EP2647435B1 - System with a fluidic cell and a tempering element - Google Patents
System with a fluidic cell and a tempering element Download PDFInfo
- Publication number
- EP2647435B1 EP2647435B1 EP12163321.8A EP12163321A EP2647435B1 EP 2647435 B1 EP2647435 B1 EP 2647435B1 EP 12163321 A EP12163321 A EP 12163321A EP 2647435 B1 EP2647435 B1 EP 2647435B1
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- temperature
- temperature control
- composite film
- fluid
- film
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- 238000005496 tempering Methods 0.000 title description 4
- 239000010408 film Substances 0.000 claims description 102
- 239000002131 composite material Substances 0.000 claims description 52
- 239000012530 fluid Substances 0.000 claims description 46
- 239000000758 substrate Substances 0.000 claims description 34
- 229920003023 plastic Polymers 0.000 claims description 15
- 239000004033 plastic Substances 0.000 claims description 15
- 229910052751 metal Inorganic materials 0.000 claims description 13
- 239000002184 metal Substances 0.000 claims description 13
- 238000003860 storage Methods 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 230000003321 amplification Effects 0.000 claims description 5
- 238000003199 nucleic acid amplification method Methods 0.000 claims description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 229920000098 polyolefin Polymers 0.000 claims description 2
- 239000010409 thin film Substances 0.000 claims description 2
- 239000004411 aluminium Substances 0.000 claims 1
- 230000005540 biological transmission Effects 0.000 claims 1
- 230000002093 peripheral effect Effects 0.000 claims 1
- 238000000034 method Methods 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- 238000003825 pressing Methods 0.000 description 4
- 238000003466 welding Methods 0.000 description 4
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 238000004026 adhesive bonding Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 239000013039 cover film Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001746 injection moulding Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Images
Classifications
-
- 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
-
- 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
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
- B01L3/502707—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the manufacture of the container or its components
-
- 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
-
- 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
- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
- B01L2200/06—Fluid handling related problems
- B01L2200/0684—Venting, avoiding backpressure, avoid gas bubbles
-
- 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
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0809—Geometry, shape and general structure rectangular shaped
- B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
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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
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
- B01L2300/0877—Flow chambers
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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
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0887—Laminated structure
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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
- 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
- B01L2300/1822—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks using Peltier elements
-
- 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
- B01L2300/1838—Means for temperature control using fluid heat transfer medium
- B01L2300/185—Means for temperature control using fluid heat transfer medium using a liquid as fluid
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T137/00—Fluid handling
- Y10T137/6416—With heating or cooling of the system
- Y10T137/6579—Circulating fluid in heat exchange relationship
Description
Die Erfindung betrifft eine Anordnung aus einer Flusszelle und einem Temperierelement gemäß Anspruch 1.The invention relates to an arrangement of a flow cell and a temperature control element according to
Mikrofluidische Flusszellen werden, insbesondere als Einwegprodukte, in zunehmendem Maße in der Analytik und Diagnostik oder in der Medizin zur Konditionierung von Flüssigkeiten, bevor sie in den menschlichen Körper appliziert werden, sowie auch zu Synthesezwecken eingesetzt.Microfluidic flow cells are used increasingly, in particular as disposable products, in analysis and diagnostics or in medicine for the conditioning of liquids before they are applied to the human body, and also for synthetic purposes.
Während sich die Funktion einer Flusszelle in der Temperierung eines Fluids erschöpfen kann, bilden Temperiereinrichtungen häufig nur Bestandteile von Flusszellen mit weitaus umfangreicherer Funktionalität. Insbesondere in Flusszellen zur Durchführung molekulargenetischer Analysen einschließlich von PCR- oder anderer Nukleinsäure amplifizierender Prozessen ist die Temperierfunktion von großer Bedeutung, indem die Amplifikationsreaktion konstante oder wechselnde, über der Umgebungstemperatur liegende Reaktionstemperaturen, typischerweise zwischen 30°C und 95°C, erfordert. Die Herstellung temperaturbeständiger Flusszellen mit reproduzierbaren Temperierungseigenschaften, welche einen besonders schnellen und homogenen Temperaturübergang zwischen einem aktiven Temperierelement und dem zu temperierenden Fluid erlauben, insbesondere die Herstellung solcher Flusszellen als preiswerte Einwegprodukte, stellt die Fertigung vor erhebliche Probleme.While the function of a flow cell in the temperature control of a fluid can be exhausted, temperature control devices often only form components of flow cells with far more extensive functionality. The temperature control function is particularly important in flow cells for carrying out molecular genetic analyzes, including processes that amplify PCR or other nucleic acids, since the amplification reaction requires constant or changing reaction temperatures, typically between 30 ° C. and 95 ° C., which are above ambient temperature. The production of temperature-resistant flow cells with reproducible temperature control properties, which allow a particularly rapid and homogeneous temperature transition between an active temperature control element and the fluid to be temperature-controlled, in particular the production of such flow cells as inexpensive disposable products, poses considerable problems for production.
Eine Flusszelle mit einer Temperiereinrichtung ist aus der
Anordnungen der eingangs erwähnten Art mit einer eine Metallschicht aufweisenden Verbundfolie gehen aus der
Flusszellen mit Temperierkammern und Temperierelemente umfassende Anordnungen gehen aus der
Die Metallschicht der Folie sorgt aufgrund ihrer hohen, im Vergleich zum Kunststoff typischerweise ca. 1000fach höheren Wärmeleitfähigkeit für eine schnelle Wärmeausbreitung auch lateral, d.h. parallel zur Folienebene. Selbst bei nur teilweisem Anliegen eines Temperierelements an der Folie nimmt die Folie daher ausreichend schnell und gleichmäßig die Temperatur des Temperierelements an und überträgt sie weiter auf das Fluid. Fertigungsbedingte Schwankungen der Größe der Kontaktfläche zwischen Temperierelement und Folie fallen nicht ins Gewicht.Due to its high thermal conductivity, which is typically approx. 1000 times higher than that of plastic, the metal layer of the film also ensures rapid heat spreading laterally, ie parallel to the film plane. Even if a temperature control element is only partially in contact with the film, the film therefore assumes the temperature of the temperature control element sufficiently quickly and uniformly and transfers it further to the fluid. Production-related fluctuations in the size of the contact surface between the temperature control element and the film are negligible.
In einer bevorzugten Ausführungsform der Erfindung besteht die dem Fluid zugewandte Kunststoffschicht aus einem mit der Amplifikationsreaktion kompatiblen Kunststoff, vorzugsweise einem Olefinpolymer, wie PP, PE, COC oder PC.In a preferred embodiment of the invention, the plastic layer facing the fluid consists of a plastic compatible with the amplification reaction, preferably an olefin polymer such as PP, PE, COC or PC.
Die wenigstens eine Metallschicht weist vorzugsweise Aluminium oder ein magnetisierbares Metall, wie z.B. Nickel, auf. In letzterem Fall lässt sich durch Magnetkraft die Anhaftung eines Temperierelements an der Folie und damit der Wärmeübergang zwischen dem Temperierelement und der Folie verbessern.The at least one metal layer preferably comprises aluminum or a magnetizable metal, e.g. Nickel, on. In the latter case, the adhesion of a temperature control element to the film and thus the heat transfer between the temperature control element and the film can be improved by magnetic force.
Auch die dem Temperierelement zugewandte Folienschicht der Verbundfolie kann aus einem Kunststoff bestehen, insbesondere demjenigen Kunststoff, aus dem auch die dem Fluid zugewandte Schicht hergestellt ist. Zweckmäßig besteht die dem Temperierelement zugewandte Schicht aus einem Material, das einer Klebeanhaftung der Folie am Temperierelement entgegenwirkt.The film layer of the composite film facing the temperature control element can also consist of a plastic, in particular the plastic from which the layer facing the fluid is also made. The layer facing the temperature control element expediently consists of a material which counteracts adhesive adhesion of the film to the temperature control element.
In der bevorzugten Ausführungsform der Erfindung liegt die Dicke der die Folie bildenden Schichten jeweils zwischen 1 µm und 100 µm.In the preferred embodiment of the invention, the thickness of the layers forming the film is in each case between 1 μm and 100 μm.
Während es möglich wäre, die Temperierkammer ausschließlich aus der dünnen Verbundfolie herzustellen, beispielsweise durch zwei in entgegengesetzten Richtungen tiefgezogene, miteinander verschweißte oder verklebte Folienteile oder ein tiefgezogenes Folienteil verschweißt mit einem ebenen unverformten Folienteil, ist gemäß der Erfindung die Temperierkammer durch eine mit der Verbundfolie abgedeckte Ausnehmung in einem bevorzugt unter preiswertem Spritzgießen hergestellten Substrat gebildet und die Verbundfolie mit dem Substrat verbunden, vorzugsweise verschweißt oder verklebt.While it would be possible to produce the temperature control chamber exclusively from the thin composite film, for example by means of two film parts that are thermoformed, welded or glued in opposite directions, or a thermoformed film part is welded to a flat, undeformed film part, according to the invention the temperature control chamber is covered by a film that is covered with the composite film Recess is formed in a substrate, which is preferably produced using inexpensive injection molding, and the composite film is connected to the substrate, preferably welded or glued.
Vorzugsweise ist die Folie mit einer ebenen, an die Ausnehmung grenzenden Oberfläche des Substrats verbunden.The film is preferably connected to a flat surface of the substrate bordering the recess.
Das Substrat kann aus dem gleichen Kunststoff wie die dem Fluid zugewandte Schicht der Verbundfolie bestehen und somit die gesamte Temperierkammer aus nur einem Material gebildet sein, welches mit den zu temperierenden Fluiden kompatibel ist.The substrate can consist of the same plastic as the layer of the composite film facing the fluid and the entire temperature control chamber can thus be formed from only one material which is compatible with the fluids to be temperature-controlled.
Gemäß der Erfindung weist das Temperierelement einen festen, zur Wärmeübertragung gegen die Verbundfolie anlegbaren Temperierkörper auf.According to the invention, the temperature control element has a fixed temperature control body that can be placed against the composite film for heat transfer.
Das Temperierelement kann gemäß der Erfindung nur in einem an die Temperierkammer angrenzenden Randbereich, in dem die Verbundfolie z.B. mit der Oberfläche des Substrats verbunden ist, anliegen. Zweckmäßig ist die Folie in dem Randbereich derart abgestützt, dass das Temperierelement unter hohem Anpressdruck an die Folie anlegbar ist. Ist die Temperierkammer während der Temperierung hermetisch abgeschlossen, so hat das Anlegen des Temperierelements nur an einen Teil der die Temperierkammer bildenden Verbundfolie den Vorteil, dass ein durch Erwärmung und damit verbundene Ausdehnung des Fluids in der Kammer erzeugter Druckaufbau durch eine Ausdehnung der Verbundfolie und die damit einhergehende Vergrößerung des Volumens der Temperierkammer wenigstens teilweise kompensiert werden kann. Der dadurch verhinderte Druckaufbau in der Temperierkammer verringert wiederum die Anforderungen an Ventile die ggf. für einen hermetischen Abschluss der Kammer notwendig sind.According to the invention, the temperature control element can only be used in an edge area adjacent to the temperature control chamber, in which the composite film e.g. is connected to the surface of the substrate. The film is expediently supported in the edge region in such a way that the temperature control element can be applied to the film under high contact pressure. If the temperature control chamber is hermetically sealed during temperature control, the application of the temperature control element to only a part of the composite film forming the temperature control chamber has the advantage that a pressure build-up generated by heating and the associated expansion of the fluid in the chamber due to expansion of the composite film and thus accompanying increase in the volume of the temperature control chamber can be at least partially compensated for. The pressure build-up prevented in the temperature control chamber in turn reduces the valve requirements which may be necessary for a hermetic seal of the chamber.
In weiterer Ausgestaltung der Erfindung können Einrichtungen zum Ansaugen der Verbundfolie an den Temperierkörper gebildet sein. Durch festeren Andruck des Temperierkörpers gegen die Folie verbessert sich der Wärmekontakt. Besitzt die Verbundfolie eine magnetisierbare Metallschicht, kann der Temperierkörper mit einem Dauer- oder Elektromagneten versehen sein, um den Andruck des Temperierkörpers gegen die Folie durch magnetischer Wechselwirkung zu verbessern.
In einer Ausführungsform der Erfindung ist die Verbundfolie unter Vergrößerung ihrer das Fluid kontaktierenden Oberfläche tiefgezogen.In a further embodiment of the invention, devices for sucking the composite film onto the temperature control body can be formed. The thermal contact is improved by pressing the temperature control body against the film. If the composite film has a magnetizable metal layer, the temperature control body can be provided with a permanent magnet or electromagnet in order to improve the pressure of the temperature control body against the film by magnetic interaction.
In one embodiment of the invention, the composite film is deep-drawn while increasing its surface contacting the fluid.
Die Verbundfolie kann innerhalb der Flusszelle weitere Funktionen erfüllen, z.B. Abdeckfunktionen oder eine Ventilfunktion.The composite film can perform further functions within the flow cell, for example covering functions or a valve function.
Es versteht sich, dass die Flusszelle mit der Temperierkammer einen Zu- und Abfluss für das Fluid, ggf. zum Durchfluss des Fluids durch die Kammer während der Temperierung, aufweisen kann. Ebenso kann die Flusszelle ferner Kanalstrukturen, Misch- und Verteilerelemente für die Fluide, Flüssigkeitsspeicher, Reaktions- und Detektionskammern und dergleichen Elemente aufweisen, welche nach dem Stand der Technik für die Durchführung von Analysen und Synthesen in mikrofluidischen Flusszellen gebräuchlich sind. Zweckmäßig erstreckt sich die Verbundfolie nur über den Teilbereich der Flusszelle, welcher die Temperierkammer beinhaltet, um zu sichern, dass während des Temperierprozesses keine oder wenig Wärme in die übrigen Bereiche der Flusszelle abfließt.It goes without saying that the flow cell with the temperature control chamber can have an inflow and outflow for the fluid, possibly for the flow of the fluid through the chamber during the temperature control. Likewise, the flow cell can also have channel structures, mixing and distribution elements for the fluids, liquid storage, reaction and detection chambers and the like elements which are customary in the prior art for carrying out analyzes and syntheses in microfluidic flow cells. The composite film expediently extends only over the partial area of the flow cell which contains the temperature control chamber in order to ensure that little or no heat flows into the other areas of the flow cell during the temperature control process.
Da das Temperieren eines Fluids in einer Temperierkammer immer mit einer Veränderung des Volumens des Fluids verbunden ist, kann es vorteilhaft sein, dass sich die Temperierkammer während des Temperierprozesses hermetisch gegenüber angrenzenden Kanal- oder/und Funktionsbereichen verschließen lässt. Dies kann insbesondere bei Erwärmungen bis nahe an die Siedetemperatur des Fluids erforderlich sein. Dadurch wird ein aus Volumenänderung und/oder partieller Dampfbildung resultierender Abgang des Fluids aus der Temperierkammer unterbunden. Durch Lösbarkeit des Verschlusses kann das Fluid nach dem Temperierprozess weitertransportiert, -verarbeitet oder, wie z.B. bei molekulargenetischen Analysen, analysiert werden. Zum Verschließen ist es vorteilhaft, im kanalförmigen Zu- und Abfluss der Temperierkammer einen Ventilsitz zu bilden, wobei im Bereich des Ventilsitzes die Verbundfolie nicht fest mit dem Substrat verbunden ist, sondern lose und eben am Substrat anliegt. Die Dehnbarkeit der Verbundfolie erlaubt es, dass ein Fluid unter Druck vor oder nach dem Temperierprozess zwischen dem Ventilsitz und der Verbundfolie hindurchtreten und in die Kammer oder aus der Kammer heraustransportiert werden kann. Während der Temperierung werden der Zu- und Ablauf hermetisch verschlossen, indem mechanische Stempel einer externen Aktuierungseinrichtung an die im Bereich der Ventilsitze an dem Substrat anliegende Verbundfolie angedrückt werden.Since the temperature control of a fluid in a temperature control chamber is always associated with a change in the volume of the fluid, it can be advantageous for the temperature control chamber to be hermetically sealed against adjacent channel and / or functional areas during the temperature control process. This may be necessary especially when heating up to close to the boiling point of the fluid. This prevents the fluid from leaving the temperature control chamber resulting from a change in volume and / or partial vapor formation. Due to the releasability of the closure, the fluid can be transported, processed or, e.g. in molecular genetic analyzes. To close it, it is advantageous to form a valve seat in the channel-shaped inflow and outflow of the temperature control chamber, the composite film not being firmly connected to the substrate in the region of the valve seat, but lying loosely and evenly on the substrate. The extensibility of the composite film allows a fluid to pass under pressure before or after the tempering process between the valve seat and the composite film and to be transported into or out of the chamber. During the temperature control, the inlet and outlet are hermetically sealed by pressing mechanical stamps of an external actuation device against the composite film lying on the substrate in the region of the valve seats.
Die erfindungsgemäße Temperierkammer kann ferner als Flüssigkeitsspeicher dienen, um z.B. ein Reagenz vor dessen Verwendung in der Flusszelle zu speichern. Das Volumen der gespeicherten Reagenz kann dabei kleiner als das der Temperier- und Speicherkammer sein, sodass die Kammer z.B. vor einer Temperierung noch mit einem zu analysierenden und mit dem Reagenz zu mischenden Fluid vollständig oder teilweise aufgefüllt werden kann. Bei Nutzung der Temperierkammer als Speicherkammer kann vorteilhaft ein kanalförmiger Zu- und Abfluss der Temperierkammer geometrisch unterbrochen und im unterbrochenen Kanalbereich die Verbundfolie fest mit dem Substrat z.B. durch Schweißen unter Bildung einer den Kanal verschließenden Siegelnaht verbunden werden. Nach Öffnen der Siegelnaht lassen sich die Fluide mittels Druck in die Kammer hinein- und aus dieser heraustransportieren und die Verschlussstellen fortan als Ventile nutzen. Die Metallschicht in der die Speicherkammer begrenzenden Verbundfolie verhindert einen Flüssigkeits- oder Gasdurchtritt durch die Kammerwand während der Lagerung.The temperature control chamber according to the invention can also serve as a liquid store, for example to store a reagent in the flow cell before it is used. The volume of the stored reagent can be smaller than that of the tempering and storage chamber, so that the chamber, for example, before or with a fluid to be analyzed and mixed with the reagent completely or can be partially replenished. When the temperature control chamber is used as a storage chamber, a channel-shaped inflow and outflow of the temperature control chamber can advantageously be geometrically interrupted and the composite film can be firmly connected to the substrate in the interrupted channel area, for example by welding to form a sealing seam closing the channel. After opening the sealing seam, the fluids can be transported into and out of the chamber by means of pressure, and the closure points can then be used as valves. The metal layer in the composite film delimiting the storage chamber prevents liquid or gas from passing through the chamber wall during storage.
Die Erfindung wird nachfolgend anhand von Ausführungsbeispielen und der beiliegenden, sich auf diese Ausführungsbeispiele beziehenden Zeichnungen weiter erläutert. Es zeigen:
- Fig. 1
- einen Ausschnitt aus einer eine Temperierkammer aufweisenden Flusszelle,
- Fig. 2
- die Flusszelle von
Fig. 1 mit einem angesetzten Temperierelement, - Fig. 3
- die Flusszelle von
Fig. 1 mit einem Ansaugkanäle aufweisenden Temperierelement, - Fig. 4
- eine Flusszelle mit einer tiefgezogen Folie und ein Temperierelement,
- Fig. 5
- eine weitere Flusszelle mit einer tiefgezogenen Folie,
- Fig. 6
- eine Flusszelle mit einer in eine Ausnehmung in einem Substrat hinein durch Temperierelemente dehnbaren Folie,
- Fig. 7
- eine Flusszelle mit einer aus zwei dehnbaren Verbundfolien durch Auslenkung eines Temperierelements gebildeten Temperierkammer,
- Fig. 8
- eine Flusszelle mit einer aus zwei dehnbaren Verbundfolien gebildeten Temperierkammer mit Temperierelementen auf einander gegenüberliegenden Seiten,
- Fig. 9
- eine Flusszelle gemäß
Fig. 1 mit einem ein Temperierfluid führenden Temperierelement, - Fig. 10
- eine Flusszelle mit sich an eine Temperierkammer anschließenden Ventilbereichen, und
- Fig. 11
- eine Flusszelle mit einer als Speicherkammer dienenden Temperierkammer.
- Fig. 1
- a section of a flow cell having a temperature control chamber,
- Fig. 2
- the flow cell of
Fig. 1 with an attached temperature control element, - Fig. 3
- the flow cell of
Fig. 1 with a temperature control element with suction channels, - Fig. 4
- a flow cell with a thermoformed film and a temperature control element,
- Fig. 5
- another flow cell with a thermoformed film,
- Fig. 6
- a flow cell with a film which can be stretched into a recess in a substrate by means of temperature control elements,
- Fig. 7
- a flow cell with a temperature chamber formed from two stretchable composite films by deflecting a temperature control element,
- Fig. 8
- a flow cell with a temperature chamber formed from two stretchable composite films with temperature elements on opposite sides,
- Fig. 9
- a flow cell according to
Fig. 1 with a temperature control element carrying a temperature control fluid, - Fig. 10
- a flow cell with valve regions adjoining a temperature control chamber, and
- Fig. 11
- a flow cell with a tempering chamber serving as a storage chamber.
Eine in
Durch eine Ausnehmung in dem Substrat 1 und der Folie 2, welche diese Ausnehmung abdeckt, ist eine ein Fluid aufnehmende Temperierkammer 3 gebildet. Die Temperierkammer 3 steht über Kanäle 4 und 5 mit je einem Ein-/ Auslass 6 bzw. 7 in Verbindung. Es versteht sich, dass die Temperierkammer hiervon abweichend mit anderen, in der Flusszelle zu anderen Zwecken vorgesehenen Kammern verbunden oder verbindbar sein könnte.A temperature-absorbing
Die Folie 2 besteht in dem gezeigten Ausführungsbeispiel aus einem Verbund mehrerer Schichten, einer Innenschicht 8 aus einem mit Amplifikationsreaktionen verträglichen Kunststoff, einer Metallschicht 9, in dem gezeigten Beispiel aus einer Schicht Aluminium, und einer Außenschicht 10, die wie die Innenschicht 8 aus Kunststoff besteht. Die Innenschicht 9 und das Substrat 1 können aus dem gleichen Material gebildet sein, was die fluiddichte Verschweißung der Folie 2 mit dem Substrat 1 erleichtert.In the exemplary embodiment shown, the
In den nachfolgenden
Um ein in der Temperierkammer 3 befindliches Fluid auf eine gewünschte, z.B. im Rahmen der Gesamtfunktion der Flusszelle erforderliche Reaktionstemperatur zu bringen, wird gemäß
Je nach gewünschter Fluidtemperatur kann es sich bei dem Temperierelement 11 um ein Heiz- oder Kühlelement handeln. In ersterem Fall geht Wärme vom Temperierelement 11 auf das Fluid in der Temperierkammer 3 über, im zweiten Fall fließt umgekehrt Wärme vom Fluid zum Temperierelement 11.Depending on the desired fluid temperature, the
Infolge hoher Flexibilität der dünnen Folie 2, deren Gesamtschichtdicke sich im Bereich zwischen 3 µm und 300 µm bewegt, kann das Temperierelement 11 an der Folie 2 nicht derart plan anliegen, dass sich ein über die gesamte Anlagefläche gleichmäßiger Wärmeübergang ergibt. Durch die hohe Wärmeleitfähigkeit der in der Folie 2 enthaltenen Metallschicht 9 jedoch, die vor allem zur Wärmeleitung in lateraler Richtung parallel zur Folienebene imstande ist, kommt es dennoch zu einem schnellen Wärmeaustausch zwischen dem Temperierelement 11 und dem Fluid in der Temperierkammer 3, wobei sich bei gleichmäßiger Erwärmung des Fluids dessen Temperatur der Temperatur des Temperierelements 11 angleicht.As a result of the high flexibility of the
Es versteht sich, dass das Fluid während der Temperierung in der Temperierkammer 3 stillstehen oder die Temperierkammer 3 mit einer den Temperaturausgleich zulassenden Geschwindigkeit durchströmen kann.It goes without saying that the fluid can stand still in the
Ein in
In den nachfolgenden Figuren sind gleiche oder gleichwirkende Teile mit derselben Bezugszahl wie in den vorangehenden Figuren bezeichnet, wobei der betreffenden Bezugszahl der Buchstabe a, b usw. beigefügt ist.In the following figures, parts that are the same or have the same function are designated with the same reference number as in the previous figures, the relevant reference number being accompanied by the letters a, b, etc.
Bei einem in
Auch ein in
Eine Anordnung aus dem Temperierelement 11d und weiteren Temperierelementen 11d' und 11d" lässt sich gemäß Pfeil 16 verschieben, sodass wahlweise eines der Temperierelemente 11d, 11d', 11d" gemäß Pfeil 17 unter Dehnung der Folie 2d bis an den Anschlag 15 ausfahrbar ist. Das Fluid lässt sich dann aufeinanderfolgend entsprechend Temperaturen T1, T2 und T3 der Temperierelemente 11d, 11d', 11d" unterschiedlich temperieren.An arrangement of the
Ein in
Außer in einem Bereich vor einer Durchgangsöffnung 25 in dem Substrat 24 und einer an diesen Bereich angrenzenden Umgebung sind die Verbundfolien 2e, 2e' auch miteinander durch Verschweißung oder Verklebung verbunden.In addition to an area in front of a through-opening 25 in the
Ein in der Durchgangsöffnung 25 gemäß Pfeil 17e bewegbares Temperierelement 11e, kann die Verbundfolien 2e, 2e' in der in
In die Temperierkammer 3e einmündende Zu- oder Abflüsse sind in
Aus
Einem gemäß Pfeil 17f bewegbaren Temperierelement 11f liegen zwei in entgegengesetzten Richtung bewegbare, an die Verbundfolie 2f' ansetzbare Temperierelemente 26 und 27 gegenüber. Während das Temperierelement 11f die gesamte, ihm zugewandte Seite der Temperierkammer 3f und angrenzende Bereiche abdeckt, liegen die Temperierelemente 26, 27 nur gegen an die Temperierkammer 3f angrenzende Bereiche an. Entsprechend wird Wärme lateral in die Temperierkammer geleitet. Der freie, durch die tiefgezogene Verformung 13f gebildete Bereich kann sich bei Druckaufbau in der Temperierkammer 3f unter teilweisem Ausgleich des Drucks ausdehnen.A temperature control element 11f which is movable according to
Ein Temperierelement 11g ist in dem gezeigten Ausführungsbeispiel jedoch nicht, wie bei den vorangehenden Ausführungsbeispielen, durch einen festen Temperierkörper gebildet, sondern umfasst eine symmetrisch zu der Temperierkammer 3g angeordnete Kammer 18 für die Aufnahme eines temperierenden Fluids. Die Kammer 18 befindet sich in einer Ausnehmung in einem Substrat 19, das mit der Verbundfolie 2g in gleicher Weise verbunden ist, wie das Substrat 1g. Die Kammer 18 nimmt ein auf einer bestimmten Temperatur gehaltenes Fluid auf, das in dem gezeigten Ausführungsbeispiel über einen Einlass 20 und einen Kanal 21 in die Kammer 18 hinein gelangt und über einen Kanal 22 und einen Auslass 23 abfließt. In dem gezeigten Ausführungsbeispiel bestehen das Substrat 1g und das Substrat 19 aus dem gleichen Material. Auch eine Innenschicht 8g der Folie 2g gleicht im Material der dem Substrat 19 zugewandten Außenschicht 10g.In the exemplary embodiment shown, however, a temperature control element 11g is not formed by a fixed temperature control body, as in the previous exemplary embodiments, but rather comprises a
Eine in
Ein Temperierelement 11 h weist in der Mitte seiner gegen die Folie 2h anlegbaren Temperierfläche eine Ausnehmung 32 auf, in die hinein sich während einer Temperierung die Verbundfolie 2h bei in der Temperierkammer 3h steigendem Innendruck ausdehnen kann.A
Die Aktuatoren 28, 29 können einstückig mit dem Temperierelement 11h verbunden und gemeinsam mit diesem bewegbar sein.The
Claims (12)
- Arrangement comprising a flow cell and a temperature-control element, with a temperature-control chamber (3), which receives a fluid to be controlled in its temperature and the boundary wall of which is formed at least partially by a thin film (2) transmitting heat between the temperature-control element (11) and the fluid, the film being formed as a composite film (2) comprising multiple interconnected layers (8, 10), the layer (8) facing the fluid being a layer of plastic, at least one further layer (9) consisting of a metal, the temperature-control chamber (3) being formed by a recess in a substrate (1) covered with the composite film (2) and the composite film (2) being connected to the substrate,
characterized
in that the composite film (2a) can be drawn against the temperature-control element (11a) by suction channels (12) formed in the temperature-control element (11a) or in that the temperature-control element (11, 11b, 11c) only lies against the composite film (2, 2b, 2c) in a peripheral region that is adjacent to the recess in the substrate (1, 1b, 1c) and in which the composite film (2, 2b, 2c) is connected to the surface of the substrate (1, 1b, 1c). - Arrangement according to Claim 1,
characterized
in that the layer of plastic (8) facing the fluid consists of a plastic compatible with an amplification reaction, preferably an olefin polymer, such as PP, PE, COC or PC. - Arrangement according to Claim 1 or 2,
characterized
in that the at least one metal layer consists of aluminium or a magnetizable metal, for example nickel. - Arrangement according to one of Claims 1 to 3,
characterized
in that the film layer (10) facing the temperature-control element (11) consists of a plastic, in particular the same plastic as the layer (8) facing the fluid. - Arrangement according to one of Claims 1 to 4,
characterized
in that the respective layer thickness lies between 1 µm and 100 µm. - Arrangement according to one of Claims 1 to 5,
characterized
in that the composite film (2) is welded or adhesively bonded to the substrate (1). - Arrangement according to one of claims 1 to 6,
characterized
in that the temperature-control chamber (3h) can be closed by at least one valve, and in particular a valve seat (30, 31), against which the composite film (2h) loosely lies, is formed in a channel (4h, 5h), which is connected to the temperature-control chamber (3h), and which is covered by the composite film (2h) . - Arrangement according to Claim 6 or 7,
characterized
in that the substrate (1) consists of the same plastic as the layer (8) of the composite film (2) facing the fluid. - Arrangement according to one of Claims 1 to 8,
characterized
in that the temperature-control chamber (3i) can be used as a storage chamber and is formed with at least one closure, closing the storage chamber, as a predetermined breaking point (34, 35) for forming an opening. - Arrangement according to one of Claims 1 to 9,
characterized
in that the composite film (2c) is thermoformed to enlarge its surface adjacent to the fluid. - Arrangement according to one of Claims 1 to 10,
characterized
in that, in addition to the heat transmission, as a further function the composite film (2) within the flow cell is given at least one covering function and/or valve function. - Arrangement according to one of Claims 1 to 11,
characterized
in that the flow cell has an inflow and an outflow (6, 7) for the fluid, for the through-flow through the temperature-control chamber during the temperature control.
Priority Applications (2)
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EP12163321.8A EP2647435B1 (en) | 2012-04-05 | 2012-04-05 | System with a fluidic cell and a tempering element |
US13/856,194 US9149802B2 (en) | 2012-04-05 | 2013-04-03 | Flow cell with a temperature-control chamber |
Applications Claiming Priority (1)
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EP12163321.8A EP2647435B1 (en) | 2012-04-05 | 2012-04-05 | System with a fluidic cell and a tempering element |
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EP2647435B1 true EP2647435B1 (en) | 2020-08-05 |
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EP12163321.8A Active EP2647435B1 (en) | 2012-04-05 | 2012-04-05 | System with a fluidic cell and a tempering element |
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JPWO2012086168A1 (en) * | 2010-12-21 | 2014-05-22 | 日本電気株式会社 | Sample heating method and heating control apparatus |
GB2516675A (en) | 2013-07-29 | 2015-02-04 | Atlas Genetics Ltd | A valve which depressurises, and a valve system |
GB2516669B (en) | 2013-07-29 | 2015-09-09 | Atlas Genetics Ltd | A method for processing a liquid sample in a fluidic cartridge |
GB2516672B (en) | 2013-07-29 | 2015-05-20 | Atlas Genetics Ltd | A system and method for expelling liquid from a fluidic cartridge |
GB2516667A (en) | 2013-07-29 | 2015-02-04 | Atlas Genetics Ltd | An improved cartridge, cartridge reader and method for preventing reuse |
GB2516666B (en) | 2013-07-29 | 2015-09-09 | Atlas Genetics Ltd | Fluidic cartridge for nucleic acid amplification and detection |
WO2015105797A1 (en) | 2014-01-07 | 2015-07-16 | Daktari Diagnostics, Inc. | Fluid delivery devices, systems, and methods |
EP2962758B1 (en) | 2014-07-01 | 2017-07-19 | ThinXXS Microtechnology AG | Flow cell having a storage space and a transport channel that can be opened at a predetermined breaking point |
EP3124118B1 (en) * | 2015-07-28 | 2018-02-28 | Panasonic Intellectual Property Management Co., Ltd. | Microchannel apparatus and pcr method |
CN109803763B (en) * | 2016-10-07 | 2022-09-16 | 勃林格殷格翰维特梅迪卡有限公司 | Cartridge, analysis system and method for testing a sample |
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WO2008157801A2 (en) * | 2007-06-21 | 2008-12-24 | Gen-Probe Incorporated | Instrument and receptacles for performing processes |
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US5074196A (en) * | 1990-09-28 | 1991-12-24 | Calspan Corporation | Flexible gas impermeable sandwich diaphragm |
US6613560B1 (en) | 1994-10-19 | 2003-09-02 | Agilent Technologies, Inc. | PCR microreactor for amplifying DNA using microquantities of sample fluid |
US6627159B1 (en) * | 2000-06-28 | 2003-09-30 | 3M Innovative Properties Company | Centrifugal filling of sample processing devices |
US6692700B2 (en) * | 2001-02-14 | 2004-02-17 | Handylab, Inc. | Heat-reduction methods and systems related to microfluidic devices |
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EP1710016A3 (en) * | 2005-03-30 | 2011-03-30 | Roche Diagnostics GmbH | Device having a self sealing fluid port |
EP1878495A1 (en) * | 2006-07-14 | 2008-01-16 | Roche Diagnostics GmbH | Analytical device for thermally treating a fluid and/or monitoring a property thereof |
EP1886727A1 (en) * | 2006-07-14 | 2008-02-13 | Roche Diagnostics GmbH | Analytical device |
EP1878497A1 (en) * | 2006-07-14 | 2008-01-16 | Roche Diagnostics GmbH | Disposable for analyzing a liquid sample by nucleic acid amplification |
WO2009054493A1 (en) * | 2007-10-26 | 2009-04-30 | Toppan Printing Co., Ltd. | Reaction chip and method for manufacturing the same |
DE102009009728A1 (en) * | 2009-02-19 | 2010-09-02 | Thinxxs Microtechnology Ag | Flow cell with integrated fluid storage |
JP5797926B2 (en) * | 2011-04-21 | 2015-10-21 | 株式会社エンプラス | Fluid handling apparatus, manufacturing method thereof, and fluid handling system |
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WO2008157801A2 (en) * | 2007-06-21 | 2008-12-24 | Gen-Probe Incorporated | Instrument and receptacles for performing processes |
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US20130263940A1 (en) | 2013-10-10 |
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