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WO1999063324A1 - Procede et dispositif pour preparer un specimen biologique - Google Patents

Procede et dispositif pour preparer un specimen biologique Download PDF

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Publication number
WO1999063324A1
WO1999063324A1 PCT/SE1999/000830 SE9900830W WO9963324A1 WO 1999063324 A1 WO1999063324 A1 WO 1999063324A1 SE 9900830 W SE9900830 W SE 9900830W WO 9963324 A1 WO9963324 A1 WO 9963324A1
Authority
WO
WIPO (PCT)
Prior art keywords
specimen
fluid
atomised
applying
spun
Prior art date
Application number
PCT/SE1999/000830
Other languages
English (en)
Inventor
Christer FÅHRAEUS
Liana SANDSTRÖM
Original Assignee
Cellavision Ab
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 SE9801724A external-priority patent/SE515346C2/sv
Application filed by Cellavision Ab filed Critical Cellavision Ab
Priority to EP99928307A priority Critical patent/EP1078240A1/fr
Priority to AU45402/99A priority patent/AU4540299A/en
Publication of WO1999063324A1 publication Critical patent/WO1999063324A1/fr

Links

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
    • G01N1/30—Staining; Impregnating ; Fixation; Dehydration; Multistep processes for preparing samples of tissue, cell or nucleic acid material and the like for analysis
    • 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
    • G01N1/30—Staining; Impregnating ; Fixation; Dehydration; Multistep processes for preparing samples of tissue, cell or nucleic acid material and the like for analysis
    • G01N1/31—Apparatus therefor
    • G01N1/312—Apparatus therefor for samples mounted on planar substrates
    • 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
    • G01N1/30—Staining; Impregnating ; Fixation; Dehydration; Multistep processes for preparing samples of tissue, cell or nucleic acid material and the like for analysis
    • G01N1/31—Apparatus therefor
    • G01N2001/317—Apparatus therefor spraying liquids onto surfaces

Definitions

  • the present invention relates to a method for preparing a biological specimen, comprising the step of applying at least one fluid to the specimen.
  • the inven- tion also relates to a device for carrying out the method.
  • the differential white cell count is carried out entirely manually.
  • a blood specimen is taken from a patient whose blood is to be analysed.
  • a few drops of the specimen are placed on a slide and are spread in a thin layer over the surface of the slide with the aid of an oblique, smaller slide. Subsequently, the specimen is fixed on the slide with the aid of a fixative.
  • the standard method used in Sweden is the so-called May-Grunwald-Giemsa method, in which the specimen is stained with the aid of the stains eosin and tiazin (one or more members of the group azureA, azureB, azureC, and methylene blue) .
  • the specimen is immersed in a solution of these stains, which is allowed to take effect for 20-45 minutes.
  • the preparation of the specimen is complete.
  • the slide is placed in a microscope. Subsequently, a laboratory technician counts the white blood cells within a suitable area on the slide and determines the main type to which each of these cells belongs.
  • staining kits have been developed in which the staining with eosin and tiazin is carried out sequentially. This results in faster absorption of the stains by the cells and, consequently, the stains do not need as long to take effect as in the May-Gr ⁇ nwald-Giemsa method, in which they are mixed in a solution.
  • the specimens are essentially handled using the same immersion technique as was previously used.
  • One object of the present invention is to provide a method for preparing a biological specimen by which the above problems are eliminated or at least diminished. Another object of the invention is to provide such a method which produces results of sufficiently high quality to permit both automatic image processing and manual microscopy of the specimen.
  • a further object of the invention is to provide a device for carrying out the above method.
  • a method for preparing a biologi- cal specimen comprises the step of applying at least one fluid to the specimen, the method being characterised by the step of atomising said fluid prior to applying it to the specimen.
  • An advantage of atomising the fluid prior to apply- ing it to the specimen is that it allows the shortening of the time required for the fluid to take effect after it has been applied. This is believed to be due to the fact that it is easier for the cells to absorb the fluid in atomised form through the cell membranes.
  • Another advantage of the atomisation is that much smaller amounts of the different fluids are required than when the specimen is immersed into the fluids according to the prior art.
  • the fluid will spread like a mist over the specimen, which is advantageously arranged in a horizontal position, resulting in very good coverage of the specimen.
  • fresh fluid is always used on the specimens, which thus improves their quality.
  • a further advantage is that the atomised solution appears to be gentler to the specimen and, consequently, provides better quality stained specimens. For example, fewer cell parts are washed away with the atomised solution, which may be due to the fact that there is less excess fluid on the specimen surface than when the specimen is immersed into the fluid.
  • Yet another advantage is that the atomised fluid provides good wetting of the surface, since it does not collect in large drop formations.
  • atomising refers to fluid being broken into drops having an average diameter of about 10-100 ⁇ m, preferably 20-60 ⁇ m.
  • the diameter of as many as possible of the drops, and in any case 50% of the drops, is within said range .
  • preparing a specimen refers to any preparation which can make the specimen suitable for analy- sis. Arranging the specimen on a slide may form part of the preparation, but it is not a requirement.
  • the fluid is atomised essentially without the fluid accelerating towards the specimen.
  • a certain small degree of acceleration is necessary for the drops to come loose from the nozzle, but it is advantageous to keep the acceleration at a low level so as to avoid the risk of the drops breaking structures, such as cells, of the specimen when striking against the specimen.
  • fluid is atomised with the aid of ultrasound.
  • the ultrasonic technique has the advantage that it can atomise the fluid without accelerating it towards the specimen.
  • Other known techniques for atomising fluids, such as atomisers, must utilise air pressure to achieve the atomisation. This means that there is a risk that drops may be accelerated in the direction of the specimen and that these drops break structures, such as cells, on the specimen when they strike against the specimen.
  • a further advantage of the ultrasonic technique is that it is possible to control the size of the drops by the choice of frequency of the ultrasound and that it thus is possible to obtain drops within a desirable range.
  • the specimen is suitably spun to remove excess fluid from the same.
  • spinning refers to placing a slide upon which the specimen is located in a horizontal position and rotating it about an axis extending perpendicular to the surface upon which the specimen is located so that the fluid on the slide is moved towards the periphery of the slide. It should be noted that the expression centrifuging is sometimes used instead of spinning.
  • the fluid which is applied to the specimen can be any fluid which is to be applied to the specimen in order to prepare the latter to make it suitable for analysis in a microscope or in some other instrument .
  • a common method of preparing a specimen is to stain some structures in the specimen so that they can be studied.
  • a fixative is usually first applied in order to fix the specimen, fol- lowed by at least one staining fluid, and finally a rinsing fluid to finish the staining.
  • each of these fluids is atomised prior to being applied to the specimen.
  • the atomisation and application are suitably carried out in the man- ner described above, i.e.
  • the specimen is spun subsequent to the application of each fluid so that the excess of the most recently applied fluid is removed.
  • dilution of the subsequent fluid with the excess of the previous fluid is also avoided, which is particularly important when the fluids are applied to the specimen in the small amounts that are involved when the fluids are atomised. Furthermore, by spinning away excess fluid, reaction between two successively applied fluids is minimised.
  • the specimen should be spun at a speed such that cells in the specimen which is being prepared are not subjected to an acceleration greater than 200 g. In the case of a specimen surface having a diameter of 20 mm this corresponds to a maximum speed of 4500 rpm.
  • An advantageous embodiment of the invention further comprises the step of placing the specimen on a circular slide arranged in a holder, in which an absorbent for absorbing excess fluid extends around the slide.
  • a slide is described in SE 9601404-8.
  • excess specimen and excess fluid are moved towards the periphery of the slide and are absorbed by the absorbent.
  • the specimen and the fluid can be applied without soiling the surrounding area.
  • the specimen can be arranged in the centre of the slide, making it easier to obtain a monolayer .
  • the above method functions well for any type of biological specimen.
  • it is usable for histological , cytological, and microbiological specimens.
  • the method has been tested specifically and been found to function well with respect to blood specimens .
  • the method is particularly suitable for specimens which are to be analysed with the aid of automatic image processing since the method permits quick and easy parameter changes so that the sharp adjustment of contrasts required in automatic image processing can be easily carried out.
  • the invention also relates to a device for preparing a biological specimen, comprising preparation means for applying at least one fluid to the specimen.
  • the device is characterised in that the preparation means comprise an atomiser nozzle for atomising the fluid prior to applying it to the specimen.
  • the device comprises a receptacle for said fluid and supply means for supplying said fluid to the atomiser nozzle, the receptacle and the supply means being arranged in such manner that the fluid is supplied to the atomiser nozzle by gra- vity only.
  • the fluid thus is supplied to the atomiser nozzle without utilisation of air pressure, pumping or other means which may result in acceleration of the fluid towards the specimen in connection with the atomisation.
  • Fig. 1 is a schematic view of an embodiment of a device according to the invention which is usable for preparing a blood specimen
  • Fig. 2 is a flowchart of an embodiment of a method according to the invention relating to the preparation of a blood specimen.
  • a preparation device comprises a centrifuge (sometimes called a spinner) 1.
  • a centrifuge sometimes called a spinner
  • the space is designed so as to act as a holder holding the slide during centrifuga- tion.
  • the centrifuge When the centrifuge is activated, it rotates the slide at high speed about an axis A, whereby any excess fluid on the surface of the slide is moved towards the edges of the slide and is removed from the slide.
  • Centrifuges of this type are commercially available.
  • One example is a centrifuge with the brand name "Horizonten" from Hettich Zentrifugen, Tuttlingen, Germany.
  • the device further comprises a preparation unit P containing four receptacles 4 for different preparation fluids, one being intended for fixa- tive, one for eosin solution, one for tiazin solution, and one for rinsing fluid.
  • Each receptacle 4 is connected by the intermediary of supply means in the form of a tube 5 to an ultrasonic nozzle 6, which is used for atomising the respective fluids.
  • an ultrasonic nozzle 6 In each tube there is a valve 7 for opening and closing the tube.
  • the device comprises a control unit 8 for controlling the centrifuge 1 and the preparation unit P, its connection to these units being highly schematically shown.
  • the control unit controls the start-up and the shut-off of the centrifuge 1, the opening and closing of the valves 7 and the activation and the shut-off of the ultrasonic nozzles 6.
  • the control unit 8 which may con- sist of a suitably programmed computer, also enables fully automatic preparation of specimens.
  • ⁇ l of blood are pipetted in the centre of a circular slide 3 having a diameter of 39 mm which has been placed in the centrifuge 1.
  • the slide with the blood is spun for 2 s at a speed of 4500 rpm, whereby a monolayer is obtained over a major part of the surface of the slide (step 201 in Fig. 2) .
  • a staining kit from Wescor Inc., 459 South Main Street, Logan, Utah 84321, USA is employ- ed.
  • the kit contains a fixative, Basofix Pre-Dip SS-049P, a first staining solution, Eosin red SS-049C, a second staining solution, Methylene blue SS-035B, and a rinsing fluid, Basofix Rinse SS-049A.
  • the working times recommended by the manufacturer, with respect to immersion of the specimen in the solutions are 100 s for the fixative, 33 s for each of the eosin solution and the methylene blue solution, and 30 s for the rinsing fluid, i.e. 196 s in total.
  • the solutions are instead atomised prior to being applied to the specimen and the specimen is spun subsequent to each application of a solution so that any excess solution is removed.
  • the blood specimen is first fixed with the aid of the fixative Basofix Pre-Dip, SS-049P (step 202) .
  • the solution is atomised with the aid of one of the ultrasonic nozzles 6, whereby a "mist" is obtained which falls down on the specimen.
  • An ultrasonic nozzle which has been tested and which can be used for the atomisation is the ultrasonic nozzle US1 from Lechler GmbH in Germany. With this nozzle, an average diameter of the drops of 36 ⁇ m is achieved.
  • the fixative is allowed to take effect for 10-25 s, preferably 15 s, after which excess fixative is spun away for 1 s at a speed of 1000 rpm (step 203) . It should be mentioned that the fixative contains the stain azureB which provides a cer- tain amount of pre-staining of the specimen.
  • the specimen is stained with an Eosin red, SS-049C (step 204) .
  • the solution is atomised and applied to the blood specimen, where the solution is allowed to take effect for 10-60 s, preferably 30 s, after which the specimen is spun for 1 s at a speed of 1000 rpm to remove excess solution (step 205) .
  • the specimen is stained with the methylene blue solution SS-035B (step 206) which is also atomised and applied to the blood specimen, where it is allowed to take effect for 20-60 s, preferably 30 s, after which excess solution is spun away for 1 s at a speed of 1000 rpm (step 207) .
  • the rinsing fluid Basofix SS-049A is atomised (step 208) and is applied to the blood specimen, where it is allowed to take effect for 10-30 s, pre- ferably 25 s. Subsequently, the specimen is spun for 1 s at a speed of 3000 rpm. The purpose of the higher spinning speed subsequent to the application of the final fluid is to dry the specimen.
  • the specimen has now been prepared and is ready to be analysed in a microscope or with the aid of automatic image processing.
  • the total preferred time for the preparation solutions to take effect is 104 s, i.e. a substantially shorter time than in the traditional immersion method.
  • the total amount of solution used in this example is 500-800 ⁇ l, while in the traditional immersion method about 10 times more solution is required for the equivalent staining. In the assessment made by experienced laboratory technicians, the result of the staining is as good as in connection with traditional immersion staining.
  • blood is pipetted onto a slide and spun, after which the staining is immediately carried out.
  • the staining can also be carried out on specimens which in an earlier stage have been arranged in a monolayer on a slide and which subsequent- ly have been allowed to air dry or have been prefixed in methanol .

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Physics & Mathematics (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Sampling And Sample Adjustment (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

L'invention concerne un procédé pour préparer un spécimen biologique, par exemple par coloration. Selon ce procédé, des fluides devant être appliqués sur le spécimen sont atomisés au moyen d'ultrasons avant leur application. On obtient ainsi de fines gouttelettes qui sont non agressives pour le spécimen et permettent de préparer la totalité du spécimen rapidement et avec seulement une faible quantité de fluide. Entre l'application des différents fluides, le spécimen est centrifugé pour retirer le fluide en excès de façon à empêcher le mélange de fluides successivement appliqués. L'invention concerne également un dispositif pour mettre en oeuvre ledit procédé.
PCT/SE1999/000830 1998-05-15 1999-05-14 Procede et dispositif pour preparer un specimen biologique WO1999063324A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP99928307A EP1078240A1 (fr) 1998-05-15 1999-05-14 Procede et dispositif pour preparer un specimen biologique
AU45402/99A AU4540299A (en) 1998-05-15 1999-05-14 A method and a device for preparing a biological specimen

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
SE9801724A SE515346C2 (sv) 1998-05-15 1998-05-15 Sätt och anordning för preparering av ett biologiskt prov
SE9801724-7 1998-05-15
US9132198P 1998-06-30 1998-06-30
US60/091,321 1998-06-30

Publications (1)

Publication Number Publication Date
WO1999063324A1 true WO1999063324A1 (fr) 1999-12-09

Family

ID=26663307

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE1999/000830 WO1999063324A1 (fr) 1998-05-15 1999-05-14 Procede et dispositif pour preparer un specimen biologique

Country Status (3)

Country Link
EP (1) EP1078240A1 (fr)
AU (1) AU4540299A (fr)
WO (1) WO1999063324A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1540330A1 (fr) * 2002-08-29 2005-06-15 Wescor, Inc. Procede et reactifs de coloration pour colorer des echantillons hematologiques dans un appareil de coloration automatique
WO2009127394A3 (fr) * 2008-04-14 2010-01-07 Hartmut Merz Dispositif automatique pour la mise en œuvre de réactions de détection, et procédé de dosage de réactifs sur des porte-objets
CN102519775A (zh) * 2011-11-15 2012-06-27 深圳市科软科技有限公司 一种自动染片机
US8454908B2 (en) 2010-11-10 2013-06-04 Constitution Medical, Inc. Automated systems and methods for preparing biological specimens for examination
US9017610B2 (en) 2008-04-25 2015-04-28 Roche Diagnostics Hematology, Inc. Method of determining a complete blood count and a white blood cell differential count
US9083857B2 (en) 2008-04-25 2015-07-14 Roche Diagnostics Hematology, Inc. Systems and methods for analyzing body fluids
US9891147B2 (en) 2013-04-05 2018-02-13 Roche Diagnostics Hematology, Inc. Automated systems and methods for preparing biological specimens for examination
CN109307614A (zh) * 2018-12-19 2019-02-05 孝感市森茂激光数控设备有限公司 一种染色液体无泵自动注入沉降式制片机及方法
US10379016B1 (en) * 2018-09-18 2019-08-13 King Saud University Apparatus for inoculating agar plate
CN112430528A (zh) * 2020-11-24 2021-03-02 华中科技大学 一种基于喷雾辅助的高通量微生物接种装置

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4004550A (en) * 1973-11-29 1977-01-25 White Ronald D Apparatus for preparing microscope slides
SU1704847A2 (ru) * 1986-12-10 1992-01-15 Азербайджанский политехнический институт им.Ч.Ильдрыма Устройство дл ультразвукового распылени жидкой среды
US5180606A (en) * 1989-05-09 1993-01-19 Wescor, Inc. Apparatus for applying a controlled amount of reagent to a microscope slide or the like
WO1997039329A1 (fr) * 1996-04-15 1997-10-23 Cellavision Ab Dispositif d'analyse optique des prelevements

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4004550A (en) * 1973-11-29 1977-01-25 White Ronald D Apparatus for preparing microscope slides
SU1704847A2 (ru) * 1986-12-10 1992-01-15 Азербайджанский политехнический институт им.Ч.Ильдрыма Устройство дл ультразвукового распылени жидкой среды
US5180606A (en) * 1989-05-09 1993-01-19 Wescor, Inc. Apparatus for applying a controlled amount of reagent to a microscope slide or the like
WO1997039329A1 (fr) * 1996-04-15 1997-10-23 Cellavision Ab Dispositif d'analyse optique des prelevements

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1540330A4 (fr) * 2002-08-29 2007-10-17 Wescor Inc Procede et reactifs de coloration pour colorer des echantillons hematologiques dans un appareil de coloration automatique
EP1540330A1 (fr) * 2002-08-29 2005-06-15 Wescor, Inc. Procede et reactifs de coloration pour colorer des echantillons hematologiques dans un appareil de coloration automatique
WO2009127394A3 (fr) * 2008-04-14 2010-01-07 Hartmut Merz Dispositif automatique pour la mise en œuvre de réactions de détection, et procédé de dosage de réactifs sur des porte-objets
US10764538B2 (en) 2008-04-25 2020-09-01 Roche Diagnostics Hematology, Inc. Systems and methods for analyzing body fluids
US9017610B2 (en) 2008-04-25 2015-04-28 Roche Diagnostics Hematology, Inc. Method of determining a complete blood count and a white blood cell differential count
US9083857B2 (en) 2008-04-25 2015-07-14 Roche Diagnostics Hematology, Inc. Systems and methods for analyzing body fluids
US10094764B2 (en) 2008-04-25 2018-10-09 Roche Diagnostics Hematology, Inc. Systems and methods for determining a complete blood count and a white blood cell differential count
US8454908B2 (en) 2010-11-10 2013-06-04 Constitution Medical, Inc. Automated systems and methods for preparing biological specimens for examination
US9116087B2 (en) 2010-11-10 2015-08-25 Roche Diagnostics Hematology, Inc. Automated systems and methods for preparing biological specimens for examination
US10175153B2 (en) 2010-11-10 2019-01-08 Roche Diagnostics Hematology, Inc. Automated systems and methods for preparing biological specimens for examination
US10775282B2 (en) 2010-11-10 2020-09-15 Roche Diagnostics Hematology, Inc Automated systems and methods for preparing biological specimens for examination
CN102519775A (zh) * 2011-11-15 2012-06-27 深圳市科软科技有限公司 一种自动染片机
US9891147B2 (en) 2013-04-05 2018-02-13 Roche Diagnostics Hematology, Inc. Automated systems and methods for preparing biological specimens for examination
US12117381B2 (en) 2013-04-05 2024-10-15 Roche Diagnostics Hematology, Inc. Automated systems and methods for preparing biological specimens for examination
US10379016B1 (en) * 2018-09-18 2019-08-13 King Saud University Apparatus for inoculating agar plate
CN109307614A (zh) * 2018-12-19 2019-02-05 孝感市森茂激光数控设备有限公司 一种染色液体无泵自动注入沉降式制片机及方法
CN112430528A (zh) * 2020-11-24 2021-03-02 华中科技大学 一种基于喷雾辅助的高通量微生物接种装置
CN112430528B (zh) * 2020-11-24 2022-05-20 华中科技大学 一种基于喷雾辅助的高通量微生物接种装置

Also Published As

Publication number Publication date
AU4540299A (en) 1999-12-20
EP1078240A1 (fr) 2001-02-28

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