WO2004068131A1 - Ionisateur et analyseur de zone de dimension reduite - Google Patents

Ionisateur et analyseur de zone de dimension reduite Download PDF

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Publication number
WO2004068131A1
WO2004068131A1 PCT/JP2004/000843 JP2004000843W WO2004068131A1 WO 2004068131 A1 WO2004068131 A1 WO 2004068131A1 JP 2004000843 W JP2004000843 W JP 2004000843W WO 2004068131 A1 WO2004068131 A1 WO 2004068131A1
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WO
WIPO (PCT)
Prior art keywords
laser
field light
probe
matrix
sample
Prior art date
Application number
PCT/JP2004/000843
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English (en)
Japanese (ja)
Inventor
Katsutoshi Takahashi
Original Assignee
National Institute Of Advanced Industrial Science And Technology
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Publication date
Application filed by National Institute Of Advanced Industrial Science And Technology filed Critical National Institute Of Advanced Industrial Science And Technology
Publication of WO2004068131A1 publication Critical patent/WO2004068131A1/fr

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Classifications

    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/02—Details
    • H01J49/10—Ion sources; Ion guns
    • H01J49/16—Ion sources; Ion guns using surface ionisation, e.g. field-, thermionic- or photo-emission
    • H01J49/161—Ion sources; Ion guns using surface ionisation, e.g. field-, thermionic- or photo-emission using photoionisation, e.g. by laser
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/0004—Imaging particle spectrometry

Definitions

  • the present invention relates to an apparatus and a method capable of performing analysis with high resolution in a minute area. More specifically, the present invention relates to an ionization apparatus and an ionization method for ionizing a sample by irradiating a sample-mixed matrix with near-field light or laser using a probe, and to a mass spectrometer and a micro-area analyzer equipped with the ionization apparatus .
  • Matrix-assisted laser desorption / ionization (MALD I) mass spectrometers are highly useful in that they can mass-analyze molecules that are difficult to ionize, such as proteins. Mass spectrometers are usually used for the purpose of detecting a very small amount of sample with high sensitivity, but are not commonly used for observing microscopic areas like a microscope. As an example of observation of a micro area using a MALD I mass spectrometer, an example of imaging a brain cell section is known (see Non-Patent Documents 1 to 4). On the other hand, the technology using near-field light has been applied to a scanning near-field optical microscope (SNOM), and has realized an optical microscope with high resolution exceeding the diffraction limit of light.
  • SNOM scanning near-field optical microscope
  • an ultraviolet laser is incident on a near-field light probe and irradiated with the generated near-field light to decompose the triazane compound.
  • mass spectrometry see Non-Patent Document 5.
  • Non-Patent Document 1 Caprio1i, R.M.eta1., Ana1.Chem., 1997, 69, 4751-4760
  • Non-Patent Document 2 Stoeckli, M. etal., J. Am. Soc. Mass Spectrom, 1999, 10, 67—71.
  • Non-Patent Document 3 Caur and, P. eta 1., An a 1. Chem., 1999, 71, 5263—5270
  • Non-Patent Document 4 Stoeclkli, M.eta 1., NATURE MED I CINE, 2001, 7, 493
  • Non-Patent Document 5 Stoec1e, R.eta1., Anal.Chem., 2001, Vol. 73, pl999—1402
  • the laser is focused by a lens and irradiates the matrix, so the diameter of the laser that can be focused is limited to 12 of the wavelength of one laser by the diffraction limit of light.
  • the resolution was as low as about 25 m.
  • Non-Patent Document 5 cannot be directly used for mass analysis of proteins and the like because the analyte is a synthetic compound and decomposes the analyte into nitrogen molecules. .
  • An object of the present invention is to provide an apparatus and a method for performing analysis in a minute area with high resolution without excessively damaging a sample using a mass spectrometer.
  • the present inventors have studied to solve the above problems, and as a result, have found that the above problems can be solved by applying laser irradiation using near-field light or a probe to MAL DI, thereby completing the present invention. Reached.
  • the present invention includes a laser emitting unit, and a near-field light generating unit that receives a laser emitted from the laser emitting unit and generates near-field light when the laser is emitted from the near-field light generating unit.
  • the present invention relates to an ionization apparatus that irradiates a sample mixed with Matritas by irradiating a near-field light to a matrix.
  • the present invention provides a laser emitting means, an optical fiber for guiding a laser emitted from the laser emitting means, and a laser irradiation probe connected to a tip of the optical fiber.
  • the present invention relates to an ionization apparatus for irradiating a matrix with a laser emitted from the laser irradiation probe to ionize a sample mixed with the matrix.
  • the present invention relates to an ionization apparatus and an ionization method for irradiating a sample mixed with a matrix by irradiating the matrix with near-field light.
  • the present invention relates to a mass spectrometer provided with the above-mentioned ionization device.
  • the present invention provides the above ionization apparatus, information input means for inputting information on an area to be analyzed to be scanned,
  • Drive mechanism control means for controlling a drive mechanism based on the area information
  • Analysis result analysis means for analyzing the result obtained from the mass analysis means
  • Storage means for storing position information transmitted from the drive mechanism control means and analysis results obtained from the analysis result analysis means
  • Image means for performing imaging from the position information and the analysis result stored in the storage means
  • the present invention relates to a micro-area analysis device provided with:
  • the present invention provides a method for ionizing a sample using the above-mentioned ionization apparatus,
  • region can be performed with high resolution using a mass spectrometer, without excessively damaging a sample.
  • FIG. 1 is an enlarged view near the near-field optical probe of the ionization apparatus of the present invention.
  • FIG. 2 is a schematic configuration diagram of the ionization device and the mass spectrometer of the present invention.
  • FIG. 3 is an enlarged view near the near-field optical probe of the ionization apparatus of the present invention.
  • FIG. 4 is an enlarged view near the near-field optical probe of the ionization device of the present invention.
  • FIG. 5 is a schematic configuration diagram of the micro region analysis device of the present invention.
  • FIG. 6 is a view showing a laser irradiation probe used in the present invention.
  • near-field light is light that is generated near the surface of an irradiation target when the irradiation target is irradiated with light and propagates only along the surface, and critical light from a medium having a high refractive index to a medium having a low refractive index. It includes both non-propagating light (so-called evanescent light) that penetrates into the low-refractive-index medium when light is introduced at an angle above the angle.
  • the minute region means a region having a diameter of 15 m or less.
  • the ionizer has an ultraviolet laser oscillator 1, an optical fiber 13 connected to the ultraviolet laser oscillator 1, and a near-field optical probe 5 connected to the other end of the optical fiber 1.3. Further, a suction tube 12 is arranged near the near-field optical probe 5. The suction tube 12 is connected to a suction controller 30, and the suction controller 30 is connected to a mass spectrometer 50. The near-field optical probe 5 Below the sample, a protein sample 8 mixed with a matrix 9 is arranged.
  • the ultraviolet laser oscillator 1, the near-field light probe 5, and the suction tube 12 constitute the laser emitting means, the near-field light generating means, and the sample transferring means of the present invention, respectively.
  • the first embodiment of the present invention is configured as described above, and its operation will be described below.
  • the laser light emitted from the ultraviolet laser oscillator 1 enters the near-field optical probe 5 through the optical fiber 3.
  • near-field light 7 is generated near the tip of the near-field optical probe 5.
  • the generated near-field light 7 irradiates the matrix 9 mixed with the protein sample 8.
  • the matrix 9 irradiated with the near-field light 7 evaporates together with the protein sample 8, the protein sample 8 is ionized, and protein ions 10 are generated.
  • the generated protein ions 10 are sucked into the suction tube 12 through the suction port 11.
  • the protein ions 10 sucked into the suction tube 12 pass through the suction control section 30 and are sent to the mass spectrometry section 50.
  • the mass spectrometer 50 performs mass spectrometry of the protein ions 10. As a result, it is possible to irradiate near-field light only to a small region smaller than the wavelength width of the ultraviolet laser, and mass spectrometry can be performed with high resolution.
  • FIG. 3 shows a second embodiment of the ionization device of the present invention.
  • an ultraviolet laser oscillator is provided, whereas in the present embodiment, an infrared laser oscillator (not shown) is provided.
  • the ionizer has a hollow optical fiber 130 connected to an infrared laser oscillator (not shown), and a near-field optical probe 5 connected to the other end of the hollow optical fiber 130.
  • a suction tube 12 is disposed near the near-field optical probe 5.
  • the suction tube 12 is connected to a mass spectrometer (not shown).
  • a cell section 100 is arranged below the near-field optical probe 5, and the cell section 100 is fixed to a sample stage 150.
  • the sample stage 150 is connected to a stage drive mechanism (not shown), and the stage drive mechanism is connected to a drive mechanism controller.
  • the infrared laser oscillator, near-field light probe 5, suction tube 12, and cell section 100 constitute the laser emitting means, near-field light generating means, sample transfer means, and analysis object of the present invention, respectively. I do.
  • the second embodiment of the present invention is configured as described above, and its operation will be described below.
  • Laser light emitted from the infrared laser oscillator passes through the hollow optical fiber 130 and enters the near-field optical probe 5. When the laser light is incident, near-field light 7 is generated near the tip of the near-field light probe 5. The generated near-field light 7 is applied to a matrix existing in the cell section 100.
  • the matrix is mixed with a protein sample present in the cell section 100, and when the matrix is irradiated with near-field light 7 and vaporized together with the protein sample, the protein sample is ionized and the protein ion 1 0 is generated.
  • the generated protein ions 10 are sucked into the suction tube 12 through the suction port 11.
  • the protein ions 10 sucked into the suction tube 12 are sent to the mass spectrometer.
  • the mass spectrometer performs mass spectrometry of protein ions 10.
  • the cell section 100 is fixed to a sample stage 150, and the sample stage 150 can be slid in a horizontal direction by a stage driving mechanism.
  • the stage and the drive mechanism are controlled by the drive mechanism control unit, and slide the sample stage 150 back and forth, left and right.
  • the near-field light probe 5 can scan the surface of the cell slice 100. Then, the mass spectrometry of the protein sample existing at each position of the cell section can be performed, and it is possible to examine what portion of the cell section contains what kind of protein.
  • FIG. 4 shows a third embodiment of the ionization device of the present invention.
  • an infrared laser oscillator is also provided in this embodiment.
  • the ionizer is provided with a mirror 210 for receiving a laser from an infrared laser oscillator and an atomic force microscope (AFM) probe 230.
  • the AFM probe 230 has a pinhole 235 open.
  • a skimmer 250 is arranged above the AFM probe 230, and a mass analyzer (not shown) is arranged ahead of the skimmer 250.
  • a cell sample 280 is arranged below the pinhole 235, and the cell sample 280 is fixed to a sample stage 270.
  • the sample stage 270 is connected to a stage drive mechanism (not shown), and the stage drive mechanism is connected to a drive mechanism control unit.
  • the infrared laser oscillator, the AFM probe 230, the skimmer 250, and the cell sample 280 correspond to the laser emitting means of the present invention.
  • the means for generating the in-field light, the means for transferring the sample, and the object to be analyzed are configured.
  • the third embodiment of the present invention is configured as described above, and its operation will be described below.
  • the laser light emitted from the infrared laser oscillator is reflected by the mirror 210 and enters the AFM probe 230.
  • Near-field light 7 is generated from the pinhole 2 35 of the AFM probe 230 into which the laser beam has entered.
  • the generated proximity light 7 is applied to the matrix existing inside or on the surface of the cell membrane 290 of the cell sample 280.
  • the matrix is mixed with the membrane protein sample 300, and when the near-field light 7 is applied to the matrix and evaporates together with the membrane protein sample 300, the membrane protein sample 300 is ionized and the membrane is sampled. Protein ions 310 are produced.
  • the generated membrane protein ion 310 is sucked by the skimmer 250, and the membrane protein ion 310 sucked by the skimmer 250 is sent to the mass spectrometer.
  • mass spectrometry section mass spectrometry of the membrane protein ion 310 is performed.
  • the cell sample 280 is fixed to a sample stage 270, and the sample stage 270 can be slid in a horizontal direction by a stage driving mechanism.
  • the stage driving mechanism is controlled by a driving mechanism control unit, and slides the sample stage 270 forward and backward and left and right.
  • the AFM probe 230 can scan the surface of the cell membrane 290.
  • mass spectrometry of the membrane protein sample present at each position of the cell membrane can be performed, and it is possible to examine what part of the cell membrane contains what kind of membrane protein.
  • FIG. 5 is a diagram showing an embodiment of the micro region analysis device of the present invention.
  • the control unit 500 is configured by a computer including a drive mechanism control unit 520, an analysis result analysis unit 540, an imaging unit 550, and a storage unit 560.
  • the control section 500 is connected to the drive mechanism 510 via the drive mechanism control section 5200, and the drive mechanism 5100 is connected to the sample stage 150. Further, the control section 500 is connected to the mass analysis section 50 via the analysis result analysis section 540. Further, the control unit 500 is connected to the keyboard 530 via the drive mechanism control unit and to the display 570 via the imaging unit 550, respectively.
  • Other configurations are the same as in FIG.
  • the keyboard 530, drive mechanism controller 520, mass spectrometer 50, analysis result analyzer 540, storage 560, imager 550, and display 570 Departure
  • the information input means, the drive mechanism control means, the mass analysis means, the analysis result analysis means, the storage means, the imaging means, and the display means are constituted respectively.
  • the microregion analyzer of the present invention is configured as described above, and its operation will be described below.
  • the area information of the cell section 100 to be scanned is input to the keyboard 5300, and the input area information is transmitted to the drive mechanism control section 5200.
  • the region means a scanning range of the cell section 100, and the region is specified by, for example, the coordinates of the sample stage 150 on which the cell section 100 is fixed.
  • the drive mechanism control section 520 slides the sample stage 150 forward, backward, left, and right by the drive mechanism 510 based on the input area information.
  • the position information of the sample stage 150 that is, the position information indicating which part of the cell slice 100 is irradiated with the near-field light 7 is stored from the drive mechanism control unit 520. Transmitted to part 560.
  • the 40 analyzes the result obtained from the mass spectrometry unit 50 and transmits the analysis result to the storage unit 560.
  • the storage unit 560 stores an analysis result corresponding to the position information.
  • the imaging unit 550 uses the position information and the analysis result stored in the storage unit 560 to determine which substance is present at which position in the cell slice 100, for example, for each substance. Create an image as a color-coded plot. The imaged result is displayed on the display
  • the near-field light generating means used in the present invention is not particularly limited as long as it can generate near-field light.
  • a near-field light probe for SNOM, an AFM probe, or the like can be used.
  • the material of the probe include a material in which glass or a transparent plastic is coated in a single layer or a multilayer with aluminum, magnesium fluoride, silver, or the like.
  • a probe for SNOM can be a cantilever type, a straight fiber type, or a small scatterer type.
  • the wavelength of the incident laser is 0.1 to 15 m, it exceeds the diffraction limit of the laser beam and is close to the minute area of about 0.01 to L wm on the analysis target.
  • Field light can be applied.
  • the irradiation distance of near-field light in the case of the SNOM probe is about 1/2 of the wavelength of the laser, and the distance between the SNOM probe and the analysis target is small. The distance is also within this irradiation distance.
  • a pinhole is formed as shown in FIG. 4, and the diameter of the pinhole can be, for example, about 0.1 ⁇ m.
  • the near-field light exceeds the diffraction limit of the laser beam and reaches a minute area with a diameter of about 0.1 to 1111 on the analysis target. Can be irradiated.
  • a hollow fiber can be used as shown in FIGS. 3 and 5, in addition to the solid optical fiber and the fiber probe. As a result, laser scattering in the fiber is suppressed, and the sample can be efficiently irradiated with near-field light with little energy.
  • FIG. 6 is a diagram showing an example of the structure of the laser irradiation probe 700 used in the present invention.
  • the distal end portion 705 of the laser irradiation probe 700 is thinner and open than the main body portion 702.
  • the diameter of the opening 707 is not particularly limited, and can be appropriately determined according to the area of the region to be irradiated with the laser beam. From the viewpoint of irradiating the laser beam to the minute region, the diameter of the opening 707 is preferably 15 m or less, more preferably 5 or less, further preferably l ⁇ m or less, and most preferably 0.1 m or less. There is no particular lower limit on the diameter of the opening 707, but it is preferably at least 0.01 m from the viewpoint of ease of processing. Further, from another viewpoint, it is preferable that the diameter of the opening is smaller than the wavelength of the laser incident on the probe.
  • FIGS. 1 to 3 and 5 another embodiment of the present invention is shown by using a laser irradiation probe 700 instead of the near-field light probe 5.
  • the laser can be applied to a minute area of 0.1 to 15 m.
  • the irradiation distance can be increased and the energy of the laser to be irradiated can be increased as compared with the case where the near-field optical probe 5 is used. It becomes possible.
  • the subject to be scanned in the present invention is not particularly limited.
  • a cell membrane is a preferred example.
  • scanning can be performed by sliding the sample stage on which the object to be analyzed is fixed and scanning, or by using a near-field optical probe or the like with the sample stage fixed. It is also possible to scan by moving the field light generating means or the laser irradiation probe. Further, both the sample stage, the near-field light generating means, or the laser irradiation probe may be moved. There is no particular limitation on the sample stage as long as it can fix the analysis target.However, when scanning cell sections or cell membranes, from the viewpoint of maintaining the shape of cells at a very low temperature, for example, 4 Those that can maintain the temperature around K are preferred.
  • the method of controlling the distance between the near-field light generating means or the laser irradiation probe used in the present invention and the object to be analyzed There are no particular restrictions on the method of controlling the distance between the near-field light generating means or the laser irradiation probe and the object to be analyzed, and any method can be used as long as it can be placed within the distance that the near-field light or laser is irradiated. Is also good.
  • the thickness of the object to be analyzed is measured in advance, and the near-field light generating means or the laser irradiation probe is fixed within the range where the near-field light or the laser is irradiated according to the thickness, and the predetermined distance is set.
  • a method of keeping the distance between the object and the analysis target may be used. That is, by applying the principle of the atomic force microscope (AFM), the near-field light generating means or the laser By detecting the distance between the irradiation probe and the object to be analyzed, the distance can be set to a predetermined value.
  • AFM atomic force microscope
  • the near-field light generating means or the laser irradiation probe is once brought into contact with the object to be analyzed, and the near-field light generating means or the laser irradiation probe is separated from the contacted state by a predetermined distance, so that the near-field light can be obtained.
  • the generating means or the laser or laser irradiation probe and the object to be analyzed can be placed at a predetermined distance.
  • the deflection of the near-field light generating means or the laser irradiation probe is detected using an optical lever, or a near-field light generating means or a pressure sensor such as a tuning fork attached to the laser irradiation probe is used.
  • a near-field light generating means or a pressure sensor such as a tuning fork attached to the laser irradiation probe is used.
  • the laser emitting means is not particularly limited as long as it can emit a laser.
  • an infrared laser is preferred from the viewpoint of not damaging protein samples.
  • the matrix used in the present invention is not particularly limited as long as it can be vaporized together with the sample by near-field light or laser to ionize the sample.
  • glycerol derivatives such as those used in ordinary MAL DI, such as cinnamic acid derivatives, can be used.
  • glycerol is used because it is difficult to alter cells. Is preferably used.
  • the sample transfer means used in the present invention is not particularly limited as long as the sample can be sent to the mass spectrometry means.
  • a suction suction means is used. Examples include tubing and electrically skimmed skimmers.
  • the sample may be directly introduced into the mass spectrometer without using the sample moving means.
  • the atmospheric pressure for ionization in the present invention is not particularly limited, and it can be performed under vacuum, as in ordinary MALDI, or under normal pressure or low pressure.
  • the low pressure is not particularly limited as long as it is a pressure at which a sample such as a cell is not easily damaged, and examples thereof include a pressure of 0.1 to 100 Pa.
  • the mass spectrometer used in the present invention is not particularly limited as long as it can perform mass spectrometry, and examples thereof include a time-of-flight mass spectrometer, a quadrupole mass spectrometer, and a tandem mass spectrometer. It can be appropriately selected and used depending on the purpose.

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  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Spectroscopy & Molecular Physics (AREA)
  • Optics & Photonics (AREA)
  • Engineering & Computer Science (AREA)
  • Plasma & Fusion (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
  • Electron Tubes For Measurement (AREA)

Abstract

L'invention concerne un ionisateur, un procédé d'ionisation, un analyseur de masse et un analyseur de zone de dimension réduite à l'aide d'un analyseur de masse. On utilise un ionisateur comprenant des moyens d'émission laser et des moyens de génération de lumière à champ proche servant à générer une lumière à champ proche à la réception d'un faisceau laser émis par les moyens d'émission laser, et ionisant un échantillon mélangé à une matrice par irradiation de la matrice à l'aide d'une lumière à champ proche générée par les moyens de génération de lumière à champ proche. En variante, on utilise un ioniateur comprenant des moyens d'émission laser, une fibre optique de guidage d'un faisceau laser émis par les moyens d'émission laser, et une sonde d'irradiation laser connectée à l'extrémité de la fibre optique, et ionisant un échantillon mélangé à une matrice par irradiation de la matrice à l'aide d'un faisceau laser émis par la sonde d'irradiation laser. De plus, un analyseur de zone de dimension réduite est obtenu par combinaison dudit ionisateur et d'un analyseur de masse.
PCT/JP2004/000843 2003-01-31 2004-01-29 Ionisateur et analyseur de zone de dimension reduite WO2004068131A1 (fr)

Applications Claiming Priority (2)

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JP2003023548A JP2004264043A (ja) 2003-01-31 2003-01-31 イオン化装置および微小領域分析装置
JP2003-023548 2003-01-31

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