FLOW CELL HAVING A HOUSING COMPONENT

Abstract

A microfluidic flow cell for carrying out an analysis, having a substrate of synthetic material, which has cavities for the formation of channel structures and chambers, wherein the cavities are closed on one side of the substrate by a film adhesively bonded or welded to the substrate, and having a housing component that is produced with a hard and a soft component, which, on the side of the substrate facing away from the film, is connected to the substrate, completing functional sections respectively fulfilling the function of the flow cell. The housing component is formed as a multifunctional part completing more than two functional sections.

Claims

1-15. (canceled)

16. A microfluidic flow cell for carrying out an analysis, comprising: a plastic substrate having cavities for forming channel structures and chambers; a film adhesively bonded or/and welded to the substrate so as to close the cavities on one side of the substrate; and a housing produced as a composite part having a hard component and a soft component, the housing being connected to the substrate on a side of the substrate facing away from the film while respectively complementing functional sections that respectively fulfill a function of the flow cell, wherein the housing is configured as a multifunctional part that complements more than two functional sections.

17. The flow cell according to claim 16, wherein the housing is a multiconstitiuent injection molded part.

18. The flow cell according to claim 16, wherein the housing component is welded, thermally riveted and/or adhesively bonded to the substrate.

19. The flow cell according to claim 16, further comprising a tiltable closure element, wherein the housing is connected in one piece to the tiltable closure element.

20. The flow cell according to claim 19, wherein the tiltable closure element is retainable in a closed position.

21. The flow cell according to claim 16, wherein the housing part has a plurality of elastically deformable soft constituent sections.

22. The flow cell according to claim 21, wherein the soft constituent sections comprise an elastomer material.

23. The flow cell according to claim 21, wherein the soft constituent sections comprise at least partially transparent soft constituent sections.

24. The flow cell according to claim 21, wherein the soft constituent sections comprise soft constituent sections locally welded and/or adhesively bonded to the substrate.

25. The flow cell according to claim 16, wherein the housing is configured to bound a storage chamber forming one of the functional sections of the flow cell.

26. The flow cell according to claim 25, further comprising a predetermined breaking barrier arranged in a feed and discharge channel so as to close the storage chamber.

27. The flow cell according to claim 26, wherein one of the functional sections is a device for breaking the predetermined breaking barrier, the device including a section of the soft component of the housing that is externally deformable.

28. The flow cell according to claim 27, wherein the soft component section comprises an outwardly curved or outwardly curvable membrane.

29. The flow cell according to claim 16, wherein one of the functional sections is a septum that comprises a section of the soft component of the housing that can be pierced with a cannula.

30. The flow cell according to claim 16, wherein one of the functional sections is a valve device that comprises a section of the soft component of the housing that is resiliently deformable from outside while closing a valve opening.

31. The flow cell according to claim 30, wherein the section of the soft component comprises a membrane.

32. The flow cell according to claim 31, wherein an inner side of the membrane is covered by a film.

33. The flow cell according to claim 16, wherein one of the functional sections is a gas cushion that comprises a section of the soft component of the housing that is deformable by an internal pressure in the flow cell while changing a volume of the gas cushion.

Description

[0024] The invention is explained in more detail below with the aid of exemplary embodiments and the appended drawings which relate to these exemplary embodiments, in which:

[0025] FIG. 1 shows a flow cell according to the invention in a plan view obliquely from above with the sample introduction opening open and closed,

[0026] FIG. 2 shows the flow cell of FIG. 1 in an exploded representation,

[0027] FIG. 3 shows a substrate of the flow cell of FIGS. 1 and 2,

[0028] FIGS. 4 to 7 show representations explaining connections between a substrate and the housing component of the flow cell of FIGS. 1 to 3,

[0029] FIG. 8 shows various embodiments of a storage chamber in a flow cell according to the invention,

[0030] FIG. 9 shows a device for breaking a predetermined breaking barrier of a storage chamber,

[0031] FIG. 10 shows a further device for breaking a predetermined breaking barrier of a storage chamber,

[0032] FIGS. 11 to 13 show further exemplary embodiments of functional sections of a flow cell according to the invention,

[0033] FIGS. 14 and 15 show exemplary embodiments of the valves in a flow cell according to the invention,

[0034] FIGS. 16 and 17 show exemplary embodiments of pump devices in a flow cell according to the invention,

[0035] FIG. 18 shows an exemplary embodiment of a gas cushion in a flow cell according to the invention,

[0036] FIG. 19 shows an exemplary embodiment of a clamp connection in a flow cell according to the invention,

[0037] FIG. 20 shows a flow cell according to the invention having a sealing ring, formed by a soft constituent of a housing component, for sealing a sensor element,

[0038] FIG. 21 shows a sample introduction opening of a flow cell according to the invention, which is covered by a slitted soft constituent section of the housing component,

[0039] FIG. 22 shows an arrangement for removing gas bubbles from a fluid flowing in a flow cell according to the invention, and

[0040] FIGS. 23 and 24 show exemplary embodiments of flow cells according to the invention having a device for measuring a sample quantity.

[0041] A flow cell for carrying out analysis comprises an essentially plate-shaped substrate 1 which is produced by the injection molding method from a plastic, preferably from PP, PE, PMMA, PC, COC or COP.

[0042] The substrate 1 is connected to a housing component 2, which is configured in its basic shape as a plate and covers, in the example shown partially, the substrate 1 on a plate side. The housing component 2 is produced as a composite part from a hard constituent and a soft constituent by the two-constituent injection molding method. The hard constituent consists for example of PP, and the soft constituent of an elastomer, in particular a thermoplastic elastomer, or silicone. The soft constituent could be at least partially transparent.

[0043] On its side facing away from the housing component 2, the substrate 1 is connected to a film 3, which closes cavities formed in the substrate 1 and is adhesively bonded or welded to the substrate 1. Preferably, the film 3 consists of the same material as the substrate 1.

[0044] The substrate 1 comprises a sample chamber 4, which is configured as an outward curvature of the substrate plate, is covered by the film 3 and has a sample introduction opening 5. The sample introduction opening 5 can be closed by a tab 6, which is articulatedly connected by means of a film hinge to the housing component 2 and can be latched in an opening 7 of a profiled grip part 8 of the substrate 1.

[0045] The substrate 1 furthermore comprises a recess 9 which, together with a bulge 10, oriented towards the recess 9, in the hard constituent of the housing component 2, forms a storage chamber 11 for a liquid reagent. As may be seen particularly in FIG. 3, a channel 12 having a predetermined breaking barrier 22 is formed between the recess 9, which forms the storage chamber 11, and a channel structure 13, and by means of the channel structure 13 a connection may be established both to the sample chamber 4 and to an analysis section 14, which is essentially formed by the substrate 1 and film 3. In the example shown, the analysis section 14 comprises four insertion openings for plug-shaped carriers 15 of a dry reagent.

[0046] By means of a further channel 16 having a predetermined breaking barrier 26, the storage chamber 11 can be connected to a pump volume 18 which is formed by a curved section 17 of the soft constituent of the housing component 2. A further pump volume 20, formed by a curved section 19 of the soft constituent, is connected via a channel 21 to the sample chamber 4.

[0047] In order to use the flow cell described above, a sample to be analyzed is introduced through the sample introduction opening 5 into the sample chamber 4, and the sample chamber 4 is subsequently closed by pressing down the closure tab 6. It is to be understood that, on its side facing toward the sample introduction opening 5, the closure tab 6 comprises a sealing element that closes the opening, as is described in more detail below with the aid of FIG. 13. Optionally, a pressing force of the closure tab 6 against the sample introduction opening 5, achieved by latching with the opening 7, is reinforced with the aid of an operating instrument (not shown here or below) that receives the flow cell, for example by mechanical plunger pressure.

[0048] The hermetically closed flow cell is arranged in a predetermined position in an operating instrument so that sample material accumulates at the exit of the sample chamber 4 because of the force of gravity, and air bubbles that may occur rise in the desired direction upward inside the hermetically closed flow cell.

[0049] By mechanical actuation of the curved section 17 forming a pump element and a consequent reduction in the pump volume 18, after opening of the predetermined breaking barriers 22 and 26 and of a valve 23 by the operating instrument, liquid reagent is conveyed from the storage chamber 11 into the sample chamber 4 while building up an internal pressure in the flow cell which is higher than atmospheric pressure. Actuation of the section 19 forming a further pump while reducing the pump volume 20 allows transport of the liquid reagent mixed with the sample back into the storage chamber 11, this reagent coming in contact with a dry reagent of a plug-shaped dry reagent carrier 24 both during the forward transport and during the backward transport. By alternate actuation of the sections or pump elements 17, 19, full washing of the dry reagent from the dry reagent carrier 24 and mixing of the liquid reagent with the sample take place. The mixture of sample material and reagents, which is again located in the sample chamber 11 after completed washing out, is transferred from the storage chamber 11 into the analysis section 14 after the valve 23 is closed and a valve 25 is opened, and the fluid material is divided into four aliquots. In the hermetically closed flow cell, the movement of the liquid inside the analysis section takes place against the pressure of an air cushion 27, as is described in FIG. 18. By actuation of the pump element 17, the fluid material inside the analysis section can be moved to and fro as required. During the transport of the fluid material against the air cushion 27, a pressure buildup takes place, which typically lies in the range of from 0.1 to 5 bar above atmospheric pressure. An internal pressure of 1-2 bar is advantageous for carrying out the heat treatment steps in the analysis section 14, as are conventional for example in PCR or lysis processes, liquids being heated up to 100 C. The internal pressure built up by the liquid transport can prevent or reduce degassing of the heat-treated liquids. The analysis section comprises detection sections for recording the analysis result.

[0050] After the end of the analysis, all the actuation elements of an operating instrument are brought into the initial position at the instant of inserting the flow cell into the operating instrument. The pump elements 17 and 19 therefore return to their initial shape and the internal pressure advantageously increased in the flow cell during the analysis is reduced back to atmospheric pressure. In conjunction with hermetic closure of the flow cell, this reduction advantageously prevents undesired egress of the analyzed sample mixture when disposing of the flow cell.

[0051] Exemplary embodiments of functional sections, which fulfil various functions, of flow cells, are described below, such as may for example be used in the above-described flow cell comprising a housing component having a hard and a soft constituent.

[0052] A first variant of the connection of the housing component 2 to the substrate 1, in particular for fluid-tight and/or hermetically connection of the soft constituent of the housing component 2 to the substrate 1, relates to thermal riveting according to FIG. 4. Rivet pins 95 connected in one piece to the substrate 1 and protruding from the substrate 1 extend through corresponding openings 28 in the hard constituent of the housing component 2, as may be seen from FIG. 4a.

[0053] According to FIG. 4b, the rivet pins 95 are thermally deformed to form mushroom heads 29 engaging behind the openings 28, so that the housing component 2 is clamped between the substrate 1 and the mushroom heads 29.

[0054] FIG. 5 indicates the possibility of ultrasound welding of the housing component 2 to the substrate 1, the hard constituent of the housing component 2 being provided with prismatic direction guides 30 optionally extending around a soft constituent section. When ultrasound is applied, the direction guides 90 melt and weld to the surface of the substrate 1.

[0055] In the exemplary embodiments shown in FIGS. 4 and 5, fluid-tight or hermetic connection takes place between the soft constituent of the housing component 2 and the substrate 1 by pressure and clamping.

[0056] FIG. 6 shows an exemplary embodiment in which the housing component 2 and the substrate 1 are adhesively bonded to one another, in the example shown by a double-adhesive adhesive tape 31.

[0057] FIG. 7 shows connection of a housing part 2 to a substrate 1, in the case of which a soft constituent section of the housing component 2 is adhesively bonded or welded at 32 locally to the substrate 1. The connection could also be configured continuously circumferentially.

[0058] FIG. 8 shows three different possibilities of the formation of a storage chamber for a liquid. In the case of the exemplary embodiment of FIG. 8a, a storage chamber 33 is formed only by a bulge of the hard constituent of the housing component 2.

[0059] In the case of the exemplary embodiment of 8b, the formation of a storage chamber 33 takes place only using a recess in the substrate 1.

[0060] FIG. 8c shows a storage chamber 33, corresponding to the storage chamber 11 described above, which is formed both by a bulge of the housing component 2 and by a recess in the substrate 1. In all variants 8a to 8c, the storage chamber 33, 33 or 33 is respectively closed on the entry and exit sides by breakable predetermined breaking barriers 34, 34. A prismatic barrier member closes the channel and is adhesively bonded or welded at the apex to the film 3.

[0061] In order to break the predetermined breaking barriers 34, 34, an arrangement provided in FIG. 9 by way of example for the predetermined breaking position 34 is respectively envisioned. A membrane 35, made of an elastomer material, welded fluid-tightly circumferentially to the substrate 1 is a part of the soft constituent of the housing component 2 and can be stretched by an actuation element 36 of an operating instrument into a through-opening 37 in the substrate 1 until it deflects the film 3 adhesively bonded or welded to the substrate 1 according to the dashed line 38 so that the predetermined breaking barrier 34 breaks. By the deflection of the film 3, the film 3 tears off from the apex of the prismatic barrier member closing the channel.

[0062] A predetermined breaking barrier shown in FIG. 10 is formed by a barrier film 39 which covers a through-opening 40 in the substrate 1 that is in fluid connection with the storage chamber 33 and, in particular, bears against an annular projection enclosing the through-opening 40 and is welded tightly thereto, in order to ensure hermetic closure of the storage chamber at least partially filled with the liquid for the period of time between production and use of the flow cell. An actuation element 36 of an operating instrument stretches an elastomer membrane 35, which is a part of the soft constituent of the housing component 2, in such a way that the barrier film 39 breaks while opening the predetermined breaking barrier. Advantageously, the elastomer membrane 35 does not come in contact with the liquid stored in the storage chamber 33 so long as the predetermined breaking barrier is not removed. A material that is compatible in the long term with the liquid in the flow cell is therefore not needed for the membrane 35.

[0063] A functional section, shown in FIG. 11 and fulfilling a pump function, as already similarly described above with the aid of FIGS. 1 to 3, of a flow cell comprises a curved pump element 41, made of elastomer material, forming a pump volume 42. The pump element 41 is a part of the soft constituent of the housing component 2 connected to the substrate 1 in this case by riveting. The pump element 41 is intended for actuation by an actuation element 43 of an operating instrument. The delivery flow may be controlled by adjusting the rate of advance of the actuation element 43 and furthermore depends on the geometry of the actuation element 43. The pump element 41 is resilient and has a restoring moment such that a delivery flow in the opposite direction can be produced by the pump element when being restored.

[0064] A functional section, represented in FIG. 12, of a flow cell comprises a membrane 45 made of elastomer material, which is formed by the soft constituent of the housing component 2 connected to the substrate 1. The membrane 45 made of elastomer material forms a septum, which can be pierced with a cannula 44 and through which material can be introduced into the flow cell before or after an analysis.

[0065] FIG. 13 shows a closure tab 47, connected in one piece to the housing component 2 by means of a film hinge 46, for covering a sample introduction opening 48 of the flow cell. The tab comprises an elastomer membrane 49, which is a part of the soft constituent of the housing component 2 and seals the sample introduction opening 48. An actuation element 50 of an operating instrument ensures hermetic closure of the sample introduction opening.

[0066] FIGS. 14 and 15 show exemplary embodiments of a functional section, fulfilling a valve function, of a flow cell. An elastomer membrane 52, which is a part of the housing component 2 connected to the substrate 1, may in the closed state of the valve be pressed by an actuation element 51 of an operating instrument against a raised valve seat 53. The valve opens when the pressure due to the actuation element 51 is released.

[0067] The functional section of FIG. 15 differs from the functional section of FIG. 14 in that the elastomer membrane 52 is covered on its side facing toward the valve seat 53 by a plastic film 54 that prevents direct contact of the elastomer membrane 52 with liquid inside the flow cell.

[0068] FIG. 16 shows a pump (or a valve) which can be actuated by applying a pressure p and has a housing component 2, comprising an elastomer membrane 55, and a substrate 1. The housing component 2 is connected to the substrate 1 by means of an extensible film 56, which can be stretched over a pressure application channel 57 according to the dashed line 58, the elastomer membrane 55 being stretched and a volume 59 being generated between the elastomer membrane 55 and the film 56. Respectively, the film 56 is connected to the substrate 1 by an annular weld seam 60 and the elastomer membrane 55 is connected to the film 56 by an annular weld seam 61.

[0069] A pump shown in FIG. 17, operating according to the peristaltic principle comprises three pump chambers 62, 62, 62 connected in series, which are formed between the substrate 1 and outwardly curved pump elements 63, 63, 63. The pump elements, consisting of elastomer material, are a part of the soft constituent of the housing component 2. In order to convey fluid, actuation elements 64, 64, 63 of an actuation instrument act successively on the outwardly curved pump elements 63, 63, 63. In order to form the pump chambers 62, 62, 62, in the example shown the substrate 1 is respectively indented.

[0070] In an alternative variant, the soft constituent, forming the pump elements 63, 63, 65, of the housing component 2 is covered by a barrier film so that the soft constituent does not come in contact with the fluid in the flow cell and materials incompatible with the fluid may be used for the soft constituent.

[0071] FIG. 18 shows a flow cell having a substrate 1 and a housing component 2, the soft constituent of which comprises an elastomer membrane 65 that bounds a gas cushion. Air pressure increasing in a channel 66 makes the elastomer membrane 65 bulge out according to the dashed line 67. An actuation element 68 of an operating instrument can control the deflection of the elastomer membrane and therefore the volume of the gas cushion. It is to be understood that a gas cushion volume may be formed not just by deflection but in advance by shaping of the elastomer membrane and/or by indentation of the substrate 1.

[0072] FIG. 19 shows a functional section of a flow cell, by which section a hermetically tight connection to a line, leading for example to a pump, of an operating instrument may be established. An elastomer membrane 69, which is a part of the soft constituent of the housing component 2, comprises an opening 70 to which, for example, a connecting line 71 of an operating instrument may be connected while exerting an application pressure. A channel 72 in the substrate 1, which is connected to the opening, is covered by a film 73 which is adhesively bonded or welded to the substrate and is permeable for air but impermeable for liquids and vapors. The flow cell may therefore have pressure applied to it through the line 71 and, for example in conjunction with a pneumatic valve of an operating instrument, form a switchable vent opening or switchable gas cushion for controlling the liquid transport in the flow cell.

[0073] FIG. 20 shows a functional section of a flow cell, which is used for clamp connection of the flow cell to a sensor element 74 or other component made of a material which cannot be connected directly either to the substrate 1 or to the housing component 2. An annular sealing element 75 made of elastomer, which seals the sensor element 74 against the substrate 1, is a part of the soft constituent of the housing component 2. For the clamp connection between the sensor element 74 and the substrate 1, rivet pins 76 protruding from the substrate 1 are used which are deformed to form a mushroom head 77 pressing the sensor element 74 against the sealing ring 75.

[0074] FIG. 21 shows a functional section of a flow cell having a substrate 1 and a housing component 2, the soft constituent of which comprises an elastomer membrane 78. The elastomer membrane 78 closes a sample introduction opening 79 of the flow cell. A slit 80 in the elastomer membrane ensures that a pipette 81 introducing the sample is firmly enclosed and spraying of sample material or reagent liquid cannot occur. After the sample introduction, the sample introduction opening 79 is hermetically sealed by a closure element (not shown).

[0075] The elastomer membrane 78, which closes the introduction opening and comprises the slit 80, may also advantageously be used when the flow cell comprises devices for generating reduced pressure in the sample introduction channel, in which case the reduced pressure may, for example, be generated by outwardly curved pump elements described above. For example, a capillary tube, which has a blood sample and is inserted through the slit, may then be drained by the reduced pressure, the elastomer membrane 78 closing and sealing the tube.

[0076] FIG. 22 shows a functional section of a flow cell having a substrate 1 and a housing component 2, the functional section being used to remove air bubbles from a liquid flowing in a channel 82. The channel 82 is connected to a pump volume 84 by means of a membrane 83 which is air-permeable but impermeable for liquids. By means of an outwardly curved pump element 85, which is a part of the soft constituent of the housing component 2, a reduced pressure may be generated as described above, so that air can pass from the liquid into the pump volume.

[0077] FIG. 23 shows a functional section of a flow cell comprising a substrate 1 and a housing component 2, which section makes it possible to meter a sample quantity to be processed in the flow cell.

[0078] A flow chamber 56, which is formed by an indentation in the substrate 1 and has a defined volume, is covered by an elastomer membrane 87 which is a part of the soft constituent of the housing component 2. An entry channel 88 of the flow chamber 86 is connected to the sample introduction opening of the flow cell, and one exit channel 89 connects the flow chamber 86 to a vent opening (not shown). A further exit channel 90 of the flow chamber 86 connects the flow chamber to the channel system, required for the processing and analysis, of the flow cell and is closed outward. A sample is pressed by the user into the sample introduction opening of the flow cell, the flow chamber 86 being filled and excess material escaping through the channel 89. The channel 90 (perpendicular to the channels 88, 89) is not vented. After the sample introduction, the sample introduction opening at the entry of the flow cell, i.e. of the channel 88, as well as a vent opening at the exit of the channel 89 are tightly closed by means of a cap, a stopper or a tape (with or without assistance by the operating instrument). The lowering of a plunger 91 in an operating instrument leads to a volume displacement of the sample volume metered in the flow chamber 86 into the channel 90 and the subsequent channel system, required for the processing and analysis, of the flow cell. In the same way, an aliquot of a sample mixture or of another liquid quantity may also be metered during the analysis or sample processing.

[0079] FIG. 24 shows a functional section of a flow cell having a component 2 and a flow chamber 92. An elastomer membrane 93, which is transparent and is a part of the soft constituent of the housing component 2, forms an inspection window for monitoring the filling of the flow cell with liquid sample or for monitoring the liquid transport during the analysis.