WO2005033668A1 - Microdissection - Google Patents

Microdissection Download PDF

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Publication number
WO2005033668A1
WO2005033668A1 PCT/EP2004/010905 EP2004010905W WO2005033668A1 WO 2005033668 A1 WO2005033668 A1 WO 2005033668A1 EP 2004010905 W EP2004010905 W EP 2004010905W WO 2005033668 A1 WO2005033668 A1 WO 2005033668A1
Authority
WO
WIPO (PCT)
Prior art keywords
preparation
dissectate
gripper
slide
layer
Prior art date
Application number
PCT/EP2004/010905
Other languages
German (de)
English (en)
Inventor
Norbert Leclerc
Kay Haupt
Original Assignee
Norbert Leclerc
Kay Haupt
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE2003146130 external-priority patent/DE10346130B4/de
Priority claimed from DE200410004205 external-priority patent/DE102004004205A1/de
Application filed by Norbert Leclerc, Kay Haupt filed Critical Norbert Leclerc
Publication of WO2005033668A1 publication Critical patent/WO2005033668A1/fr

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Classifications

    • 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
    • G01N1/2813—Producing thin layers of samples on a substrate, e.g. smearing, spinning-on
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/34—Microscope slides, e.g. mounting specimens on microscope slides

Definitions

  • the m-RNA is a very short-lived product of the cells, which is why the concentration of m-RNA in the cells is very low. If you want the m-RNA z. B. determine a tumor cell, the largest possible number of tumor cells must therefore be collected. To do this, the tumor cells must be from diseased tissue be isolated. For this purpose, the tumor cells can be cut out (dissected) from tissue sections and collected in isolation. The isolated tumor cells are then disrupted. The m-RNA is isolated from the cells by suitable purification steps. It is then translated into c-DNA using the reverse transcriptase. This is usually amplified using linear PCR. The c-DNA thus obtained is z. B. qualitatively or quantitatively analyzed using suitable DNA chips.
  • the present invention is concerned with the isolation or cutting out of cells to be examined, with so-called dissection. If individual cells - with diameters in the range of a few micrometers - are cut out of tissue, this is also called microdissection.
  • Microdissection may a. to work extremely cleanly, i.e. in particular to work without RNAsen, since these break down the m-RNA. Avoid touching it with your bare hand.
  • the tissue section is prepared in air, for example on a slide.
  • a closed curve around the diseased tissue (dissectate) is described with the help of a laser.
  • the tissue is ablated on the curve, separating the diseased tissue to be isolated from the rest of the tissue.
  • the cut dissectate can, for example, be sucked into a pipette if it is in liquid.
  • DE 198 04 800 C2 describes a method in which dissectates are cut out of a preparation. After cutting out, the dissected specimens are sucked in by a gripper.
  • the gripper has a hollow channel with a small round opening, in front of which the dissectates adhere after suction. With the help of the gripper, the dissected specimens can be transported into a collecting vessel.
  • a disadvantage of this method is that the dissectates are not fixed during ablation and therefore often roll up. Complete ablating is then not possible, nor is suctioning with the gripper.
  • WO 03/008934 AI describes slides and methods for producing the slide, which can be used for dissecting a preparation, for example a biological sample.
  • a preparation section i.e. the area of a carrier substrate, which can be separated from the carrier substrate together with a preparation section when dissecting a preparation
  • mobilization means are provided for forming an electromagnetic force interaction in response to an application of an electromagnetic force, so that the dissecting section is targeted as a result of the force interaction shifted, ie can be transported.
  • a disadvantage of this method is that the dissectates are not fixed during ablation, so that complete ablation is difficult or is no longer possible.
  • the object of the invention is to provide a microdissection method which is suitable for automation.
  • a suitable microdissection method must fix the specimen during cutting so that the latter is not affected by the action of e.g. B. the laser moves. After cutting, the dissectate must be safely isolated from the rest of the tissue. A reliable transport of the dissectate by means of a gripper into different collecting vessels and the safe detachment from the gripper for depositing the dissectate in the different collecting vessels must be guaranteed. A high degree of automation should be achievable with comparatively little effort.
  • the layer of biological material is first applied to one side of a stabilization layer.
  • the stabilization layer can be omitted if the mechanical properties of the layer of biological material permit this.
  • the layer of biological material, possibly together with the stabilizing layer, is referred to below as a preparation.
  • the layer of biological material can e.g. B. a tissue section, a cell smear, seeded cells or a cell culture.
  • Glass slides are particularly suitable for microscopy.
  • other fixed documents can also be used, provided they are dielectric. You also don't have to be transparent.
  • An electric field of sufficient strength (for example between approximately 100 kV / m and 10 MV / m, preferably 1 MV / m) is then applied between the side of the slide facing away from the specimen and the side of the specimen facing away from the specimen slide. This results in dielectric polarization of both the slide and the specimen. If the charge carriers collecting on the side of the specimen facing away from the specimen slide are removed by a suitable first electrode (e.g. a wire with zero potential / grounding that is not insulated from the specimen), a residual charge remains in the specimen. This causes an increased areal attraction between the dielectrically polarized slide and the electrically charged preparation, which goes far beyond the naturally existing adhesion. The specimen for the dissection to be carried out is thus securely fixed.
  • a suitable first electrode e.g. a wire with zero potential / grounding that is not insulated from the specimen
  • the described method for electrostatically fixing a layer of biological material (preparation) on a specimen slide can also be used in parts to lift a dissectate from a specimen or from a specimen slide, since electrostatic fixation is always accompanied by an electrostatic charge that is required for the removal can be exploited.
  • the focus of a laser beam describes a closed or approximately closed curve around the dissectate.
  • the preparation is ablated on this curve, i. H. essentially evaporated. This separates the dissectate from the rest of the specimen.
  • the dissectate initially remains together with the preparation in its original position on the slide, especially since it adheres electrostatically to the slide. However, it is - at least essentially - mechanically separated from the rest of the preparation.
  • a second electrode is brought up to the dissectate from the side of the specimen facing away from the slide.
  • the direction of the applied electric field is then reversed and, if necessary, its strength is changed in such a way that the dissectate detaches from the slide and moves along the field lines to the second electrode.
  • the electrode is preferably covered with an electrically insulating plastic. An electrical high voltage applied from the outside is therefore used to fix the specimen and to isolate the dissectate.
  • the dissectate adheres to the second electrode, it can be transported to a vessel holding the dissectate. There it can be separated from the second electrode by removing the electrostatic adhesion of the dissectate to the second electrode. This can e.g. B. can be achieved by charging the second electrode with an electric charge of the same sign as the electric charge of the dissectate.
  • the dissectate can be specifically cut out, isolated, transported and set down. This creates the possibility of extensive automation.
  • the second electrode can also be designed such that it, as a whole or individual parts, can be fed together with the collected dissectates for further biochemical processing.
  • the gripper is either brought into contact with the preparation or in its immediate vicinity.
  • the gripper preferably has a continuous hollow channel with an opening on the preparation side that is smaller than the part of the preparation to be isolated.
  • the gripper can be a thin pipette.
  • the opening can be round or slit-shaped. It is crucial that at least one dimension of the opening is smaller than the dissectate. This prevents the dissectate from entering the opening.
  • a preferably largely flat contact surface is formed, with which the gripper can touch the preparation.
  • the contact surface of the gripper can also consist of a porous material with irregular openings.
  • the part of the preparation to be isolated is sucked onto the gripper by a pressure difference. As a rule, this is done by reducing the pressure in the hollow channel or ..- in the openings of the gripper and an associated
  • the fixation is preferably carried out before the part of the layer of biological material to be isolated has been cut out of the preparation.
  • the part to be insulated is fixed by the gripper during the cut.
  • the dissectate is then cut out of the specimen. This is preferably done with the help of laser microdissection.
  • the gripper is advantageously transparent in order to avoid disturbing reflections and scattering. It also makes sense to manufacture the gripper from a transparent material so that the illumination of the preparation is not impaired.
  • the dissectate can also be cut out first and only then can the gripper pick up the dissectate.
  • the specimen is fixed electrostatically on the slide beforehand.
  • the dissectate remains attached to the gripper, even if the gripper is removed from the specimen.
  • At least one opening of the gripper must be at least partially covered by the dissectate. This can be achieved by positioning the gripper before the dissection. This isolates the dissectate from the rest of the layer.
  • the dissectate With the help of the gripper, the dissectate is sucked in but not sucked in. This allows the dissectate to be transported and put down again in a collecting vessel. To do this, it is sufficient to change the pressure difference in such a way that the dissectate is no longer held by the gripper and falls off the gripper. For this purpose, the pressure difference z. B. weakened or vice versa.
  • a collecting vessel is a place where the dissectate is kept for further processing or is fed to further processing.
  • the described method is relatively easy to carry out. It fixes the specimen during cutting and allows the dissectate to be reliably transported to a collecting vessel, where it can be placed or deposited in a targeted manner.
  • the method described is therefore particularly suitable for automation.
  • the gripper can have a plurality of preparation-side openings that are smaller than the dissectates and enable a corresponding plurality of dissectates to be fixed in front of the respective preparation-side openings.
  • the gripper is placed again on the preparation and / or at the same time is placed on the preparation with its plurality of openings on the preparation side, so that the plurality of dissectates can be picked up and fixed at different positions. This makes it easy to collect multiple dissectates on one gripper.
  • An advantage of this procedure is that the gripper always picks up the sample or picks up the complete dissectate without complicated grasping and aiming, which is a considerable relief from the previously known methods. In this way, several samples can be taken or additional samples taken. A plurality of grippers can also be attached in a common holder and successively go through different phases of the method.
  • the gripper can travel with the cutting, for example when the cutting movement through the table on which e.g. the gripper is attached, is executed.
  • the gripper can also be used for the cutting movement e.g. follow a moving laser focus.
  • a layer also provided with openings can be located between the gripper and the preparation. This is referred to below as the intermediate layer.
  • the intermediate layer Before the gripper is lowered onto the specimen, one of the openings in this intermediate layer is brought into alignment with an opening of the gripper. The diameters of the openings do not have to match. It is only important that one of the openings - preferably the opening in the intermediate layer - is smaller than the dissectate to be picked up.
  • the intermediate layer can be moved in such a way that: a) another free opening is covered with an opening of the gripper; b) the opening covered with a dissectate reaches a device equivalent to the gripper, on which the dissectate is detached by changing the pressure difference.
  • the intermediate layer can be made of, for example. Polycarbonate exist.
  • the receptacle can be stored, the process is very flexible. Furthermore, the isolated dissectates can easily be checked on the gripper, since the gripper can be examined with the existing microscope.
  • the described processes complement each other and can be combined appropriately to improve the automation options.
  • the preparation can first be applied to a dielectric slide. It can be fixed electrostatically on the slide in the manner described. The part to be isolated (dissectate) of the preparation is then cut out of the preparation. Finally, the dissectate is created using the second electrode described above or separated from the rest of the preparation with the aid of the gripper.
  • the dissectates adhere to the gripper or the second electrode are cut out and are to be placed and / or placed in a targeted manner, they can also be placed on an adhesive base, for example on an adhesive film and / or a silicone rubber base. To place it on an adhesive surface, the pressure difference may not have to be changed for the gripper, nor the voltage difference for the second electrode reversed.
  • Such an adhesive base also opens up the possibility of storing the dissectates in a regular pattern, for example in the form of a matrix.
  • the adhesive base can be flat and form a reaction vessel with an attached frame, in size and shape thereby z. B. similar to a microtiter plate.
  • Another possibility for the spatial separation of the cut dissectates from the rest of the preparation is to lift the rest of the preparation from the slide in a suitable manner, e.g. B. with tweezers.
  • the electrostatically adhering dissectates then remain on the slide. These can be transferred to a collecting vessel using the gripper.
  • 1A shows a schematic illustration of the polarization step of the electrostatic fixing of a preparation on a slide
  • 1B shows a schematic illustration of the charging step of the electrostatic fixing of a preparation on a slide
  • FIG. 2 shows a schematic illustration of the electrostatic lifting of a dissectate
  • 3A shows a schematic illustration of the approach of a pneumatic gripper to a preparation
  • 3B the suction of the preparation or dissectate onto the gripper
  • 3C the lifting off of the dissectate with the aid of the gripper
  • 3D the depositing of the dissectate in a collecting vessel
  • FIG. 4 shows a schematic illustration of the use of an intermediate layer between the gripper and the preparation.
  • FIG. 1A In the following, reference is made to FIG. 1A.
  • Tissue embedded or frozen in paraffin is broken up into thin tissue sections 10 by a planer. These usually roll up.
  • a dielectric microscope slide 12 is sprayed with alcohol.
  • the film 14 is, for. B. from 2 micron thick, UV absorbing PET or PEN. It serves as a stabilization layer. The paper is then removed.
  • the rolled-up tissue section 10 is then brought onto the film 14.
  • the microscope slide 12 with film 14 and tissue section 10 is heated to 60 °, as a result of which the paraffin melts and the tissue section 10 rolls out.
  • the structure of film 14 and tissue section 10 - which is referred to collectively as a preparation - can then be turned over, as a result of which the tissue section 10 comes to lie on the slide 12.
  • the tissue section 10 then lies between the slide and the stabilization layer or film 14.
  • the specimen is placed together with the dielectric slide 12 in the object plane of an inverted microscope in such a way that the slide is at the bottom and the layer of biological material is accessible from above.
  • the microscope has a motorized x-y table that can move the specimen. Collection vessels are also attached to the table, into which the parts to be insulated are to be placed after the dissection.
  • an electric field 18 (see FIG. 1A) of sufficient strength (preferably 1 MV / m) between that of the The side of the slide 12 facing away from the specimen and the side of the specimen, ie the film 14, facing away from the slide.
  • an electric field 18 (see FIG. 1A) of sufficient strength (preferably 1 MV / m) between that of the The side of the slide 12 facing away from the specimen and the side of the specimen, ie the film 14, facing away from the slide.
  • two electrodes, an electrode 15 on the specimen side and an electrode 16 on the slide side are used.
  • the latter has a cutout 17 so as not to hinder the objective of the inverse microscope.
  • Slide 12 collects positive charges.
  • negative charges accumulate on the side of the tissue section 10 lying on the slide 12 and positive charges in turn accumulate on the side of the film 14 facing away from the slide.
  • a suitable electrode 20 for example by a wire with zero potential / grounding that is not insulated from the specimen
  • a residual charge remains in the specimen (FIG. 1B).
  • the positive charges are drawn off on the side of the film 14 facing away from the slide 12. The preparation remains negatively charged.
  • the preparation is then cut using laser microdissection. If the microdissection takes place on a closed contour, the dissectate 22 remains together with the preparation in the original position on the slide 12. It is now mechanically separated from the rest of the preparation.
  • a second electrode 24 is brought up to the dissectate 22 from the side of the specimen facing away from the slide 12. Now the direction of the applied electric field is reversed and, if necessary, its
  • the dissectate 22 will detach itself from the slide 12 and move along the field lines to the second electrode 24. In order to prevent immediate transfer of the dissectate 22, this electrode must be electrically insulated from the dissectate 22. This is preferably done by a plastic coating 26.
  • a transparent gripper 28 is attached over the specimen (Fig. 3A). It can be lowered onto the specimen and moved in the lowered state with the specimen on the microscope stage if the microscope stage for the ablation or microdissection moves relative to the laser focus.
  • the gripper 28 has at its lower end a largely flat contact surface 30 which has a number of small openings 32.
  • the contact surface 30 is expediently so large that that several dissectates can fit on it.
  • the contact surface 30 preferably has a diameter of 500 ⁇ m.
  • the openings 32 have a diameter of approximately 8 ⁇ m and are arranged in the form of a 10 ⁇ 10 matrix.
  • openings 32 are connected via hollow channels 34 to a pneumatic device (not shown) which can generate negative and positive pressure.
  • the part 22 of the preparation to be insulated is selected and the transparent gripper 28 is brought into contact with the preparation from above such that an opening 32 of the contact surface 30 lies within the contour to be cut.
  • the direction of movement of the gripper 28 is indicated in FIG. 3A by an arrow printed in bold.
  • a negative pressure is then generated in the hollow channel 34 of the gripper 28 and the preparation is thereby sucked onto the gripper and thus fixed.
  • the different pressures are indicated in Fig. 3B by thin arrows.
  • the negative pressure can be distributed equally over all openings or channels, or can be formed individually for each channel.
  • 3D schematically indicates how the dissectate 22, after being lifted off the specimen slide 12, is transported to a collecting vessel 36 with the aid of the gripper 28.
  • the hollow channel 34 is subjected to an overpressure (indicated by a thin arrow). This dissolves the dissectate 22 from the opening 32. The dissectate 22 then falls (indicated by the bold arrow) into the collecting vessel 36.
  • the gripper 28 is always brought into contact with the stabilization layer 14 on the side facing away from the specimen. Contamination and carryover of biological material is effectively prevented in this way since the gripper 28 never comes into direct contact with the biological layer 10.
  • a layer 38 can be located between the gripper 28 and the preparation. This is referred to below as the intermediate layer 38.
  • One of the openings 40 of this intermediate layer 38 is brought into alignment with an opening 32 of the gripper 28 before the gripper 28 is lowered onto the preparation.
  • the diameters of the openings do not have to match. It is only important that one of the openings - preferably the opening 40 in the Intermediate layer 38 - is smaller than the dissectate 22 to be picked up.
  • the intermediate layer can be moved (indicated by the bold arrow in FIG. 4) such that: a) again a free opening 40 with an opening 32 of the gripper 28 comes to cover; or b) the opening 40 covered with a dissectate 22 arrives at a device equivalent to the gripper 28, on which the dissectate 22 is detached as described above.
  • the gripper 28 is lifted off and the collecting vessel 36 is transported to the gripper 28 or else the gripper 28 is transported to the collecting vessel 36 22. They then fall into the collecting vessel 36.
  • the pressure can be increased, for example, by one or more short pressure surges or by sound waves.

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  • Physics & Mathematics (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Optics & Photonics (AREA)
  • Sampling And Sample Adjustment (AREA)

Abstract

Procédé de microdissection selon lequel une préparation (10, 14) est d'abord fixée de manière électrostatique ou à l'aide d'un élément de saisie sur un objet de support (12). Ensuite, une partie est prélevée de la préparation par microdissection au laser. L'adhérence électrostatique empêche le déplacement de la partie prélevée pendant la microdissection au laser. La partie prélevée peut alors être soulevée de manière électrostatique. Alternativement, la partie prélevée peut être soulevée par aspiration à l'aide de l'élément de saisie, ladite partie prélevée adhérant à la face externe dudit élément, en face d'un petit orifice.
PCT/EP2004/010905 2003-10-01 2004-09-30 Microdissection WO2005033668A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE2003146130 DE10346130B4 (de) 2003-10-01 2003-10-01 Vorrichtung und Verfahren zum Isolieren eines Teils einer Schicht biologischen Materials oder eines Präparats
DE10346130.2 2003-10-01
DE102004004205.5 2004-01-27
DE200410004205 DE102004004205A1 (de) 2004-01-27 2004-01-27 Mikrodissektion

Publications (1)

Publication Number Publication Date
WO2005033668A1 true WO2005033668A1 (fr) 2005-04-14

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Application Number Title Priority Date Filing Date
PCT/EP2004/010905 WO2005033668A1 (fr) 2003-10-01 2004-09-30 Microdissection

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WO (1) WO2005033668A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1882924A2 (fr) * 2006-07-28 2008-01-30 P.A.L.M. Microlaser Technologies GmbH Procédé, support et dispositif destinés au traitement d'objets biologiques
DE102006045620B4 (de) * 2006-09-25 2009-10-29 Roland Dr. Kilper Vorrichtung und Verfahren für Aufnahme, Transport und Ablage mikroskopischer Proben
WO2014184005A1 (fr) * 2013-05-15 2014-11-20 Koninklijke Philips N.V. Séparation de tissus d'un échantillon

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19804800A1 (de) * 1998-02-08 1999-08-12 Malte Dr Med Boehm Verfahren zur automatisierten Bergung planar ausgebrachter Objekte vom Objekttisch und zu deren Transfer in nachgeordnete Reaktonsträger
DE10003588A1 (de) * 2000-01-25 2001-08-02 Sl Microtest Wissenschaftliche Verfahren zum Isolieren eines Teils einer Schicht biologischen Materials und dafür geeignetes Halteteil
WO2003008934A1 (fr) * 2001-07-15 2003-01-30 Universitätsklinikum Charite Medizinische Fakultät Der Humboldt-Universität Zu Berlin Lame porte-objets de dissection et procede de fabrication associe

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19804800A1 (de) * 1998-02-08 1999-08-12 Malte Dr Med Boehm Verfahren zur automatisierten Bergung planar ausgebrachter Objekte vom Objekttisch und zu deren Transfer in nachgeordnete Reaktonsträger
DE10003588A1 (de) * 2000-01-25 2001-08-02 Sl Microtest Wissenschaftliche Verfahren zum Isolieren eines Teils einer Schicht biologischen Materials und dafür geeignetes Halteteil
WO2003008934A1 (fr) * 2001-07-15 2003-01-30 Universitätsklinikum Charite Medizinische Fakultät Der Humboldt-Universität Zu Berlin Lame porte-objets de dissection et procede de fabrication associe

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1882924A2 (fr) * 2006-07-28 2008-01-30 P.A.L.M. Microlaser Technologies GmbH Procédé, support et dispositif destinés au traitement d'objets biologiques
EP1882924A3 (fr) * 2006-07-28 2012-07-04 P.A.L.M. Microlaser Technologies GmbH Procédé, support et dispositif destinés au traitement d'objets biologiques
DE102006045620B4 (de) * 2006-09-25 2009-10-29 Roland Dr. Kilper Vorrichtung und Verfahren für Aufnahme, Transport und Ablage mikroskopischer Proben
US8268265B2 (en) 2006-09-25 2012-09-18 Roland Kilper Apparatus and method for picking up, transporting, and depositing microscopic samples
WO2014184005A1 (fr) * 2013-05-15 2014-11-20 Koninklijke Philips N.V. Séparation de tissus d'un échantillon
CN105229442A (zh) * 2013-05-15 2016-01-06 皇家飞利浦有限公司 组织从样本分离

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