that the weight 51 and the weight mounting portion 52 are mounted on a portion other than the vicinity of the free end so as not to prevent formation of the liquid bridge 4 at the free end and generation of electrospray.

  If the weight 51 is attached in a direction perpendicular to the vibration direction of the probe 1, when the probe 1 vibrates, a force in a direction other than the vibration direction is applied to the probe 1, and the probe 1 may be twisted. When the probe 1 is twisted, it becomes difficult to accurately control the position of the liquid bridge 4 formed between the probe 1 and the substrate 3. For this reason, the weight 51 and the weight mounting portion 52 are preferably mounted so that the center of gravity of the weight 51 and the weight mounting portion 52 exists on a plane through which the probe 1 vibrates.

  The weight mounting portion 52 preferably fixes the weight 51 so that the weight 51 mounted on the weight mounting portion 52 does not move on the probe 1 while the probe 1 is vibrating. As a method of attaching the weight 51 to the weight attaching portion 52, for example, a screw type, a magnet type, an adhesive type, or the like can be used. Moreover, as a material of the weight mounting part 52, it is good to use a metal from a viewpoint of durability.

  The shape and material of the weight 51 are not particularly limited. As the weight 51, a hollow weight 51 in which the inside of the weight 51 is hollow may be used. In this case, the mass of the weight 51 can be changed by taking a fluid such as a liquid into and out of the cavity inside the weight 51. Note that a weight having a plurality of cavities may be used as the weight 51, and the weight of the weight may be changed by injecting a fluid such as a liquid into an arbitrary number of cavities. Thus, when using the weight 51 which has a cavity inside, the weight 51 may be fixed to the probe 1.

  The fluid to be injected is not particularly limited. However, when a fluid having a low viscosity is used as the fluid, the fluid injected into the weight 51 moves when the probe 1 vibrates. The natural frequency of may not be constant. Therefore, it is preferable to use a highly viscous fluid as the fluid to be injected. Moreover, the variable range of the mass of the weight 51 can be expanded by using a plurality of types of fluids having different specific gravities in combination. As a result, the variable range of the natural frequency of the vibration part 19 can be expanded.

  Alternatively, a cavity may be provided in the probe 1 separately from the flow path for flowing the liquid supplied from the liquid supply means 9. It is also possible to change the natural frequency of the vibrating portion 19 by injecting fluid into the cavity as described above.

[Fourth Embodiment]
The natural frequency changing means according to the fourth embodiment will be described with reference to FIG. FIG. 7 is a schematic diagram schematically showing the configuration of the natural frequency changing means according to the fourth embodiment.

  In the present embodiment, a multiple tube in which at least two tubes are concentrically stacked is used as the probe 1. The changing means 20 according to the present embodiment changes the natural frequency of the vibrating portion 19 by moving at least one of the tubes constituting the multiple tube relative to the other tubes.

  FIG. 7 is an enlarged view of the free end side of the probe 1 when a double tube in which two tubes are concentrically stacked is used as the probe 1. In the present embodiment, the probe 1 has a flow path for supplying the liquid supplied from the liquid supply means 9 to the substrate 3 inside the probe 1. The probe 1 discharges the liquid supplied from the liquid supply means 9 from the tip of the probe 1. Therefore, the probe 1 discharges the liquid from the distal end of the tube that is far from the fixed end of the probe 1, of the two tubes constituting the probe 1. In the present embodiment, of the two tubes constituting the probe 1, the tube having the free end of each tube far from the fixed end of the probe 1 is not moved, and only the tube closer to the tube is moved. As a result, the natural frequency of the vibrating portion 19 can be changed while maintaining the position at which the liquid bridge 4 is formed on the substrate 3 without changing the position at which the solution is discharged from the probe 1.

  Of the two tubes constituting the probe 1, the tube whose free end is far from the fixed end of the probe 1 may be moved. In this case, similarly to the above-described embodiment, the change amount of the position where the liquid bridge 4 is formed is acquired using the computer 22, and the sample stage 8 is controlled based on the change amount. Thereby, the natural frequency of the vibration part 19 can be changed without changing the position in the sample 18 of the region where the liquid bridge 4 is formed. Or you may correct | amend the coordinate information of data based on the acquired variation | change_quantity.

FIG. 7A shows a configuration in which the natural frequency of the vibrating portion 19 is changed by moving the inner tube 62 in the longitudinal direction of the probe 1 out of the double tubes constituting the probe 1. When the inner tube 62 having an inner diameter d ₂ is inserted into the outer tube 61 having an inner diameter d ₁ , the inner diameter of the entire double tube after insertion is d ₂ . Since d ₂ is smaller than d ₁ , the inner diameter d of the probe 1 can be reduced by inserting the inner tube 62 into the outer tube 61. When the inner diameter d is decreased, the sectional secondary moment I is increased from the equation (2), and accordingly, the natural frequency of the vibrating portion 19 is also increased from the equation (1).

On the other hand, FIG. 7B shows a configuration in which the natural frequency of the vibrating portion 19 is changed by moving the outer tube 61 in the longitudinal direction of the probe among the double tubes constituting the probe 1. . The outer tube 61 of the outer diameter D _1, the outer diameter is inserted into the outer tube 62 of d _2, the outer diameter of the entire double tube after insertion becomes D _1. Since D ₁ is larger than D ₂ , the outer diameter D of the probe 1 can be increased by inserting the outer tube 61 outside so as to cover the inner tube 62. When the outer diameter D increases, the sectional secondary moment I increases from the equation (2), and accordingly, the natural frequency of the vibrating portion 19 also increases from the equation (1).

  Thus, in this embodiment, the probe 1 is a tube in which at least two tubes are concentrically stacked, and the relative position of the tubes constituting the probe 1 is changed. Thereby, the outer diameter D or inner diameter d of the probe 1 can be changed, and the natural frequency of the vibration part 19 can be changed.

  In the present embodiment, the vibrating portion 19 may include a portion where the outer tube 61 and the inner tube 62 overlap and a portion where the two tubes do not overlap. That is, the vibration part 19 may have a single pipe part and a double pipe part. In this case, the cross-sectional secondary moment I of the entire vibration part 19 can be treated approximately as a weighted average value obtained by weighting the cross-sectional secondary moment of each part, for example, with the length of each part. That is, the natural frequency of the vibrating portion 19 can be adjusted by adjusting the depth of insertion of the tube. In addition, you may taper the thickness of the wall surface of the pipe | tube to move among the pipe | tubes which comprise the probe 1. FIG. When a pipe having a taper is used as the pipe to be moved, the natural frequency of the vibrating portion 19 can be adjusted more finely by adjusting the depth of insertion of the pipe. In addition, when a tube is further inserted inside or outside the double tube constituting the probe 1 to form a tube of a triple tube or more, the natural frequency of the vibration portion 19 can be further greatly changed.

  Note that, as shown in FIG. 7C, a thread 65 may be cut between the tubes adjacent to at least two tubes constituting the probe 1. Thereby, the insertion depth of a pipe | tube can be adjusted by rotating at least one pipe | tube. The tube to be rotated may be either the inner tube 62 or the outer tube 61. The tube can be rotated by the same mechanism as in the first embodiment. Further, it is preferable that the non-rotated tube is fixed to the non-moving portion of the entire apparatus so that it does not rotate together with the rotated tube. Further, a sealing material may be provided between the outer tube 61 and the inner tube 62. Thereby, the liquid flowing inside the probe 1 can be prevented from leaking from the inside of the probe 1.

  The material of the tubes used in the present embodiment, such as the outer tube 61 and the inner tube 62, is not particularly limited, and may be a conductive material or an insulating material. In addition, if the tube to be inserted is exchangeable and a plurality of types of tubes having different hardnesses are inserted, the natural frequency can be greatly changed. Further, as long as a liquid flow path is secured inside or outside the probe 1, a rod or a plate that does not have a cavity inside may be used as the tube to be inserted, and it is not necessarily coaxial with the probe 1. Also good.

  Further, the outer tube 61 and the inner tube 62 may each be a tube formed by combining a plurality of members. A plurality of members can be handled as an integral tube by joining. FIG. 7D shows a cross-sectional view in the longitudinal direction when the outer tube 61 or the inner tube 62 is a tube formed by combining a plurality of members. For example, as the outer member 66 of the outer tube 61, a metal material that has high durability and can be machined with high machining accuracy can be used. Further, as the inner member 67 of the outer tube 61, a material such as Teflon (registered trademark) having a low friction coefficient and high water repellency and chemical stability can be used. Thereby, it is possible to achieve both the smooth insertion and removal of the inner tube 62 with respect to the outer tube 61 and the improvement of the control of the natural frequency of the probe 1.

  Similarly to the outer tube 61, the inner tube 62 may be a tube formed by combining a plurality of members. In the case of the inner tube 62, if the outer member 66 is made of a material such as Teflon (registered trademark), the inner tube 62 can be smoothly inserted into the outer tube 61. The inner member 67 of the inner tube 62 is not particularly limited, but a resin material having a high chemical stability, a metal material having a high Young's modulus, or the like can be used.

[Fifth Embodiment]
The natural frequency changing means according to the fifth embodiment will be described with reference to FIG. FIG. 8 is a schematic diagram schematically showing the configuration of the natural frequency changing means according to the fifth embodiment.

  In the present embodiment, as shown in FIG. 8A or FIG. 8D, the spring 71 is arranged outside or inside the probe 1. The changing means 20 according to the present embodiment changes the natural frequency of the vibrating portion 19 by expanding and contracting the spring 71 by the spring control mechanism 73.

  The changing unit 20 according to the present embodiment includes a spring 71, a spring stopper 72, and a spring control mechanism 73. In the present embodiment, the spring 71 is arranged so that at least a part of the spring 71 vibrates together with the probe 1. That is, the vibration part 19 in the present embodiment includes at least a part of the spring 71.

  The spring control mechanism 73 has a function of expanding and contracting the natural state spring 71 of FIG. 8A as shown in FIG. 7B or a function of twisting as shown in FIG. 7C.

  The spring control mechanism 73 shown in FIG. 8B expands and contracts the spring 71 in the direction of the arrow in FIG. The changing means 20 according to the present embodiment can harden the spring 71 by compressing the spring 71 with the spring control mechanism 73. When the spring 71 becomes hard, the Young's modulus E of the vibrating portion 19 increases. On the other hand, the changing means 20 according to the present embodiment can soften the spring 71 by extending the spring 71 with the spring control mechanism 73. When the spring 71 becomes soft, the Young's modulus E of the vibration part 19 becomes small.

  As described above, the changing unit 20 according to the present embodiment can change the Young's modulus E of the vibrating portion 19 by expanding and contracting the spring 71 by the spring control mechanism 73. Thereby, the natural frequency of the vibration part 19 can be changed from Formula (1).

  The spring control mechanism 74 shown in FIG. 8C twists the spring 71 in the direction of the arrow in FIG. The changing means 20 according to the present embodiment can increase the outer diameter of the spring 71 by twisting the spring 71 in the direction in which the number of turns of the spring 71 decreases. On the other hand, the changing means 20 according to the present embodiment can reduce the outer diameter of the spring 71 by twisting the spring 71 in the direction in which the number of turns of the spring 71 increases.

  That is, the changing means 20 according to the present embodiment can change the outer diameter of the spring 71 by twisting the spring 71. Thereby, the cross-sectional secondary moment of the spring 71 can be changed. Note that the overall cross-sectional secondary moment of the vibrating portion 19 including the spring 71 and the probe 1 is a value obtained by adding the cross-sectional secondary moment of the spring 71 and the cross-sectional secondary moment of the probe 1. Therefore, the natural frequency of the probe frequency 19 can be changed. In this embodiment, it is necessary to provide the probe 1 with the spring stopper 72 and fix the free end side of the spring 71 by the spring stopper 72. When the spring control mechanism 73 extends and contracts the spring 71 as shown in FIG. 8B, the spring 71 may be fixed by the spring stopper 72 so that the spring 71 does not get over the spring stopper 72 when the spring 71 expands and contracts. On the other hand, when the spring control mechanism 73 twists the spring 71 as shown in FIG. 8C, it is further necessary to fix the free end side to the probe 1 by the spring stopper 72 so that one end of the spring 71 does not rotate. In this case, the fixed end side of the spring 71 also needs to be fixed to the fixed end (spring control mechanism 73) so that the spring 71 after twisting does not rotate.

  In addition, although this embodiment demonstrated embodiment which attached the spring 71 to the outer side of the probe 1, you may attach the spring 71 to the inner side of the probe 1 like FIG.8 (d).

[Sixth Embodiment]
The natural frequency changing means according to the sixth embodiment will be described with reference to FIG. FIG. 9 is a schematic diagram schematically showing the configuration of the natural frequency changing means according to the sixth embodiment.

  The changing means 20 according to the present embodiment changes the natural frequency of the vibrating portion 19 by moving the vibrating means 2 and changing the position at which the probe 1 is provided with vibration. The vibrating means 20 in this embodiment vibrates the probe 1 by vibrating the vibrating means 20 and transmitting the vibration to the probe 1. As shown in FIG. 9, the changing unit 20 according to the present embodiment includes a slide part 81, a support part 82, a fixing part 83, and a slide mechanism 84.

  The support portion 82 is a portion that supports the vibration means 2. The vibration means 2 is fixed by a support portion 82. In addition, the support portion 82 is fixed to the slide portion 81. The slide part 81 is supported by the fixed part 83.

  The slide mechanism 84 is a part that slides the slide part 81, the support part 82, and the vibration means 2 in the arrow direction (the longitudinal direction of the probe 1) in FIG. 9.

  In the present embodiment, the vibrating means 2 is arranged so as to always contact the probe 1 while vibrating the probe 1. Therefore, in this embodiment, the position where the vibration means 2 contacts is the fixed end of the probe 1. Therefore, the portion of the probe 1 on the free end side from the position where the vibrating means 2 contacts is the vibrating portion 19. The changing unit 20 according to the present embodiment changes the length of the vibrating portion 19 by changing the position of the vibrating unit 2 by the slide mechanism 84. As described above, the changing unit 20 according to the present embodiment changes the natural frequency of the probe 19 by changing L in Expression (1).

[Seventh Embodiment]
The natural frequency changing means according to the seventh embodiment will be described with reference to FIG. FIG. 11A is a schematic diagram schematically showing the configuration of the natural frequency changing means according to the seventh embodiment.

  The changing unit 20 according to this embodiment includes a probe temperature control unit 101. Further, the probe 1 according to the present embodiment includes a thermosoftening material or a thermosetting material in at least a part of the material constituting the probe 1. Note that the thermosoftening material is a material that softens when heated, that is, a material with a reduced Young's modulus E. The thermosetting material is a material that is cured by heating, that is, a material that increases the Young's modulus E. As the thermosoftening material or the thermosetting material, a thermoplastic resin or a thermosetting resin can be used.

  The changing means 20 according to this embodiment changes the Young's modulus E of the probe 1 by adjusting the temperature of the probe 1 by applying heat to the probe 1 by the probe temperature control means 101. Thereby, the natural frequency of the vibration part 19 can be changed from Formula (1).

  As the probe temperature control means 101, a heating means such as a heater or a cooling means such as a Peltier element can be used, and the heating means and the cooling means may be combined. If the thermometer such as a thermocouple is further provided, the temperature of the probe 1 can be maintained at an arbitrary temperature.

  The probe 1 used in this embodiment may be a probe made by combining a metal material having high heat conductivity and high heat resistance and a heat softening material. Thereby, even if the Young's modulus E is changed by heating or cooling, the strength and mechanical accuracy of the probe 1 can be maintained. FIG. 11B and FIG. 11C schematically show a cross section in the longitudinal direction of the probe 1 according to this embodiment. The probe 1 may have a structure in which the outer side of the metal capillary 102 is covered with a thermosoftening material 103 as shown in FIG. 11B, or the inner side of the metal capillary 102 as shown in FIG. 10C. A structure in which the material 103 is arranged may be used.

  The probe temperature control means 101 may transmit heat to the entire vibration part 19 of the probe 1 or may transmit heat to a part of the vibration part 19 of the probe 1. The probe temperature control means 101 is preferably in contact with the probe 1, but may not be in direct contact with the probe 1. For example, as shown in FIG. 11 (d), the probe temperature control means 101 is installed in the conductive flow path 11 or the liquid supply means 9 between the probe 1 and the liquid supply means 9, and the probe 1 is connected via the liquid. It is good also as a structure which transmits heat to. In FIG. 11 (d), the fixed portion 104 is a fixed end of the vibrating portion 19 of the probe 1.

  Further, the probe temperature control means 11 may be disposed in the vicinity of the probe 1. In this case, the temperature of the gas around the probe 1 is adjusted by the probe temperature control means 11, and the temperature of the probe 1 can be adjusted by this gas. Alternatively, means for transferring heat to the probe 1 by infrared radiation may be used as the probe temperature control means 11. Alternatively, the probe temperature control means 11 may be a means for irradiating the probe 1 with a laser to heat the probe 1 or may be configured to heat the probe by irradiating a heating element mounted on the probe with the laser. . Or it is good also as a structure which heats an analysis target object and transmits heat to the probe 1 through the liquid bridge | crosslinking which generate | occur | produces between an analysis target object and the probe 1. FIG.

  In the present embodiment, as described above, the probe temperature control means 11 can change the Young's modulus E of the vibrating portion 19 of the probe 1 to change the natural frequency. In the present embodiment, the following effects are further expected. That is, when the probe 1 is heated, the liquid attached to the tip of the probe 1 is also heated, and the Taylor cone 5 and the liquid bridge 4 are also heated. Heating the Taylor cone 5 has the effect of promoting the generation of electrospray from the Taylor cone 5. Further, heating the liquid bridge 4 has an effect that the dissolution of the substance in the sample 18 into the liquid bridge 4 is promoted. According to the present embodiment, ionization efficiency can be improved by any of these effects as compared to the case where the probe 1 is not heated.

[Eighth Embodiment]
The natural frequency changing means according to the eighth embodiment will be described with reference to FIG. FIG. 12A is a schematic diagram schematically showing the configuration of the natural frequency changing means according to the eighth embodiment.

  The changing unit 20 according to the present embodiment includes a probe rotating unit 121 that rotates the probe 1 in the direction indicated by the arrow in FIG. The probe rotating means 121 can be realized by the thread 32, the gear 33, the rotating mechanism 34, the bearing 35, and the like in the first embodiment. The probe rotating means 121 can rotate the probe 1 by an arbitrary angle θ in the direction indicated by the arrow in FIG.

  In the present embodiment, a probe having a different natural frequency depending on the vibration direction is used as the probe 1. As a probe having a different natural frequency with respect to the vibration direction, a probe having a different Young's modulus E with respect to the vibration direction may be used, or a probe having a different cross-sectional second moment I with respect to the vibration direction may be used. . Probes having different Young's modulus E with respect to the vibration direction can be produced using, for example, members having different microstructures depending on directions or anisotropic materials having different crystal structures depending on directions. The probe 1 may be made of a single material, or may be created by bonding a plurality of members such as bonding them.

  FIG. 12B shows a cross-sectional view when the probe 1 is cut along a plane orthogonal to the longitudinal direction of the probe 1 applicable to the present embodiment. Here, a probe having a different cross-sectional secondary moment I with respect to the vibration direction is used as the probe 1.

  An arrow 124 indicates the direction of vibration applied to the probe 1 by the vibration unit 2 (hereinafter referred to as “y direction”). An arrow 125 indicates the vibration direction of the probe 1 that vibrates when vibration is applied by the vibration means 2. As shown in FIG. 12B, the rotation angle θ is such that the direction in which the cross-sectional secondary moment I of the probe 1 increases (the dotted line direction in FIG. 12B) is orthogonal to the y direction (hereinafter referred to as “x direction”). It represents how much it is tilted with respect to ".

  In the case of FIG. 12B, the probe 1 has a higher natural frequency in the y direction as the rotation angle θ increases within a range of θ from 0 ° to 90 °. In the present embodiment, by controlling the rotation angle θ, the cross-sectional secondary moment I of the probe 1 in the y direction can be changed, and the natural frequency of the probe 1 in the y direction can be controlled.

  In the apparatus 100 according to the present embodiment, it is preferable to suppress the vibration of the probe 1 in the x direction in order to stabilize the position on the substrate 3 formed by the liquid bridge 4. In the present embodiment, as the probe 1 is rotated to change the rotation angle θ, the position, angle, and contact area where the vibration means 20 and the probe 1 are in contact may change. For this reason, the probe 1 is likely to vibrate in the x direction. Therefore, as shown in FIG. 12C, the vibration of the probe 1 can be stabilized by installing the guide 126 as a vibration suppressing means for suppressing the vibration of the probe 1 in the x direction. In the case of the present embodiment, the vibration in the x direction of the probe 1 can also be suppressed by limiting the range in which the rotation angle θ is changed to near 0 ° or 90 °. Further, when the rotation angle θ is set to 0 ° or 90 °, the vibration of the probe 1 in the x direction can be suppressed.

  When the guide 126 is used, as shown in FIG. 12D, the guide 126 can be used regardless of the width of the probe 1 if the distance between the guides 126 (arrow 128) can be adjusted to an arbitrary distance. Can do. In FIG. 12D, the guide support portion 127 that supports the guide 126 and the guide support rod 129 are threaded. The interval between the guides 126 can be adjusted by rotating the guide support rods 129 by a rotation mechanism using a motor or the like.

  The guide 126 is preferably installed at any position between the portion in contact with the vibration means 20 of the probe 1 and the tip (free end) of the probe 1, but the vibration means 20 of the probe 1 from the fixed end of the probe 1. You may install between the part which contacts with. Increasing the width of the guide 126 in the longitudinal direction of the probe 1 is preferable because vibration in the x direction of the probe 1 can be efficiently suppressed.

[Ninth Embodiment]
A mass image display system according to a ninth embodiment will be described with reference to FIG. The mass image display system according to the present embodiment includes a mass spectrometer, a computer 22 that is a mass image generation device, and a display device 23.

  The mass spectrometer according to the present embodiment includes the apparatus 100 according to any one of the first to eighth embodiments described above, and the mass spectrometer 15.

  The apparatus 100 ionizes the substance contained in the sample 18 in the region where the liquid bridge 4 is formed. The generated ions are taken into the ion take-in unit 7, fly in a gas phase, and reach the mass analysis unit 15.

  In the present embodiment, the mass analyzer 15 is a time-of-flight mass analyzer. That is, the mass spectrometer 15 measures the time during which ions fly inside the vacuum flight tube, thereby measuring the mass-to-charge ratio of ions and performing mass analysis of the ionized substance. The mass analyzer 15 may be a known mass analyzer such as a quadrupole type, a magnetic field deflection type, an ion trap type, or an ion cyclotron type in addition to the time-of-flight mass analysis means.

  The computer 22 instructs the sample stage control means 13 of the position of the region on the surface of the sample 18 that forms the liquid bridge 4. Based on this instruction, the sample stage control means 13 controls the position of the sample stage 8 connected to the sample stage control means 13.

  The computer 22 acquires position information of the region where the liquid bridge 4 is formed from the stage control unit 13, and acquires mass information (mass spectrum) of the sample 18 at the position from the mass analysis unit 15. In the mass image display system according to this embodiment, the position of the region where the liquid bridge 4 is formed is changed by moving the sample stage 8, and mass spectrometry is performed at a plurality of locations on the surface of the sample 18. The computer 22 forms image data representing the distribution of the substance contained in the sample 18 by using the obtained mass spectra and position information.

  At this time, as described above, the natural frequency of the vibrating portion 19 of the probe 1 may be changed, and the sample 18 may be ionized at different natural frequencies to form two or more image data.

  The computer 22 outputs the formed image data to an image display unit 23 such as a display connected to the computer 22 to display an image. The image data may be two-dimensional data or three-dimensional data.

  When displaying an image, not only the position information of each substance but also the amount of the substance may be displayed together. For example, the amount of the substance can be displayed by changing the color or brightness of the pixel corresponding to each position depending on the amount of the substance. When there are a plurality of types of substances to be analyzed in the sample 18, each substance can be displayed in a different color, and the amount of each substance can be displayed by changing the brightness.

  Alternatively, an optical microscope image of the sample 18 may be acquired in advance, and the optical microscope image and the mass microscope image of the sample acquired by the mass spectrometer according to the present embodiment may be superimposed and displayed by the computer 22. good.

  In the present embodiment, the image display system having the display device 23 has been described, but the display device 23 may not be provided. That is, an image generation system having a mass spectrometer and an image generation device is also included in the present invention.

  Moreover, in the system comprised from the combination of the some apparatus to which this invention is applied, each apparatus may be connected partially or entirely by the network containing the internet. For example, the data acquired by the mass spectrometer may be transmitted to a server connected to a network, a mass image may be formed on the server, and the obtained result may be received from the server to display an image.

[Other Embodiments]
As mentioned above, although preferable embodiment of this invention was described, this invention is not limited to these embodiment, A various deformation | transformation and change are possible within the range of the summary. Further, the above embodiments can be used in combination with each other.

[Example]
Examples of the present invention will be described below.

  Using a mass spectrometer as shown in FIG. 1, the sample was subjected to mass analysis. When performing mass spectrometry, the sample was ionized while discharging a solution of water: MeOH: formic acid = 50: 50: 0.2 from the tip of the probe 1 at a speed of 1 nL / min as a liquid.

  As the probe 1, a probe 1 having a movable weight 41 attached to the probe 1 as shown in FIG. As the probe 1, a glass capillary was used. Also, a rubber piece (having a weight of 0.05 g) with a hole was used as the movable weight 41, and the probe 1 was attached to the probe 1 through the hole of this rubber piece. The rubber piece (movable weight 41) was in close contact with the probe 1 and did not move while the probe 1 was vibrating.

  The probe 1 was arranged so as to be pressed against the vibration means 2. While the vibrating means 2 was vibrating, the probe 1 and the vibrating means 2 were always in contact. Therefore, in this embodiment, the vibrating portion 19 of the probe 1 is a portion between the contact portion with the vibrating means 2 that is a fixed end and the tip of the probe 1 that is a free end. The length from the fixed end to the free end was about 2 cm.

  First, the movable weight 41 was set at a position 5 mm from the free end. When vibration was applied to the probe 1 while gradually changing the frequency by the vibration means 2, the vibration portion 19 of the probe 1 resonated at about 300 Hz. Therefore, it was found that the natural frequency of the vibrating portion 19 of the probe 1 when the movable weight 41 is set at a position 5 mm from the free end is about 300 Hz.

  Subsequently, the movable weight 41 was manually moved and set at a position 15 mm from the free end. When the natural frequency of the vibration part 19 was examined in the same procedure as described above, the natural frequency of the vibration part 19 of the probe 1 when the movable weight 41 was set at a position 15 mm from the free end was about 500 Hz. I found out.

  Next, mass spectrometry was performed by changing the natural frequency of the vibrating portion 19 of the probe 1.

  As sample 18, a mixture of bovine insulin and phosphatidylcholine coated on a glass slide as substrate 3 and dried was used. As the sample 18, five samples having different mixing ratios of the two components were used. In each sample, the amount of phosphatidylcholine is 0 equivalent (sample 1), 0.01 equivalent (sample 2), 0.1 equivalent (sample 3), 1 equivalent (sample 4) with respect to bovine insulin, Prepared to be 10 equivalents (sample 5).

  Table 1 shows the measurement results when the probe 1 is driven at 300 Hz and the probe 1 is driven at 500 Hz by changing the natural frequency of the vibration portion 19 of the probe 1. Table 1 shows the counts of ions of mass-to-charge ratio corresponding to pentavalent insulin and hexavalent insulin generated when bovine insulin is ionized.

  In a sample that does not contain phosphatidylcholine as in sample 1, the signal is obtained when the probe 1 is driven at 300 Hz for both insulin pentavalent and hexavalent insulin (that is, when the natural frequency of the vibration part 19 is 300 Hz). The strength of was strong.

  However, when the driving frequency of the probe 1 was 300 Hz, it was found that the insulin signal rapidly decreased as the amount of phosphatidylcholine mixed was increased (sample 2 and sample 3). Furthermore, for sample 4 and sample 5 in which the amount of phosphatidylcholine mixed was large, no insulin signal could be detected when the driving frequency of probe 1 was 300 Hz.

  On the other hand, when the probe 1 was driven at 500 Hz, the intensity of insulin signal was weaker in the sample (sample 1) containing no phosphatidylcholine than in the case where the driving frequency of the probe 1 was 300 Hz.

  It was also found that the intensity of the insulin signal decreased as the amount of phosphatidylcholine mixed was increased, as in the case where the drive frequency of the probe 1 was 300 Hz. However, when the driving frequency of the probe 1 is 300 Hz, the insulin signal cannot be detected for the samples 4 and 5, but when the driving frequency is 500 Hz, the insulin signal is also detected for the samples 4 and 5. I was able to. Thus, it was found that when the amount of phosphatidylcholine mixed is large, it is easier to detect the insulin signal in the 500 Hz drive than in the 300 Hz drive.

  As for the signal of ions derived from phosphatidylcholine, the intensity of the signal was stronger when driving at 300 Hz than when driving the probe 1 at 500 Hz.

  Therefore, in this example, the driving frequency of the probe 1 was driven at 300 Hz in the case of a sample containing no phosphatidylcholine, and 500 Hz in the case of a sample containing phosphatidylcholine, so that bovine insulin was ionized. Further, when ionizing phosphatidylcholine, the probe was driven at 300 Hz for ionization. As described above, by changing the frequency of the probe 1 in accordance with the component to be ionized and the state of the sample, the target component can be efficiently ionized.

  In this embodiment, the natural frequency of the vibrating portion 19 of the probe 1 is changed by moving the movable weight 41 in the longitudinal direction of the probe 1. Thereby, the natural frequency of the vibration part 19 of the probe 1 could be changed without removing the probe 1.

  At this time, the position on the substrate 3 where the liquid bridge 4 is formed did not change before and after the change of the natural frequency of the vibration portion 19 of the probe 1. That is, by using the mass spectrometer according to the present example, the same measurement point could be measured even when the natural frequency of the vibration part 19 of the probe 1 was changed. Therefore, according to this embodiment, it is not necessary to recalibrate the position of the tip of the probe 1 after changing the natural frequency of the vibrating portion 19 of the probe 1. For this reason, when the mass spectrometer according to the present embodiment is used, it is possible to continuously change the natural frequency of the vibrating portion 19 of the probe 1 and perform mass analysis, thereby improving the analysis efficiency.

DESCRIPTION OF SYMBOLS 1 Probe 2 Vibration means 4 Liquid bridge | crosslinking 9 Liquid supply means 10, 14 Voltage application means (electric field generation means)
16 Fixing part 17 Ion extraction electrode 18 Sample 20 Natural frequency changing means 100 Ionizer

Claims (20)

An ionization apparatus for ionizing the sample contained in a region where the probe is brought into proximity or contact with a sample surface and the probe is in proximity or contact with the sample surface,
A fixing portion for fixing the probe to the ionization device;
Liquid supply means for supplying a liquid to the end of the probe;
An ion extraction electrode;
An electric field generating means for generating an electric field between the liquid adhering to the end of the probe and the ion extraction electrode;
The liquid adhering to the end of the probe contacts the sample to form a liquid bridge, and the end of the probe approaches the ion extraction electrode, and the liquid is Vibration means for applying vibration to the probe so as to periodically repeat the state of flying toward the extraction electrode;
A natural frequency changing means for changing a natural frequency of a vibrating part of the probe that vibrates by the vibrating means in a state where the probe is fixed to the fixing portion;
Ionizer characterized by having.   The ionization apparatus according to claim 1, wherein the vibration unit imparts vibration of the natural frequency to the probe.   The natural frequency changing means changes the natural frequency without changing the position on the surface of the sample in the region where the liquid adhering to the end of the probe forms the liquid bridge. The ionization apparatus of Claim 1 or Claim 2.   The said changing means changes the said natural frequency by changing any one of the length of the said vibration part of the said probe, mass, a cross-sectional secondary moment, or a Young's modulus. The ionization apparatus as described in any one of Claims 3. The probe further has a weight movable in the longitudinal direction of the probe,
5. The ionization apparatus according to claim 1, wherein the natural frequency changing unit changes the natural frequency by moving the weight in a longitudinal direction of the probe. 6. . The vibration means is means for vibrating the probe by contacting the probe,
5. The ionization apparatus according to claim 1, wherein the natural frequency changing unit changes the natural frequency by changing a position where the vibrating unit is in contact with the probe. 6. . The probe further includes a weight mounting portion,
5. The ionization apparatus according to claim 1, wherein the natural frequency changing unit changes the natural frequency by attaching and detaching a weight to and from the weight mounting portion. The probe has a cavity inside the probe;
The ionization apparatus according to any one of claims 1 to 4, wherein the natural frequency changing unit changes the natural frequency by injecting a fluid into the cavity. The probe is a multiple tube in which at least two tubes are concentrically overlapped,
The natural frequency changing means changes the natural frequency by moving at least one of the tubes constituting the probe relative to another tube. The ionization apparatus as described in any one of thru | or 4 thru | or 4. The probe has a structure in which a spring is arranged inside or outside the tube,
5. The ionization apparatus according to claim 1, wherein the natural frequency changing unit changes the natural frequency by performing expansion and contraction of the spring. The probe includes a thermosoftening material or a thermosetting material in at least a part of the probe;
The ionization apparatus according to any one of claims 1 to 4, wherein the natural frequency changing unit changes the natural frequency by changing a temperature of the probe. The probe is a probe having a different natural frequency depending on a vibration direction,
5. The ionization apparatus according to claim 1, wherein the natural frequency changing unit changes the natural frequency by rotating the probe to change a vibration direction. 6.   The ionization apparatus according to any one of claims 1 to 12, wherein ionization of the sample is performed at least twice at the different natural frequencies.   The ionization apparatus according to claim 1, further comprising a vibration suppression unit that suppresses vibration of the probe in a direction other than the direction given by the vibration unit. It further has an amplitude measuring means for measuring the amplitude of the probe,
The amplitude of the probe is measured by changing the natural frequency by the amplitude measuring means,
The natural frequency changing means changes the natural frequency so that the amplitude is maximized. An ionization apparatus according to any one of claims 1 to 15,
And a mass spectrometer that performs mass analysis of the ions generated by the ionizer.   The mass spectrometer according to claim 16, wherein the mass analyzer is a time-of-flight mass analyzer. A mass spectrometer according to claim 16 or claim 17,
An image generation device for creating image data representing a distribution of a component of a substance contained in the sample from mass information acquired by the mass spectrometer and position information of the region on the sample surface. Image generation system. An image generation system according to claim 18,
And a display device that displays the image data as an image. A first step in which a liquid bridge containing a substance contained in the sample is formed between the end of the probe having a liquid disposed at the end thereof in proximity to or in contact with the sample, and the sample;
By vibrating the probe, the end of the probe to which the liquid is attached is brought close to the ion extraction electrode, and the liquid is extracted by an electric field generated between the ion extraction electrode and the end of the probe. A second step of flying toward the electrode, comprising:
An ionization method, wherein the natural frequency of a vibration part of the probe is changed without removing the probe, and the first step and the second step are performed at different natural frequencies.