DE102020215981A1 - Processing unit, analysis cartridge with processing unit, method for producing a processing unit and method for producing an analysis cartridge - Google Patents

Abstract

The invention relates to a processing unit (105) for use in a microfluidic analysis cartridge (100), the processing unit (105) comprising a reaction layer (110) with cavities for carrying out a reaction. In addition, the processing unit (105) has a contact element (120) arranged opposite the reaction layer (110) for contacting a temperature control element (122) and additionally or alternatively for transferring heat into or out of the reaction layer (110).

Description

State of the art

The invention is based on a processing unit, an analysis cartridge with a processing unit, a method for producing a processing unit and a method for producing an analysis cartridge according to the species of the independent claims. The subject matter of the present invention is also a computer program.

Microarray chips are used in so-called lab-on-chip cartridges to process a fluid or other sample. For this purpose, the microarray chip is glued into a recess of a so-called PL layer of the cartridge in the production process before the several layers of the lab-on-chip cartridge are joined by welding with a so-called mask laser process. In the production flow of the cartridge structure, a drop of adhesive is dispensed into the recess of the PL layer, the microarray chip is then inserted from above with a gripper, and the adhesive is cured by UV exposure.

Disclosure of Invention

Against this background, with the approach presented here, an improved processing unit, an improved analysis cartridge with a processing unit, an improved method for producing a processing unit and an improved method for producing an analysis cartridge, a device that uses one of these methods, and finally a corresponding one Computer program according to the main claims presented. Advantageous developments and improvements of the device specified in the independent claim are possible as a result of the measures listed in the dependent claims.

When processing different samples or sample liquids in a microfluidic analysis cartridge, so-called microarray chips can be used, in whose cavities, or microarray cells, different reactions can be carried out. In order to carry out some polymerase chain reactions, such as qPCR reactions, it is also necessary to heat up the reagents used in the cavities relatively quickly or allow them to cool down relatively quickly. With the analysis cartridge presented here and the presented processing unit, thermal cycling in the area of the processing unit is advantageously facilitated, as a result of which the performance of temperature-dependent reactions can be optimized.

A processing unit for use in a microfluidic analysis cartridge is presented, the processing unit comprising a reaction layer with cavities for carrying out a reaction. In addition, the processing unit has a contact element arranged opposite the reaction layer for contacting a temperature control element and additionally or alternatively for transferring heat into or out of the reaction layer. A contact element arranged opposite the reaction layer can be understood in particular as meaning an arrangement in which the contact element is positioned on a side of the reaction layer which faces away from or is opposite to the cavities of the reaction layer. In other words, the cavities are preferably arranged on a first surface of the reaction layer, while the contact element is arranged on a second surface of the reaction layer opposite the first surface.

The processing unit can be a silicon microarray chip, for example, in the cavities of which various reactions can be carried out, for example to determine a characteristic of a sample liquid. The reaction layer can have a height of 380 μm, for example, while the contact element can have a contact element height of 500 μm, for example. Both heights can thus correspond to typical wafer thicknesses, for example with standard 6-inch wafers (150mm diameter), and can therefore be obtained very cheaply as blanks. The processing unit can be used in a microfluidic analysis cartridge, in which case the analysis cartridge can be made, for example, from different plastic layers, for example from polycarbonate. The thermal conductivity of the analysis cartridge can differ from the thermal conductivity of the processing unit. For example, the processing unit can have a higher thermal conductivity than the plastic layers of the analysis cartridge. In order to optimize the heat transfer of the processing unit, the processing unit includes a contact element with which a temperature control element arranged outside the analysis cartridge, for example a heating or cooling finger of an analysis device, can be contacted. The contact element can be understood here as a section of the processing unit which is designed to absorb heat or cold (for example from the temperature control element) and to transfer it to or from the reaction layer. This can be avoided that the temperature of the processing unit takes place through heat transport through the plastic of the analysis cartridge with its poor thermal conductivity. In this way, reactions which require rapid thermal cycling of the processing unit by heating or cooling from the outside can advantageously be carried out in the cavities of the reaction layer. This enables, for example, so-called qPCR reactions in the cavities of the reaction layer.

According to one embodiment, the contact element can have a contact element width that can be less than a width of the reaction layer and/or wherein a contact element height of the contact element corresponds to at least half the height of the reaction layer. The contact element width can, for example, correspond to a maximum of half or, for example, a maximum of one third of the width of the reaction layer, with the contact element being able to be arranged centrally on a side of the reaction layer arranged opposite the cavities. Thus, the processing unit can be approximately T-shaped. Advantageously, when inserting the processing unit into an analysis cartridge, the reaction layer can be firmly connected to a portion of the analysis cartridge, for example, while the contact element can be arranged largely exposed in order to make contact with a temperature control element outside the analysis cartridge.

According to a further embodiment, an intermediate layer can be arranged between the reaction layer and the contact element, which intermediate layer can in particular be embodied as an etching stop layer. For example, the reaction layer, which can be, for example, a standard silicon wafer with a thickness of, for example, 380 μm, can be bonded to the contact element via an intermediate oxide with a thickness of, for example, 1 to 3 μm, preferably 2 μm. Additionally or alternatively, the contact element, which can be, for example, a second standard silicon wafer with a thickness of, for example, 500 μm, can also carry the intermediate oxide. The intermediate layer can be applied to the wafer or wafers, for example, by thermal oxidation or, for example, by means of CVD deposition (Chemical Vapor Deposition), such as LPCVD (Low-Pressure CVD) or PECVD (Plasma-Enhanced CVD) . A thermal direct bonding of the two wafers, for example, can be carried out as a bonding method. The intermediate layer serves in particular as an etch stop layer in the manufacturing process. If, for example, the reaction layer and the contact element are made of silicon, then the intermediate layer can be a silicon dioxide, for example. Due to the high selectivity with regard to the etching of silicon versus silicon dioxide, for example, an automated process of deep etching during the production of the contact element of the processing units can automatically stop on the intermediate layer. This so-called etch stop can enable a high tolerance to overetching, so that inhomogeneities in the etching process over the wafer surface or inaccuracies in the etch rate control can be compensated for by overetching. As a result, savings in costs and time expenditure can advantageously be achieved during a production process and, at the same time, precise shaping of the contact element of the processing units can be optimized. In addition, the etch stop can, for example, enable the use of endpoint detection methods, for example the use of an optical endpoint control by what is known as optical emission spectroscopy, or laser-based etch stop techniques. The etch stop can in particular have the effect that an underside of the reaction element or reaction layer that has been etched free can particularly advantageously be optically reflected, ie it can be produced in an atomically smooth or mirror-smooth manner with minimal roughness. A high level of light reflection can thus advantageously be available on the underside of the reaction layer that has been etched free. In addition, a buried etch stop layer has the advantage that the desired step height of the contact element can be precisely controlled independently of process fluctuations and endpoint control techniques can even be used to monitor the etch process in the sense of monitoring.

According to a further embodiment, the reaction layer and the contact element can at least partially comprise the same material. For example, the reaction layer and the contact element can be made entirely of the same material. As a result, the reaction layer and the contact element can advantageously have comparable material-related properties, for example the same thermal conductivity.

In addition, the reaction layer and the contact element can be formed from silicon wafers. Silicon has excellent thermal conductivity, which means that it can advantageously be very well suited for fast cyclic temperature exposure, for example for carrying out a fast qPCR in the cavities of the reaction layer.

In addition, a microfluidic analysis cartridge for analyzing a sample is presented, the analysis cartridge having at least one carrier backing layer with at least one backing layer opening and at least one membrane arranged along a surface of the backing layer and having at least one membrane opening. In addition, the analysis cartridge comprises at least one variant of the processing unit presented above, wherein the contact element of the processing unit is arranged or can be arranged in the carrier layer opening and additionally or alternatively in the membrane opening. The carrier layer, which can also be referred to as the “PC-seal transparent” layer, can have a carrier layer height of 375 μm, for example. A membrane with a membrane height of, for example, 100 μm can be arranged along a surface of the carrier layer, in which case the membrane can also be referred to as a “PC-seal black” layer. "Black" enables a laser welding process in this layer because the laser light can be absorbed there. "Transparent" allows laser light to pass through to the "black" layer of sweat, since it is not absorbed in the transparent layer and thus reaches the "black" layer. In this case, the carrier layer opening and the membrane opening can overlap one another, so that overall there can be a through-opening through the analysis cartridge. The processing unit can be inserted into this through-opening formed from the carrier layer opening and the membrane opening, with the reaction layer of the processing unit being able to rest on a membrane surface, while the contact element can lead through the membrane opening and the subsequent carrier layer opening. Since the processing unit, which can also be referred to as a microarray chip, can thus be guided through the analysis cartridge instead of sitting on a plastic layer, thermal cycling of the microarray chip by heating and cooling from the outside is advantageously possible, even if, for example, the The plastic polycarbonate chosen for the analysis cartridge has a comparatively poor thermal conductivity. For example, heating and cooling can take place via a heating or cooling finger of a laboratory device with a predetermined cycle time, thus advantageously enabling qPCR reactions to be carried out in the cavities of the processing unit, for example. Rapid temperature cycling can be made possible through the openings in the plastic layers of the analysis cartridge between the processing unit and the outside world, for example the heating or cooling fingers in an analysis device. This has the advantage that the analysis cartridge presented here with the processing unit can be used both for isothermal amplification reactions, e.g. in the manner of an rITA reaction, in which there is no need for temperature cycling, and for temperature-controlled reactions, such as qPCR reactions . Advantageously, the area of use of the analysis cartridge presented here can be expanded as a result, in particular when great importance is attached to quantization of the amplification results in the sense of a qPCR.

According to one embodiment, the analysis cartridge can comprise at least one absorption layer with at least one absorption layer opening, in which case the membrane can be arranged between the absorption layer and the carrier layer and the reaction layer can be arranged or can be arranged in the absorption layer opening, in particular the absorption layer opening being formed with a larger diameter can be used as the backing layer opening and additionally or alternatively as the membrane opening. The receiving layer, which can also be referred to as a PL layer, can have a receiving layer height of 1.7 mm, for example, and can be welded to the carrier layer via the membrane at least in a partial area. The receiving layer can have, for example, various fluid channels and additionally or alternatively fluid chambers, through which, for example, a sample liquid can advantageously be conducted to the processing unit. A diameter of the receiving layer opening can correspond to at least one diameter of the reaction layer of the processing unit or be formed larger than this in order to advantageously optimize insertion of the processing unit into the analysis cartridge.

According to a further embodiment, a bearing surface of the reaction layer can be connected or can be connected to the membrane by means of an adhesive. The bearing surface can, for example, correspond to a surface of the membrane covered by the reaction layer. Accordingly, the processing unit and the membrane can be firmly connected to one another by means of the adhesive, as a result of which a secure positioning of the processing unit in the analysis cartridge can advantageously be achieved. The adhesive can be cured, for example, by UV radiation from a side of the membrane that is opposite the reaction layer. As an adhesive that can be cured by UV radiation, for example, an acrylic adhesive can be used, which can also have sealing properties at the same time. For example, for a corresponding UV curing process, the transmission T% of the membrane can be scaled by a factor of 1/T% for the UV radiation dose applied for curing. That is, when a specific UV dose D, which can be the product of radiation power and exposure time, is needed to cure the adhesive then the UV dose actually used can be D'=D/T%. This factor, which can be realized both by a higher power and by a longer irradiation period or a combination of both, can be between e=2.718 to 10, for example 5, in a favorable design. In addition, when gluing using UV radiation, you can also benefit from UV scattered light, which, starting from the peripheral outer edge or from possible perforation openings in the carrier layer and the membrane, laterally penetrates into the adhesive layer between the underside of the processing unit and the top side of the membrane can be reflected into it and, in addition to any UV intensity transmitted through the layer, can contribute to its hardening. The fact that the underside of the microarray chip can be highly reflective for UV radiation thanks to the above-described etch stop layer can also help here, and thus most of the UV radiation striking the silicon or silicon oxide surface can be reflected back into the adhesive layer. The lateral illumination of the adhesive gap, starting from the peripheral outer edge or from the perforation openings, can be additionally promoted by selecting a correspondingly large divergence or convergence of the UV radiation. The adhesive areas, which are primarily UV-cured, can immediately create a high strength connection between the microarray chip and the membrane. In addition, starting from these areas, the adhesive layer can polymerize more slowly over time, ie the polymerization can progress laterally starting from the so-called seeds produced by UV radiation, so that after a certain time the entire adhesive gap can be cured. Alternatively, a UV-curable adhesive can also be pre-cured by UV radiation from the top before inserting the processing unit, or a polymerization chain reaction can already be induced, which can continue to progress rapidly after the microarray chip has been inserted and initialized for the first time.

In addition, the carrier layer can have at least one carrier layer perforation opening, which can be larger than a membrane perforation opening arranged on the membrane. For example, the carrier layer can have one or more carrier layer perforation openings in an area covered by the bearing surface of the reaction layer, which can have a larger diameter than the membrane perforation opening correspondingly arranged in the membrane. In other words, the carrier layer perforation openings can always comprise smaller membrane perforation openings. Curing of an adhesive, for example by means of UV radiation, between the processing unit and the membrane can advantageously be improved through the openings. Due to the size ratios of the membrane perforation openings and the carrier layer perforation opening, it can be achieved that protruding adhesive can only penetrate into the membrane perforation openings, while the carrier layer can remain unaffected. This has the advantage that the transition from the membrane to the carrier layer can remain free of adhesive, or that no undesired adhesion can take place. In this way, bonding processes can be improved or some bonding variants made possible in the first place.

According to a further embodiment, the membrane can be detachably connected to the carrier layer at least in a partial area. The partial area can correspond, for example, to the contact surface of the reaction layer or also to the entire area of the receiving layer opening. Thus, for example, the membrane can be lifted off the carrier layer in a resilient manner in the area of the receiving layer opening by applying a corresponding force and placed back on, while outside the receiving layer opening the receiving layer, the membrane and the carrier layer can be firmly connected to one another, for example by welding. Accordingly, the detachable portion of the membrane can function as an elastic, resilient element in the analysis cartridge. When the processing unit is inserted and connected to the membrane via the contact surface, height differences between the contact element and the carrier layer combined with the membrane arranged along the carrier layer can advantageously be compensated for by means of the elasticity thus provided. For example, the contact element can be formed with a contact element height of 500 μm, while the carrier layer can have a carrier layer height of 375 μm, for example, and the membrane can have a membrane height of 100 μm. According to this example, when the processing unit is used, the height difference between the height of the contact element and the height of the carrier layer and the height of the membrane can be 25 µm, whereby, for example, up to 10 µm can be added to the height of the carrier layer and the height of the membrane due to an adhesive applied between the reaction layer and the membrane. Accordingly, the difference in height can still be 15 μm, for example. Since the processing unit is glued to the detachable and thus elastically resilient portion of the membrane, the contact element can advantageously press onto any surface, for example surfaces in the production line, tabletops, documents, etc., without being damaged. In addition, this embodiment has the advantage that a very good thermal cal connection of the processing unit to a heating or cooling finger when using the analysis cartridge in an analysis device is made possible.

In addition, a method for producing a variant of the processing unit presented above is presented, the method comprising a step of connecting the reaction layer to a contact element layer and a step of producing the cavities in the reaction layer and of producing at least one contact element in the contact element layer in order to form the processing unit to manufacture.

In addition, a method for producing a variant of the analysis cartridge presented above is presented, the method comprising a step of providing the carrier layer with the carrier layer opening and providing the membrane with the membrane opening and a step of inserting the processing unit into the carrier layer opening and additionally or alternatively the Membrane opening to create a microfluidic analysis cartridge. In this case, the step of inserting the processing unit can be carried out using an adhesive, for example.

These methods can be implemented, for example, in software or hardware or in a mixed form of software and hardware, for example in a control unit.

The approach presented here also creates a device that is designed to carry out, control or implement the steps of a variant of a method presented here in corresponding devices. The object on which the invention is based can also be achieved quickly and efficiently by this embodiment variant of the invention in the form of a device.

For this purpose, the device 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 in sensor signals from the sensor or for outputting data or control signals to the Have actuator and / or at least one communication interface for reading or outputting data that are embedded in a communication protocol. The arithmetic unit can be, for example, a signal processor, a microcontroller or the like, with the memory unit being able to be a flash memory, an EEPROM or a magnetic memory unit. The communication interface can be designed to read in or output data wirelessly and/or by wire, wherein a communication interface that can read in or output wire-bound data can, for example, read this data electrically or optically from a corresponding data transmission line or can output it to a corresponding data transmission line.

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

A computer program product or computer program with program code, which can be stored on a machine-readable carrier or storage medium such as a semiconductor memory, a hard disk memory or an optical memory and for carrying out, implementing and/or controlling the steps of the method according to one of the embodiments described above, is also advantageous used, especially when the program product or program is run on a computer or device.

• 1 einen schematischen Teilquerschnitt eines Ausführungsbeispiels einer Analysekartusche mit eingesetzter Prozessierungseinheit;
• 2 einen schematischen Teilquerschnitt eines Ausführungsbeispiels einer Analysekartusche;
• 3 einen schematischen Teilquerschnitt eines Ausführungsbeispiels einer Analysekartusche;
• 4 einen schematischen Teilquerschnitt eines Ausführungsbeispiels einer Prozessierungseinheit während eines Herstellungsprozesses;
• 5 einen schematischen Teilquerschnitt eines Ausführungsbeispiels einer Prozessierungseinheit während eines Herstellungsprozesses;
• 6 einen schematischen Teilquerschnitt eines Ausführungsbeispiels einer Prozessierungseinheit während eines Herstellungsprozesses;
• 7 ein Ablaufdiagramm eines Ausführungsbeispiels eines Verfahrens zum Herstellen einer Prozessierungseinheit;
• 8 ein Ablaufdiagramm eines Ausführungsbeispiels eines Verfahrens zum Herstellen einer Analysekartusche; und
• 9 ein Blockschaltbild eines Ausführungsbeispiels einer Vorrichtung zum Herstellen einer Prozessierungseinheit.

Exemplary embodiments of the approach presented here are shown in the drawings and explained in more detail in the following description. It shows:

• 1 a schematic partial cross section of an embodiment of an analysis cartridge with inserted processing unit;
• 2 a schematic partial cross section of an embodiment of an analysis cartridge;
• 3 a schematic partial cross section of an embodiment of an analysis cartridge;
• 4 a schematic partial cross section of an embodiment of a processing unit during a manufacturing process;
• 5 a schematic partial cross section of an embodiment of a processing unit during a manufacturing process;
• 6 a schematic partial cross section of an embodiment of a processing unit during a manufacturing process;
• 7 a flowchart of an embodiment of a method for producing a processing unit;
• 8th a flowchart of an embodiment of a method for producing an analysis cartridge; and
• 9 a block diagram of an embodiment of a device for producing a processing unit.

In the following description of favorable exemplary embodiments of the present invention, the same or similar reference symbols are used for the elements which are shown in the various figures and have a similar effect, with a repeated description of these elements being dispensed with.

1 shows a schematic partial cross section of an exemplary embodiment of an analysis cartridge 100 with a processing unit 105 inserted. The processing unit 105, which can also be referred to as a microarray chip, comprises a reaction layer 110 with cavities 115 for carrying out a reaction. In addition, the processing unit 105 has a contact element 120 which is arranged opposite the reaction layer 110 and which can also be referred to as a microchip bump, microarray bump, silicon bump or Si bump. The contact element 120 is designed to be an externally connectable or removable and in the 1 temperature control element 122 shown in dashed lines and to transfer heat into and out of the reaction layer 110 . For this purpose, the contact element 120 in this exemplary embodiment has a contact element height 125 of only 500 μm, for example, while the reaction layer 110 has a lower height 130 in comparison to the contact element height 125 of only 380 μm, for example. The height of the reaction layer is in itself irrelevant, but a thinner reaction layer leads to improved heat supply and heat dissipation to and from the cavities. At the same time, the contact element 120 in this exemplary embodiment is formed with a smaller contact element width 135 in relation to the reaction layer 110, which corresponds to one third of the width 140 of the reaction layer 110, merely by way of example. In this exemplary embodiment, both the contact element 120 and the reaction layer 110 are formed from silicon, with an intermediate layer 145 being arranged between the contact element 120 and the reaction layer 110 . The intermediate layer 145 in this exemplary embodiment is silicon dioxide, purely by way of example, which is why the intermediate layer 145 can also be referred to as an intermediate oxide. Due to a high selectivity with regard to the etching of silicon versus silicon dioxide, the intermediate layer 145 is in the form of an etching stop layer in this exemplary embodiment. At the same time, the intermediate layer 145 in this exemplary embodiment forms what is known as a bonding interface, via which the reaction layer 110 and the contact element 120 can be connected to one another by a bonding process before the structuring.

In the present representation, the processing unit 105 is arranged within the analysis cartridge 100 . In this exemplary embodiment, the analysis cartridge 100 comprises a carrier layer 150 with a carrier layer height 155 of only 375 μm, for example, with the carrier layer 150 being connected to a receiving layer 170 via a membrane 160 arranged along a surface 157 with a membrane height 165 of only 100 μm, for example. The recording layer 170, which can also be referred to as the PL layer, has a recording layer height 175 of only 1.7 mm, for example. The carrier layer 150, which can also be referred to as "PC seal transparent", comprises a carrier layer opening 180, which is arranged directly at a membrane opening 183, the membrane opening 183 being formed with a smaller cross section than the carrier layer opening 180, so that the membrane 160 Backing sheet 150 slightly overlapped into backing sheet opening 180 . Both the carrier layer opening 180 and the membrane opening 183 are formed with a smaller diameter than the receiving layer opening 186 of the receiving layer 170.

In this exemplary embodiment, the contact element 120 of the processing unit 105 is arranged approximately centrally in the carrier layer opening 180 and in the membrane opening 183 . In this case, the reaction layer 110 is firmly connected to the membrane 160 by means of an adhesive 190 on a bearing surface 187 opposite the cavities 115, for example only. In this exemplary embodiment, the adhesive 190, which can also be referred to as adhesive, is applied over the entire area provided for the bonding. In another exemplary embodiment, the adhesive can be dispensed around the membrane opening, for example in the form of a closed adhesive joint, or directly onto the edge of the recess around the opening.

In this exemplary embodiment, the processing unit 105 can be inserted into the analysis cartridge 100 by a gripper, not shown in this figure, and the adhesive fabric 190 is subsequently curable. For example only, the curing takes place by UV radiation from the underside. Accordingly, the adhesive 190 used in this embodiment is a UV-curable acrylic adhesive that also has sealing properties. The transmission T% of the membrane 160 is taken into account for the UV curing process purely by way of example, in that the UV radiation dose applied for the curing is scaled by a factor of 1/T%. i.e. at a specific UV dose D, which is the product of radiation power and irradiation time required for curing the adhesive, the UV dose used is D' = D/T%. This factor, which can be realized both by a higher power and by a longer irradiation time or a combination of both, is only 5 as an example. In another exemplary embodiment, this factor can be between e=2,718 to 10.

In this exemplary embodiment, the adhesive 190 engages in a circumferential adhesive gap 191 between the outer edge of the membrane 160 and the contact element 120. In this exemplary embodiment, the membrane 160 also has membrane perforation openings 193, which are arranged on corresponding carrier layer perforation openings 195, the membrane perforation openings 193 having a smaller Diameter are formed as the carrier layer perforation openings 195. The adhesive 190 therefore engages in addition to the adhesive gap 191 in the membrane perforation openings 193, which allows a particularly high strength of the bond with the microarray chip. By dimensioning the membrane perforation openings 193 with smaller diameters in comparison to the larger diameters of the carrier layer perforation openings 195 or by a corresponding spacing of the edges of both layers from one another, undesired sticking of the membrane 160 to the carrier layer 150 due to protruding adhesive 190 is prevented. The membrane perforation openings 193 and the carrier layer perforation openings 195 also enable an advantageous concentration of the UV radiation onto the perforation openings in addition to the adhesive gap 191, as a result of which the UV intensity is increased. When the microarray chip is placed and pressed on the membrane 160 with the adhesive 190 dispensed on, the adhesive 190 is forced into this circumferential gap and into the perforation openings, into which there is unhindered or unimpaired UV radiation, so that the maximum there in a few seconds the bond strength of the bond is achievable.

2 shows a schematic partial cross section of an embodiment of an analysis cartridge 100. This can be the 1 Act described analysis cartridge. In this embodiment, the analysis cartridge 100 comprises a 1.7 mm thick receiving layer 170, which can also be referred to as a PL layer, and which has a continuous receiving opening 186 for receiving a processing unit, as is shown in FIG 1 has been described. In addition, the analysis cartridge 100 includes a carrier layer 150, which is only 375 μm thick, which can also be referred to as a modified “PC-seal transparent” layer, with a continuous carrier layer opening 180. Between the carrier layer 150 and the receiving layer 170 there is a 100 μm thickness, which is only an example thick membrane 160 arranged, which can also be referred to as a modified "PC-seal black" layer. The membrane 160 has a continuous membrane opening 183 congruent to the carrier layer 150 and the acquisition layer 170, which is formed with a smaller diameter than the carrier layer opening 180, the carrier layer opening 180 in turn having a smaller diameter than the acquisition layer opening 186 is formed. Since the carrier layer opening 180, the membrane opening 183 and the absorption layer opening 186 are arranged one above the other on a line shown vertically in this figure, taken together they result in a continuous opening through the analysis cartridge 100. In this exemplary embodiment, a through-opening opens to the outside with a total height of 100 µm + 375 µm = 475 µm.

In this exemplary embodiment, the membrane 160 comprises membrane perforation openings 193 which are arranged close to the membrane opening 183 and which are arranged directly on the carrier layer perforation openings 195 . In another exemplary embodiment, the membrane and the carrier layer can be formed continuously, ie without perforation openings. In this exemplary embodiment, the partial area 200 of the membrane 160 arranged within the receiving layer opening 186 is detachably connected to the carrier layer 150, while another partial area 205 of the membrane 160 arranged between the carrier layer 150 and the receiving layer 170 is firmly welded to the carrier layer 150 and the receiving layer 170 is.

The structure of the analysis cartridge 100 can be implemented by means of mask laser welding, it being possible for the three layers, ie the carrier layer 150, the membrane 160 and the receiving layer 170, to be welded to one another in the region of the overlap. For a laser penetration welding process with mask laser welding from one side, a transparency of the membrane 160 of 1/e=1/2.718=0.368 is optimal, ie a proportion 2/e=2/2.718=0.632 of the irradiated laser power is over the thickness of the Layers absorbable and melts it evenly for optimal welding at both interfaces. In other exemplary embodiments, the values for the transmission of the membrane can be selected in the range T%=10-40%, for example T%=20%.

3 shows a schematic partial cross section of an exemplary embodiment of an analysis cartridge 100. This can be the analysis cartridge described in the previous figures. The present figure is similar to that in 2 shown representation, with the difference of a force 300 on a portion 200 of the membrane 160. Since the portion 200, which is arranged in this embodiment within the receiving layer opening 186, is detachably connected to the carrier layer 150, the force 300 causes a curvature of the membrane 160 in partial area 200. In other words, the "PC seal black" layer is resiliently lifted from the "PC seal transparent" layer in the area of the passage opening by a corresponding force 300 and can be put back on, since the welding only starts below the PL layer PC seal layers joined together. An elastic, resilient element is thus created and available in the lab-on-chip cartridge structure or in a submodule of the lab-on-chip cartridge structure. In this exemplary embodiment, too, the membrane 160 comprises membrane perforation openings 193 which are arranged directly on the carrier layer perforation openings 195 . In another exemplary embodiment, the membrane and the carrier layer can be formed continuously, ie without perforation openings.

4 shows a schematic partial cross section of an embodiment of a processing unit 105 during a manufacturing process. This can be the in 1 Act processing unit described. In this exemplary embodiment, the reaction layer 110, which is formed merely by way of example as a standard silicon wafer with a thickness of 380 μm, is protected against a second standard silicon wafer with a thickness of only 500 µm bonded as an example. As below in 6 described, the second standard silicon wafer shown here can be formed into a contact element. In another exemplary embodiment, the intermediate layer 145, which can also be referred to as an intermediate oxide, can have a thickness of 1 to 3 μm. In addition, in an alternative exemplary embodiment, the second silicon wafer can also carry the intermediate oxide, or both silicon wafers can each carry an intermediate oxide. In this exemplary embodiment, the intermediate layer 145 is applied by thermal oxidation of the wafer. In another exemplary embodiment, the intermediate layer can also be applied by CVD deposition (chemical vapor deposition), such as, for example, LPCVD (low-pressure CVD) or PECVD (plasma-enhanced CVD). In this exemplary embodiment, direct thermal bonding of the two wafers can be carried out as the bonding method.

5 shows a schematic partial cross section of an embodiment of a processing unit 105 during a manufacturing process. This can be the in 1 and 4 Act processing unit described. In this exemplary embodiment, cavities 115 are etched into the reaction layer 110, which cavities can also be referred to as microarray cells. For the process of deep etching of silicon, a method of photolithography combined with plasma etching technology can be used as an example. As a result, the microarray cells can be etched to the desired target depth in a time-controlled manner. In a variant that is not shown in this illustration, during such an etching process, fracture streets or auxiliary structures for later separation into individual chips by breaking can also be etched into the upper wafer.

6 shows a schematic partial cross section of an embodiment of a processing unit 105 during a manufacturing process. This can be the in 1 , 4 and 5 Act processing unit described. In this exemplary embodiment, a contact element 120 is formed from the second standard silicon wafer. A photolithographic masking of the second standard silicon wafer and a subsequent deep etching can be used for the formation only by way of example, with the silicon being able to be etched back down to the intermediate oxide, so that a silicon bump with a height of only 500 μm, by way of example, remains. The intermediate layer 145 is accordingly formed in this exemplary embodiment as an etch stop layer or as a so-called etch stop, since there is a high selectivity with regard to the etching of silicon versus silicon dioxide. The etch stop represents a high tolerance to overetching, so that inhomogeneities in the etching process across the wafer surface or inaccuracies in the etch rate control can be compensated for by overetching. In addition, the etch stop allows the use of endpoint detection methods, e.g. B. an optical endpoint control by a so-called Optical Emission Spectroscopy, or laser-based etch stop techniques such. B. Reflectometry.

In other words, the previous figures can be summarized as follows. An elastic connection of a modified microarray chip in a lab-on-chip cartridge is provided. The microarray chip is particularly advantageously constructed from two bonded wafer levels with a buried etch stop layer, of which an upper wafer level carries the so-called microarray cells and so-called silicon bumps with a precisely defined height were etched out of a lower wafer level. Furthermore, a modified cartridge structure is provided for this purpose with through openings and, if necessary, additional perforation openings in a so-called “PC-seal black” and a “PCseal transparent” layer, with the “PC-seal black” layer providing an elastically resilient connection structure for gluing in the microarray chip . The "PC-seal black" layer has sufficient residual transparency T% for the curing UV light for gluing in using UV-curable adhesives, e.g. B. T% = 1/e for optimal transmission welding from only one side, and/or the UV radiation for the bonding process is applied to the adhesive gap between the microarray bump and the recess edge of the "PC-Seal black" layer and to the perforation openings in the "PC seal black” layer or in the “PC seal black” and “PC seal transparent” layers. Appropriate dimensioning ensures that the microarray chip is glued into the lab-on-chip structure in an elastically resilient manner or is integrated therein and the underside in the form of the silicon bump can then be placed non-destructively on any base, in particular on heating or .Cold fingers of an analyzer during a later diagnostic workflow to ensure a very good thermal contact. This enables rapid thermal cycling and thus makes it possible to carry out qPCR reactions in the array cells of the microarray chip in the cartridges.

7 shows a flow chart of an embodiment of a method 700 for producing a processing unit. The method 700 comprises a step 705 of connecting the reaction layer to a contact element layer and a step 710 of producing the cavities in the reaction layer and at least one contact element in the contact element layer in order to produce the processing unit. It is essential to adhere to the order "upper wafer - lower wafer" during plasma etching, since after the production of the silicon bumps reliable helium cooling of the wafer on a substrate electrode of a plasma etching system can no longer be guaranteed if e.g. B. subsequently only the microarray cells should be etched into the upper wafer. For example, the wafers can subsequently be cleaned, made hydrophilic, functionalized and the microarray cells can be equipped with biocontent. The singulation into microarray chips can then take place, either by breaking along previously created fracture trenches and/or auxiliary structures, or by Mahoh or stealth dicing by means of laser writing and subsequent expansion or breaking of the wafer into individual chips.

Furthermore, an analysis cartridge can also be manufactured using the manufactured processing unit. For this purpose, for example, a carrier layer with the carrier layer opening and a membrane with the membrane opening are provided and in a subsequent step the processing unit is inserted into the carrier layer opening and/or the membrane opening in order to produce a microfluidic analysis cartridge. In this exemplary embodiment, the step of inserting the processing unit takes place using an adhesive.

8th FIG. 8 shows a flowchart of an embodiment of a method 800 for operating an analysis cartridge. The method 800 includes a step 805 of providing the microfluidic analysis cartridge according to a variant presented here in an analysis system according to a variant presented here. In addition, the method 800 includes a step 810 of temperature control of the contact element using the temperature control element in order to operate the analysis cartridge. In this way, for example, a reagent that is located in the cavities can be activated or processed by tempering, in particular by heating, so that a desired or intended effect can be achieved with the analysis cartridge in this way.

In an alternative embodiment, after the installation of the processing unit, which can also be referred to as a Si microarray chip, in the submodule of the analysis cartridge in the usual production flow of the cartridge manufacturing process, the upper levels TPU and FL as well as the reagent containers and PCR bead(s) are added and also welded on by mask laser welding. As a result, the lab-on-chip cartridge has an elastically resilient interface between the silicon of the microarray chip with its excellent thermal conductivity properties and a heating finger of an analysis device, so that rapid thermal cycling, e.g. B. is made possible for the implementation of qPCR reactions in the microarray cells of the microarray chip. In this case, other dimensioning of the wafer thicknesses can also be provided, in particular in order to suitably modify the height and thus the size of the projection of the silicon bumps. The preceding exemplary embodiments with the dimensions mentioned are only to be understood as examples and only serve to explain the Functions with a numerical example. Alternatively, it is also possible to dispense with a bonded pair of wafers with an intermediate oxide layer and instead use a thick monolithic wafer that is correspondingly structured on both sides. Since the latter variant does not contain an etch stop layer, as time-controlled processing it places very high demands on the accuracy and control of the etch rate setting and the homogeneity of the etch over the wafer surface.

9 shows a block diagram of an embodiment of a device for producing a processing unit. The device comprises a connecting unit 905 for connecting the reaction layer to a contact element layer. In addition, the device 900 includes a production unit 910 for producing the cavities in the reaction layer and at least one contact element in the contact element layer.

If an embodiment includes an "and/or" link between a first feature and a second feature, this should be read in such a way that the embodiment according to one embodiment includes both the first feature and the second feature and according to a further embodiment either only that having the first feature or only the second feature.

Claims (15)

Processing unit (105) for use in a microfluidic analysis cartridge (100), the processing unit (105) comprising the following features: a reaction layer (110) with cavities (115) for carrying out a reaction; and a contact element (120) arranged opposite the reaction layer (110) for contacting a temperature control element (122) and/or for transferring heat into or out of the reaction layer (110). Processing unit (105) according to claim 1 , wherein the contact element (120) has a contact element width (135) which is less than a width (140) of the reaction layer (110) and/or wherein a contact element height (125) of the contact element (120) is at least half a height (130) of the Reaction position (110) corresponds. Processing unit (105) according to one of the preceding claims, wherein an intermediate layer (145) is arranged between the reaction layer (110) and the contact element (120), in particular wherein the intermediate layer (145) is designed as an etching stop layer. Processing unit (105) according to one of the preceding claims, wherein the reaction layer (110) and the contact element (120) at least partially comprise the same material and/or wherein the reaction layer (110) and the contact element (120) are formed from silicon wafers. Microfluidic analysis cartridge (100) for analyzing a sample, the analysis cartridge (100) having the following features: at least one backing (150) having at least one backing aperture (180); at least one membrane (160) arranged along a surface (157) of the carrier layer (150) and having at least one membrane opening (183); and at least one processing unit (105) according to one of the preceding claims, wherein the contact element (120) of the processing unit (105) is arranged or can be arranged in the carrier layer opening (180) and/or in the membrane opening (183). Analysis cartridge (100) according to claim 5 , having at least one acquisition layer (170) with at least one acquisition layer opening (186), wherein the membrane (160) is arranged between the acquisition layer (170) and the carrier layer (150) and wherein the reaction layer (110) is arranged in the acquisition layer opening (186). or can be arranged, in particular wherein the receiving layer opening (186) is formed with a larger diameter than the carrier layer opening (180) and/or than the membrane opening (183). Analysis cartridge (100) according to any one of Claims 5 or 6 , wherein a bearing surface (197) of the reaction layer (110) is connected or can be connected to the membrane (160) by means of an adhesive (200). Analysis cartridge (100) according to any one of Claims 5 until 7 , wherein the carrier layer (150) has at least one carrier layer perforation opening (195) which is larger than a membrane perforation opening (193) arranged on the membrane (160). Analysis cartridge (100) according to any one of Claims 5 until 8th , wherein the membrane (160) is detachably connected to the carrier layer (150) at least in a partial area (200). Analysis system with a microfluidic analysis cartridge (100) according to one of Claims 5 until 9 and a temperature control element (122) for temperature control of the contact element (120) of the analysis cartridge (100). Method (700) for producing a processing unit (105) according to one of Claims 1 until 4 , wherein the method (700) comprises the following steps (705, 710): connecting (705) the reaction layer (110) to a contact element layer; and producing (710) the cavities in the reaction layer and at least one contact element (120) in the contact element layer in order to form the processing unit (105) according to one of Claims 1 until 4 to manufacture. Method (800) for operating an analysis cartridge (100) according to one of Claims 5 until 9 , wherein the method (800) comprises the following steps (805, 810): providing (805) the microfluidic analysis cartridge (100) according to one of Claims 5 until 9 in an analysis system according to claim 10 ; and temperature control (810) of the contact element (122) by means of the temperature control element (122) in order to operate the analysis cartridge (100). Device (900) which is set up to carry out the steps (705, 710; 805, 810) of one of the methods (700; 800) according to one of the preceding ones Claims 11 or 12 to be carried out and/or controlled in corresponding units (905, 910). Computer program that is set up to perform the steps (705, 710; 805, 810) of one of the methods (700; 800) according to one of the preceding ones Claims 11 or 12 execute and/or control. Machine-readable storage medium on which the computer program Claim 14 is saved.

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