Patent Application
20200156069
The invention relates to a microfluidic flow cell for carrying out an analysis, having a substrate made of plastic, which comprises cavities for forming channel structures and chambers, the cavities being closed on one side of the substrate by a film adhesively bonded or welded to the substrate, and having a housing component which is produced as a composite part having a hard and a soft constituent and is 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.
A microfluidic flow cell having these features is disclosed by WO 16/051272 A1. Inter alia, a pump device comprising the soft constituent of the housing component is formed as a functional section.
Such a microfluidic flow cell is developed further by the invention in such a way that the housing component is configured as a multifunctional part that complements more than two functional sections.
Advantageously, complexly structured flow cells having the multifunctional housing component according to the invention may be produced extremely efficiently with final assembly optionally of all functional sections in a single connection process. The invention thus provides an extraordinarily fabrication-friendly solution for a flow cell.
The housing component is expediently produced by the multiconstituent injection molding method. It is to be understood that injection molding may also be envisioned as a preferred production method for the substrate.
The housing component may be welded or/and thermally riveted to the substrate. Adhesive bonding is also possible. In the case of thermal riveting, leaktightness is established between the housing component and the substrate by clamping forces, by rivet pins that protrude from the substrate or housing component into through-openings in the respective other component being deformed under the effect of heat, so that they engage behind the through-opening. It is to be understood that lips preferably in the connection region may also be present on one or both components. For welding by ultrasound, projections as direction guides are expediently formed in the connection region.
The housing component may be connected in one piece to a tiltable closure element, particularly in order to cover a sample introduction opening example by means of a film hinge. Expediently, the closure element can be retained in the closure position and, for example, hermetically covers the sample introduction opening of the flow cell after introduction of a sample. The covering force, optionally reinforced by an actuation element of an operating instrument, of the closure element may additionally ensure the hermetic closure or on its own be essential for the hermetic closure.
In one particularly preferred embodiment of the invention, the housing part comprises a plurality of soft constituent sections, which in particular consist of an elastomer material. The soft constituent sections may comprise at least partially transparent soft constituent sections, such sections forming for example an inspection window.
In another configuration of the invention, the soft constituent sections comprise soft constituent sections locally welded or/and adhesively bonded to the substrate, in which case such local connection positions may, for example, be configured extending annularly around a cavity.
For example, curved pump elements or/and outwardly curvable membranes may be envisioned as soft constituent sections. Curved pump elements may be deformed manually, or by an actuation element of an operating instrument, in such a way that a pump volume formed by the pump element is modified.
Besides pump devices, for example, a storage chamber bounded by the housing component may be envisioned as s a functional section of the flow cell, in which case the storage chamber may be bounded only by the hard constituent of the housing component.
In the latter case, the storage chamber is expediently closed by predetermined breaking barriers in a feed and discharge channel.
A device, which comprises a soft constituent section, which can be deformed from the outside, of the housing component, for breaking a predetermined breaking barrier may furthermore be formed as a functional section of the flow cell. It is to be understood that such a device for breaking the predetermined breaking barriers may be used for the storage chamber described above. In order to form a storage chamber, which would be bounded by a deformable soft constituent of the housing component, breaking of a predetermined breaking barrier may be carried out, optionally by deformation of the chamber wall in question.
The soft constituent section of the device for breaking a predetermined breaking barrier expediently comprises an outwardly curvable membrane.
A septum, which comprises a soft constituent section, which can be pierced with a cannula, of the housing component may be formed as a further functional section of the flow cell.
In another configuration of the invention, a valve device, which comprises a soft constituent section, which can be deformed resiliently from the outside while closing a valve opening, of the housing component is formed as a functional section of the flow cell.
The soft constituent section of the valve device expediently comprises a membrane, which is optionally covered on the inside by a film.
A gas cushion, which comprises a soft constituent section, which can be deformed by an internal pressure in the flow cell while changing the gas cushion volume, may furthermore be envisioned as a functional section.
Such a soft constituent section may, for example, be formed by a membrane, the deflection of which by a plunger device of an operating instrument can be limited and may be adjusted. Such a soft constituent section may furthermore for example be formed by a curved pump element, the deflection of which by a plunger element simultaneously causes a pump action besides a modification of the gas cushion volume. In particular, a combination of at least two pump/gas cushion elements formed by soft constituent sections in combination with actuation elements, which deformed them, of an operating instrument, inside a flow cell hermetically closed from the surroundings may form a transport apparatus for fluids. Expediently, to this end, one of the pump elements is arranged upstream and a further one downstream of the fluid volume to be transported. In the case of an increased internal pressure of the flow cell compared to the ambient pressure, such an arrangement allows movements of the fluid volume both downstream and upstream, in which case the internal pressure may be adjusted in a controlled way by the degree of deflection of one or both pump/gas cushion elements.
In another configuration of the invention, a degassing apparatus, which removes a gas volume that is located between two fluid volume sections separated by a gas section, so that the two fluid volume sections are connected to one another after the degassing and may be fed to a further processing device of the flow cell, for example a sensor or a mixing or reaction chamber, is formed as a functional section of the flow cell. To this end, a deflectable soft constituent section, for example in the form of a curved pump element, is connected to a channel region, through which the fluid volume sections flow, of the flow cell, in such a way that a gas-permeable membrane that bounds the channel region is located between a volume, formed by the deflectable soft constituent section, and the channel region. For the degassing, the soft constituent section is deflected at an instant before the first fluid volume section has reached the channel region bounded by the membrane. The deflection is preferably carried out by the soft constituent section being pressed in by a plunger of an operating instrument. When the first fluid volume section has been pumped into the channel region close by the membrane, the plunger is retracted but the deflection of the soft constituent section remains because of the lack of venting.
In the volume region between the soft constituent section and the permeable membrane, a reduced pressure is created by the resilient restoring force of the soft constituent section, the effect of which is that the gas volume between the successive fluid volume sections pumped through the channel region escapes through the membrane and the successive fluid volume sections are thus connected to one another.
A chamber that receives the sample being introduced may be elongatedly shaped in such a way that sample introduction is possible by means of a rod carrying a swab, the rod having a predetermined breaking position. An elongate opening for introducing the rod with the swab may have a constriction at one end, which makes it possible to break the rod off at the predetermined breaking position, the swab containing the sample material and the rod end broken off remaining in the sample chamber.
It is to be understood that the above-described embodiments of functional sections could also be used in a flow cell when fewer than three functional sections are complemented by the housing component.
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:
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.
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.
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.
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.
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
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.
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
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.
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
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.
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.
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
According to
In the exemplary embodiments shown in
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.
In order to break the predetermined breaking barriers 34, 34′, an arrangement provided in
A predetermined breaking barrier shown in
A functional section, shown in
A functional section, represented in
The functional section of
A pump shown in
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.
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.
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.
| Number | Date | Country | Kind |
|---|---|---|---|
| 17172994.0 | May 2017 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2018/058670 | 4/5/2018 | WO | 00 |
