EP2393586B1 - Vorrichtung zur thermischen validierung, vorrichtung zur thermischen behandlung von biologischen proben und verfahren zu seiner herstellung - Google Patents

Vorrichtung zur thermischen validierung, vorrichtung zur thermischen behandlung von biologischen proben und verfahren zu seiner herstellung Download PDF

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Publication number
EP2393586B1
EP2393586B1 EP09805781.3A EP09805781A EP2393586B1 EP 2393586 B1 EP2393586 B1 EP 2393586B1 EP 09805781 A EP09805781 A EP 09805781A EP 2393586 B1 EP2393586 B1 EP 2393586B1
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EP
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Prior art keywords
thermal
intended
processing device
thermal processing
validation
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EP09805781.3A
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English (en)
French (fr)
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EP2393586A1 (de
Inventor
Laurent Dilly
Martin Benjamin Klugman
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Bio Rad Innovations SAS
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Bio Rad Innovations SAS
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
    • B01L3/50851—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates specially adapted for heating or cooling samples
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/14—Process control and prevention of errors
    • B01L2200/143—Quality control, feedback systems
    • B01L2200/147—Employing temperature sensors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0645—Electrodes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0663—Whole sensors

Definitions

  • Thermal treatment devices for biological samples are known in the state of the art. These are for example thermal cyclers, also called thermal cyclers or PCR machines (acronym for "Polymerase Chain Reaction”), or incubators.
  • a thermal cycler is a biological sample heater that automates the PCR reaction.
  • the device is usually provided with a heat block with heating cavities into which wells containing the reaction mixture of the PCR is to be inserted.
  • the wells are usually delimited by a plastic support, for example a "microplate” type support.
  • the jacket surrounding the temperature probe is made of metal and separated from the temperature sensor by air.
  • An object of the invention is to provide a thermal validation apparatus of an apparatus for heat treatment of biological samples, to reliably evaluate the temperature taken by the reaction mixture comprising the biological samples during the heat treatment.
  • an object of the invention is a thermal validation apparatus according to claim 1.
  • the inventors have noticed that, in the apparatus of the state of the art, the metal jacket was very quickly put to the temperature of the heating cavities, so that the temperature measured by the temperature probe corresponds in fact to that of the thermal block of the device heat treatment.
  • the inventors have further noted that, during a heat treatment of biological samples, the temperature of the reaction mixture differs substantially from the temperature of the reaction block. Thanks to the invention, the temperature probe is in conditions close to those of the reaction mixture, enabling it to measure the temperature that the reaction mixture would take, and not the temperature taken by the thermal block.
  • the invention also relates to a thermal validation system according to claim 8.
  • An optional feature of the thermal validation system is in claim 9.
  • the invention also relates to an assembly according to claim 10.
  • Optional features of the assembly are in claims 11 and 12.
  • the invention also relates to a method of manufacturing a thermal validation apparatus according to claim 13.
  • Optional features of the manufacturing method are in claims 14 and 15.
  • the thermal cycler 100 comprises a body 102 delimiting a space 104 intended to receive a microplate 106, and a cover 108 attached to the body 102 and intended to close the space 104 receiving the microplate 106.
  • the microplate 106 which is for example marketed by Bio-Rad, forms a plastic support for biological samples. More specifically, the microplate 106 comprises a rectangular main wall 110 comprising an upper face 112. The microplate 106 further comprises wells 114 for receiving biological samples.
  • each well 114 is delimited by a liner 116 carried by the main wall 110, and of a shape adapted to that of the heating cavities 120 which will be described below.
  • the liner 116 is conical, or half-cup or test tube.
  • Well 114 thus corresponds to the volume extending inside the liner 116.
  • the wells 114 open through the upper face 112.
  • the wells 114 are arranged in a matrix, generally 12 per well, ie 96 wells.
  • the space 104 comprises a bottom 118 (also called thermal block), opposite the cover 108 in the closed position, in which heating cavities 120 are formed.
  • Each liner 116 is intended to be inserted into a respective heating cavity 120, so that the heating cavity 120 can heat the biological samples contained in the corresponding well 114.
  • the shirts 116 have a shape matching that of the heating cavities 120 in order to be in contact with the heat block 118.
  • the lid 108 comprises a movable plate 122, intended to bear against the upper face 112 of the microplate 106, when the latter is received in the space 104 and the lid 108 is closed.
  • a thermal validation system 300 of the thermal cycler 100 is shown on the figure 3 .
  • the validation system 300 includes an internal thermal validation apparatus 302, intended to be introduced into the space 104 of the thermal cycler 100, and an external processing module 304, intended to remain outside the thermal cycler 100.
  • the internal apparatus 302 and the external module 304 are interconnected by an information exchange web 306, intended to pass between the cover 108 in the closed position and the body 102 of the thermal cycler 100.
  • the internal thermal validation apparatus 302 comprises a microplate 308, identical to the microplate 106 of the figure 1 .
  • the microplate 308 thus comprises a main wall 310 provided with an upper face 312, and shirts 316 (visible on the figure 5 ) delimiting wells 314 opening on the upper face 312.
  • the microplate 308, and in particular the shirts 316, are made of plastic and have a thickness of less than 0.5 mm.
  • the plastic is polypropylene.
  • the microplate 308 is designed to withstand the repeated temperature variations imposed by the thermocycler thermal block 100 during a PCR reaction, in particular repeated temperature variations between 20 ° C and 100 ° C. ° C, preferably between 20 ° C and 120 ° C.
  • microplate 308 is intended to remain inert to the chemical and biological agents used for the PCR.
  • the internal thermal validation apparatus 302 further comprises a first printed circuit board 318 forming a cover for attachment to the upper face 312 of the microplate 308, in order to close the wells 314 thereof.
  • the internal thermal validation apparatus 302 further comprises a cover 320 for attachment to the microplate 308 for covering both the first printed circuit board 318 and the microplate 308.
  • the cover 320 includes an upper outer face 322, extending over the upper face 312 of the microplate 308, on which the movable plate 122 of the cover 108 of the thermal cycler 100 is intended to come to bear when the cover 108 is closed with the internal validation apparatus 302 placed in the space 104.
  • the upper surface 312 of the microplate 308 and the upper outer face 322 of the cover 320 are separated by a distance of less than 8 mm, preferably less than 4 mm, so that the apparatus internal thermal validation 302 is not too thick compared to a "simple" microplate (like that of the figure 1 ), which could prevent the closure of the lid 108 of the thermal cycler 100.
  • the external module 304 comprises a two-part housing 324 and 326, and a second printed circuit board 328 enclosed in the housing 324, 326.
  • the two printed circuit boards 318, 328 are interconnected by the sheet 306.
  • the sheet 306 extends in continuity with the conductive layers of the printed circuit boards 318, 328, so that the sheet 306 (or at least its conductive portion) and these conductive layers form a single piece. This design avoids the use of connectors and / or solder between the web 306 and the printed circuit boards 318, 328, which could introduce noise in the information exchanged.
  • the external module 304 further comprises a connector 330 for enabling connection to a computer for transferring the data collected by the internal thermal validation apparatus 302.
  • the internal thermal validation apparatus 302 is placed in the space 104 of the thermal cycler 100, and the cover 108 of the latter is closed.
  • Each liner 316 is then inserted into a respective heating cavity 120 of the thermal cycler 100. It will be noted that each liner 316 conforms to the shape of the corresponding heating cavity 120 and is thus in contact with the heat block 118.
  • At least a portion of the wells 314 are measuring wells for collecting temperature measurements.
  • the figure 5 is a sectional view of a measuring well 314.
  • a thermal grease 332 is placed at the bottom of each measuring well 314.
  • the thermal grease 332 has a temperature response identical to that of water to within 5% (that is to say that the thermal grease subjected to a temperature set point will have a temperature at each moment equal to 5% close to that which would take water subjected to the same instruction), at least for the speeds in the thermal cycler 100, in particular for heating rates between 3 ° C per second and 5 ° C per second.
  • the temperature of the thermal fat Tg is always less than 5% of the water temperature Te.
  • the water temperature stabilizes at 88.7 ° C, while that of thermal grease stabilizes at 89 ° C, less than 5% difference.
  • the thermal grease 332 Due to its viscosity, the thermal grease 332 remains at the bottom of the heat sink 314 and is unlikely to stick on the first circuit board 318, even when the device is upside down, which can happen when 'a transport.
  • a temperature probe 334 is placed in each measurement well 314, and is immersed in the thermal grease 332. Specifically, each temperature probe 334 is attached to the first printed circuit board 318. To provide the measured temperature value at the first printed circuit board 318, each electrical wire 336 of each probe is soldered directly thereto.
  • the thermal grease is intended to simulate the aqueous liquid present in the reaction mixture of a PCR. Thus, the probe is in conditions even closer to real conditions.
  • the temperature probe 334 is separated from the thermal block only by the thickness of the plastic jacket and by a thickness of thermal grease.
  • a microplate 308 is obtained, which is a micro-plate adapted to the heating device 100, that is to say adapted for use in the context of a PCR with the thermal cycler 100.
  • At least one temperature probe 334 is attached to a printed circuit board 318 for forming a cover.
  • Each well 314 for receiving a temperature probe 334 is filled with thermal grease 332.
  • the cover 318 is fixed on the upper face 312 of the main wall in order to place each temperature probe 334 in a respective well 314 filled with thermal grease 332, and in order to close at least each of these wells 314.
  • the invention is not limited to this type of thermal treatment device for biological samples.
  • the invention could in particular also apply to incubators of biological samples.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Clinical Laboratory Science (AREA)
  • Hematology (AREA)
  • Analytical Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Sampling And Sample Adjustment (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)

Claims (15)

  1. Einrichtung (302) zur thermischen Validierung einer thermischen Behandlungsvorrichtung (100) für biologische Proben, wobei die thermische Behandlungsvorrichtung (100) einen Körper (102), der einen zur Aufnahme einer Mikrotiterplatte (106) vorgesehenen Raum (104) begrenzt, und einen Deckel (108), der an dem Körper (102) befestigt ist und vorgesehen ist, den Raum (104) abzudecken, umfasst, wobei die Einrichtung zur thermischen Validierung vorgesehen ist, in den Raum (104) der Vorrichtung (100) zur thermischen Behandlung eingesetzt zu werden und umfasst:
    - eine Mikrotiterplatte (308), umfassend:
    - eine Hauptwand (310), und
    - eine Mehrzahl von Schalen (316) aus Kunststoff, wobei jede Schale (316) eine Vertiefung (314) begrenzt und vorgesehen ist, in einen jeweiligen Hohlraum (120) der Vorrichtung (100) zur thermischen Behandlung eingesetzt zu werden, der vorgesehen ist, biologische Proben aufzuheizen oder abzukühlen,
    - einen jeweiligen Temperaturfühler (334), der mindestens in einer der Vertiefungen (314) angeordnet ist, und
    - eine Abdeckung (318), die an der oberen Fläche (312) der Hauptwand (310) befestigt ist und mindestens jede Vertiefung (314) abschließt, in der ein Temperaturfühler (334) angeordnet ist, wobei jeder Temperaturfühler (334) an der Abdeckung (318) befestigt ist.
  2. Einrichtung (302) nach Anspruch 1, außerdem dadurch gekennzeichnet, dass jede Schale (316) aus Polypropylen besteht.
  3. Einrichtung (302) nach Anspruch 1 oder 2, außerdem dadurch gekennzeichnet, dass jede Schale (360) vorgesehen ist, wiederholten Temperaturänderungen zwischen 20°C und 100°C, vorzugsweise zwischen 20°C und 120°C zu widerstehen.
  4. Einrichtung (302) nach einem beliebigen der Ansprüche 1 bis 3, außerdem dadurch gekennzeichnet, dass jede Schale (316) eine Tiefe kleiner als 0,7 mm, vorzugsweise kleiner als 0,5 mm aufweist.
  5. Einrichtung (302) nach einem beliebigen der Ansprüche 1 bis 4, außerdem dadurch gekennzeichnet, dass sie ein jede Vertiefung ausfüllendes thermisches Material umfasst, in dem der Temperaturfühler (334) schwimmt, und dass das thermische Material eine Temperaturreaktion mit etwa 5% Abweichung identisch zu der des Wassers zumindest für Heizgeschwindigkeiten zwischen 3°C pro Sekunde und 5°C pro Sekunde aufweist.
  6. Einrichtung (302) nach Anspruch 5, außerdem dadurch gekennzeichnet, dass das thermische Material ein thermisches Fett (332) ist.
  7. Einrichtung (302) nach einem beliebigen der vorhergehenden Ansprüche, außerdem dadurch gekennzeichnet, dass sie eine obere Außenfläche (322) umfasst, die von der Hauptwand (310) um eine Entfernung kleiner als 8 mm, vorzugsweise kleiner als 4 mm getrennt ist.
  8. System zur thermischen Validierung einer thermischen Behandlungsvorrichtung, wobei das System zur thermischen Validierung eine Einrichtung zur thermischen Validierung nach einem beliebigen der vorhergehenden Ansprüche, die vorgesehen ist, in die Aufnahmeraum (104) der Vorrichtung zur thermischen Behandlung eingesetzt zu werden, und ein externes Behandlungsmodul (304) umfasst, das vorgesehen ist, außerhalb der thermischen Behandlungsvorrichtung zu verbleiben.
  9. System zur thermischen Validierung nach Anspruch 8, bei dem die Einrichtung (302) zur thermischen Validierung und das externe Modul (304) untereinander durch eine Bahn (306) zum Austausch von Informationen verbunden sind, die vorgesehen ist, zwischen einem Deckel (108) in geschlossener Stellung und einem Körper (102) der Vorrichtung zur thermischen Behandlung (100) hindurchzugehen.
  10. Anordnung einer Vorrichtung (100) zur thermischen Behandlung von biologischen Proben und einer Einrichtung (302) zur thermischen Validierung dieser Vorrichtung (100) zur thermischen Behandlung nach einem beliebigen der Ansprüche 1 bis 7.
  11. Anordnung nach Anspruch 10, dadurch gekennzeichnet, dass die Vorrichtung (100) zur thermischen Behandlung ein Thermocycler ist.
  12. Anordnung nach Anspruch 10, dadurch gekennzeichnet, dass die Vorrichtung zur thermischen Behandlung ein Inkubator ist.
  13. Verfahren zur Herstellung einer Einrichtung (302) zur thermischen Validierung nach einem beliebigen der Ansprüche 1 bis 7 einer Vorrichtung (100) zur thermischen Behandlung, die zum Aufheizen und Abkühlen von in einer Mikrotiterplatte (106) aufgenommenen biologischen Proben vorgesehen ist, wobei die Vorrichtung (100) zur thermischen Behandlung einen Körper (102), der einen zur Aufnahme einer Mikrotiterplatte (106) vorgesehenen Raum begrenzt, und einen Deckel (108), der an dem Körper (102) befestigt ist und vorgesehen ist, den Raum (104) abzuschließen, umfasst, wobei die Einrichtung zur thermischen Validierung vorgesehen ist, in den Raum (104) der Vorrichtung (100) zur thermischen Behandlung eingesetzt zu werden, dadurch gekennzeichnet, dass es umfasst:
    - Bereitstellen einer Mikrotiterplatte (308), die an die Vorrichtung (100) zur thermischen Behandlung angepasst ist und umfasst:
    + eine Hauptwand (310), und
    + eine Mehrzahl von Schalen (310) aus Kunststoff, die von der Hauptwand (310) abgestützt sind und eine Mehrzahl von Vertiefungen (314) zur Aufnahme von biologischen Proben begrenzen, die zu einer oberen Fläche (312) der Hauptwand (310) münden,
    - Befestigen mindestens eines Temperaturfühlers (334) an einer Abdeckung (318),
    - Befestigen der Abdeckung (318) an der oberen Fläche (312) der Hauptwand, um jeden Temperaturfühler (334) in einer jeweiligen Vertiefung (314) anzuordnen und um mindestens jede dieser Vertiefungen (314) zu verschließen.
  14. Verfahren zur Herstellung nach Anspruch 13, außerdem dadurch gekennzeichnet, dass es vor dem Befestigen der Abdeckung (318) umfasst:
    - Auffüllen jeder zur Aufnahme eines Temperaturfühlers (334) vorgesehenen Vertiefung (314) mit einem thermischen Material, das eine Temperaturreaktion mit etwa 5% Abweichung identisch zu der des Wassers zumindest für Heizgeschwindigkeiten zwischen 3°C pro Sekunde und 5°C pro Sekunde aufweist.
  15. Verfahren zur Herstellung nach Anspruch 14, außerdem dadurch gekennzeichnet, dass das thermische Material ein thermisches Fett (332) ist.
EP09805781.3A 2009-02-06 2009-12-22 Vorrichtung zur thermischen validierung, vorrichtung zur thermischen behandlung von biologischen proben und verfahren zu seiner herstellung Active EP2393586B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0950751A FR2941876B1 (fr) 2009-02-06 2009-02-06 Appareil de validation thermique, ensemble d'un dispositif de traitement d'echantillons biologiques et d'un tel appareil, et procede de fabrication d'un tel appareil.
PCT/FR2009/052666 WO2010089470A1 (fr) 2009-02-06 2009-12-22 Appareil de validation thermique, ensemble d'un dispositif de traitement thermique d'échantillons biologiques et d'un tel appareil, et procédé de fabrication d'un tel appareil.

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EP2393586A1 EP2393586A1 (de) 2011-12-14
EP2393586B1 true EP2393586B1 (de) 2017-04-12

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US (1) US9221054B2 (de)
EP (1) EP2393586B1 (de)
JP (1) JP5536105B2 (de)
AU (1) AU2009339202B2 (de)
CA (1) CA2751387C (de)
FR (1) FR2941876B1 (de)
WO (1) WO2010089470A1 (de)

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EP2883611A1 (de) * 2013-12-12 2015-06-17 Hain Lifescience GmbH Thermocycler mit einer Temperaturanalyse- und/oder Überprüfungseinheit und Verfahren zur Analyse oder Überprüfung einer thermischen Leistung eines Thermocyclers und zum Kalibrieren des Thermocyclers
JP6686800B2 (ja) * 2016-08-31 2020-04-22 ウシオ電機株式会社 光学測定器

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Publication number Publication date
CA2751387A1 (fr) 2010-08-12
US9221054B2 (en) 2015-12-29
WO2010089470A1 (fr) 2010-08-12
JP2012517220A (ja) 2012-08-02
CA2751387C (fr) 2016-11-29
FR2941876B1 (fr) 2012-12-07
AU2009339202B2 (en) 2015-04-02
JP5536105B2 (ja) 2014-07-02
FR2941876A1 (fr) 2010-08-13
AU2009339202A1 (en) 2011-08-25
US20120039354A1 (en) 2012-02-16
EP2393586A1 (de) 2011-12-14

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