EP3386637B1 - Temperature-control device having a reaction vessel - Google Patents

Temperature-control device having a reaction vessel Download PDF

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Publication number
EP3386637B1
EP3386637B1 EP16816179.2A EP16816179A EP3386637B1 EP 3386637 B1 EP3386637 B1 EP 3386637B1 EP 16816179 A EP16816179 A EP 16816179A EP 3386637 B1 EP3386637 B1 EP 3386637B1
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European Patent Office
Prior art keywords
cover
control device
heater
reaction vessel
temperature
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EP16816179.2A
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German (de)
French (fr)
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EP3386637A1 (en
Inventor
Claus Knippschild
Robert MÖLLER
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Analytik Jena AG
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Analytik Jena AG
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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
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F27—FURNACES; KILNS; OVENS; RETORTS
    • F27B—FURNACES, KILNS, OVENS, OR RETORTS IN GENERAL; OPEN SINTERING OR LIKE APPARATUS
    • F27B5/00—Muffle furnaces; Retort furnaces; Other furnaces in which the charge is held completely isolated
    • F27B5/06—Details, accessories, or equipment peculiar to furnaces of these types
    • F27B5/14—Arrangements of heating devices
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F27—FURNACES; KILNS; OVENS; RETORTS
    • F27B—FURNACES, KILNS, OVENS, OR RETORTS IN GENERAL; OPEN SINTERING OR LIKE APPARATUS
    • F27B5/00—Muffle furnaces; Retort furnaces; Other furnaces in which the charge is held completely isolated
    • F27B5/06—Details, accessories, or equipment peculiar to furnaces of these types
    • F27B5/18—Arrangement of controlling, monitoring, alarm or like devices
    • 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
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/025—Align devices or objects to ensure defined positions relative to each other
    • 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
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/028—Modular arrangements
    • 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
    • B01L2300/04—Closures and closing means
    • B01L2300/041—Connecting closures to device or container
    • 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
    • B01L2300/18—Means for temperature control
    • 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
    • B01L2300/18—Means for temperature control
    • B01L2300/1805—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
    • B01L2300/1827—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks using resistive heater
    • 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
    • B01L2300/18—Means for temperature control
    • B01L2300/1883—Means for temperature control using thermal insulation
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F27—FURNACES; KILNS; OVENS; RETORTS
    • F27B—FURNACES, KILNS, OVENS, OR RETORTS IN GENERAL; OPEN SINTERING OR LIKE APPARATUS
    • F27B5/00—Muffle furnaces; Retort furnaces; Other furnaces in which the charge is held completely isolated
    • F27B5/06—Details, accessories, or equipment peculiar to furnaces of these types
    • F27B5/14—Arrangements of heating devices
    • F27B2005/143—Heating rods disposed in the chamber

Definitions

  • PCR polymerase chain reaction
  • the nucleic acids are amplified by incubating them in a special reagent mix at defined temperatures until a finished PCR product is created.
  • a special reagent mix at defined temperatures until a finished PCR product is created.
  • thermal cyclers which normally incubate a larger number of samples (e.g. 24, 48 or 96) in a reaction vessel consisting of a tube closed on one side and a cap.
  • thermal cyclers are usually relatively large as table-top units and are not designed for the analysis of individual samples.
  • the caps are removed from the reaction vessels and then the PCR product is picked up with a pipette and transferred.
  • the reaction vessels can also be sealed with foils and the reagent mix can be covered with overlay media (oil, liquid wax, chill-out wax, etc.).
  • overlay media oil, liquid wax, chill-out wax, etc.
  • the foils and, if necessary, the overlay media are pierced with a pipette tip, a cannula or the like.
  • a buffer can also be added in this way. The resulting mix is often heated again after pipetting on.
  • reaction vessels are removed from the thermal cycler and, if necessary, they are inserted again into the thermal cycler.
  • a temperature control device here a metal block thermostat, known, with a cover which completely covers the sample container inserted into a metal block.
  • the cover can either indirectly through good thermal contact with the metal block or directly over the Cover existing heating elements to be heated. Avoiding condensation on the lids of the sample containers is specified as the decisive effect for the heating.
  • the disadvantage of indirect heating is that the temperature profile of the cover is dependent on the heating of the metal block.
  • the lid of the sample container can actually be heated to the same temperature as the sample in the sample container, a great deal of insulation is required to avoid any heat loss on the way to the lid.
  • the temperature of the lid will always be at least slightly below the temperature of the metal block, so that condensation cannot be avoided 100%.
  • the sample containers are positioned in the temperature control device in such a way that the heated cover is pressed directly onto the cover of the sample container in order to heat it up to a corresponding temperature via heat conduction.
  • a thermal cycle device for performing the PCR as described in the WO 98/43740 A2 is set out to solve the problem that samples which are each arranged in a reaction vessel in a sample block are heated differently.
  • a peripheral heating device around the sample block.
  • the peripheral heater is not connected to the sample block. It should only warm up the air in the immediate vicinity to the temperature of the sample block if possible.
  • the device has a heated lid. With the heated lid, pressure is exerted on the caps of the reaction vessels, so that the reaction vessels remain tightly closed on the one hand and on the other have good thermal contact with the sample block, via which the bottom of the reaction vessel and thus the sample is heated.
  • the heating plate integrated in the lid is controlled so that it always reaches a temperature above the sample temperature in order to ensure that the sample does not condense on the cap of the reaction vessel.
  • the heating plate has recesses in which, if necessary, curvatures of the caps can be positioned, on which no direct pressure is then exerted in order to avoid their deformation.
  • thermocontrol device with which the course of the nucleic acid amplification can be optically monitored.
  • This temperature control device includes a reaction chamber consisting of a tube closed on one side, in which the optically tracked reaction mixture is located, and a cap. In order to avoid condensation of the reaction mixture on walls of the reaction chamber which are in the optical path of the device, these walls are heated.
  • the cap represents the part of the wall that lies in the optical path. It is heated indirectly via a thermally conductive circuit board (printed circuit board) with a heating element, without the circuit board or the heating element limiting the optical path.
  • a temperature control device in particular a thermal cycler, which is designed to accommodate a large number of reaction vessels, is inappropriate because of the disproportionately high purchase costs and the space and energy requirements.
  • thermocycler The additional step of opening the thermocycler to remove or insert the reaction vessel after or before pipetting up or down further increases the disproportion, since after each opening and closing of the thermocycler, a disproportionately large volume of space has to be reset to a defined temperature .
  • thermoblock for heating the test tubes and a cover that can be heated with a resistance heater to cover the test tubes. Openings are provided in the lid, which are arranged coaxially to the sample tubes and through which a pipetting needle can be inserted into the sample tubes.
  • the publication G 92 05 824 U1 discloses a metal block thermostat with a metal block in which a large number of sample vessels can be inserted and a cover which can be removed from the metal block.
  • the cover can be heated independently of the metal block or can be heated by thermal contact with the metal block.
  • a temperature control device with a reaction vessel, with a thermally insulated interior in which the reaction vessel is accommodated, and with a cover which covers the interior, the reaction vessel consisting of a hollow body which is symmetrical about an axis of symmetry and closed on one side with a base and a cap.
  • a heatable heating block in the interior. It has an inner surface which is adapted to the bottom of the reaction vessel and is in contact with it, to heat a sample in the reaction vessel.
  • the lid is made of a heat-conducting material, the temperature control device having a heat-insulating cover, from which the lid is covered, and the lid abutting the cap.
  • the thermal conductivity of the heat-insulating cover is necessarily lower than that of the heat-conducting material of the cover. It is essential to the invention that a heatable heating element is present which surrounds the hollow body and on the latter
  • the radiator is connected to the lid via a heat-conducting contact area, so that the radiator heats the hollow body directly and the cap indirectly via the lid.
  • the lid has a hole through which a cannula, through the cap, can be inserted into the hollow body.
  • the contact area is advantageously formed by a conical jacket-shaped radiator outer surface formed on the radiator and a conical jacket-shaped lid outer surface formed on the cover.
  • the outer surface of the radiator is favorably arranged on the inside, ie facing the hollow body.
  • the radiator is formed from at least two radiator shells arranged symmetrically to the axis of symmetry and the radiator shells are mounted in the interior via at least one spring element, so that the radiator shells are applied to the hollow body with a restoring force of the at least one spring element.
  • the radiator shells are advantageously held together by at least one elastic ring.
  • the cover is formed from two cover shells which are spring-loaded to one another.
  • Each temperature control device according to the invention shown for example in the 1a and 1b , is specially designed for a reaction vessel 1, that is, it is individually adapted to the geometric shape and dimension of the reaction vessel 1, which is why it is not universal in connection with a reaction vessel of any geometric Shape and dimension can be used. Accordingly, the features of the temperature control device can also be described only in connection with a reaction vessel 1.
  • the reaction vessel 1 consists of a hollow body 1.1 which is symmetrical about an axis of symmetry 1.0 and is closed on one side by a base 1.2 and a cap 1.3.
  • the temperature control device is not limited to the application for the PCR and cell suspensions, reagent mixes, e.g. B. consisting of reactants and catalysts, as well as finished PCR products, in liquid form, to be understood.
  • the temperature control device has a thermally insulated interior 2, closed by a lid 3, in which there is a heatable heating block 7, which has an inner surface 7.1 which is adapted to the bottom 1.2 of the reaction vessel 1.
  • the reaction vessel 1 is arranged standing on the heating block 7 such that its bottom 1.2 is in contact with the inner surface 7.1 in order to heat a sample 8 located in the reaction vessel 1.
  • the cover 3 is made of a heat-conducting material, is covered by a heat-insulating cover 9 and is in contact with the cap 1.3.
  • a heatable radiator 4 which surrounds the hollow body 1.1 and is adapted to its shape and which is connected to the lid 3 via a heat-conducting contact area 5, so that the heater 4 directly connects the hollow body 1.1 and the cap 1.3 over the lid 3 indirectly heated.
  • a temperature control device which is a thermal cycler in connection with the PCR
  • the cap 1.3 advantageously has a screw cap and is filled with a septum.
  • the lid 3 has a hole 3.3. Providing such a hole 3.3 in the cover 3 is possible in an uncomplicated manner, since the cover 3 according to the invention has no heating, but is heated by heat conduction via the heating element 4, with which it is in contact via the contact area 5 when the temperature control device is closed. The lid 3 is therefore not heated by active heating, but passively via heat conduction. Since the cover 3 bears on the cap 1.3 at least over the area of the hole 3.3, the interior 2 of the temperature control device is closed despite the hole 3.3.
  • the contact area 5 is formed by an outer surface 4.1 of the heater formed on the radiator 4 and an outer surface 3.1 formed on the cover 3.
  • the outer surface 4.1 of the radiator and the outer surface 3.1 of the cover are arranged in a ring and in a radial plane to the axis of symmetry 1.0.
  • the outer surface 4.1 of the radiator and the outer surface 3.1 of the cover may be conical. The larger the cone angle is selected, the larger the contact area 5 becomes, with otherwise the same dimensions of the temperature control device.
  • the outer surface 4.1 of the radiator can be arranged inside the outer surface 3.1 of the cover.
  • the radiator 4 not only has the task of heating the lid 3, but is also intended to heat the hollow body 1.1 of the reaction vessel 1 and thus the gas volume of the reaction vessel 1, which is inevitably located above the sample 8. In this way, condensation on the inner wall of the hollow body 1.1 is primarily avoided. Furthermore, the pressure of the gas volume can be changed by changing the temperature, which is often used as a so-called thermopneumatic effect in fluidics.
  • a manipulation (pipetting off, Aliquoting, mixing) of the sample is also possible without a pump [ Keller, M .; Focke, M .; Strohmeier, O .; Reith, P .; Roth, G .; Mark, D .; Zengerle, R .; von Stetten, F .: "Centrifugal-thermopneumatic aliquoting on the LabDisk and application for DNA-based detection of various bacteria"; in: Microsystem Technology Congress 2013, Aachen, October 14-16, 2013, pp. 31 - 34 ].
  • a cannula When a cannula is inserted into the sample 8, it is pushed into the cannula while expanding the gas volume.
  • the cannula must be closed at the outer first end during insertion until the inner second end is in contact with the sample 8. If the first end is then opened, the gas volume can expand in that the sample 8 rises in the cannula until a normal pressure is established in the gas volume or the sample 8 is completely absorbed.
  • the heater 4 enclosing the hollow body 1.1 thus not only enables the use of a passively heated cover 3 but also a quasi-passive removal of the sample 8.
  • the radiator 4 can be a tubular body or advantageously consist of at least two radiator shells 4.2 arranged symmetrically with respect to the axis of symmetry 1.0, with exactly two radiator shells 4.2 in the form of half-shells being advantageous. While a tubular heating element 4 is arranged in a fixed position within the interior 2 with respect to the axis of symmetry 1.0, in one embodiment of the heating element 4 as two element shells 4.2 the two element shells 4.2 with respect to the axis of symmetry 1.0 are mounted radially elastically via at least one spring element 6 in the interior 2 and are supported via at least one elastic ring 11 held together.
  • the hollow body 1.1 of the reaction vessel 1 is a conical jacket with a small cone angle, so that when the reaction vessel 1 is introduced into the temperature control device and thus between the radiator shells 4.2, the latter are increasingly pressed apart, with an increasingly large restoring force on the radiator shells 4.2 acts, which ensures that the radiator shells 4.2 nestle against the hollow body 1.1.
  • This restoring force is determined by the elasticity and the spring characteristic of the at least one elastic ring 11, for example a rubber ring and the at least one spring element 6 influenced.
  • the cover 3 can advantageously also be made from two cover shells 3.2, advantageously in the form of half-shells.
  • the lid outer surface 3.1 and the radiator outer surface 4.1 as in FIG Fig. 1a shown, cone-shaped.
  • the lid shells 3.2 are then spread apart and the lid outer surfaces 3.1 are pressed against the outer heater surfaces 4.1 by restoring forces.
  • the restoring forces are generated by a spiral spring 10 enclosing the cover shells 3.2.
  • the cover outer surface 3.1 remains firmly positioned with respect to the symmetry axis 1.0, while the position of the radiator outer surface 4.1 shifts radially to the symmetry axis 1.0.
  • the outer surface 3.1 of the cover and the outer surface 4.1 of the radiator are designed as ring surfaces, only the contact area 5 is thereby reduced.
  • the outer surface 3.1 of the cover is placed on the outer surface 4.1 of the radiator at a different height in the axial direction of the axis of symmetry 1.0, depending on how far apart the radiator shells 4.2 are, which is why the cover 3 in the cover 9 is mounted axially sprung.

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  • Chemical & Material Sciences (AREA)
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  • Mechanical Engineering (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
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  • Devices For Use In Laboratory Experiments (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Description

Eine Hauptanalysetechnik für Nukleinsäuren ist die Polymerase-Kettenreaktion (engl. Polymerase Chain Reaction), allgemein als PCR bezeichnet. Dabei werden die Nukleinsäuren vervielfältigt, indem sie in einem speziellen Reagenzienmix bei definierten Temperaturen inkubiert werden, bis ein fertiges PCR-Produkt entstanden ist. Dies wird heute routinemäßig in speziellen Temperiervorrichtungen, sogenannten Thermocyclern, durchgeführt, welche normalerweise eine größere Anzahl von jeweils in einem Reaktionsgefäß, bestehend aus einem einseitig geschlossenen Röhrchen und einer Kappe, befindlichen Proben (z. B. 24, 48 oder 96) parallel inkubieren. Diese Thermocycler sind meist relativ groß als Tischgeräte ausgeführt und nicht für die Analyse von Einzelproben ausgelegt.A major analysis technique for nucleic acids is the polymerase chain reaction, commonly referred to as PCR. The nucleic acids are amplified by incubating them in a special reagent mix at defined temperatures until a finished PCR product is created. Today, this is routinely carried out in special temperature control devices, so-called thermal cyclers, which normally incubate a larger number of samples (e.g. 24, 48 or 96) in a reaction vessel consisting of a tube closed on one side and a cap. These thermal cyclers are usually relatively large as table-top units and are not designed for the analysis of individual samples.

Zur Analyse des fertigen PCR-Produkts muss dieses in ein entsprechendes Analysegerät überführt werden. Dazu werden die Kappen von den Reaktionsgefäßen entfernt und anschließend wird das PCR-Produkt mit einer Pipette aufgenommen und transferiert. Die Reaktionsgefäße können alternativ auch mit Folien verschlossen und der Reagenzienmix kann mit Überschichtungsmedien (Öl, liquid wax, chill-out wax, etc.) bedeckt sein. Zum Transferieren des Reagenzienmix bzw. des fertigen PCR-Produktes werden die Folien und gegebenenfalls die Überschichtungsmedien mit einer Pipettenspitze, einer Kanüle oder Ähnlichem durchstochen. Ebenso kann auf diesem Weg ein Puffer zugemischt werden. Oft wird nach dem Aufpipettieren der entstandene Mix nochmals erhitzt.To analyze the finished PCR product, it must be transferred to an appropriate analyzer. For this purpose, the caps are removed from the reaction vessels and then the PCR product is picked up with a pipette and transferred. Alternatively, the reaction vessels can also be sealed with foils and the reagent mix can be covered with overlay media (oil, liquid wax, chill-out wax, etc.). To transfer the reagent mix or the finished PCR product, the foils and, if necessary, the overlay media are pierced with a pipette tip, a cannula or the like. A buffer can also be added in this way. The resulting mix is often heated again after pipetting on.

Zum Auf- oder Abpipettieren werden die Reaktionsgefäße aus dem Thermocycler entnommen und bei Bedarf eines nochmaligen Erhitzens erneut in den Thermocycler eingesetzt.For pipetting up or down, the reaction vessels are removed from the thermal cycler and, if necessary, they are inserted again into the thermal cycler.

Um ein Kondensieren der Probe während der PCR an der Kappe des Reaktionsgefäßes zu verhindern, sind derzeitige Thermocycler mit einer Deckelheizung ausgestattet. So ist z. B. aus der DE 92 05 824 U1 eine Temperiervorrichtung, hier ein Metallblock-Thermostat, bekannt, mit einer Abdeckung, welche in einen Metallblock eingesetzte Probenbehälter vollständig abdeckt. Die Abdeckung kann entweder indirekt über einen guten thermischen Kontakt mit dem Metallblock oder direkt über an der Abdeckung vorhandene Heizelemente beheizt werden. Als maßgeblicher Effekt für die Beheizung ist das Vermeiden der Kondensation an den Deckeln der Probenbehälter angegeben. Für die indirekte Beheizung ergibt sich der Nachteil, dass das Temperaturprofil der Abdeckung von der Beheizung des Metallblockes abhängig ist. Damit der Deckel des Probenbehälters tatsächlich auf eine gleiche Temperatur wie die Probe in dem Probenbehälter aufgeheizt werden kann, bedarf es eines hohen Aufwandes der Isolation, um jeglichen Wärmeverlust auf dem Weg zum Deckel zu vermeiden. Praktisch wird die Temperatur des Deckels immer wenigstens geringfügig unterhalb der Temperatur des Metallblockes liegen, sodass eine Kondensation nicht 100% vermeidbar ist. Unabhängig davon, ob die Abdeckung direkt oder indirekt beheizt wird, sind die Probenbehälter so in der Temperiervorrichtung positioniert, dass die beheizte Abdeckung direkt auf die Deckel der Probenbehälter gepresst wird, um diese über Wärmeleitung auf eine entsprechende Temperatur aufzuheizen.In order to prevent the sample from condensing on the cap of the reaction vessel during the PCR, current thermal cyclers are equipped with a lid heater. So z. B. from the DE 92 05 824 U1 a temperature control device, here a metal block thermostat, known, with a cover which completely covers the sample container inserted into a metal block. The cover can either indirectly through good thermal contact with the metal block or directly over the Cover existing heating elements to be heated. Avoiding condensation on the lids of the sample containers is specified as the decisive effect for the heating. The disadvantage of indirect heating is that the temperature profile of the cover is dependent on the heating of the metal block. So that the lid of the sample container can actually be heated to the same temperature as the sample in the sample container, a great deal of insulation is required to avoid any heat loss on the way to the lid. In practice, the temperature of the lid will always be at least slightly below the temperature of the metal block, so that condensation cannot be avoided 100%. Regardless of whether the cover is heated directly or indirectly, the sample containers are positioned in the temperature control device in such a way that the heated cover is pressed directly onto the cover of the sample container in order to heat it up to a corresponding temperature via heat conduction.

Mit einer Temperiervorrichtung, hier Thermo-Zyklus-Vorrichtung zur Ausführung der PCR, wie sie in der WO 98/43740 A2 dargelegt ist, soll das Problem gelöst werden, dass Proben, die jeweils in einem Reaktionsgefäß gemeinsam in einem Probenblock angeordnet sind, unterschiedlich erwärmt werden. Unter anderem wird vorgeschlagen, eine Umfangsheizeinrichtung um den Probenblock anzuordnen. Die Umfangsheizung ist nicht mit dem Probenblock verbunden. Sie soll lediglich die Luft in unmittelbarer Nähe möglichst auf die Temperatur des Probenblockes aufwärmen. Darüber hinaus weist die Vorrichtung einen beheizten Deckel auf. Mit dem beheizten Deckel wird auf die Kappen der Reaktionsgefäße Druck ausgeübt, sodass die Reaktionsgefäße zum einen dicht verschlossen bleiben und zum anderen einen guten thermischen Kontakt mit dem Probenblock aufweisen, über den der Boden des Reaktionsgefäßes und damit die Probe erwärmt wird. Die in dem Deckel integrierte Heizplatte wird so angesteuert, dass sie stets eine Temperatur oberhalb der Probentemperatur erreicht, um sicherzustellen, dass die Probe nicht an der Kappe des Reaktionsgefäßes kondensiert. Die Heizplatte weist Ausnehmungen auf, in denen gegebenenfalls Wölbungen der Kappen positioniert werden können, auf die dann kein direkter Druck ausgeübt wird, um deren Verformung zu vermeiden. Mit einer solchen Ausführung der Verschlusskappen kann diesen neben der Funktion des Verschließens des Reagenzgefäßes auch eine optische Funktion zugeordnet werden, sodass ein fertiges PCR-Produkt, ohne dass die Verschlusskappe entfernt oder ausgetauscht wird, einem optischen Lesegerät zugeführt werden kann und die Probe durch die jeweilige Ausnehmung optisch zugängig ist.With a temperature control device, here a thermal cycle device for performing the PCR as described in the WO 98/43740 A2 is set out to solve the problem that samples which are each arranged in a reaction vessel in a sample block are heated differently. Among other things, it is proposed to arrange a peripheral heating device around the sample block. The peripheral heater is not connected to the sample block. It should only warm up the air in the immediate vicinity to the temperature of the sample block if possible. In addition, the device has a heated lid. With the heated lid, pressure is exerted on the caps of the reaction vessels, so that the reaction vessels remain tightly closed on the one hand and on the other have good thermal contact with the sample block, via which the bottom of the reaction vessel and thus the sample is heated. The heating plate integrated in the lid is controlled so that it always reaches a temperature above the sample temperature in order to ensure that the sample does not condense on the cap of the reaction vessel. The heating plate has recesses in which, if necessary, curvatures of the caps can be positioned, on which no direct pressure is then exerted in order to avoid their deformation. With such a design of the closure caps, in addition to the function of closing the reagent vessel, an optical function can also be assigned to them, so that a finished PCR product without the Cap is removed or replaced, an optical reader can be supplied and the sample is optically accessible through the respective recess.

In der EP 0 706 649 B1 ist eine Temperiervorrichtung offengelegt, mit der der Verlauf der Nukleinsäurenamplifikation optisch verfolgt werden kann. Zu dieser Temperiervorrichtung gehört eine Reaktionskammer, bestehend aus einer einseitig geschlossenen Röhre, in der sich die optisch verfolgte Reaktionsmischung befindet, und einer Kappe. Zur Vermeidung der Kondensation der Reaktionsmischung an Wänden der Reaktionskammer, die im optischen Weg der Vorrichtung liegen, werden diese Wände beheizt. In dem gezeigten Ausführungsbeispiel stellt die Kappe den Teil der Wand dar, der im optischen Weg liegt. Sie wird mittelbar über eine wärmeleitfähige Platine (Leiterplatte) mit einem Heizelement beheizt, ohne dass die Platine oder das Heizelement den optischen Weg begrenzt.In the EP 0 706 649 B1 discloses a temperature control device with which the course of the nucleic acid amplification can be optically monitored. This temperature control device includes a reaction chamber consisting of a tube closed on one side, in which the optically tracked reaction mixture is located, and a cap. In order to avoid condensation of the reaction mixture on walls of the reaction chamber which are in the optical path of the device, these walls are heated. In the exemplary embodiment shown, the cap represents the part of the wall that lies in the optical path. It is heated indirectly via a thermally conductive circuit board (printed circuit board) with a heating element, without the circuit board or the heating element limiting the optical path.

Neben einer parallelen Inkubation und Durchführung der PCR von zunehmend mehr Proben, wie sie beispielsweise mit einer aus der vorgenannten WO 98/43740 A2 bekannten Temperiervorrichtung durchführbar ist, haben sich in den letzten Jahren auch verschiedene Anwendungen etabliert, bei denen die PCR nur an einer einzelnen Probe ausgeführt wird.In addition to a parallel incubation and implementation of the PCR of increasingly more samples, such as those from the aforementioned WO 98/43740 A2 Known temperature control device can be carried out, various applications have also become established in recent years, in which the PCR is only carried out on a single sample.

Hierfür eine Temperiervorrichtung, insbesondere einen Thermocycler zu verwenden, der zur Aufnahme einer Vielzahl von Reaktionsgefäßen ausgelegt ist, ist aufgrund der unverhältnismäßig hohen Anschaffungskosten sowie des Raum- und Energiebedarfes unzweckmäßig.For this purpose, using a temperature control device, in particular a thermal cycler, which is designed to accommodate a large number of reaction vessels, is inappropriate because of the disproportionately high purchase costs and the space and energy requirements.

Der zusätzliche Arbeitsschritt des Öffnens des Thermocyclers zur Entnahme bzw. des Einsetzens des Reaktionsgefäßes nach bzw. vor einem Auf- oder Abpipettieren verstärkt die Unverhältnismäßigkeit noch mehr, da nach jedem Öffnen und Schließen des Thermocyclers ein unverhältnismäßig großes Raumvolumen wieder auf eine definierte Temperatur eingestellt werden muss.The additional step of opening the thermocycler to remove or insert the reaction vessel after or before pipetting up or down further increases the disproportion, since after each opening and closing of the thermocycler, a disproportionately large volume of space has to be reset to a defined temperature .

Aus der Druckschrift US 2008/0254532A1 ist eine Temperiervorrichtung für eine symmetrische chemische Reaktionskammer mit einem Innenvolumen zum Aufnehmen einer Probe bekannt, die einen verschließbaren Einlass aufweist. Die Reaktionskammer sitzt in einem Trägergehäuse mit einer dünnen, elastischen Material-Wand, die Heizelemente aufweist, die an die Umfangsfläche der Reaktionskammer Wärme abgeben.From the publication US 2008 / 0254532A1 is known a temperature control device for a symmetrical chemical reaction chamber with an inner volume for receiving a sample, which has a closable inlet. The The reaction chamber sits in a carrier housing with a thin, elastic material wall that has heating elements that emit heat to the peripheral surface of the reaction chamber.

Eine weitere Temperiervorrichtung zur Durchführung einer PCR geht aus der Druckschrift US 6,558,947 B1 hervor. Sie besteht aus einer Vielzahl von Hülsen in die Reaktionsgefäße eingeführt werden können und die individuell über ihre Umfangsflächen beheizbar sind.Another temperature control device for carrying out a PCR can be found in the publication US 6,558,947 B1 forth. It consists of a large number of sleeves into which the reaction vessels can be inserted and which can be heated individually over their circumferential surfaces.

Aus der Druckschrift US 2008/0057544 A1 ist eine Temperiervorrichtung mit einem teilbaren Heizblock bekannt mit dem ebenfalls eine Erwärmung von Reaktionsgefäßen über deren Umgangsfläche erfolgt.From the publication US 2008/0057544 A1 a temperature control device with a divisible heating block is known, which is also used to heat reaction vessels via their surrounding area.

Aus EP 642 831 A1 ist eine Vorrichtung zur automatischen Durchführung von Temperaturzyklen in einer Vielzahl von Proberöhrchen bekannt. Die Vorrichtung weist einen Thermoblock zur Beheizung der Proberöhrchen und einen mit einer Widerstandsheizung beheizbaren Deckel zur Abdeckung der Proberöhrchen auf. Im Deckel sind Öffnungen vorgesehen, die koaxial zu den Proberöhrchen angeordnet sind, und über die eine Pipettiernadel in die Proberöhrchen eingeführt werden kann.Out EP 642 831 A1 a device for the automatic execution of temperature cycles in a large number of test tubes is known. The device has a thermoblock for heating the test tubes and a cover that can be heated with a resistance heater to cover the test tubes. Openings are provided in the lid, which are arranged coaxially to the sample tubes and through which a pipetting needle can be inserted into the sample tubes.

Die Druckschrift G 92 05 824 U1 offenbart ein Metallblock-Thermostat, mit einem Metallblock in den eine Vielzahl von Probengefäße einsetzbar sind und einer vom Metallblock abnehmbaren Abdeckung. Die Abdeckung kann unabhängig vom Metallblock beheizbar sein oder aber durch thermischen Kontakt mit dem Metallblock erwärmt werden.The publication G 92 05 824 U1 discloses a metal block thermostat with a metal block in which a large number of sample vessels can be inserted and a cover which can be removed from the metal block. The cover can be heated independently of the metal block or can be heated by thermal contact with the metal block.

Es ist die Aufgabe der Erfindung, eine Temperiervorrichtung mit nur einem Reaktionsgefäß zu finden, bei der ein Auf- und Abpipettieren einer Probe ohne eine Entnahme des Reaktionsgefäßes aus der Temperiervorrichtung möglich ist.It is the object of the invention to find a temperature control device with only one reaction vessel in which pipetting up and down of a sample is possible without removing the reaction vessel from the temperature control device.

Die Aufgabe wird gelöst durch eine Temperiervorrichtung mit einem Reaktionsgefäß, mit einem wärmegedämmten Innenraum, in dem das Reaktionsgefäß aufgenommen ist, und mit einem Deckel, der den Innenraum abdeckt, wobei das Reaktionsgefäß aus einem zu einer Symmetrieachse symmetrischen, mit einem Boden einseitig verschlossenen Hohlkörper und einer Kappe besteht. In dem Innenraum ist ein beheizbarer Heizblock vorhanden. Er weist eine Innenfläche auf, die an den Boden des Reaktionsgefäßes angepasst ist und mit diesem in Kontakt steht, um eine in dem Reaktionsgefäß befindliche Probe zu beheizen. Der Deckel besteht aus einem wärmeleitenden Material, wobei die Temperiervorrichtung eine wärmedämmende Abdeckung aufweist, von der der Deckel abgedeckt ist, und wobei der Deckel an der Kappe anliegt. Die Wärmeleitfähigkeit der wärmedämmenden Abdeckung ist zwingend geringer als die des wärmeleitenden Materials des Deckels. Es ist erfindungswesentlich, dass ein beheizbarer Heizkörper vorhanden ist, der den Hohlkörper umschließt und an dessenThe object is achieved by a temperature control device with a reaction vessel, with a thermally insulated interior in which the reaction vessel is accommodated, and with a cover which covers the interior, the reaction vessel consisting of a hollow body which is symmetrical about an axis of symmetry and closed on one side with a base and a cap. There is a heatable heating block in the interior. It has an inner surface which is adapted to the bottom of the reaction vessel and is in contact with it, to heat a sample in the reaction vessel. The lid is made of a heat-conducting material, the temperature control device having a heat-insulating cover, from which the lid is covered, and the lid abutting the cap. The thermal conductivity of the heat-insulating cover is necessarily lower than that of the heat-conducting material of the cover. It is essential to the invention that a heatable heating element is present which surrounds the hollow body and on the latter

Form angepasst ist. Der Heizkörper steht mit dem Deckel über einen wärmeleitenden Kontaktbereich in Verbindung, sodass der Heizkörper den Hohlkörper unmittelbar und die Kappe über den Deckel mittelbar erwärmt. Der Deckel weist ein Loch auf, durch das hindurch eine Kanüle, durch die Kappe, in den Hohlkörper eingeführt werden kann.Shape is adjusted. The radiator is connected to the lid via a heat-conducting contact area, so that the radiator heats the hollow body directly and the cap indirectly via the lid. The lid has a hole through which a cannula, through the cap, can be inserted into the hollow body.

Vorteilhaft ist der Kontaktbereich durch eine an dem Heizkörper ausgebildete kegelmantelförmige Heizkörperaußenfläche und eine an dem Deckel ausgebildete kegelmantelförmige Deckelaußenfläche gebildet.The contact area is advantageously formed by a conical jacket-shaped radiator outer surface formed on the radiator and a conical jacket-shaped lid outer surface formed on the cover.

Günstig ist die Heizkörperaußenfläche innenliegend, das heißt dem Hohlkörper zugewandt, angeordnet.The outer surface of the radiator is favorably arranged on the inside, ie facing the hollow body.

Es ist von Vorteil, wenn der Heizkörper wenigstens aus zwei zur Symmetrieachse symmetrisch angeordneten Heizkörperschalen gebildet ist und die Heizkörperschalen im Innenraum über wenigstens ein Federelement gelagert sind, sodass die Heizkörperschalen mit einer Rückstellkraft des wenigstens einen Federelementes an den Hohlkörper angelegt sind.It is advantageous if the radiator is formed from at least two radiator shells arranged symmetrically to the axis of symmetry and the radiator shells are mounted in the interior via at least one spring element, so that the radiator shells are applied to the hollow body with a restoring force of the at least one spring element.

Vorteilhaft werden die Heizkörperschalen über wenigstens einen elastischen Ring zusammengehalten.The radiator shells are advantageously held together by at least one elastic ring.

Ebenso ist es von Vorteil, wenn der Deckel aus zwei Deckelschalen gebildet ist, die zueinander federnd gelagert sind.It is also advantageous if the cover is formed from two cover shells which are spring-loaded to one another.

Die Erfindung wird nachfolgend anhand eines Ausführungsbeispiels und von Zeichnungen beschrieben.The invention is described below using an exemplary embodiment and drawings.

Hierzu zeigen:

Fig. 1a
eine Temperiervorrichtung im Längsschnitt und
Fig. 1
b eine Temperiervorrichtung nach Fig. 1a im Querschnitt.
Show:
Fig. 1a
a temperature control device in longitudinal section and
Fig. 1
b a temperature control device Fig. 1a in cross section.

Eine jede erfindungsgemäße Temperiervorrichtung, beispielhaft gezeigt in den Fig. 1a und 1b, ist für ein Reaktionsgefäß 1 speziell ausgelegt, dass heißt, sie ist individuell auf die geometrische Form und Dimension des Reaktionsgefäßes 1 angepasst, weshalb sie nicht universell in Verbindung mit einem Reaktionsgefäß beliebiger geometrischer Form und Dimension verwendbar ist. Entsprechend können die Merkmale der Temperiervorrichtung auch nur in Verbindung mit einem Reaktionsgefäß 1 beschrieben werden.Each temperature control device according to the invention, shown for example in the 1a and 1b , is specially designed for a reaction vessel 1, that is, it is individually adapted to the geometric shape and dimension of the reaction vessel 1, which is why it is not universal in connection with a reaction vessel of any geometric Shape and dimension can be used. Accordingly, the features of the temperature control device can also be described only in connection with a reaction vessel 1.

Das Reaktionsgefäß 1 besteht aus einem zu einer Symmetrieachse 1.0 symmetrischen, mit einem Boden 1.2 einseitig verschlossenen Hohlkörper 1.1 und einer Kappe 1.3.The reaction vessel 1 consists of a hollow body 1.1 which is symmetrical about an axis of symmetry 1.0 and is closed on one side by a base 1.2 and a cap 1.3.

Die Temperiervorrichtung ist nicht auf die Anwendung für die PCR beschränkt und unter einer Probe 8 sollen nachfolgend Zellsuspensionen, Reagenzienmixe, z. B. bestehend aus Reaktanten und Katalysatoren, sowie fertige PCR-Produkte, in flüssiger Form vorliegend, verstanden werden.The temperature control device is not limited to the application for the PCR and cell suspensions, reagent mixes, e.g. B. consisting of reactants and catalysts, as well as finished PCR products, in liquid form, to be understood.

Die Temperiervorrichtung weist einen wärmegedämmten, durch einen Deckel 3 verschlossenen Innenraum 2 auf, in dem ein beheizbarer Heizblock 7 vorhanden ist, der eine Innenfläche 7.1 aufweist, die an den Boden 1.2 des Reaktionsgefäßes 1 angepasst ist. Das Reaktionsgefäß 1 ist so auf dem Heizblock 7 stehend angeordnet, dass dessen Boden 1.2 mit der Innenfläche 7.1 in Kontakt steht, um eine in dem Reaktionsgefäß 1 befindliche Probe 8 zu beheizen. Der Deckel 3 besteht aus einem wärmeleitenden Material, ist von einer wärmedämmenden Abdeckung 9 abgedeckt und liegt an der Kappe 1.3 an.The temperature control device has a thermally insulated interior 2, closed by a lid 3, in which there is a heatable heating block 7, which has an inner surface 7.1 which is adapted to the bottom 1.2 of the reaction vessel 1. The reaction vessel 1 is arranged standing on the heating block 7 such that its bottom 1.2 is in contact with the inner surface 7.1 in order to heat a sample 8 located in the reaction vessel 1. The cover 3 is made of a heat-conducting material, is covered by a heat-insulating cover 9 and is in contact with the cap 1.3.

Es ist erfindungswesentlich, dass ein den Hohlkörper 1.1 umschließender, an dessen Form angepasster beheizbarer Heizkörper 4 vorhanden ist, der mit dem Deckel 3 über einen wärmeleitenden Kontaktbereich 5 in Verbindung steht, sodass der Heizkörper 4 den Hohlkörper 1.1 unmittelbar und die Kappe 1.3 über den Deckel 3 mittelbar erwärmt.It is essential to the invention that there is a heatable radiator 4 which surrounds the hollow body 1.1 and is adapted to its shape and which is connected to the lid 3 via a heat-conducting contact area 5, so that the heater 4 directly connects the hollow body 1.1 and the cap 1.3 over the lid 3 indirectly heated.

Mit einer erfindungsgemäßen Temperiervorrichtung, die in Verbindung mit der PCR einen Thermocycler darstellt, ist es möglich, eine Kanüle, eine Detektionssonde, einen Mixstab, eine Pipettenspitze oder Ähnliches durch den Deckel 3 der Temperiervorrichtung und durch die Kappe 1.3 des Reaktionsgefäßes 1 hindurch einzuführen und so z. B. die Probe ab- oder aufzupipettieren, zu detektieren oder zu mixen, ohne die Temperiervorrichtung zu öffnen. Da hierbei der Deckel 3 geschlossen bleibt, bleibt auch das definierte Raumklima in der Temperiervorrichtung erhalten. Der Arbeitsgang des Entnehmens und gegebenenfalls Wiedereinsetzens in die Temperiervorrichtung entfällt. Darüber hinaus ist es mit einer erfindungsgemäßen Temperiervorrichtung möglich, ohne zusätzliche Mittel abzupipettieren, was an späterer Stelle erläutert wird. Die Kappe 1.3 weist vorteilhaft einen Schraubverschluss auf und ist mit einem Septum gefüllt.With a temperature control device according to the invention, which is a thermal cycler in connection with the PCR, it is possible to insert a cannula, a detection probe, a mixing stick, a pipette tip or the like through the lid 3 of the temperature control device and through the cap 1.3 of the reaction vessel 1 and so on e.g. B. pipette off or on, detect or mix the sample without opening the temperature control device. Since the cover 3 remains closed, the defined room climate is also maintained in the temperature control device. The removal and, if necessary, reinstallation in the Temperature control device is not required. In addition, with a temperature control device according to the invention, it is possible to pipette off without additional means, which will be explained later. The cap 1.3 advantageously has a screw cap and is filled with a septum.

Um ein Auf- und Abpipettieren bei geschlossener Temperiervorrichtung durchführen zu können, ist es erfindungswesentlich, dass der Deckel 3 ein Loch 3.3 aufweist. Ein solches Loch 3.3 im Deckel 3 vorzusehen, wird auf unkomplizierte Weise möglich, da der Deckel 3 erfindungsgemäß keine Heizung aufweist, sondern durch Wärmeleitung über den Heizkörper 4 erwärmt wird, mit dem er über den Kontaktbereich 5 bei geschlossener Temperiervorrichtung in Kontakt steht. Die Erwärmung des Deckels 3 erfolgt somit nicht durch eine aktive Beheizung sondern passiv über Wärmeleitung. Da der Deckel 3 wenigstens über den Bereich des Loches 3.3 an der Kappe 1.3 anliegt, ist der Innenraum 2 der Temperiervorrichtung trotz des Loches 3.3 geschlossen.In order to be able to carry out a pipetting up and down with the temperature control device closed, it is essential to the invention that the lid 3 has a hole 3.3. Providing such a hole 3.3 in the cover 3 is possible in an uncomplicated manner, since the cover 3 according to the invention has no heating, but is heated by heat conduction via the heating element 4, with which it is in contact via the contact area 5 when the temperature control device is closed. The lid 3 is therefore not heated by active heating, but passively via heat conduction. Since the cover 3 bears on the cap 1.3 at least over the area of the hole 3.3, the interior 2 of the temperature control device is closed despite the hole 3.3.

Der Kontaktbereich 5 wird durch eine an dem Heizkörper 4 ausgebildete Heizkörperaußenfläche 4.1 und eine an dem Deckel 3 ausgebildete Deckelaußenfläche 3.1 gebildet. In einfachster Form sind die Heizkörperaußenfläche 4.1 und die Deckelaußenfläche 3.1 ringförmig und in einer radialen Ebene zur Symmetrieachse 1.0 angeordnet. Um den Kontaktbereich 5 für eine bessere Wärmeleitung größer auszubilden, können die Heizkörperaußenfläche 4.1 und die Deckelaußenfläche 3.1 kegelmantelförmig sein. Je größer der Kegelwinkel gewählt wird, desto größer wird der Kontaktbereich 5, bei ansonsten gleichen Abmaßen der Temperiervorrichtung. Für ein einfaches Verschließen des Innenraumes 2 der Temperiervorrichtung mit dem Deckel 3 kann die Heizkörperaußenfläche 4.1 innerhalb der Deckelaußenfläche 3.1 angeordnet sein.The contact area 5 is formed by an outer surface 4.1 of the heater formed on the radiator 4 and an outer surface 3.1 formed on the cover 3. In the simplest form, the outer surface 4.1 of the radiator and the outer surface 3.1 of the cover are arranged in a ring and in a radial plane to the axis of symmetry 1.0. In order to make the contact area 5 larger for better heat conduction, the outer surface 4.1 of the radiator and the outer surface 3.1 of the cover may be conical. The larger the cone angle is selected, the larger the contact area 5 becomes, with otherwise the same dimensions of the temperature control device. For a simple closing of the interior 2 of the temperature control device with the cover 3, the outer surface 4.1 of the radiator can be arranged inside the outer surface 3.1 of the cover.

Der Heizkörper 4 hat nicht nur die Aufgabe, den Deckel 3 zu beheizen, sondern soll auch den Hohlkörper 1.1 des Reaktionsgefäßes 1 und damit das Gasvolumen des Reaktionsgefäßes 1, welches sich zwangsläufig oberhalb der Probe 8 befindet, beheizen. Auf diese Weise wird primär auch eine Kondensation an der Innenwand des Hohlkörpers 1.1 vermieden. Weiterhin kann durch die Veränderung der Temperatur der Druck des Gasvolumens verändert werden, was als sogenannter thermopneumatischer Effekt vielfach in der Fluidik genutzt wird. Eine Manipulation (Abpipettieren, Aliquotieren, Mischen) der Probe ist damit auch ohne Pumpe möglich [ Keller, M.; Focke, M.; Strohmeier, O.; Reith, P.; Roth, G.; Mark, D.; Zengerle, R.; von Stetten, F.: "Zentrifugo-thermopneumatisches Aliquotieren auf der LabDisk und Anwendung zum DNA-basierten Nachweis verschiedener Bakterien"; in: Mikrosystemtechnik Kongress 2013, Aachen, 14. -16.10.2013, S. 31 - 34 ].The radiator 4 not only has the task of heating the lid 3, but is also intended to heat the hollow body 1.1 of the reaction vessel 1 and thus the gas volume of the reaction vessel 1, which is inevitably located above the sample 8. In this way, condensation on the inner wall of the hollow body 1.1 is primarily avoided. Furthermore, the pressure of the gas volume can be changed by changing the temperature, which is often used as a so-called thermopneumatic effect in fluidics. A manipulation (pipetting off, Aliquoting, mixing) of the sample is also possible without a pump [ Keller, M .; Focke, M .; Strohmeier, O .; Reith, P .; Roth, G .; Mark, D .; Zengerle, R .; von Stetten, F .: "Centrifugal-thermopneumatic aliquoting on the LabDisk and application for DNA-based detection of various bacteria"; in: Microsystem Technology Congress 2013, Aachen, October 14-16, 2013, pp. 31 - 34 ].

Beim Einführen einer Kanüle in die Probe 8 wird diese unter Ausdehnung des Gasvolumens in die Kanüle gedrängt. Dazu muss die Kanüle während des Einführens am äußeren ersten Ende verschlossen sein, bis das innere zweite Ende mit der Probe 8 in Kontakt steht. Wird dann das erste Ende geöffnet, kann sich das Gasvolumen ausdehnen, indem die Probe 8 in der Kanüle aufsteigt, bis sich im Gasvolumen ein Normaldruck einstellt bzw. die Probe 8 vollständig aufgenommen ist. Der den Hohlkörper 1.1 umschließende Heizkörper 4 ermöglicht somit nicht nur die Verwendung eines passiv beheizten Deckels 3 sondern auch eine quasi passive Entnahme der Probe 8.When a cannula is inserted into the sample 8, it is pushed into the cannula while expanding the gas volume. For this purpose, the cannula must be closed at the outer first end during insertion until the inner second end is in contact with the sample 8. If the first end is then opened, the gas volume can expand in that the sample 8 rises in the cannula until a normal pressure is established in the gas volume or the sample 8 is completely absorbed. The heater 4 enclosing the hollow body 1.1 thus not only enables the use of a passively heated cover 3 but also a quasi-passive removal of the sample 8.

Der Heizkörper 4 kann ein rohrförmiger Körper sein oder aber vorteilhaft aus wenigstens zwei zur Symmetrieachse 1.0 symmetrisch angeordneten Heizkörperschalen 4.2 bestehen, wobei genau zwei Heizkörperschalen 4.2 in Form von Halbschalen vorteilhaft sind. Während ein rohrförmiger Heizkörper 4 ortsfest innerhalb des Innenraumes 2 zur Symmetrieachse 1.0 angeordnet ist, sind bei einer Ausführung des Heizkörpers 4 als zwei Heizkörperschalen 4.2 die beiden Heizkörperschalen 4.2 zur Symmetrieachse 1.0 radial elastisch über wenigstens ein Federelement 6 im Innenraum 2 gelagert und werden über wenigstens einen elastischen Ring 11 zusammengehalten.The radiator 4 can be a tubular body or advantageously consist of at least two radiator shells 4.2 arranged symmetrically with respect to the axis of symmetry 1.0, with exactly two radiator shells 4.2 in the form of half-shells being advantageous. While a tubular heating element 4 is arranged in a fixed position within the interior 2 with respect to the axis of symmetry 1.0, in one embodiment of the heating element 4 as two element shells 4.2 the two element shells 4.2 with respect to the axis of symmetry 1.0 are mounted radially elastically via at least one spring element 6 in the interior 2 and are supported via at least one elastic ring 11 held together.

Üblicherweise und auch vorteilhaft stellt der Hohlkörper 1.1 des Reaktionsgefäßes 1 einen Kegelmantel mit einem kleinen Kegelwinkel dar, sodass mit dem Einführen des Reaktionsgefäßes 1 in die Temperiervorrichtung und damit zwischen die Heizkörperschalen 4.2 diese zunehmend auseinander gedrückt werden, wobei eine zunehmend große Rückstellkraft auf die Heizkörperschalen 4.2 wirkt, welche für ein Anschmiegen der Heizkörperschalen 4.2 an den Hohlkörper 1.1 sorgt. Diese Rückstellkraft wird durch die Elastizität und die Federkennlinie des wenigstens einen elastischen Ringes 11, z.B. einem Gummiring und des wenigstens einen Federelements 6 beeinflusst.Usually and also advantageously, the hollow body 1.1 of the reaction vessel 1 is a conical jacket with a small cone angle, so that when the reaction vessel 1 is introduced into the temperature control device and thus between the radiator shells 4.2, the latter are increasingly pressed apart, with an increasingly large restoring force on the radiator shells 4.2 acts, which ensures that the radiator shells 4.2 nestle against the hollow body 1.1. This restoring force is determined by the elasticity and the spring characteristic of the at least one elastic ring 11, for example a rubber ring and the at least one spring element 6 influenced.

Im Falle der Ausführung des Heizkörpers 4 als zwei Heizkörperschalen 4.2 kann der Deckel 3 vorteilhaft ebenfalls aus zwei Deckelschalen 3.2, vorteilhaft in Form von Halbschalen gefertigt sein. Vorteilhaft sind hierfür die Deckelaußenfläche 3.1 und die Heizkörperaußenfläche 4.1, wie in Fig. 1a gezeigt, kegelmantelförmig. Beim Schließen des Deckels 3 werden dann die Deckelschalen 3.2 auseinandergespreizt und die Deckelaußenflächen 3.1 durch Rückstellkräfte gegen die Heizkörperaußenflächen 4.1 gepresst. In dem in Fig. 1a gezeigten Ausführungsbeispiel werden die Rückstellkräfte durch eine die Deckelschalen 3.2 umschließende Spiralfeder 10 erzeugt.In the case of the design of the radiator 4 as two radiator shells 4.2, the cover 3 can advantageously also be made from two cover shells 3.2, advantageously in the form of half-shells. The lid outer surface 3.1 and the radiator outer surface 4.1, as in FIG Fig. 1a shown, cone-shaped. When the lid 3 is closed, the lid shells 3.2 are then spread apart and the lid outer surfaces 3.1 are pressed against the outer heater surfaces 4.1 by restoring forces. In the in Fig. 1a In the embodiment shown, the restoring forces are generated by a spiral spring 10 enclosing the cover shells 3.2.

Ist der Deckel 3 aus einem Stück gefertigt, dann bleibt die Deckelaußenfläche 3.1 gegenüber der Symmetrieachse 1.0 fest positioniert, während sich die Position der Heizkörperaußenfläche 4.1 radial zur Symmetrieachse 1.0 verlagert.If the cover 3 is made from one piece, then the cover outer surface 3.1 remains firmly positioned with respect to the symmetry axis 1.0, while the position of the radiator outer surface 4.1 shifts radially to the symmetry axis 1.0.

Im Falle der Ausführung der Deckelaußenfläche 3.1 und der Heizkörperaußenfläche 4.1 als Ringflächen wird dadurch nur der Kontaktbereich 5 verkleinert. Im Falle einer kegelmantelförmigen Ausführung der Deckelaußenfläche 3.1 und der Heizkörperaußenfläche 4.1 wird die Deckelaußenfläche 3.1 in axialer Richtung der Symmetrieachse 1.0 in Abhängigkeit davon, wie weit die Heizkörperschalen 4.2 auseinander gespreizt sind, in einer unterschiedlichen Höhe auf die Heizkörperaußenfläche 4.1 aufgesetzt, weshalb der Deckel 3 in der Abdeckung 9 axial gefedert gelagert ist.If the outer surface 3.1 of the cover and the outer surface 4.1 of the radiator are designed as ring surfaces, only the contact area 5 is thereby reduced. In the case of a cone-shaped design of the outer cover surface 3.1 and the outer surface of the radiator 4.1, the outer surface 3.1 of the cover is placed on the outer surface 4.1 of the radiator at a different height in the axial direction of the axis of symmetry 1.0, depending on how far apart the radiator shells 4.2 are, which is why the cover 3 in the cover 9 is mounted axially sprung.

BezugszeichenlisteReference list

11
ReaktionsgefäßReaction vessel
1.01.0
SymmetrieachseAxis of symmetry
1.11.1
HohlkörperHollow body
1.21.2
Bodenground
1.31.3
Kappecap
22nd
Innenrauminner space
33rd
Deckelcover
3.13.1
DeckelaußenflächeLid outer surface
3.23.2
DeckelschaleLid shell
3.33.3
Lochhole
44th
Heizkörperradiator
4.14.1
HeizkörperaußenflächeRadiator outer surface
4.24.2
HeizkörperschaleRadiator shell
55
KontaktbereichContact area
66
FederelementSpring element
77
HeizblockHeating block
7.17.1
InnenflächeInner surface
88th
Probesample
99
Abdeckungcover
1010th
SpiralfederCoil spring
1111
elastischer Ringelastic ring

Claims (6)

  1. Temperature-control device with a reaction vessel (1), with a thermally insulated interior area (2) in which the reaction vessel (1) is accommodated, and with a cover (3), which covers the interior area (2), wherein the reaction vessel (1) consists of a hollow body (1.1) and a cap (1.3), said hollow body being closed on one side with a floor (1.2) and being symmetrical in relation to a symmetrical axis (1.0), and wherein a heating block (7) is provided in the interior area (2), said heating block having an interior surface (7.1), which is adapted to the floor (1.2) of the reaction vessel (1) and is in contact with said vessel in order to heat a sample (8) located in the reaction vessel (1), wherein the cover (3) is made from a thermally conductive material, and wherein the temperature-control device has a thermally insulating enclosure (9) by which the cover (3) is covered, and wherein the cover (3) rests on the cap (3.1), characterized in that a heatable heater (4) that surrounds the hollow body (1.1) and is adapted to its shape is provided, wherein the heater is in contact with the cover (3) via a thermally conductive contact zone (5) in such a way that the heater (4) directly heats the hollow body (1.1) and indirectly heats the cap (1.3) via the cover (3), and wherein the cover (3) has a hole (3.3) via which a tube can be introduced into the hollow body (1.1) through the cap (1.3).
  2. Temperature-control device as claimed in Claim 1, characterized in that the contact zone (5) is formed by a heater outer surface (4.1) in the shape of a lateral surface of a cone formed on the heater (4), and a cover outer surface (3.1) in the shape of a lateral surface of a cone formed on the cover (3).
  3. Temperature-control device as claimed in Claim 2, characterized in that the heater outer surface (4.1) is arranged on the interior.
  4. Temperature-control device as claimed in one of the previous claims, characterized in that the heater (4) at least consists of two heater shells (4.2) symmetrically arranged in relation to the symmetrical axis (1.0), and the heater shells (4.2) are mounted in the interior area (2) via at least one spring element (6) in such a way that the heater shells (4.2) are applied on the hollow body (1.1) with a restoring force of the at least one spring element (6).
  5. Temperature-control device as claimed in Claim 4, characterized in that the heater shells (4.2) are kept together via at least an elastic ring (11).
  6. Temperature-control device as claimed in Claim 5, characterized in that the cover (3) consists of two cover shells (3.2), which are mounted in an elastic manner in relation to one another.
EP16816179.2A 2015-12-08 2016-12-05 Temperature-control device having a reaction vessel Active EP3386637B1 (en)

Applications Claiming Priority (2)

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DE102015121362.1A DE102015121362B4 (en) 2015-12-08 2015-12-08 Temperature control device with a reaction vessel
PCT/DE2016/100567 WO2017097289A1 (en) 2015-12-08 2016-12-05 Temperature-control device having a reaction vessel

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EP3386637A1 EP3386637A1 (en) 2018-10-17
EP3386637B1 true EP3386637B1 (en) 2020-04-15

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KR102423452B1 (en) * 2017-09-19 2022-07-20 제네리치 바이오테크놀로지 코포레이션 Heating apparatus of biochemical reaction device
CN111939994A (en) * 2019-05-14 2020-11-17 重庆好德译信息技术有限公司 Heat preservation type effusion censorship test tube for endocrinology department and heat preservation method thereof
CN112756030A (en) * 2021-01-12 2021-05-07 许昌学院 Heating device for calorifics is experimental
CN116179333B (en) * 2023-04-19 2023-07-04 鲲鹏基因（北京）科技有限责任公司 Temperature-controlled amplification device and PCR instrument

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CA2130013C (en) 1993-09-10 1999-03-30 Rolf Moser Apparatus for automatic performance of temperature cycles
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EP3386637A1 (en) 2018-10-17
DE102015121362A1 (en) 2017-06-08
US20180361387A1 (en) 2018-12-20
WO2017097289A1 (en) 2017-06-15
DE102015121362B4 (en) 2018-05-24
US10898901B2 (en) 2021-01-26
CN108348916B (en) 2021-03-09
CN108348916A (en) 2018-07-31

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