EP2647435A1 - Fluid cell with a tempering chamber - Google Patents

Abstract

The flow cell has a moderate temperature chamber (3) to maintain fluid in moderate temperature. A boundary wall is formed between moderate temperature element and fluid transmitting film (2). The fluid transmitting film is formed of several interconnected layers with inner plastic layer (8), metal layer (9) and outer plastic layer (10). The metal layer is formed between inner plastic layer and outer plastic layer. The plastic layer is made of polypropylene, polyethylene, cyclic olefin copolymer or propylene carbonate. The metal layer is made of aluminum or nickel.

Description

The invention relates to a flow cell with a tempering chamber receiving a fluid to be tempered, the boundary wall of which is formed at least partially by a thin film transferring heat between a tempering element and the fluid.

Microfluidic flow cells, in particular as disposable products, are increasingly used in analytics and diagnostics or in medicine for the conditioning of liquids before they are applied to the human body, as well as for synthesis purposes.
While the function of a flow cell can exhaust itself in the temperature control of a fluid, tempering devices often only form components of flow cells with far greater functionality. Particularly in flow cells for carrying out molecular genetic analyzes, including PCR or other nucleic acid amplifying processes, the temperature control function is of great importance in that the amplification reaction requires constant or changing, above ambient reaction temperatures, typically between 30 ° C and 95 ° C. The production of temperature-resistant flow cells with reproducible Temperierungseigenschaften, which allow a particularly fast and homogeneous temperature transition between an active tempering and the fluid to be tempered, in particular the production of such flow cells as inexpensive disposable products, the production of significant problems.

A flow cell with a tempering of the type mentioned is from the US 6,613,560 B1 known. The flow cell is used to carry out the PCR process. A reaction chamber for the PCR process simultaneously forms the tempering chamber. The tempering chamber is bounded by a recess in a substrate and the aforementioned thin, heat-transferring film which covers the recess. A disadvantage of the tempering process is the low thermal conductivity of plastics, which is why films with a low film thickness in the range of 50-200 μm are preferred. The production, handling and assembly of such thin films is very expensive. The disadvantage is that the cover film does not form an exact plane due to its low mechanical rigidity. Likewise, thermal and mechanical influences during assembly of the film by means of adhesive or welding processes can easily lead to deformations of the film and thus deviations from the plane in the range of a few 10-100 microns. This complicates the coupling of heat by pressing a Temperierelements, in particular remaining air gaps affect the heat transfer and prevent a quick balance between the temperature of the Temperierelements and the temperature of the fluid in the temperature control chamber, in particular its uniform heating or cooling. Reproducible Temperierungseigenschaften can not be achieved, especially under the conditions of inexpensive mass production of this flow cell.

The invention has for its object to provide a new flow cell with tempering, which can be produced as an inexpensive mass product with reproducible Temperierungseigenschaften.

The flow cell according to the invention which achieves this object is characterized in that the film has a plurality of interconnected layers as a composite film, wherein the layer facing the fluid is a plastic layer and wherein at least one further layer consists of a metal.

According to the invention, the metal layer of the film, due to its high thermal conductivity, which is typically about 1000 times higher than that of the plastic, also ensures lateral thermal propagation, also lateral, ie parallel to the film plane. Therefore, even with only a partial application of a tempering of the film, the film takes on the temperature of the tempering sufficiently quickly and uniformly and transmits it further to the fluid. Manufacturing-related fluctuations in the size of the contact surface between tempering and film are not significant.

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.

The at least one metal layer preferably comprises aluminum or a magnetizable metal, e.g. Nickel, up. In the latter case, the adhesion of a tempering element to the film and thus the heat transfer between the tempering element and the film can be improved by magnetic force.

The film layer of the composite film facing the tempering element may also consist of a plastic, in particular that plastic from which the layer facing the fluid is also produced. The layer facing the tempering element expediently consists of a material which counteracts an adhesive adhesion of the film to the tempering element.

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.

While it would be possible to produce the tempering exclusively from the thin composite film, for example by two deep-drawn in opposite directions, welded together or glued together foil parts or a deep-drawn film part welded to a flat undeformed film part, in the preferred embodiment of the invention, the tempering by a with the composite film covered recess formed in a preferably produced under inexpensive injection molding substrate and the composite film bonded to the substrate, preferably welded or glued.

Preferably, the film is connected to a flat, adjacent to the recess surface of the substrate.

The substrate may consist of the same plastic as the layer of the composite film facing the fluid, and thus the entire tempering chamber may be formed of only one material, which is compatible with the fluids to be tempered.

In one embodiment of the invention, the tempering has a fixed, for heat transfer against the composite film can be applied tempering or a composite film wetting, preferably flowing parallel to the composite film, liquid or gaseous tempering.

In one embodiment of the invention, the tempering element can only be provided in an edge region adjoining the tempering chamber, in which the composite film is e.g. is connected to the surface of the substrate, abut. Suitably, the film is supported in the edge region in such a way that the tempering element can be applied to the film under high contact pressure. If the tempering chamber is hermetically sealed during tempering, the application of the tempering element to only a part of the tempering chamber-forming composite film has the advantage that a pressure build-up produced by heating and associated expansion of the fluid in the chamber is caused by an expansion of the composite film and thus accompanying enlargement of the volume of the tempering chamber can be at least partially compensated. The thus prevented pressure build-up in the temperature control chamber in turn reduces the requirements for valves which may be necessary for a hermetic completion of the chamber.

The composite foil may be stretchable through the tempering element in the temperature-control chamber, preferably up to a limit-limiting stop. This elongation results in a reproducible thermal contact between tempering element and foil. In addition, further, separate from the tempering chamber spaces into which the composite film is stretchable, could be provided.

In a further embodiment of the invention, means for sucking the composite film may be formed on the tempering. By firmer pressure of the tempering against the film improves the thermal contact. If the composite foil has a magnetizable metal layer, the tempering body can be provided with a permanent magnet or electromagnet in order to improve the pressure of the tempering body against the foil by magnetic interaction.

In one embodiment of the invention, the composite film is deformed, in particular deep-drawn, by enlarging its surface contacting the fluid.

The composite foil can fulfill additional functions within the flow cell, eg covering functions or a valve function.

It is understood that the flow cell with the tempering chamber can have an inflow and outflow for the fluid, possibly for the passage of the fluid through the chamber during the temperature control. Likewise, the flow cell may further include channel structures, mixing and distribution elements for the fluids, liquid reservoirs, reaction and detection chambers, and the like elements commonly used in the art for performing analyzes and syntheses in microfluidic flow cells. Suitably, the composite film extends only over the portion of the flow cell, which includes the tempering to ensure that during the tempering no or little heat flows into the remaining areas of the flow cell.

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 may 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 in particular for heating to near the boiling temperature of the fluid. As a result, a resulting from volume change and / or partial vapor formation outflow of the fluid is prevented from the temperature control. Due to the solubility of the closure, the fluid can be transported, processed or processed after the tempering process, or, as described in US Pat. in molecular genetic analyzes. For closing it is advantageous to form a valve seat in the channel-shaped inflow and outflow of the tempering chamber, wherein in the region of the valve seat, the composite film is not firmly connected to the substrate, but loosely and flat against the substrate. The extensibility of the composite foil allows fluid under pressure to pass between the valve seat and the composite foil before or after the tempering process and be transported out into the chamber or out of the chamber. During the temperature control of the inlet and outlet are hermetically sealed by mechanical stamps of an external actuator are pressed against the voltage applied to the substrate in the region of the valve seat foil.

The tempering chamber according to the invention can also serve as a liquid storage, for example, to store a reagent prior to its use in the flow cell. The volume of the stored reagent can be smaller than that of the tempering and storage chamber, so that the chamber completely or, for example, before a temperature control with a fluid to be analyzed and mixed with the reagent can be partially filled. When using the tempering chamber as a storage chamber can advantageously a channel-shaped inflow and outflow of the tempering interrupted geometrically and in the interrupted channel region, the composite film firmly connected to the substrate, for example by welding to form a seal 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 henceforth be used as valves. The metal layer in the storage chamber bounding composite foil prevents liquid or gas passage through the chamber wall during storage.

Fig. 1

einen Ausschnitt aus einer erfindungsgemäßen, 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

ein Ausführungsbeispiel einer Flusszelle nach der Erfindung mit einer tiefgezogen Folie,

Fig. 5

ein weiteres Ausführungsbeispiel für eine Flusszelle nach der Erfindung mit einer tiefgezogenen Folie,

Fig. 6

ein Ausführungsbeispiel einer erfindungsgemäßen Flusszelle mit einer in eine Ausnehmung in einem Substrat hinein dehnbaren Folie,

Fig. 7

ein Ausführungsbeispiel einer erfindungsgemäßen Flusszelle mit einer aus zwei dehnbaren Verbundfolien durch Auslenkung des Temperierelements gebildeten Temperierkammer,

Fig. 8

ein Ausführungsbeispiel einer erfindungsgemäßen 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 nach der Erfindung mit sich an eine Temperierkammer anschließenden Ventilbereichen, und

Fig. 11

eine Flusszelle nach der Erfindung mit einer als Speicherkammer dienenden Temperierkammer.

The invention will be explained below with reference to embodiments and the accompanying, relating to these embodiments drawings. Show it:

Fig. 1

a section of a flow cell according to the invention, having a tempering chamber,

Fig. 2

the flow cell of Fig. 1 with an attached tempering element,

Fig. 3

the flow cell of Fig. 1 having a tempering element with an intake duct,

Fig. 4

An embodiment of a flow cell according to the invention with a deep-drawn film,

Fig. 5

a further embodiment of a flow cell according to the invention with a thermoformed film,

Fig. 6

An embodiment of a flow cell according to the invention with a stretchable into a recess in a substrate in the film,

Fig. 7

An embodiment of a flow cell according to the invention with a two-stretchable composite films formed by deflection of the tempering temperature control,

Fig. 8

An embodiment of a flow cell according to the invention with a temperature control chamber formed from two stretchable composite films with tempering on opposite sides,

Fig. 9

a flow cell according to Fig. 1 with a tempering fluid leading tempering,

Fig. 10

a flow cell according to the invention with adjoining a temperature control valve areas, and

Fig. 11

a flow cell according to the invention with a temperature chamber serving as a storage chamber.

An in Fig. 1 A microfluidic flow cell which is shown in sections and which in the exemplary embodiment shown serves to carry out an amplification process comprises a plate-shaped substrate 1 and a foil 2 which is welded or glued to the substrate 1 in a fluid-tight manner.

Through a recess in the substrate 1 and the film 2, which covers this recess, a temperature-receiving chamber 3 receiving a fluid is formed. The tempering chamber 3 is connected via channels 4 and 5, each with an inlet / outlet 6 and 7 in combination. It is self-evident that the tempering chamber could be connected or connectable with other chambers provided in the flow cell for other purposes.

The film 2 consists in the embodiment shown of a composite of several layers, an inner layer 8 of a compatible with amplification reactions plastic, a metal layer 9, in the example shown from a layer of aluminum, and an outer layer 10, which is like the inner layer 8 made of plastic , The inner layer 9 and the substrate 1 may be formed of the same material, which facilitates the fluid-tight welding of the film 2 to the substrate 1.

In the following FIGS. 2 to 6 For reasons of simplicity, the multilayer composite film 2 is shown without the individual layers.

In order to bring a fluid located in the temperature control chamber 3 to a desired reaction temperature, for example, within the framework of the overall function of the flow cell, is carried out according to Fig. 2 a tempering element 11 is applied to the wall of the tempering chamber 3 formed by the film 2, which is held at a temperature which corresponds to the desired temperature of the fluid in the tempering chamber 3.

Depending on the desired fluid temperature, the tempering element 11 may be a heating or cooling element. In the former case, heat is transferred from the temperature control element 11 to the fluid in the temperature control chamber 3, in the second case, heat flows from the fluid to the temperature control element 11.

As a result of high flexibility of the thin film 2 whose total layer thickness is in the range between 3 μm and 300 μm, the tempering element 11 can not rest on the film 2 in such a way that results in a uniform heat transfer over the entire contact surface. Due to the high thermal conductivity of the metal layer 9 contained in the film 2, however, which is capable of heat conduction in a lateral direction parallel to the film plane, there is still a rapid heat exchange between the temperature control element 11 and the fluid in the temperature control chamber 3, wherein at uniform heating of the fluid whose temperature equalizes the temperature of the tempering 11.

It is understood that the fluid during the temperature control in the temperature control chamber 3 stand still or the temperature control chamber 3 can flow with a temperature compensation allowing speed.

An in Fig. 3 Temperierelement shown 11a has suction channels 12, through which a film 2a against the tempering 11a pulling negative pressure can be generated, so that there is a uniform over the contact surface heat transfer between the tempering 11a and the film 2a.

In the following figures, the same or equivalent parts are designated by the same reference numerals as in the preceding figures, wherein the relevant reference number of the letter a, b, etc. is attached.

At an in Fig. 4 In the embodiment shown, a tempering chamber 3b is essentially formed by a cap or chamber-like deformation 13 of a composite foil 2b. An annular tempering element 11b abuts around the deformation 13 against the film 2b connected to a substrate 1b. The support of the film 2b by the substrate 1b allows an increased contact force of the tempering 11b against the film 2b. Heat therefore spreads more uniformly and is guided laterally into the middle by the metal layer contained in the film 2b, so that a temperature compensation between a fluid contained in the tempering chamber 3b and the tempering element 11b can take place in a short time.

Also a in Fig. 5 shown embodiment used as the embodiment of Fig. 4 , an annular tempering 11c. A tempering chamber 3c is, as in the embodiments of Fig. 1 to 3 formed by a recess in a substrate 1 c. A composite foil 2c covering the recess has a deformation 14 in the region of the recess, which enlarges the surface of the foil 2c adjoining the fluid while increasing the heat transfer capacity, so that in comparison with the exemplary embodiment of FIG Fig. 4 an even faster alignment of the temperature of the fluid in the temperature-control chamber 3c to the temperature of the temperature-control element 11c results.

Fig. 6 shows an embodiment with a film 2d, which is in a region in which it forms a wall of a temperature control chamber 3d, by a tempering 1 1 d in a temperature control chamber 3d forming recess in a substrate 1 d in stretchable. A stop 15 at the bottom of the tempering chamber 3d limits the strain. In the in Fig. 1 shown expansion state is the tempering 11d uniformly against the elastically or plastically stretchable film 2d, so that there is a uniform over the entire contact surface heat transfer and temperature exchange between the tempering and the fluid.

An arrangement of the temperature-control element 11d and further temperature-control elements 11d 'and 11d "can be moved according to arrow 16 so that either one of the tempering 1 1 d, 11 d', 11d" according to arrow 17 under extension of the film 2d extendable to the stop 15 is. The fluid can then be heated differently in succession according to temperatures T1, T2 and T3 of the temperature-control elements 11d, 11d ', 11d ".

An in Fig. 7 The illustrated embodiment for a flow cell comprises a substrate 24 which is welded or glued to an assembly of composite foils 2e and 2e '.

Except in an area in front of a through-hole 25 in the substrate 24 and an environment adjacent to this area, the composite foils 2e, 2e 'are also joined together by welding or gluing.

A in the passage opening 25 according to arrow 17e movable tempering 1 1 e, the composite films 2e, 2e 'in the in Fig. 7 shown manner to form a tempering 3e between the composite films 2e, 2e 'expand. In the embodiment shown, both composite films 2e, 2e 'as in Fig. 1 shown film formed with a metal layer. Deviating from the shown Embodiment, only the film 2e facing the tempering element 11e could also be designed as such a composite film.

In the tempering 3e incoming inflows or outflows are in Fig. 7 Not shown.

Out Fig. 8 shows an embodiment of a flow cell with a tempering 3f forth. The tempering chamber 3f is formed from two composite foils 2f and 2f 'welded or glued together. While the composite foil 2f is flat, the composite foil 2f 'has a deformation 13f formed by deep drawing and is further connected to inlets / outlets 6f, 7f.

A tempering element 11f which can be moved in accordance with arrow 17f is offset by two tempering elements 26 and 27 which can be moved in the opposite direction and can be attached to the composite film 2f '. While the tempering element 11f covers the entire side of the tempering chamber 3f facing it and adjacent areas, the tempering elements 26, 27 abut only against regions adjacent to the tempering chamber 3f. Accordingly, heat is conducted laterally into the tempering chamber. The free region formed by the deep-drawn deformation 13f can expand when the pressure builds up in the temperature-control chamber 3f with partial compensation of the pressure.

Fig. 9 shows an embodiment of a flow cell with a substrate 1 g and a film 2g and a tempering chamber 3g, the flow cell of Fig. 1 equivalent.

However, a tempering element 1 1 g is not formed in the embodiment shown, as in the previous embodiments, by a fixed tempering, but includes a symmetrical to the tempering chamber 3 g arranged chamber 18 for receiving a tempering fluid. The chamber 18 is located in a recess in a substrate 19, which is connected to the composite film 2g in the same way as the substrate 1 g. The chamber 18 receives a fluid held at a certain temperature, which in the embodiment shown passes through an inlet 20 and a channel 21 into the chamber 18 and flows through a channel 22 and an outlet 23. In the embodiment shown, the substrate 1 g and the substrate 19 are made of the same material. An inner layer 8g of the film 2g is similar in the material of the outer layer 10g facing the substrate 19.

An in Fig. 10 The flow cell shown differs from the flow cell of Fig. 1 in that in each case a valve with an actuator element 28 or 29 is provided in channels 4h and 5h which are connected to a temperature-control chamber 3h. The respective actuator element presses a composite foil 2h in the closed state of the valve against a valve seat 30 or 31.

In the middle of its tempering surface, which can be applied against the film 2h, a tempering element 11h has a recess 32, into which the composite film 2h can expand during a tempering process with increasing internal pressure in the tempering chamber 3h.

The actuators 28, 29 may be integrally connected to the tempering 11h and be movable together with this.

Fig. 11 shows a flow cell with a chamber 3i, which initially serves as a storage chamber for a reagent 33. At predetermined breaking points at 34 and 35 can form openings that allow access to the reagent 33 and the further use of the chamber 3i as tempering.

Claims (15)

Flow cell with a tempering chamber (3) receiving a fluid to be tempered, whose boundary wall is formed at least partially by a thin film (2) transmitting heat between a tempering element (11) and the fluid,
characterized,
that the film (2) comprises a plurality of interconnected layers (8-10), wherein the side facing the fluid layer (8) is a plastic layer and at least one further layer (9) consists of a metal. Flow cell according to claim 1,
characterized,
in that the plastic layer (8) facing the fluid consists of a plastic compatible with an amplification reaction, preferably an olefin polymer, such as PP, PE, COC or PC. Flow cell according to claim 1 or 2,
characterized,
in that the at least one metal layer consists of aluminum or a magnetisable metal, eg nickel. Flow cell according to one of claims 1 to 3,
characterized,
that facing the tempering element (11) film layer (10) consists of a plastic, especially the same plastic as the side facing the fluid layer (8). Flow cell according to one of claims 1 to 4,
characterized,
that the respective layer thickness is between 1 .mu.m and 100 .mu.m. Flow cell according to one of claims 1 to 5,
characterized,
that the temperature-control chamber (3) formed by a composite with the film (2) covered recess in a substrate (1) and connected to the composite foil (2) with the substrate (1), preferably welded or glued is. Flow cell 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 in a channel (4h, 5h) covered by the composite film (2h) with the temperature-control chamber (3h), a valve seat (30, 31) against which the composite film ( 2h) lies loosely, is formed. Flow cell according to claim 6 or 7,
characterized,
in that the substrate (1) consists of the same plastic as the fluid-facing layer (8) of the composite film (2). Flow cell according to one of claims 1 to 8,
characterized,
in that the tempering element (11) comprises a tempering body which can be applied for heat transfer to the composite film (2) or a tempering fluid which wets the composite film (2e) and preferably flows parallel to the composite film (2e). Flow cell according to claim 9,
characterized,
that the tempering element (11b, 11c) adjacent only one of the temperature chamber (3b, 3c) the edge region, in which the composite film (2b, 2c) with the surface of the substrate (1b, 1c) is connected, is present. Flow cell according to one of claims 1 to 10,
characterized,
that the composite film (2d) through the temperature-regulating element (1 1d) into the temperature chamber (3d) is in elastic, preferably to a strain-limiting stop (15). Flow cell according to one of claims 1 to 11,
characterized,
that the temperature chamber (3i) used as a storage chamber and in particular at least one storage chamber final closure as a predetermined breaking point (34,35) is formed to form an opening. Flow cell according to one of claims 1 to 11,
characterized,
that the composite film (2c) is deformed under magnification its adjacent to the fluid surface, in particular deep-drawn, is. Flow cell according to one of claims 1 to 13,
characterized,
that the composite foil (2) is satisfied within the flow cell at least one other function, in particular a covering device and / or valve function. Flow cell according to one of claims 1 to 14,
characterized,
that the cavity has an inlet and an outlet (6,7) for the fluid to flow through the cavity during the tempering.

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