EP3978132A1 - Device for transporting a fluid in a duct section of a microfluidic element - Google Patents

Abstract

The invention relates to a device for transporting a fluid in a duct system of a microfluidic element, in particular a flow cell. According to the invention, a pressure source is provided for pressurizing a front end surface (42) in the transport direction of the fluid that completely fills the ductwork in cross section. Preferably, the pressure source comprises a closed space (17; 22; 34; 36, 38, 40) in which a pressurized gas, e.g. air, can be compressed by displacement of the front end face (42) of the fluid transported in the ductwork.

Description

The invention relates to a device for transporting a fluid in a duct system of a microfluidic element, in particular a flow cell.

When operating microfluidic flow cells, which are increasingly used for analytical and diagnostic purposes or in syntheses as single-use products, liquids, e.g. blood to be examined, must be transported to specific points within the flow cell in order to bring the liquids into contact with reagents, for example, or / and feed a detection area.

A common task is to separate a specific amount of liquid from a larger bulk sample fed into the flow cell and transport the separated amount of liquid onward. The separated quantity of liquid often has to be divided further into partial quantities of the same or different sizes, with the partial quantities having to be transported further. Sometimes there is also the task of bringing together amounts of different liquids brought in via several channels in a single channel for the purpose of further transport of a mixture or sequence of the amounts.

For the transport of liquids within flow cells, the end of a quantity of liquid that is trailing in the transport direction and that completely fills a channel section in cross section is pressurized, as is the case, for example, in FIG U.S. 7,125,711 , U.S. 6,615,856 and the U.S. 6,296,020 is described. The amount of liquid filling the canal strand like a plug is counteracted by the pressurization Flow resistance moves through the ductwork. The area of the ductwork lying in front of the liquid in the direction of transport is connected to a ventilation opening.

The invention is based on the object of creating a new device of the type mentioned at the outset, which makes it possible to control transport processes in microfluidic elements more precisely and reliably than in the prior art and at the same time reduce the production costs for the microfluidic elements.

The device according to the invention that achieves this object is characterized by a pressure source for pressurizing a front end face in the transport direction of the fluid that fills the cross-section of the channel section.

According to the invention, the fluid is not only moved through the channel strand of the microfluidic element by overcoming a resistance caused by friction and capillary forces, but also by overcoming a counterforce generated by the said pressurization. The pressure applied according to the invention at the front end face of the fluid, in particular a front liquid meniscus, prevents unwanted detachment of small amounts of fluid from the end face and wetting-related advances or lagging of parts of the amount of fluid close to the delimiting channel walls and thus ensures that the transported fluid is precisely delimited at its Front. By connecting the duct line to the pressure source according to the invention instead of to a ventilation opening, the microfluidic element can be closed off in a fluid-tight manner from the outside and environmental contamination by escaping fluid can be prevented. Since coatings for hydrophilization or hydrophobicization, valves for fluid control and/or extremely high accuracy requirements for the microstructures are no longer required, the manufacturing effort is reduced.

The pressure source, which is preferably a compressed gas source, can be an integral component of the microfluidic element or, for example, a component of an operator device to which the microfluidic element can be coupled.

In a particularly preferred embodiment of the invention, the pressure source comprises a closed space in which a pressurized gas, eg air, is introduced by displacement of the front end face of the fluid transported in the ductwork is compressible. The pressure built up in the closed space depending on the position of the end surface in the ductwork is applied to the end surface, and the force generated by this pressure must be overcome in addition to the flow resistance when transporting the fluid.

The force used to transport the fluid within the microfluidic element can be of different types. While an inertial force, in particular centrifugal force, can be used to shift the fluid in the duct system, in a preferred embodiment of the invention the duct system can be connected to a transport pressure source that acts on the fluid in the transport direction. The transport pressure source can also be an integral part of the microfluidic element.

This transport pressure source can be used to apply a compressed gas, e.g. The pressure force generated must overcome the flow resistance and the pressure force applied at the opposite end against the plug-like quantity of fluid according to the invention.

In a further embodiment of the invention, the pressure generated by the pressure source at the front end face is clearly functionally related to the position of the front end face in the duct line. This condition is approximately met by the previously mentioned pressure source comprising a closed space. If necessary, a correction factor that takes the ambient temperature into account is determined.

If the stated condition is met, a device that detects the pressure on the front end face, e.g. a pressure sensor, can advantageously be provided, which uses the functional relationship to determine the position of the front end face in the duct line. In this way, the position of a quantity of fluid filling the duct line like a plug within the flow cell can also be determined and its transport precisely controlled. Advantageously, the transport of the fluid can be interrupted by setting the pressure P1 of the transport pressure source equal to the pressure P2 at the front end face.

By setting the pressure (P1) of the transport pressure source smaller than the pressure (P2) at the front end surface, the transport direction can even be reversed. A quantity of fluid that fills the duct line in the manner of a plug can therefore be pushed back and forth as desired within a duct line and positioned at the desired locations eg in reaction areas, detection areas, filters or areas in which it comes into contact with a reagent stored in the microfluidic element or with a test strip known from diagnostics.

The pressure rise characteristic of the compressed gas source having the closed space can advantageously be influenced in a desired manner in that the closed space can be expanded by the compressed gas compressed therein. For example, the closed space can have a wall on one side formed by a stretchable film.

The closed space of the pressure source can be accommodated in a plate that forms the microfluidic element and/or can be formed by a separate container that can be connected to the plate.

The duct line advantageously has at least one cross-sectional widening to form a chamber, e.g. a detection chamber, a mixing chamber, a reaction chamber or the like. In particular, the chamber may contain dry reagents, e.g., substances for performing a PCR or for capturing analytes of the fluid sample, filters, membranes, test strips, mixing blades, detection means such as optical windows, prisms and electrical conductors, and other means for analysis and synthesis.

In the direction of transport, a plurality of duct lines can run together in a single duct line which is connected or can be connected to a pressure source.

The multiple duct lines can each be connected or can be connected to a transport pressure source, so that a sequence or mixture of different fluids can be generated and transported in the single duct line by sequential activation of the transport pressure sources.

In the transport direction, a duct line can also branch into a plurality of duct lines that are each connected or can be connected to a pressure source, and in this way can further divide a quantity of fluid into partial quantities without using a plurality of pressure sources or valves. The back pressure applied according to the invention at the front end surfaces of the partial amounts of fluid allows not only an even division of the total amount into partial amounts, but also the spatial separation of the partial amounts by the transport gas flowing after the partial amounts of fluid in the channel strands.

As a result, different investigations, analyzes or syntheses can be carried out in parallel without the partial fluid quantities mutually influencing one another.

The application of back pressure to the fluid to be transported according to the invention also ensures that channel sections with different cross-sectional dimensions are completely filled. Especially in the case of cracks and dimensional changes within a duct run, zones usually occur that are not completely flown through or wetted, which can lead to air bubbles being trapped. This is avoided by the invention.

By connecting the branches to different pressure sources, a desired ratio of the subsets can be set.

Fig. 1

eine Flusszelle mit einer erfindungsgemäßen Vorrichtung zum Transportieren eines Fluids,

Fig. 2

die Flusszelle von Fig. 1 in einer Detailansicht,

Fig. 3

eine die Funktion der Flusszelle von Fig. 1 erläuternde Darstellung,

Fig. 4

eine Abwandlung der Flusszelle von Fig. 1,

Fig. 5

ein Ausführungsbeispiel für eine in ein Mikrofluidelement integrierte Transportdruckquelle,

Fig. 6 bis 8

verschiedene Ausführungsbeispiele einer erfindungsgemäßen Druck quelle mit einem geschlossenen Kompressionsraum,

Fig. 9

ein Mikrobauelement mit in einem einzigen Strang zusammenlaufenden Kanalsträngen,

Fig. 10

Ausführungsbeispiele für sich verzweigende Kanalstränge, und

Fig. 11

weitere Ausführungsbeispiele für Flusszellen mit Vorrichtungen nach der Erfindung.

The invention is explained in more detail below on the basis of exemplary embodiments and the accompanying drawings relating to these exemplary embodiments. Show it:

1

a flow cell with a device according to the invention for transporting a fluid,

2

the flow cell of 1 in a detail view,

3

a the function of the flow cell of 1 explanatory presentation,

4

a modification of the flow cell from 1 ,

figure 5

an embodiment of a transport pressure source integrated into a microfluidic element,

Figures 6 to 8

various exemplary embodiments of a pressure source according to the invention with a closed compression chamber,

9

a microdevice with channel strands merging into a single strand,

10

Exemplary embodiments for branching duct lines, and

11

further exemplary embodiments for flow cells with devices according to the invention.

A plate-shaped flow cell has an inlet opening 1 for a fluid, eg a blood sample. The inlet opening 1 is located in the bottom of a pot-like storage vessel 2 molded onto the flow cell.

A channel 3 extends from the inlet opening, which runs in a meandering manner up to a widening 4 and is led further from the widening 4 to a branch 5 .

Close to the inlet opening 1, a duct 6 opens into the duct 9, which is in communication with an opening to which a source of air pressure can be connected, as will be explained below.

Near the junction 5, a channel 8 leading to a ventilation opening branches off from the channel 3. The cross section of channel 8 is significantly smaller than the cross section of channel 3.

At the junction 5, the channel 3 divides into two branch channels 9 and 9', which are symmetrical to the longitudinal central axis of the flow cell and divide again at two further junctions 10 and 10'. The channel 3 thus merges into a total of four branches 11, 11', 11" and 11'". In the exemplary embodiment shown, the four branches have the same design and have identical volumes.

Each of the four branches 11, 11′, 11″ and 11‴ contains a first meandering channel section 12, which is followed by a channel widening 13. In the exemplary embodiment shown, the channel widening 13 contains a dry reagent. The channel widening 13 is followed by a second meandering channel section 14 The channel section 14 is followed by a further widened channel 15, which in the relevant exemplary embodiment serves as a reaction chamber and can contain a further dry reagent, e.g.

At a distance from the channel widening 15 follows a third widening 16, which forms a detection chamber. The end of each branch 11, 11′, 11″, 11″″ forms a chamber 17 with a volume that is significantly larger than the volume of the widenings 13, 15 and 16.

In the exemplary embodiment shown, the plate-shaped flow cell consists of a plastic plate in which recesses are incorporated to form the channels and cavities described above, and a film sealing the recesses and welded or glued to the plastic plate in a fluid-tight manner. The known plastic processing methods, in particular injection molding, can be used to produce the plate. Deviating from the structure described, a substrate having a plurality of layers and laminated foils could be provided. Other materials include glass, silicon and metal and composite materials. Other processing methods include hot stamping and laser cutting.

Various examples for the design of chambers or channel widenings forming reaction and detection areas can be found in the document included here German patent application 10 2009 015 395.0 of the applicant.

The functioning of the flow cell described above is explained below.

A fluid sample, for example a blood sample, is introduced into the reservoir 2 at the inlet port 1 . The channel 3 fills up to the widening 4 by capillary action. To support the capillary action, the channel 3 can be made hydrophilic by plasma treatment or wet-chemical pretreatment.

As an alternative to such a self-filling, the blood sample could be introduced into the channel 3 by applying pressure, e.g. with the aid of a pipette or syringe. This task could also be performed by an operator facility provided for the flow cell. Air can escape from the channel 3 via the ventilation channel 8 .

The widening 4 limits the filling of the channel 3 and thus the precise measurement of a sample quantity, as is shown in Figure 3a is shown.

In order to process the amount of sample in the flow cell, the inlet opening 1 and the channel 8 are closed and the opening 7 is connected to an air pressure source 18 which can be part of an operating device provided for the flow cell.

With the aid of the air pressure source 18, the measured amount of sample can be conveyed beyond the widening 4 in the channel 3 to the branch 5, where the amount of sample is divided into halves. A further division into halves takes place at the branches 10 and 10', so that each of the branches 11, 11', 11" and 11‴ receives a quarter of the measured sample quantity.

Since the branches are closed at their ends remote from the opening 7, the pressure in the chambers 17 increases as a result of compression as the fluid is transported through the channel 3. In order for the sample and aliquot to be conveyed, the air pressure P1 exerted by the compressed air source 18 must be greater than the respective air pressure P2 in the chambers 17, which is applied to the front end surfaces 42 of the fluid quantities in the transport direction.

Each position of the sub-sample quantities filling the duct line like plugs corresponds to a specific pressure P2 in the chambers 17. If the pressure P1 of the compressed air source 18 is equal to the pressure P2, the sub-sample quantities remain in place.

In Figure 3b are the sub-sample amounts just in the channel section 12. By increasing the pressure P1, the sub-sample amounts according to 3c are transferred to the expansions 13, where they each come into contact with a dry reagent. Reducing the pressure P1 causes the sub-sample quantities to flow back into the meandering channel sections 12, where mixing takes place. Another increase in pressure leads the sub-sample quantity via the widened channels 13 into the next meandering channel section 14. In the channel sections 14, the mixing is completed. A further increase in the pressure P1 results in a transfer to the expansions 15, where a reaction takes place in the exemplary embodiment shown, for example a PCR. Sample testing is completed in the flares 16 where measurements are performed on the processed samples.

The compressed air source 18 can have a measuring device for determining the respective pressure P2, which uses a predetermined relationship between the pressure P2 and the positions of the subsets to determine their position and, if necessary, automatically controls the transport of the subsets.

one inside 4 The structure of the flow cell shown largely corresponds to that of the flow cell described above. Only the ventilation channel 8 and the channel 6 with the opening 7 are missing.

In order to measure a sample quantity, in this embodiment the sample inlet 1 can be connected to a pressure source and a sample quantity filling the storage vessel 2 can be pressed into the channel 3 . The volume of the measured amount of sample thus corresponds approximately to the volume of the storage vessel 2 or to a partial amount predetermined by the person entering it. The sample quantity measured in this way is processed further as described above.

Instead of an external pressure source connected to the opening 7 or the sample inlet 1,2, as shown in FIG figure 5 shows that a pressure source can also be integrated into a flow cell. According to figure 5 such an integrated pressure source is formed by a recess 19 which is covered by a flexible membrane 20.

By pressing the flexible membrane 20 into the depression 19, the pressure in a pressure line 21 can be increased by a defined amount.

Instead of being pressurized by pressurized gas, the recess 19 could also contain a liquid. In particular, a sample liquid could flow through the space formed by the recess 19 .

Instead of the indentation and a membrane, a blister with a curved, compressible foil hood could also be used.

At the in the 1 and 4 In the embodiment shown, an "air spring" is formed by the closed chamber 17 integrated into the flow cell plate.

6 shows an embodiment of an "air spring" with a chamber 22 which is covered by a flexible membrane 23. The membrane, which is made of plastic, an elastomer, silicone or TPE, for example, can be expanded in such a way that a desired increase in pressure occurs in the chamber 22 . The dimensions of the “air spring” are therefore advantageously smaller when the flow cell is not in use than when it is in operation. The bulging of the flexible membrane 23 delimiting the chamber 22 can be determined, for example, with the aid of a simple distance sensor and used to determine the pressure P2 and thus the position of the front fluid meniscus and thus set up a regulation for the fluid transport.

It can be advantageous to limit the deflection of the flexible membrane 23 using an integrated or external stamp 24 . If necessary, the volume of the chamber 22 can be adjusted in the desired manner via the position of the plunger. The stamp can be part of an operator facility.

7 12 shows a variant of an "air spring" with a separate vessel component 25 that can be attached to a flow cell, with a sealing ring 26 surrounding an opening formed on the flow cell plate.

in a 8 In the variant of an "air spring" shown, a separate vessel component 27 can be plugged onto a flow cell, in which case, for example, a plug-in crown, a press fit and/or a LUER connection can be used.

Both in the embodiment according to 7 as well as in the embodiment 8 the slab-shaped flow cell need not have a "spring chamber" itself. Advantageously, the space required for the integrated chamber can be used for other purposes.

As 8 can be seen, the vessel component 27 has an adjustable stopper 28, through which the air volume of the vessel component can be varied, so that different conditions for the transport of a fluid within a flow cell can be set.

It is understood that the "air spring" can be part of an operator's facility and a corresponding connection to the flow cell corresponding to the connection of 7 can be made with the help of a ring seal.

while in the 1 and 4 a flow cell with only a single, multiply branching duct line for the transport of a single fluid supplied via the inlet opening 1 is shown, includes a detail in FIG 9 Flow cell shown three channel strands 29, 30 and 31 for transporting different fluids. Each of the channel strands 29, 30, 31 can be connected to an inlet opening for the relevant fluid and a pressure source. Alternatively, a pressure source common to all three duct lines could be used.

The duct runs 29 to 31 converge at a mixing point 32 from which a single duct 33 runs to a closed chamber 34 . By successively applying pressure to one of the duct lines 29 to 31, sequences of the different fluids contained in the duct lines 29 to 31 can be generated in the duct 33, the size of the subsets being controllable via the pressure applied to the respective duct line.

How out Figure 10a As can be seen, the channel 33 can branch again, with branches 35, 35' each being connected to an air spring chamber 36 or 36'.

A fluid sequence generated in the channel 33 at the mixing point 32 can be divided further, with a sequence each reaching the branches 35 and 35 ′, the components of which each have half the fluid quantity of the sequence in the channel 33 . This can be advantageous in order to limit the sequential pressurization of channels 29-31 simplify. If fluid sequences with particularly small subsets are to be generated, this would require a very short and precise pressurization. When subsequently dividing an initially larger sequence into smaller sequences passively via the volumes of the partial strands, their accuracy is decisive and this accuracy can be adjusted very precisely during production of the microfluidic element by injection molding.

It is understood that by the in Figure 10a shown arrangement with two matching branches instead of a sequence a single fluid packet can be divided into two halves.

Figure 10b Figure 13 shows a branching duct with one branch 37 connected to a chamber 38 and another branch 39 connected to a chamber 40. The volume of chamber 38 is greater than the volume of chamber 40.

When a fluid package is transported, the pressure in the smaller chamber 40 increases faster than in chamber 38. Accordingly, a larger partial package is formed at the branching point in branch 37 than in branch 39. By choosing different sizes for chambers 38, 40, the ratio can be adjusted vary as appropriate with the splitting of the fluid packet at the bifurcation point.

11 shows further exemplary embodiments for flow cells, wherein in the exemplary embodiment of FIG Figure 11a a canal branch with a matrix-like branching and in Figure 11b a ductwork with a star-shaped branching is shown. The duct line has a central inlet opening 41, which at the same time forms a branching point.

A pneumatic pressure source, for example, can be connected to the branching point. The embodiment of Figure 11b is particularly suitable for the transport of fluid by centrifugal force. For this purpose, the flow cell is rotated around the inlet opening 41 .

Claims (15)

Device for transporting a fluid in a channel line of a microfluidic element, in particular a flow cell,
characterized by a pressure source for pressurizing a front end surface (42) in the transport direction of the fluid which completely fills the channel rank in cross section. Device according to claim 1,
characterized,
that the pressure source comprises a closed space (17; 22; 34; 36, 38, 40) in which a pressurized gas, eg air, is compressible by displacement of the front end face (42) of the fluid transported in the ductwork. Device according to claim 1 or 2,
characterized,
that the duct line is connected or can be connected to a transport pressure source (18) which acts on the fluid in the transport direction. Device according to claim 3,
characterized,
that the transport pressure source (18) is provided for applying a compressed gas, eg air, to the rear end face (43) in the transport direction of a quantity of fluid filling the duct line in the manner of a plug. Device according to one of claims 1 to 4,
characterized,
that the pressure generated by the pressure source on the front end face (42) is in a clear functional relationship to the position of the front end face (42) in the ductwork. Device according to claim 5,
characterized,
that a device is provided that detects the pressure on the front end face (42) and uses the functional relationship to determine the position of the front end face (42) in the duct line. Device according to one of claims 3 to 6,
characterized,
that the transport of the fluid can be interrupted by setting the pressure (P1) of the transport pressure source (18) equal to the pressure (P2) at the front end face (42). Device according to one of claims 3 to 7,
characterized,
that the transport direction can be reversed by setting the pressure (P1) of the transport pressure source (18) smaller than the pressure (P2) on the front end face (42). Device according to one of claims 2 to 8,
characterized,
that the closed space (22) is expandable by the compressed gas compressed therein. Device according to one of claims 2 to 8,
characterized,
that the closed space (17) is arranged within a plate forming the microfluidic element and/or is formed by a container (25; 27) that can be connected to the plate. Device according to one of claims 1 to 10,
characterized,
that the duct line has at least one cross-sectional widening (13, 15, 16) to form a chamber in which means for treating and/or analyzing a fluid sample are provided. Device according to one of claims 1 to 11,
characterized,
that in the transport direction, several duct lines (29, 30, 31) converge in a single duct line (33) which is or can be connected to the pressure source (34). Device according to claim 12,
characterized,
that the multiple channel lines (29,30,31) are each connected or can be connected to a transport pressure source. Device according to one of claims 1 to 13,
characterized,
that in the direction of transport a duct line branches into several duct lines (8, 9', 11, 11', 11", 11"; 35, 35'), each connected or connectable to a pressure source (17; 36, 36'). Device according to claim 14,
characterized,
that the branches (37,39) are connected to different pressure sources (38,40).

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