Microfluidic device, evaluation device, method for manufacturing a microfluidic device and control unit

Abstract

The present approach relates to a microfluidic device (100) for processing fluids. The microfluidic device (100) comprises a base element (110) with a recess (130) and a sealing film (140) arranged on one side of the base element (110) and covering the recess (130). The microfluidic device (100) also comprises at least one microfluidic receiving element (135) for carrying out a reaction in the microfluidic device (100). The microfluidic receiving element (135) is arranged directly on the sealing film (140) in the recess (130).

Description

[0001] The present approach relates to a microfluidic device, an evaluation device, a method for producing a microfluidic device, a method for evaluating a fluid in a microfluidic device and a corresponding control device according to the main claims. State of the art

[0002] A biological analysis device such as a biochemical cartridge can contain a microfluidic device, also called a chip chamber, with an inserted chip with wells. The chip can also be referred to as an insert component or receiving element, and the wells as cavities or receiving cavities. The chip can be specifically designed to run a qPCR, i.e., a thermal-temporal sequence protocol. For this purpose, for example, the wells can be (first) filled and sealed, and (subsequently) a temporal temperature profile can be run. qPCR stands for quantitative PCR and refers to a method for amplifying nucleic acids such as DNA or RNA.

[0003] For example, with the aim of carrying out several biochemical analyses on a single biochemical sample, for example comprising a body fluid such as blood, sputum or urine, several recesses, so-called blind hole arrays or well arrays, with defined geometric dimensions can be etched into a silicon chip, for example. Reagents which react with the biochemical sample to be analyzed and can be optically evaluated and / or analyzed can be introduced into the recesses, also called wells. The receiving element can be glued into a chamber which is optically accessible from above, the microfluidic device, and can be flushed with the biochemical sample, for example.To amplify RNA in the sample (PCR), a temporal temperature profile can be used, for example, which can ensure in particular denaturation, i.e. a structural change of biomolecules, and / or annealing, i.e. pairing and formation of hydrogen bonds.

[0004] A conventionally designed microfluidic device, also referred to as a chip chamber, is often not suitable for qPCR in the chip chamber, since, particularly due to poor thermal conductivity of a cartridge material of the microfluidic device, the corresponding heating and / or cooling rates for qPCR are often not achievable. Disclosure of the invention

[0005] Against this background, the approach presented here provides a microfluidic device, an evaluation device, a method for producing a microfluidic device, a method for evaluating a fluid in a microfluidic device, a control device using such a method, a corresponding computer program, and finally a corresponding machine-readable storage medium according to the main claims. The measures listed in the dependent claims enable advantageous refinements and improvements of the device specified in the independent claim.

[0006] The present approach is based on the finding that a temporal and / or thermal sequence protocol can be successfully implemented if the receiving element, i.e., the chip, is arranged directly on the sealing foil in the recess. This allows for efficient temperature control of the receiving element without altering the desired temperature profile due to unfavorable thermal insulation properties of the housing material of the microfluidic device.

[0007] A microfluidic device for processing fluids is presented. The microfluidic device comprises a base element with a recess and a sealing film arranged on one side of the base element and covering the recess. The microfluidic device further comprises at least one microfluidic receiving element for carrying out a reaction in the microfluidic device. The microfluidic receiving element is arranged directly on the sealing film in the recess.

[0008] A microfluidic device can be understood as a chemical, biological, or biochemical analysis system, a so-called lab-on-chip (LoC for short), particularly for the automated, reliable, compact, and cost-effective processing of chemical or biological substances for medical diagnostics. Complex microfluidic process sequences can be realized by combining a variety of operations for the targeted manipulation of fluids.

[0009] An important component of such microfluidic devices can be a receiving element. Small reaction chambers of the receiving element, referred to here as recesses, depressions, or cavities, can accommodate one or more fluids to be examined, i.e., one or more liquids. A recess in the base element can also be understood, for example, as an opening, so that the receiving element can be arranged or placed in or through this recess directly on the sealing film.

[0010] The present approach can make it possible to run such a temporal and / or thermal protocol, i.e., a qPCR, particularly in the recesses of the receiving element. Especially since there is now a very thin wall, namely the sealing film, between an externally applied temperature control element and the receiving element, the temperature of the fluid or reagents in this receiving element can now very quickly follow the temperature or temperature profile specified or imposed by the temperature control element, so that a desired reaction can be reliably carried out with this temperature profile.

[0011] According to one embodiment, the microfluidic device can have a cover element that, together with the base element, forms a housing for the microfluidic device. In particular, the cover element can have a fluidic layer, i.e., a fluid layer, and / or a pneumatic layer, i.e., a pneumatic layer, which can be separated from one another, in particular, by a membrane layer. Furthermore, the cover element can, for example, be glued or pressed onto the base element, directly or indirectly via the membrane layer. By means of such a membrane arranged between the cover element and the base element, the cover element and the base element can be joined together, in particular, such that the membrane (layer) seals the fluid chamber, i.e., the microfluidic device.

[0012] According to a further embodiment, the lid element can have a projection in the region of the recess and / or the receiving element. This allows the chamber height, i.e., the height of a fluid channel for conducting a fluid, above the receiving element to be kept as low as possible so that an excessive or unnecessarily large amount of buffer solution, i.e., buffer solution, in particular, sample liquid, is not required or consumed. In other words, the projection fills part of the recess to reduce the chamber height, in particular by the projection and thus the lid element partially engaging the recess of the base element. In a layered structure, as described in particular above, the membrane layer can have an opening in the region of the recess, so that the projection of the lid element, in particular of the fluidic layer, extends through this opening partially into the recess of the base element, in particular of the pneumatic layer.

[0013] According to one embodiment, a fluid channel for guiding the fluid can be formed between the base element and the lid element. This enables, in particular, the performance of a qPCR, in which the recess can be filled and sealed with the fluid, i.e., the liquid, via the fluid channel or an inlet of the fluid channel, for example, and a temporal temperature profile can be run.

[0014] According to a further embodiment, the base element and / or the lid element can be made at least partially, in particular entirely, of a plastic material. Choosing a plastic, in particular polycarbonate, as the material for a cartridge, i.e., here for the base element and / or the lid element, enables cost-effective production of the cartridge.

[0015] According to one embodiment, the microfluidic receiving element can have a plurality of receiving cavities. In particular, a reagent required for a reaction can be at least partially stored in the receiving cavities. Reagents that react with the biochemical sample to be analyzed and can be optically evaluated and analyzed can be introduced into the receiving cavities, which can also be referred to as wells or blind holes, for example. This embodiment with multiple receiving cavities and the reagents enables multiple biochemical analyses to be performed with a (single) biochemical sample.

[0016] Furthermore, an evaluation device for evaluating a microfluidic device, in particular for evaluating a fluid, for example, a biochemical sample, in the device, is presented. According to one embodiment, the evaluation device can have a temperature control element for controlling the temperature of the microfluidic device. The temperature control element offers the advantage that a rapidly changing temporal temperature profile can be imprinted on the liquid(s) in the wells, i.e., in the receiving cavities, which (in turn) ensures or achieves successful qPCR.

[0017] According to a further embodiment, the evaluation device can comprise a detector unit for detecting an optically detectable change in the region of the microfluidic receiving element. The microfluidic device can be positioned, in particular, between the detector unit and the temperature control unit. Furthermore, the detector unit can be oriented toward the temperature control unit for detection. Using the evaluation device, the liquids in the receiving cavities can be evaluated and analyzed, in particular, optically. For this purpose, in particular, the chamber, i.e., the microfluidic device, can be optically accessible from a top side of the microfluidic device. Furthermore, by means of such an optical examination, i.e., evaluation or analysis, the approach presented here can be demonstrated by way of example.Using the detector unit, optically detectable changes can be detected (optically), particularly in the receiving cavities. For example, positioning the microfluidic device between the detector unit and the temperature control unit and / or aligning the detector unit toward the temperature control unit can be advantageous for such a purpose, as the detection of the detector unit can thus be implemented effectively.

[0018] Furthermore, a method for producing a microfluidic device according to a variant presented here is presented. The method comprises a step of arranging the at least one microfluidic receiving element for carrying out a reaction in the microfluidic device in a recess of the base element directly on the sealing film, which is arranged on one side of the base element and covers the recess. This embodiment of the present approach in the form of a method also allows the problem underlying the present approach to be solved quickly and efficiently.

[0019] Also, according to a further embodiment, a method for evaluating a fluid in a variant of a microfluidic device presented here is provided in a variant of an evaluation device presented here, wherein the method comprises a step of tempering the fluid in the microfluidic device by means of the tempering element and a step of analyzing the tempered fluid in the microfluidic device using the detector unit.

[0020] This method can be implemented, for example, in software or hardware or in a mixed form of software and hardware, for example in a control unit.

[0021] The approach presented here further creates a control unit configured to perform or implement the steps of a variant of the method presented here in corresponding units. This embodiment of the present approach in the form of a control unit also allows the task underlying the present approach to be solved quickly and efficiently.

[0022] For this purpose, the control unit can have at least one computing unit for processing signals or data, at least one memory unit for storing signals or data, at least one interface to a sensor or an actuator for reading sensor signals from the sensor or for outputting control signals to the actuator, and / or at least one communication interface for reading or outputting data embedded in a communication protocol. The computing unit can be, for example, a signal processor, a microcontroller, or the like, wherein the memory unit can be a flash memory or a magnetic storage unit.The communication interface can be designed to read in or output data wirelessly and / or wired, wherein a communication interface that can read in or output wired data can read this data, for example, electrically or optically from a corresponding data transmission line or output it to a corresponding data transmission line.

[0023] In this context, a control unit can be understood as an electrical device that processes sensor signals and outputs control and / or data signals depending on them. The control unit can have an interface that can be implemented in hardware and / or software. In a hardware implementation, the interfaces can, for example, be part of a so-called system ASIC, which contains a wide variety of functions of the control unit. However, it is also possible for the interfaces to be separate integrated circuits or to consist at least partially of discrete components. In a software implementation, the interfaces can be software modules that are present, for example, on a microcontroller alongside other software modules.

[0024] Also advantageous is a computer program product with program code that can be stored on a machine-readable medium such as a semiconductor memory, a hard disk memory or an optical memory and is used to carry out the method according to one of the embodiments described above when the program product is executed on a computer or a device.

[0025] Furthermore, the approach presented may comprise a machine-readable storage medium on which the computer program product is stored.

[0026] The approach presented here is explained in more detail below using the attached drawings. They show: Fig. 1 is a schematic side view of a microfluidic device according to an embodiment; Fig. 2 a schematic top view of a microfluidic receiving element for a microfluidic device according to an embodiment; Fig. 3 is a flowchart of an embodiment of a method for manufacturing a microfluidic device; Fig. 4 is a flowchart of an embodiment of a method for evaluating a fluid in a microfluidic device; and Fig. 5 a block diagram of embodiments of control units.

[0027] In the following description of advantageous embodiments, the same or similar reference numerals are used for the elements shown in the various figures and having a similar effect, whereby a repeated description of these elements is omitted.

[0028] Fig. 1 shows a schematic side view of a microfluidic device 100 according to one embodiment. The microfluidic device 100 is used in particular for processing fluids and, for this purpose, comprises a fluid channel 105 for guiding the fluid through the microfluidic device 100. The fluid channel 105 is formed between a base element 110 and a cover element 115. The base element 110 and the cover element 115 are optionally made at least partially, in particular completely, from a plastic material. The cover element 115, together with the base element 110, forms a housing 120 of the microfluidic device 100. According to one embodiment, the housing 120 is adhesively bonded; according to another embodiment not explicitly shown here, the housing 120 is pressed.A membrane 125, in particular a TPU membrane, is optionally cut free and arranged between the cover element 115 and the base element 110 in such a way that, when the cover element 115 and the base element 110 are joined together, the membrane 125 seals the fluid chamber of the microfluidic device 100 or the microfluidic device itself upwards. In other words, the cover element 115 and the base element 110 can be joined together by means of the cut-free membrane 125 arranged between the cover element 115 and the base element 110 in such a way that the membrane 125 seals the fluid chamber of the microfluidic device 100 upwards, i.e., in a direction of the cover element 115 and / or in a region of the cover element 115.

[0029] The base element 110 has a recess 130 in which a microfluidic receiving element 135 is arranged for carrying out a reaction in the microfluidic device 100. The microfluidic receiving element 135 is arranged in the recess 130 directly on a sealing film 140. The sealing film 140 is arranged on one side of the base element 110 and covers the recess 130. In order to require the smallest possible process volume for the fluid, a projection 142 is further provided in the cover element 115, which keeps the height of the fluid channel 105 above the microfluidic receiving element 135 low, so that the fluid is guided in a thin or flat channel over the microfluidic receiving element 135. As shown in Fig. 1, the membrane 125 can be interrupted in the region of the recess 130 or have an opening so that the projection 142 of the cover element 115 extends partially into the recess 130.

[0030] In order to ensure that a liquid intended or used for a qPCR, in particular a sample liquid, can quickly follow the temperature changes caused by the temperature profile in the recesses 130 in order to ensure a successful qPCR, the receiving element 135 is glued directly to the sealing film 140, which on an opposite side is in direct contact with the temperature control element, also called heater, described below.

[0031] Furthermore, an evaluation device 145 is provided for evaluating the microfluidic device 100 during operation. One evaluation device 145 comprises, for example, a temperature control element 150 for controlling the temperature of the microfluidic device 100 when it is inserted into the evaluation device 145. For this purpose, a fluid is first guided into the microfluidic device 100 via the fluid channel 105, so that this fluid reaches or enters cavities of the microfluidic receiving element 135 and reacts, for example, with a reagent stored upstream in these cavities.To achieve a desired reaction of the reagent with the substances contained in the fluid, a specific temperature profile can now be controlled or impressed via a temperature control element 150 under the sealing film 140, so that the fluid in the microfluidic receiving element 135 can also be brought to a temperature of this temperature profile through the direct contact of the microfluidic receiving element 135 with the sealing film 140 without significant thermal resistance. The reaction of the reagent with the substances contained in the fluid can result in a change in the optical properties of the fluid introduced onto or into the microfluidic receiving element 135, which can then be read out using an optical detector.The evaluation device 145 therefore optionally comprises a detector unit 155 for detecting an optically detectable change in the region of the microfluidic receiving element 135. Knowing the change in these optical properties in the detector unit, it is now possible to draw conclusions about the substances located in the cavities of the microfluidic receiving element 135. The evaluation device 145 can also be designed to control or memorize the desired temperature profile itself in order to be able to carry out a flexible evaluation of the reaction in the microfluidic device 100. For such an evaluation, the microfluidic device 100 is advantageously positioned between the detector unit 155 and the temperature control unit 150 so that the temperature control unit 150 does not obstruct the field of view of the detector unit 155 as much as possible. Alternatively, the detector unit 155 is oriented toward the temperature control unit 150 for detection.

[0032] The microfluidic device 100 can also be used as a chip chamber and this Fig. 1 can therefore alternatively be described as a sketch of the new, preferred structure of the chip chamber in a side view.

[0033] Fig. Figure 2 shows a schematic top view of a microfluidic receiving element 135 for a microfluidic device 100 according to an embodiment. The receiving element 135 has a plurality of receiving cavities 200, which are arranged in the Fig. 2 are not shown to scale, but merely by way of example. According to one embodiment, four receiving cavities 200 are located in, on, or on the receiving element 135. In particular, a reagent required for the reaction, but not shown, is at least partially stored in the receiving cavities 200.

[0034] This Fig. 2 can alternatively be described as a sketch of the new, preferred structure of the chip chamber in a top view.

[0035] Fig. 3 shows a flowchart of an embodiment of a method 300 for manufacturing a microfluidic device. According to one embodiment, prior to method 300, cartridge material, in particular polycarbonate, is or was removed from the microfluidic device due to the poor conductivity of the cartridge material, or a corresponding mold is modified for an injection molding process to form the recess in the base element 110.

[0036] The method 300 comprises a step 305 of arranging, in particular gluing, a chip, i.e., a microfluidic receiving element, for carrying out a reaction in the microfluidic device in a recess of the base element directly on the sealing film. The sealing film is arranged on one side of the base element and covers the recess. According to one embodiment, the sealing film is in direct contact with the heater, i.e., the temperature control element.

[0037] According to a further exemplary embodiment, the cover element above the receiving element is thickened or provided with the projection in such a way that a free height above the receiving element corresponds in particular approximately to a free height of a comparable or similar conventional method. In other words, this thickening is carried out, for example, in order to keep a chamber height, i.e. a height of a fluid channel for guiding a fluid, above the receiving element as low as possible so that an excessive or unnecessarily large amount of buffer solution, i.e. buffer solution, i.e. in particular sample liquid, is not required. In this method 300, therefore, merely by way of example, approximately the same amount of fluid, i.e. approximately the same amount of liquid, should be used as in a comparable or similar conventional method.

[0038] Optimally, by performing such a method 300, a successful qPCR in the recess of the receiving element can be ensured or enabled.

[0039] Fig. 4 shows a flow diagram of an embodiment of a method 400 for evaluating a fluid in a variant of a microfluidic device presented here in a variant of an evaluation device presented here, wherein the method 400 comprises a step 410 of tempering the fluid in the microfluidic device by means of the tempering element and a step 420 of analyzing the tempered fluid in the microfluidic device using the detector unit.

[0040] Fig.5 shows block diagrams of exemplary embodiments of control devices 500 and 510 presented here. A first control device 500 is designed to control step 305 of the method 300 for producing a variant of a microfluidic device presented here, for which purpose the control device 500 has a unit 515 for arranging the at least one microfluidic receiving element for carrying out a reaction in the microfluidic device in a recess of the base element directly on the sealing film, which is arranged on one side of the base element and covers the recess.

[0041] A second control unit 510, which is formed by or comprises the evaluation device, is provided for controlling steps 410 and 410 of the method 400 for evaluating a fluid in a variant of a microfluidic device presented here. The control unit 510 comprises the temperature control element 140 for controlling the temperature of the fluid in the microfluidic device and the detector unit 155 for analyzing the temperature-controlled fluid in the microfluidic device.

[0042] Furthermore, the process steps presented here can be repeated and carried out in a different order than that described.

[0043] The exemplary embodiments described and shown in the figures are selected only as examples. Different exemplary embodiments can be combined with each other in their entirety or with regard to individual features. Furthermore, one exemplary embodiment can be supplemented by features of another exemplary embodiment.

[0044] If an embodiment comprises an “and / or” link between a first feature and a second feature, this is to be read as meaning that the embodiment according to one embodiment has both the first feature and the second feature and according to another embodiment has either only the first feature or only the second feature.

[0045] The present approach can enable a temporal and / or thermal protocol to be run in the recesses of the receiving element. A low thermal resistance in the receiving element can ensure that the temperatures can follow the temperature control element during the protocol. This can reduce or minimize any lag between heater temperatures, i.e., temperatures in the temperature control element, and chamber temperatures, i.e., temperatures in the microfluidic device.

[0046] The approach presented here can alternatively be referred to as thermal chip chamber optimization for rapid temperature changes – direct chip connection with sealing foil. Here, the chip is arranged directly on the sealing foil. Optionally, the lid element engages with the base element to reduce the chamber height. Optionally, the base element is separated from the lid element by a membrane, particularly a TPU membrane.

[0047] The approach presented here can only be demonstrated by optical examination as an example. As a setup, the approach presented here is particularly suitable for use in a lab-on-a-chip system. For the implementation of such or a similar setup, modifications to the injection molding tool may be necessary or desirable.

Claims

[1] Microfluidic device (100) for processing fluids, the microfluidic device (100) having the following features: - a base element (110) with a recess (130); - a sealing film (140) arranged on one side of the base element (110) and covering the recess (130); and - at least one microfluidic receiving element (135) for carrying out a reaction in the microfluidic device (100), wherein the microfluidic receiving element (135) is arranged directly on the sealing film (140) in the recess (130). [2] Microfluidic device (100) according to claim 1, comprising a cover element (115) which, together with the base element (110), forms a housing (120) of the microfluidic device (100). [3] Microfluidic device (100) according to claim 2, wherein the cover element (115) has a projection (142) in the region of the recess (130) and / or the receiving element (135). [4] Microfluidic device (100) according to one of claims 2 or 3, wherein a fluid channel (105) for guiding the fluid is formed between the base element (110) and the cover element (115). [5] Microfluidic device (100) according to one of claims 2 to 4, wherein the base element (110) and / or the cover element (115) is or are made at least partially, in particular completely, from a plastic material. [6] Microfluidic device (100) according to one of the preceding claims, wherein the microfluidic receiving element (135) has a plurality of receiving cavities (200), in particular wherein a reagent required for the reaction is at least partially stored in the receiving cavities (200). [7] Evaluation device (145) for evaluating a microfluidic device (100), in particular for evaluating a fluid in the device (100), according to one of the preceding claims, wherein the evaluation device (145) comprises a tempering element (150) for tempering the microfluidic device (100). [8] Evaluation device (145) according to claim 7, comprising a detector unit (155) for detecting an optically detectable change in the region of the microfluidic receiving element (135), in particular wherein the microfluidic device (100) is positionable between the detector unit (155) and the tempering element (150), and / or wherein the detector unit (155) is aligned in the direction of the tempering element (150) for detection. [9] A method (300) for producing a microfluidic device according to any one of claims 1 to 6, wherein the method (300) comprises the following step: - Arranging (305) the at least one microfluidic receiving element for carrying out a reaction in the microfluidic device in a recess of the base element directly on the sealing film, which is arranged on one side of the base element and covers the recess. [10] Method (400) for evaluating a fluid in a microfluidic device (100) according to one of claims 1 to 6 in an evaluation device (145) according to claim 7 or 8, wherein the method (400) comprises the following steps: - tempering (410) the fluid in the microfluidic device (100) by means of the tempering element (140); and - analyzing (420) the tempered fluid in the microfluidic device (100) using the detector unit (155). [11] Control device (500) which is designed to carry out and / or control the step (305) of the method (300) according to claim 9 or the steps (410, 420) of the method (400) according to claim 10 in a corresponding unit (510; 520, 530). [12] Computer program product with program code for carrying out the method (300) according to claim 9 or the method (400) according to claim 10, when the program product is executed on a control device (500) according to claim 11. [13] A machine-readable storage medium on which the computer program product according to claim 12 is stored.

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