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WO2020045291A1 - Dispositif de microdissection au laser, appareil d'analyse contenant un dispositif de microdissection au laser, et procédé de collecte d'échantillon - Google Patents

Dispositif de microdissection au laser, appareil d'analyse contenant un dispositif de microdissection au laser, et procédé de collecte d'échantillon Download PDF

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Publication number
WO2020045291A1
WO2020045291A1 PCT/JP2019/033087 JP2019033087W WO2020045291A1 WO 2020045291 A1 WO2020045291 A1 WO 2020045291A1 JP 2019033087 W JP2019033087 W JP 2019033087W WO 2020045291 A1 WO2020045291 A1 WO 2020045291A1
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Prior art keywords
sample
laser
moving
moving device
light
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Ceased
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PCT/JP2019/033087
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English (en)
Japanese (ja)
Inventor
誠 澤田
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Nagoya University NUC
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Nagoya University NUC
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Priority to JP2020539421A priority Critical patent/JP7136490B2/ja
Publication of WO2020045291A1 publication Critical patent/WO2020045291A1/fr
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/02—Devices for withdrawing samples
    • G01N1/04—Devices for withdrawing samples in the solid state, e.g. by cutting
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q

Definitions

  • the disclosure in the present application relates to a laser microdissection device, an analyzer including the laser microdissection device, and a method for collecting a sample.
  • the present invention relates to a laser microdissection apparatus capable of accurately collecting a small-sized sample from a sample piece into a device, an analyzer including the laser microdissection apparatus, and a method for collecting a sample.
  • the present inventors have proposed that (1) the spatial resolution can be improved by improving the online interlocked coordinate reproduction stage (fixing device of the measurement sample) mounted on the laser microdissection device and modifying the coordinate reproduction function software. (2) Since the position is determined by using the coordinate reproducing function, the position information between successive tissue sections can be accurately reproduced, and three-dimensional mass spectrometry imaging can be realized. (See Patent Documents 1 and 2).
  • the disclosure in the present application has been made in order to solve the above-mentioned problems, and as a result of intensive research, it has been found that (1) the laser light emitted from the laser irradiation unit is once made into parallel light, and (3) By focusing the collimated light and irradiating the sample with the focused light, the accuracy of the sample can be reduced even if the sample size to be collected is smaller than before. It was newly found that a sample can be collected well.
  • an object of the disclosure in the present application is to provide a laser microdissection device, an analyzer including the laser microdissection device, and a method for collecting a sample.
  • the disclosure in the present application relates to a laser microdissection device, an analyzer including the laser microdissection device, and a method for collecting a sample described below.
  • a laser microdissection apparatus that collects a sample by irradiating a dissection laser beam
  • the laser microdissection device is A laser irradiation unit for irradiating a dissection laser beam, A first lens that converts the dissection laser light emitted from the laser irradiation unit into parallel light, A diaphragm section for blocking light in a peripheral portion of the parallel light, A laser microdissection device, comprising: a second lens that converges the parallel light converged by the diaphragm.
  • the laser microdissection device according to (1) further including an optical path adjusting member.
  • a sample moving device capable of mounting a sample and moving the sample
  • a device moving device capable of mounting a device including a heat-fusible film for collecting a collected sample, and capable of moving the mounted device
  • the laser microdissection apparatus according to the above (1) or (2), further comprising: (4) the sample moving device moves in a horizontal direction, and the device moving device moves in a horizontal direction and a vertical direction; Or The sample moving device moves horizontally and vertically, and the device moving device moves horizontally, The laser microdissection device according to the above (3).
  • a storage device that associates and stores the position coordinates of the sample where the dissection laser light is irradiated and the position coordinates of the device where the collected sample is collected;
  • a moving device drive control unit that drives and controls the sample moving device and the device moving device based on the position coordinates of the sample and the position coordinates of the device stored in the storage device;
  • the laser microdissection apparatus according to the above (4), further comprising: (6) An analyzer including the laser microdissection device according to any one of (1) to (5).
  • a method for collecting a sample using a laser microdissection apparatus The method of collecting the sample is as follows: An irradiation step of irradiating a dissection laser beam from a laser irradiation unit, A disection laser light paralleling step of converting the dissection laser light irradiated in the irradiation step into parallel light, A diaphragm step of shielding a peripheral portion of the parallel light collimated in the dissection laser light paralleling step, A condensing step of converging the parallel light converged in the converging step, In a state where the device and the sample including the hot-melt film are in close contact with each other, the device and the sample are irradiated with the dissection laser light condensed in the light condensing step, and a sample collecting step of collecting the sample into the device, A method for collecting a sample, comprising:
  • the laser microdissection apparatus disclosed in the present application can accurately collect a sample of an intended size even when the sample to be collected is small as compared with the related art.
  • FIG. 1 is a diagram schematically illustrating the LMD 1a according to the first embodiment.
  • FIG. 2 is a diagram for explaining the principle of collecting a sample.
  • FIG. 3 is a diagram for explaining the principle that the LMD 1a according to the first embodiment can collect a sample of a smaller size with higher precision as compared with the related art.
  • FIG. 4 is a diagram schematically illustrating the LMD 1b according to the second embodiment.
  • FIG. 5 is a flowchart of the first embodiment of the method for collecting a sample.
  • FIG. 6 is a diagram schematically illustrating the LMD 1c according to the third embodiment.
  • FIG. 7 is a diagram for explaining the outline of the storage device and the moving device drive control unit.
  • FIG. 1 is a diagram schematically illustrating the LMD 1a according to the first embodiment.
  • FIG. 2 is a diagram for explaining the principle of collecting a sample.
  • FIG. 3 is a diagram for explaining the principle that the LMD 1a according to the first embodiment can collect a
  • FIG. 8 is a drawing substitute photograph, which is a phase contrast photograph of a hot melt film slide after laser beam irradiation.
  • the circle is where the laser light melts.
  • 9A to 9D are photographs substituted for drawings.
  • FIG. 9A is a photograph of a sample
  • FIG. 9B is a magnified photograph of FIG. 9A, a sample portion (mitochondria) cut out by an arrow
  • FIG. 9C is a set irradiation condition.
  • FIG. 9D is a photograph when a sample is collected on a hot melt film slide when a laser beam is irradiated on the hot melt film slide.
  • FIG. 10 is a photograph as a substitute of a drawing, and is a photograph of Comparative Example 1 after a sample is collected.
  • LMD laser microdissection apparatus
  • analyzer including the LMD
  • method for collecting a sample will be described in detail with reference to the drawings.
  • members having the same functions are denoted by the same or similar reference numerals. The repeated description of the members with the same or similar reference numerals may be omitted.
  • FIG. 1 is a diagram schematically illustrating the LMD 1a according to the first embodiment.
  • the LMD 1a includes a laser irradiator 2 for irradiating the laser light L, a first lens 3 that converts the laser light L emitted from the laser irradiator 2 into parallel light, and shields light in a peripheral portion of the parallel light L. It includes at least a diaphragm unit 4 and a second lens 5 that collects the parallel light L narrowed down by the diaphragm unit 4.
  • the laser irradiation unit 2 is not particularly limited as long as the sample S and a device to be described later can be irradiated with laser light and the sample S can be collected in the device.
  • an infrared laser such as a semiconductor laser (GaAs) or an ultraviolet laser such as an N 2 laser may be used.
  • the first lens 3 is not particularly limited as long as the laser light L emitted from the laser irradiation unit 2 can be converted into parallel light, and examples thereof include a collimator lens.
  • the aperture section 4 is not particularly limited as long as it can block the peripheral portion of the parallel light L.
  • a plate member having a diameter smaller than the diameter of the cross section of the parallel light L can be used.
  • a diaphragm used in an optical device such as a camera is used. I just need.
  • the aperture section 4 may use a member having another function as long as the aperture section 4 has an aperture function.
  • a beam expander having a stop function and a function of expanding the light beam of the laser light L can be used.
  • the second lens 5 is not particularly limited as long as the parallel light L converged by the diaphragm unit 4 can be collected.
  • an objective lens can be used.
  • the principle that the LMD 1a according to the first embodiment can collect a sample of a smaller size with higher accuracy than the conventional LMD will be described.
  • the principle of collecting a sample will be described with reference to FIG.
  • the device 7 including the hot-melt film is brought into close contact with the sample S, and the laser beam L is irradiated in a state where both are in close contact, so that the hot-melt film of the device 7 melts.
  • the desired portion of the sample can be collected in the device 7.
  • the intensity of the laser light emitted from the laser irradiating unit 2 is large at the center of the laser light, the intensity decreases as the distance from the center increases, and the intensity of the laser light at the peripheral portion decreases.
  • the condition becomes mild. Therefore, when the laser light irradiated from the laser irradiation unit 2 is simply condensed by an objective lens or the like, the laser light having the intensity distribution shown in FIG. 3A is condensed as it is. Therefore, the intensity of the laser beam applied to the device 7 and the sample S greatly varies depending on the position.
  • the laser light L emitted from the laser irradiation unit 2 is once converted into parallel light by the first lens 3.
  • the laser light having a sharp intensity distribution in which the light in the peripheral part where the intensity decreases gradually is reduced. can get.
  • the laser light L having less intensity variation and a clearly different intensity between the irradiation area and the other areas as compared with the related art The device 7 and the sample S can be irradiated. Accordingly, the dissociation between the set sample size and the sample size actually collected can be reduced.
  • the amount of the laser light to be stopped down by the stop unit 4 may be appropriately determined according to the quality (intensity distribution) of the light irradiated from the laser irradiation unit 2.
  • the output of the laser irradiation unit 2 may be adjusted as needed. .
  • the outline of the LMD 1b according to the second embodiment will be described with reference to FIG.
  • the LMD 1b according to the second embodiment differs from the LMD 1a according to the first embodiment in that the LMD 1b according to the second embodiment includes an optical path adjusting member 6, and is otherwise the same as the first embodiment.
  • the “optical path adjusting member” means a member that can change the traveling direction of the laser light emitted from the laser irradiation unit 2 and / or a member that guides the traveling of the laser light.
  • the optical path adjusting member 6 is not particularly limited as long as it can change and / or guide the traveling direction of the laser beam, and examples thereof include an optical fiber, a mirror, and a mirror system including a combination of mirrors.
  • the optical fiber 6 is arranged between the diaphragm unit 4 and the second lens 5, but may be arranged between the light source 2 and the first lens 3.
  • a mirror and a mirror system may be provided. Since the LMD 1b according to the second embodiment includes the optical path adjusting member 6, the degree of freedom of arrangement of the members configuring the LDM 1b is improved.
  • FIG. 5 is a flowchart of the first embodiment of the sample collection method.
  • the first embodiment of the sample collecting method includes an irradiation step (ST1), a disection laser beam parallel step (ST2), a stop step (ST3), and a light focusing step (ST4). And a sampling step (ST5).
  • a laser irradiation unit 2 irradiates a dissection laser beam.
  • the dissection laser light paralleling step (ST2) the dissection laser light irradiated in the irradiation step (ST1) is converted into parallel light.
  • the aperture step (ST3) the light in the peripheral portion of the parallel light collimated in the dissection laser beam paralleling step (ST2) is blocked.
  • the condensing step (ST4) the parallel light converged in the constricting step (ST3) is condensed. Then, in the sample collecting step (ST5), the device 7 is melted by irradiating the dissection laser light L condensed in the condensing step (ST4) with the device 7 and the sample S in close contact with each other.
  • the sample S can be collected in the device 7 by stripping the sample S by the device melted when separating the sample 7 from the sample S.
  • the outline of the LMD 1c according to the third embodiment will be described with reference to FIG.
  • the LMD 1c according to the third embodiment is different from the LMDs 1a and 1b according to the first and second embodiments in further including a device moving device 20 and a sample moving device 21, and is similar in other respects.
  • FIG. 6 is a diagram schematically showing an LMD 1c (portion surrounded by a dotted line in FIG. 6) according to the third embodiment.
  • the example shown in FIG. 6 includes, in addition to the device moving device 20 and the sample moving device 21, a light source 22 for irradiating light for observing the sample and an imaging device 23 such as a CCD for acquiring an image.
  • the first lens and the aperture unit are provided between the laser irradiation unit 2 and the second lens 5.
  • the laser irradiation unit 2 is disposed below the device moving device 20 in order to irradiate the dissection laser light from below the device.
  • the third embodiment may include a storage device and a moving unit drive control unit.
  • the operation of bringing the device 7 including the hot-melt film into close contact with the sample S is automated.
  • the device moving device 20 is not particularly limited as long as the device can be mounted thereon and the mounted device 7 can be moved.
  • the device moving apparatus 20 includes a device mounting table on which the device 7 can be mounted, a driving source for moving the device mounting table in a horizontal direction (X and Y axis directions), and A driving force transmission mechanism for transmitting the driving force of the driving source to the device mounting table is included.
  • a driving source a pulse motor, an ultrasonic motor or the like may be used.
  • the driving force transmission mechanism a known mechanism such as a driving force transmission mechanism for driving a device (chip) mounting table used in a microscope or the like in a horizontal direction may be used.
  • the sample moving device 21 is not particularly limited as long as the slide on which the sample S is mounted can be mounted, and the mounted sample S can be moved.
  • an arm on which a slide on which the sample S is mounted can be mounted on one end and the other end can be mounted on an arm support, and the arm is rotated in the horizontal direction (X, Y axis directions).
  • an arm column that can move in the vertical direction (Z-axis direction).
  • a driving source and a driving force transmitting mechanism for transmitting the driving force of the driving source to rotate and move the arm in the vertical direction may be provided.
  • a driving source a pulse motor, an ultrasonic motor or the like may be used.
  • the driving force transmission mechanism for example, a known arm mechanism that can rotate in the horizontal direction and move in the vertical direction, such as an arm mechanism for moving a sample of an automatic analyzer, may be used.
  • the sample moving device 21 is provided above the device moving device 20, but the arrangement of the components of the LMD 1c may be appropriately changed.
  • the device moving device 20 may be provided above the sample moving device 21.
  • the sample moving device 21 may move in the horizontal direction
  • the device moving device 20 may move in the horizontal direction and the vertical direction.
  • the laser irradiation unit 2 may be provided above the LMD 1c, and the laser light L may be irradiated from above the sample S and the device 7.
  • the laser beam L may be irradiated from a direction opposite to the position where the laser irradiation unit 2 is arranged.
  • the device 7 is not particularly limited as long as the sample S adhered to the irradiated portion can be recovered as a collected sample by irradiating the laser beam L, but from the viewpoint of preventing heat denaturation of the sample S.
  • the heat-meltable film include ethyl vinyl acetate (EVA), polyolefin, polyamide, acryl, and polyurethane.
  • EVA ethyl vinyl acetate
  • the device 7 may be formed only of a heat-meltable film, or may be formed by processing a heat-meltable film.
  • a hydrophilic region and a hydrophobic region may be formed on the surface of the heat-meltable film by printing a water-repellent ink on the surface of the heat-meltable film. May be formed.
  • the heat-fusible film is suitable for the wavelength range of the laser irradiation unit 2 to be used, such as an organic dye such as a naphthalene cyanine dye, in order to selectively absorb the spectrum in the wavelength range of the laser light source.
  • Organic dyes may be added.
  • the LMD 1c according to the third embodiment may be provided with a pressing device for bringing the hot-melt film of the device 7 into close contact with the sample.
  • a pressing device for bringing the hot-melt film of the device 7 into close contact with the sample.
  • the storage device associates and stores the position coordinates of the sample S where the laser beam is irradiated and the position coordinates of the device 7 where the collected sample is collected. Further, the moving device drive control unit drives and controls the sample moving device and the device moving device based on the position coordinates of the sample S and the position coordinates of the device 7 stored in the storage device. For example, when a sample is continuously cut out from the sample S in FIG. 7A as in a, b, and c, (i) the device 7 is moved by the device moving device 20 to a position to be irradiated with laser light.
  • the sample moving device 21 moves the sample at the position indicated by a of the sample S to a position overlapping with the collection point a 'of the device 7 shown in FIG.
  • the sample S and the device 7 are brought into close contact with each other by moving the sample moving device 21 in the vertical direction.
  • the device moving device 20 may be moved in the vertical direction depending on the positional relationship between the device moving device 20 and the sample moving device 21.
  • the sample moving device 21 By irradiating the laser beam L, the sample collected from the position a of the sample S is collected at the position a ′ of the device 7, and then the sample moving device 21 (the device moving device 20) is moved vertically.
  • the sample S is separated from the device 7, and the collected sample a is collected at a predetermined location of the device 7.
  • the steps (i) to (iV) may be repeated for the collected samples b and c.
  • the spatial resolution of analysis can be improved.
  • the sample collecting method using the LMD 1c according to the third embodiment is different from the sample collecting step (ST5) shown in FIG. 5 in that the sample S and the device 7 are brought into close contact with each other using the device moving device 20 and the sample moving device 21. Is the same as in the first embodiment of the method for collecting a sample.
  • the analyzer (analysis method) including LMD1 is not particularly limited as long as the cut sample can be analyzed.
  • analyzers including chromatography such as LC-MS, HPLC-fluorescence spectrometer, HPLC-electrochemical detector; electron beam microanalyzer; elemental analyzers such as X-ray photoelectron spectrometer; genes by PCR or LCR
  • a nucleic acid sequence analyzer that amplifies and analyzes a DNA sequence contained in a sample using a sequencer; a microchip analysis such as a DNA chip that hybridizes DNA with a nucleic acid contained in the sample as a template and an antibody chip that makes an antibody react with a protein. Device; and the like.
  • the analyzer may be integrated with the LMD1 so that the sample collected by the LMD1 can be analyzed.
  • LMD1 shown in the first to third embodiments can irradiate a relatively uniform laser beam as described above. Therefore, the present invention can be used for a laser ablation treatment device, a processing device, and the like, in addition to the sample collection.
  • LMD was produced using the following members. The members were arranged so that the laser light proceeded in the order of (1) to (6).
  • Laser irradiation unit 2 Semiconductor laser driver (DS11-LA04V06, manufactured by Lumix)
  • Optical path adjusting member 6 Optical fiber (PAF-X-7-B, manufactured by Thorlabs)
  • First lens 3 Adjustable FC collimator (CFC-2X-B, manufactured by Thorlabs)
  • Optical path adjusting member 6 Highly stable kinematic mirror holder (MHG-HS30-NL, manufactured by OptoSigma)
  • Aperture part 4 5 to 10 times variable Galilei beam expander (BE02-05-B, manufactured by Thorlabs)
  • Second lens 5 objective lens 10, 20, 50, 100 times (manufactured by Olympus Corporation, LMPlanFL)
  • sample preparation A sample for laser microdissection was prepared by the following procedure.
  • OS3 glial precursor cell line (RIKEN cell bank RCB1593) was used as a sample.
  • OS3 cells were seeded at a concentration of 1 ⁇ 10 5 cells / P1.
  • the cells were cultured in Mi medium for 4 days.
  • Mi medium MEM medium supplemented with 10% FBS, 0.2% glucose, 5 mg / ml insulin
  • Mitotracker registered trademark
  • Orange manufactured by Thermo Fisher Scientific, M7511
  • Example collection (1) Adjustment of irradiation conditions of laser light
  • a hot melt film slide (TOYO CHEM CO., LTD., SG-100 slide, (NU-079)) prepared by coating a hot melt resin on a slide glass was used as a device for collecting a sample. ) was used. The manufactured LMD objective lens was set to 100 times. Next, before actually collecting the sample, the hot melt film slide was irradiated with the focused laser light while adjusting the power of the laser irradiation unit 2 of the LMD.
  • FIG. 8 is a phase contrast photograph of the hot melt film slide after the laser light irradiation, where the circle is a portion where the circle is melted by the laser light irradiation.
  • Example 1 the size of mitochondria, which is a collected sample, is about 1.2 ⁇ m. Therefore, the irradiation condition of the laser light at which the size of the hot melt film slide to be melted is about 1.2 ⁇ m was set as the irradiation condition for sampling the sample at a size of about 1.2 ⁇ m.
  • the laser power irradiation conditions of Example 1 were set to a laser power of 20% (1.56 V, 138 mA), a laser irradiation time of 15 msec / 1, and a single irradiation.
  • FIG. 9A is a photograph of a sample
  • FIG. 9B is an enlarged photograph of FIG. 9A, a sample portion (mitochondria) cut out by an arrow
  • FIG. 9C is a phase difference photograph when a hot melt film slide is irradiated with laser light under set irradiation conditions
  • FIG. 9D is a photograph of a sample taken on a hot melt film slide. As shown in FIGS. 9C and 9D, it was confirmed that when a sample was collected using the LMD of Example 1, a sample having substantially the same size as the set size could be collected on a hot melt film slide.
  • Example collection (1) Adjustment of Laser Light Irradiation Conditions
  • laser light irradiation conditions and an objective lens were adjusted so that the size of the hot melt film slide to be melted was about 1.2 ⁇ m.
  • the irradiation conditions of Comparative Example 1 were 10 times the objective lens, the laser power was 30% (0.14 V, 145 mA), the laser irradiation time was 3 msec / 1, and the number of times of irradiation was 1.
  • (2) Collection of Sample (Mitochondria) A sample was collected in the same procedure as in Example 1.
  • FIG. 10 is a photograph of the sample collected in Comparative Example 1. As is clear from FIG.
  • Example 10 even in the case where the laser beam was irradiated under the irradiation condition in which the hot melt film was melted by about 1.2 ⁇ m in the phase contrast photograph in the same manner as in Example 1, in the case of Comparative Example 1, the collected sample was The size was about 8.5 ⁇ m, which was larger than that of Example 1.
  • Comparative Example 1 a sample larger than the expected size was collected. This is because, as shown in FIG. 2A, the intensity of the laser beam of Comparative Example 1 gradually decreases from the center to the peripheral portion, and therefore, as shown in FIG. Cannot clearly distinguish the strength. Therefore, a laser beam that is weaker than the central portion is actually irradiated to the outside of the range in which the hot-melt film shown in the phase contrast photograph of FIG. 8 is dissolved.
  • the LMD disclosed in the present application can accurately collect a small sample. Therefore, it can be used as an apparatus for tissue analysis in medical institutions, research institutions such as university medical schools, general hospitals, and the like.
  • 1, 1a, 1b, 1c laser microdissection device
  • 2 laser irradiation section
  • 3 first lens
  • 4 diaphragm section
  • 5 second lens
  • 6 optical path adjusting member
  • 7 device
  • 20 device Moving device
  • 21 sample moving device
  • 22 light source
  • 23 imaging device
  • L dissection laser beam
  • S sample

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Analytical Chemistry (AREA)
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  • General Physics & Mathematics (AREA)
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Abstract

La présente invention concerne un dispositif de microdissection au laser qui peut collecter avec précision, par rapport à l'état de la technique, un échantillon ayant une taille prédéterminée même lorsque l'échantillon à collecter est petit. Le dispositif de microdissection au laser collecte un échantillon par irradiation d'un faisceau laser de dissection, le dispositif comprenant : une unité d'irradiation laser pour émettre le faisceau laser de dissection ; une première lentille qui convertit le faisceau laser de dissection émis par l'unité de rayonnement laser en un faisceau lumineux parallèle ; une partie de diaphragme qui protège une lumière de partie périphérique du faisceau de lumière parallèle ; et une seconde lentille qui collecte le faisceau de lumière parallèle focalisé par la partie de diaphragme. Le problème est résolu par le dispositif de microdissection au laser.
PCT/JP2019/033087 2018-08-28 2019-08-23 Dispositif de microdissection au laser, appareil d'analyse contenant un dispositif de microdissection au laser, et procédé de collecte d'échantillon Ceased WO2020045291A1 (fr)

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JPWO2021186577A1 (fr) * 2020-03-17 2021-09-23

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WO2015053039A1 (fr) * 2013-10-07 2015-04-16 国立大学法人名古屋大学 Dispositif de microdissection laser, dispositif d'analyse contenant un dispositif de microdissection laser, et procédé pour produire une micropuce
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