Microfluidic device, protein defect diagnostic device with microfluidic device, method for conditioning a sensor element for protein defect detection, and method for analyzing protein defects

Abstract

A microfluidic device (12) for applying blood samples to a sensor element (26) for protein defect diagnosis and / or for conditioning a sensor element (26) for protein defect diagnosis is proposed, comprising a pneumatic unit (14) and a disposable fluid guide assembly (32). Furthermore, a protein defect diagnosis device (10) with the microfluidic device (12) is disclosed. A method for conditioning a sensor element (26) for protein defect diagnosis and a method for analyzing protein defects in a blood sample (212) are also disclosed.

Description

[0001] The invention relates to a microfluidic device for applying blood samples to a sensor element for protein defect diagnosis and / or for conditioning a sensor element for protein defect diagnosis, a protein defect diagnosis device with the microfluidic device, a method for conditioning a sensor element for protein defect detection, and a method for analyzing protein defects.

[0002] Alzheimer's disease, also known as Alzheimer's, is a currently incurable neurodegenerative disorder in which nerve cells in the brain progressively die, leading to personality and behavioral changes in affected individuals. Millions of people worldwide are affected by Alzheimer's.

[0003] Early diagnosis of Alzheimer's disease is crucial for its progression, as while it is not yet curable, its steadily worsening course can be slowed by early intervention. The earlier treatment begins, the more beneficial it is. Therefore, early and reliable diagnosis presents a significant challenge in diagnostic medical technology, enabling timely intervention and slowing of the disease's progression. Prediagnostic methods play a particularly important role, as they allow for the prediction of the risk of a clinical Alzheimer's diagnosis and enable therapeutic interventions to begin even before the onset of clinical symptoms.

[0004] Established prediagnostic methods for predicting the risk of Alzheimer's disease rely on the analysis of specific protein defects that develop in the human body decades before the clinical onset of Alzheimer's. Analyzing these protein defects allows for predictions about the likelihood of developing Alzheimer's. From a scientific perspective, it is assumed that in the early stages of Alzheimer's, certain proteins, including β-amyloid (Aβ) peptides, misfold. According to current research, the misfolding and resulting aggregation of these peptides into beta-sheet-rich amyloid plaques is crucial for the course and progression of Alzheimer's.

[0005] For this reason, the presence of misfolded β-amyloid (Aβ) peptides in the blood plasma of test subjects, for example, is a sign of possible Alzheimer's disease and can be an important indicator for predicting the risk of developing Alzheimer's. Thus, misfolded β-amyloid (Aβ) peptides represent a candidate biomarker peptide that can be used in prediagnostic methods.

[0006] In the field of protein diagnostics, a number of methods exist for detecting candidate biomarker peptides in samples. For example, methods such as enzyme-linked immunosorbent assays (ELISA), surface plasmon resonance spectroscopy (SPR), or surface-based fluorescence intensity distribution analysis (sFIDA) can be used. However, it has been shown that these methods only provide indirect information about structural defects or misfolding of proteins. Furthermore, these methods are very complex in terms of sample preparation and execution and are designed for low sample throughput, making them unsuitable for large-scale clinical applications.

[0007] Another method in the field of protein diagnostics is the immuno-infrared sensor assay (hereinafter referred to as immuno-assay), which allows for the direct measurement of misfolded β-amyloid (Aβ) peptides in body fluids such as blood, blood plasma, blood serum or cerebrospinal fluid without prior isolation and preparation of candidate biomarker peptides.

[0008] An example of such an immunoassay is disclosed in US 2020 / 0141866A1. The described immunoassay focuses in particular on the protein diagnostics of misfolded amyloid-β(Aβ) peptides for the risk prognosis of Alzheimer's disease. The basic principle of the method is to bind an antibody to a sensor surface-modified with silanes or thiol linkers, which in turn can specifically bind to candidate biomarker peptides based on (Aβ) structures.

[0009] In a first preconditioning step, a sensor crystal, for example an ATR (attenuated total reflection) sensor crystal such as a germanium or silicon single crystal, is surface-treated with conditioning fluids containing silane or thiol linkers. In a second antibody conditioning step, the sensor surface is surface-treated with an antibody-containing conditioning fluid. In a third sample deposition step, the sensor is then surface-treated with a sample fluid from a test subject, such as blood plasma, blood, or blood serum, whereby candidate biomarker peptides based on (Aβ) structures bind to the antibody-coated sensor surface.In a fourth step, the measurement step, the sensor is irradiated with an IR laser that passes through it via multiple internal total reaction, thereby recording an IR spectrum of the candidate biomarker peptides bound to the sensor surface and based on (Aβ) structures. The IR spectrum recorded by the bound candidate biomarkers is then analyzed, for example, by quantifying the shift of the IR bands of the (Aβ)-based candidate biomarker peptides with comparative measurements, in order to make a risk prediction regarding the potential onset of Alzheimer's disease in relation to the sample under investigation.

[0010] However, such immunoassays for Alzheimer's risk prediction are in an early stage of development and have so far only been conducted on a laboratory scale and as conceptual trials. In particular, developing such an immunoassay from the laboratory scale to industrial, large-scale medical application presents an immense challenge.

[0011] Known immunoassays use individual devices to perform the above-mentioned steps, which have a number of disadvantages that will be discussed below.

[0012] Typically, known immunoassays are based on a flow cell with a fluid port at each of its opposite ends. Both ports are fluid-flow connected to a common reservoir, so that the sample to be analyzed is pumped along a circuit between the flow cell and the reservoir via a peristaltic pump.

[0013] However, flow cells are expensive and require extensive preparation. Therefore, time-efficient throughput of larger sample volumes is not possible, and analysis is limited to individual samples.

[0014] The use of a peristaltic pump also increases the risk of contaminating the sample fluid. To avoid this, it is necessary to clean the peristaltic pump regularly, for example by autoclaving it, to prevent cross-contamination between different sample fluids.

[0015] Furthermore, the manual setup and dismantling of the experimental setup between measurements makes the reproducibility of the immunoassay more difficult and thus hinders efficient sample throughput.

[0016] Furthermore, the conditioning of the sensor surface and the subsequent sample application with the sample fluid do not take place in the same flow cell, meaning that several specialized devices are used for sample preparation and measurement. This procedure is time-consuming and increases the risk of sample fluid contamination, as the sensor is passed back and forth between the devices for conditioning and sample application.

[0017] Parkinson's disease and amyotrophic lateral sclerosis (ALS) should also be able to be predicted early by analyzing certain protein defects in the blood. The invention should therefore include, among other things, a device and a method for conditioning sensor elements and analyzing protein defects for these diseases using the sensor elements; that is, more generally, for preparing and carrying out an analysis of protein defects.

[0018] Therefore, the object of the present invention is to provide a device that overcomes at least one disadvantage known from the prior art.

[0019] The object is solved according to the invention by a microfluidic device for applying blood samples to a sensor element for protein defect diagnosis and / or for conditioning a sensor element for protein defect diagnosis according to claim 1.

[0020] Advantageous aspects of the invention are set out in the dependent claims, which can optionally be combined with one another.

[0021] According to the invention, the microfluidic device for applying blood samples to a sensor element for protein defect diagnosis and / or for conditioning a sensor element for protein defect diagnosis comprises a disposable fluid guide assembly having several interaction chambers, which are sectionally delimited by a sensor element for protein defect detection. A first fluid channel opens into each interaction chamber at one end and a second fluid channel at the opposite end, wherein the fluid channels can be switched by valves integrated into the disposable fluid guide assembly, and the disposable fluid guide assembly further comprises pneumatic channels that actuate the integrated valves.Furthermore, the microfluidic device comprises a holder for mechanically mounting the disposable fluid guide assembly and a pneumatic unit with multiple actuator valves, wherein the pneumatic unit has free-ending pump outlets for reversible coupling to the disposable fluid guide assembly.

[0022] The invention is based on the fundamental concept of providing a fluid flow assembly designed for single use in a microfluidic device for applying blood samples to a sensor element for protein defect diagnosis and / or for conditioning a sensor element for protein defect diagnosis. By incorporating a disposable function, contamination of sample fluids with conditioning fluids or cross-contamination between different sample fluids can be easily prevented, because the used disposable fluid flow assembly can be discarded after each sample run and replaced with a fresh one. The same applies to blood sample application. This eliminates the need for the time-consuming cleaning of the fluid channels and the associated valves.

[0023] Furthermore, the integrated valves allow for precise control of the fluid flow within the disposable fluid guide assembly. This eliminates the need for complex external control systems. In particular, cleaning the valves is unnecessary, as they are integrated into the disposable fluid guide assembly and can be disposed of together.

[0024] Furthermore, the pneumatic unit enables contactless movement of fluid within the disposable fluid guide assembly. Specifically, the pneumatic unit is designed to provide a compressed air supply that can be connected to the free-ending pump outlets via the multiple actuator valves. This allows the individual fluid channels of the disposable fluid guide assembly to be pressurized with positive and negative pressure, or with positive and ambient pressure, thus enabling precise control of the fluid flow within the channels.

[0025] The term "interaction chamber" refers to a chamber in which at least one fluid flowing through the fluid channels can be brought into contact with the sensor element in order to interact with its surface. The term "chamber" is not to be interpreted restrictively; it can also refer to a section of the chamber, a channel, or a channel segment that is open and can be brought into contact with a sensor element. Therefore, at least the application of a blood sample to the surface of the sensor element takes place in the interaction chamber.

[0026] The term "blood sample" refers to the sample fluid from a test subject, which is to be examined for candidate biomarkers that may indicate a later diagnosis of Alzheimer's disease or another neurodegenerative disorder. The blood sample can include, for example, blood plasma, cerebrospinal fluid, blood, blood serum, or, more generally, processed blood. Furthermore, the terms "blood sample" and "sample fluid" are used synonymously.

[0027] Depending on the embodiments explained below, the interaction chamber can also be used for conditioning, i.e., surface treatment of the sensor element surface with a linker-containing or antibody-containing conditioning fluid, as well as for the measurement process on the sensor element surface, in addition to sample application.

[0028] In principle, the interaction chamber can have any shape and geometry. However, it is preferred that the interaction chamber has a cross-section that is larger in at least one direction compared to the other channels in the one-way fluid guide assembly, in order to slow down the fluid flow so that the fluid can interact with the sensor element for a longer period.

[0029] A "sensor element" refers to any sensor element suitable for protein diagnostics using FTIR spectroscopy.

[0030] A "channel" or "fluid channel" refers to a tubular connection designed to carry a fluid. The term "channel" or "fluid channel" can also refer to a section of a channel.

[0031] The terms “fluidic” and “fluid” used in this application refer exclusively to liquids.

[0032] The term "fluid lines" refers to fluid-carrying connections between the storage containers and the interaction chamber.

[0033] The term "reversibly coupled" means that the disposable fluid guide assembly is designed to be connected (coupled) and disconnected (decoupled) to the individual assemblies of the microfluidic device without damage.

[0034] According to a first aspect of the invention, the microfluidic device comprises a first media dosing unit which can be reversibly coupled to the first fluid channels and a second media dosing unit which can be reversibly coupled to the second fluid channels.

[0035] The term "medium" refers to a conditioning fluid or a fluid that is necessary for the conditioning process, i.e., for preparing the sensor element surface for sample application.

[0036] For example, the conditioning fluid may be selected from the group consisting of distilled water, isopropanol, rinsing fluid, PDS, NaPi, MEA, antibody fluid, TBS, various linker fluids, such as linkers based on silanes or thiol ethers, as well as Tbd.

[0037] This allows the disposable fluid guide assembly to be reversibly, i.e., detachably, connected to a first and a second media dosing unit, which can supply the disposable fluid guide assembly with medium or conditioning fluid to condition a sensor element placed in the interaction chamber. Therefore, the first and second media dosing units are each understood to be units that store at least one conditioning fluid that can be introduced into the disposable fluid guide assembly.

[0038] According to a further aspect of the invention, the first media dosing unit has several first reservoirs for conditioning fluids and the second media dosing unit has several second reservoirs for conditioning fluids, wherein a fluid channel serving as a media channel extends from each of the several first reservoirs and can be reversibly coupled via at least one media valve to either groups of first fluid channels or all first fluid channels. Furthermore, a fluid channel serving as a media channel extends from each of the several second reservoirs and can be reversibly coupled via at least one media valve to either groups of second fluid channels or all fluid channels, in particular wherein each media channel is provided with its own media valve.

[0039] The above arrangement of reservoirs and media channels allows for particularly precise routing of conditioning fluids from the respective reservoirs of the first or second media dosing unit to the interaction chamber and back out again. Because each reservoir has a separate fluid channel, isolated from the others, the conditioning fluids contained in the reservoirs can be introduced separately into the one-way fluid guide assembly. In this respect, the multiple media channels work synergistically with their associated media valves, which ensure that the fluid flows of the individual reservoirs can be controlled independently. For example, the media valves can be configured so that only one flow path from a reservoir to the interaction chamber, or to all interaction chambers, is open at any given time.

[0040] Furthermore, the provision of two separate media dosing units allows for the back-and-forth pumping of conditioning fluids between the first and second reservoirs of the media dosing units. This enables the surface of a sensor efficiency to be conditioned as efficiently as possible in several steps with different media, while simultaneously minimizing the volume of conditioning fluid used.

[0041] In particular, the first and second media dosing units are arranged as mirror images of each other, such that each media dosing unit has the same number of reservoirs containing the same conditioning fluids and is located on opposite sides of the interaction chambers. "Mirror image" does not mean that the distances to a hypothetical axis of symmetry must be exactly the same, but rather that the media dosing units are arranged largely symmetrically and opposite each other on opposite sides of the interaction chambers, or, in the case of a row arrangement of the interaction chambers, on opposite sides of this row.

[0042] In a further advantageous embodiment, the media channels of the first media dosing unit combine to form a common media collection channel, which can be reversibly coupled to the one-way fluid guide assembly with at least one central media connection, and / or the media channels of the second media dosing unit combine to form a common media collection channel, which can be selectively switched on via valves with groups of or all second fluid channels.

[0043] By incorporating a shared media collection channel, the number of media channels or fluid channels in the disposable fluid guide assembly and the interfaces to the respective media dosing unit can be reduced overall, resulting in a more compact design for the disposable fluid guide assembly. Furthermore, fewer valves are required within the disposable fluid guide assembly to switch the fluid channels connected to the respective media channels. In this way, the media valves allow only one conditioning fluid at a time to flow from a reservoir through its assigned media channel into the shared media channel and be introduced into the disposable fluid guide assembly via the central media connection. There, the central media channel continues and branches off to the fluid channels, which ultimately lead to their own interaction chambers.

[0044] A common media collection channel of the second media dosing unit, which can be selectively connected to groups or all second fluid channels via valves, allows each reservoir of the second media dosing unit to be flow-connected to the second fluid channels of the one-way fluid guide assembly. By introducing the respective, required conditioning fluid from the corresponding media reservoir of the second media dosing unit, media exiting the interaction chambers can flow to their central reservoir and back into the interaction chambers. Another fluid can then flow through all interaction chambers simultaneously and subsequently enter its reservoir, and so on.

[0045] Another aspect of the invention provides that at least one disposal channel, equipped with an outlet valve, branches off from the at least one common media collection channel and leads into a disposal container for waste medium.

[0046] This allows used or contaminated conditioning fluids to be stored separately from the storage containers in the disposal container. Consequently, the disposal container and its associated disposal channel with outlet valve allow conditioning fluids to be diverted from the disposable fluid guide assembly and disposed of as needed, without contaminating the other fluid channels. Flushing fluid can also be removed from the piping system in this way.

[0047] In a further advantageous embodiment of the invention, at least one actuator valve is assigned to the several first reservoirs for conditioning fluids and at least one actuator valve is assigned to the several second reservoirs for conditioning fluids in order to apply overpressure or underpressure to each reservoir of the several first and second reservoirs for conditioning fluids via its assigned actuator valve, in particular wherein the actuator valves of the assigned interaction chamber are alternately controlled such that one reservoir is applied overpressure and the other underpressure or ambient pressure.

[0048] The actuator valve allows the reservoirs to be connected to a compressed air and / or vacuum supply of the pneumatic unit or to the environment, enabling the contactless pumping of conditioning fluid from or into the reservoirs. Furthermore, the alternating actuation of the first and second reservoirs of the first and second media dosing units with positive or negative pressure, or ambient pressure, ensures contactless, bidirectional fluid transfer between the first and second media dosing units via the interaction chamber(s) in the one-way fluid transfer assembly.

[0049] Each reservoir can be assigned one actuator valve. However, it is also conceivable that all reservoirs of the first and / or second media dosing unit are assigned only one actuator valve.

[0050] In another aspect of the invention, the microfluidic device has at least one of the following features: - the first media dosing unit and the second media dosing unit are fluidically connected to each other via a bypass channel provided outside the one-way fluid guide assembly, the bypass channel having at least one shut-off valve; and - the microfluidic device further comprises a volume flow measurement and control unit, which is assigned to the first or second fluid channels and is in particular arranged between the first fluid channels and the first media dosing unit or the second fluid channels and the second media dosing unit in order to control the volume flow in the fluid channels, in particular to equalize it.

[0051] The first of the aforementioned aspects advantageously serves to create an equalization path for conditioning fluids between the first and second media dosing units, so that the conditioning fluids flowing from the first to the second media dosing unit, or vice versa, do not necessarily have to take a flow path through an interaction chamber. This can be advantageous, for example, to equalize the volume in the two media dosing units without contaminating a sensor element already located in the interaction chamber with the conditioning fluid being equalized between the two media dosing units.

[0052] The second aspect offers the advantage that the volume flow in the fluid channels can be controlled, and in particular balanced, so that the same volume flow or pressure is present in each of the first or second fluid channels. This allows for particularly uniform process control. Furthermore, the flow velocity can be adjusted to the residence time of the medium in the interaction chambers.

[0053] Another aspect of the invention provides that the disposable fluid guide assembly has a top and a bottom surface, with the pneumatic unit resting on the top surface and connected to the fluid channels there, and the first and second media dosing units resting on the bottom surface and connected to the media channels. In particular, the disposable fluid guide assembly is clamped between the pneumatic connection blocks of the pneumatic unit and the media connection blocks of the media dosing unit.

[0054] By positioning the pneumatic unit on the top of the disposable fluid guide assembly and the two media dosing units on the underside, the compressed air supply connection and the fluid inlet and outlet can be spatially separated, thus simplifying tubing or piping. Separating the fluid inlet and outlet from the compressed air supply is also advantageous for enabling a compact design of the microfluidic device.

[0055] For example, elastic seals are clamped between the connection blocks and the disposable fluid guide assembly to achieve a tight coupling.

[0056] Some or all of the connection blocks may be mounted to be springable perpendicular to the underside and / or tiltable in several spatial directions in order to adapt to the position of the corresponding connections on the one-way fluid guide assembly.

[0057] The connection blocks may be provided with centering geometries that engage positively with complementary centering geometries on the disposable fluid guide assembly in order to align the connection blocks with the disposable fluid guide assembly.

[0058] The device can have a base with centering projections, preferably only perpendicular to the underside, e.g. conically ending, spring-loaded pins that engage in recesses on the disposable fluid guide assembly to align the disposable fluid guide assembly with the base.

[0059] Another aspect of the invention provides that the valves on the one-way fluid guide assembly are designed as diaphragm valves which can be reversibly coupled to the pneumatic unit, wherein the pneumatic unit is further configured to actuate each diaphragm valve.

[0060] Designing the valves within the disposable fluid guide assembly as diaphragm valves is particularly cost-effective, especially considering that the fluid guide assembly is intended for single use. Furthermore, diaphragm valves allow for the precise opening and closing of fluid channels, particularly those designed for small volumes. Additionally, diaphragm valves permit contactless actuation via positive or negative pressure through the pneumatic unit, thus preventing fluid contamination during actuation. Moreover, multiple diaphragm valves can be easily and cost-effectively configured by integrating them into different sections of the same film-like diaphragm; that is, instead of requiring multiple diaphragms, a single large diaphragm forms several valves.

[0061] According to a further aspect of the invention, the microfluidic device has several interaction chambers and a group of first blood sample intakes that transition via first sample channels into the associated first fluid channels and a group of second blood sample intakes that transition via second sample channels into the associated second fluid channels, such that each interaction chamber can only be fluidically connected to its own first and second blood sample intake.

[0062] This design advantageously allows the microfluidic device to perform sample application in the interaction chamber in addition to its conditioning and measurement functions. Therefore, all steps from conditioning the surface of a sensor element to sample application and final irradiation of the sensor element's surface can now take place within the interaction chamber.

[0063] Furthermore, multiple interaction chambers allow several sensor surface sections to be conditioned, brought into contact with sample fluid, and irradiated in parallel. This enables the protein defect diagnostic device to process a higher overall sample throughput.

[0064] Another aspect of the invention provides that each sample channel is equipped with its own shut-off valve to pump a blood sample to the interaction chamber when the shut-off valve is open. The flow into the interaction chamber from the sample channel can be selectively controlled by means of the shut-off valve. In particular, this prevents the mixing of the blood sample and the conditioning fluid, since the flow of blood sample into the fluid channels of the disposable fluid guide assembly can be controlled via the shut-off valve.

[0065] A further advantageous embodiment of the invention provides that each of the several first blood sample intakes and the several second blood sample intakes is assigned its own connection to the pneumatic unit, which can be switched via at least one control valve in such a way that each blood sample intake can be subjected to overpressure and underpressure or to overpressure and ambient pressure via the at least one control valve, in particular wherein the blood sample intakes of an interaction chamber are alternately controlled in such a way that one blood sample intake is subjected to overpressure and the other to underpressure and the blood sample is pumped back and forth over the sensor element.

[0066] Similar to the first and second media dosing units, a blood sample can also be pumped back and forth between the first and corresponding second blood sample receptacles by alternately applying negative or ambient pressure and positive pressure. This enables particularly efficient sample application to the sensor element, as the sensor element's surface is exposed to a continuous flow of the blood sample fluid. This offers the particular advantage that the sensor, or rather its surface, can be treated with a small volume of sample fluid. Therefore, the volume of sample fluid required for sample application can be reduced without compromising the sensitivity of the subsequent measurement.

[0067] In a further aspect of the invention, each of the several first and / or second blood sample holders is provided with a membrane element that covers a sample inlet on the blood sample holder in a liquid-tight, resealable manner, wherein the membrane element is in particular designed as a hydrophobic, gas-permeable membrane film which can be reversibly coupled to the at least one control valve associated with the blood sample holder in order to subject the blood sample holder to overpressure and underpressure or to overpressure and ambient pressure via the membrane element.

[0068] The membrane element serves a dual purpose: it allows sample entry into the blood sample holder and, once the sample has been entered, it seals the blood sample holder in a liquid-tight manner. This ensures the safe storage of the blood sample within the blood sample holder. This is primarily due to the hydrophobic design of the membrane film. Furthermore, the blood sample holder can be connected to a compressed air supply via the membrane film, thanks to its gas permeability. This allows the blood sample within the blood sample holder to be pressurized and / or subjected to vacuum or ambient pressure, thus moving it into or out of the blood sample holder towards the disposable fluid guide assembly. This eliminates the need for a separate compressed air connection, as both sample entry and the compressed air supply are handled via the membrane element.

[0069] In a further advantageous embodiment of the invention, it is provided that the first blood sample holders and the second blood sample holders are jointly formed in one piece with the disposable fluid guide assembly.

[0070] Therefore, the two blood sample holders are integrated into the disposable fluid guide assembly, which is particularly advantageous because the blood samples are introduced directly into their respective holders and can be disposed of along with the assembly after measurement. This eliminates the need for a separate sample entry or dosing device within the microfluidic system, which would require thorough cleaning, especially autoclaving, after each sample entry to prevent cross-contamination between different blood samples. This would be particularly time-consuming and detrimental to process control.

[0071] Another aspect of the invention provides that the sample channels are each merged into associated media channels at an interface to form a common fluid channel of an interaction chamber. A diaphragm valve is located at the interface, which controls the flow of blood or medium into the common fluid channel.

[0072] By combining the sample channel and media channel, the total number of fluid channels required within the disposable fluid guide assembly can be reduced, while simultaneously ensuring fluidic separation between the medium and the blood sample. This prevents contamination of the sample fluid.

[0073] According to another aspect of the invention, two rinsing fluid containers are provided, each of which is assigned to the fluid channels at one end of the interaction chambers, wherein each channel can be individually connected to a rinsing fluid container via a valve, wherein the rinsing fluid containers are coupled to the pneumatic unit in such a way that the pneumatic unit can pump rinsing fluid back and forth through the fluid channels and the interaction chambers between the rinsing fluid containers by alternately applying overpressure and underpressure or overpressure and ambient pressure to the rinsing fluid containers.

[0074] By providing rinsing fluid containers, the disposable fluid guide assembly can be easily cleaned. In particular, cleaning the fluid channels in the disposable fluid guide assembly does not require removing it from the microfluidic device; instead, it can be cleaned as needed by introducing a rinsing fluid without any further effort. This rinsing is sometimes necessary between the application of different conditioning fluids.

[0075] The flushing fluid is not restricted in principle, and therefore any flushing fluid known from the prior art that is suitable for removing a conditioning fluid from a fluid channel can be used. Preferably, the flushing fluid is selected from the group consisting of water, buffer solution, in particular PBS solution, and combinations thereof.

[0076] The invention further relates to a protein defect diagnostic device, comprising a microfluidic device for analyzing protein defects in a blood sample according to one of the aforementioned aspects. The protein defect diagnostic device includes a sensor element that closes interaction chambers with their surface-treated upper surface. The protein defect diagnostic device further comprises an optical unit that includes an IR source, an IR detector, and a beam path connecting the IR source and the IR detector through the interaction chambers. The optical unit is configured to direct the IR radiation generated by the IR source via the beam path through the sensor element to the IR detector in order to record an IR spectrum from the surface of the sensor element.

[0077] The protein defect diagnostic device enables contactless and therefore contamination-free protein defect detection on the surface of the sensor element. This is achieved by directing IR radiation generated by the IR source onto the sensor element, which scans the candidate biomarkers bound to the surface and records their IR spectrum. The recorded IR spectrum allows conclusions to be drawn about the defects of the proteins bound to the surface. In particular, it can be determined whether the proteins bound to the antibodies on the surface exhibit misfolding, which may indicate an early neurodegenerative disease.

[0078] Furthermore, the aforementioned advantages of the microfluidic device also apply analogously to the protein defect diagnostic device. In this respect, please refer to the description above.

[0079] According to a first aspect of the invention, the protein defect diagnostic device has at least one of the following features: - a temperature control unit configured to temperature-control the sensor element to a predetermined temperature, wherein the temperature control unit in particular comprises a cooling and / or a heating element which is connected to the sensor element in a heat-transferring manner, in particular wherein the cooling and / or heating element has at least one cooling and / or heating channel which is connected to an external temperature control station via a temperature control circuit; and - the sensor element is an ATR element, in particular a germanium single crystal or a silicon single crystal.

[0080] The first of the above-mentioned aspects is particularly advantageous for bringing the surface of the sensor element to a predetermined, constant temperature. This positively influences the conditioning and / or measurement step.

[0081] Maintaining the temperature at room temperature during the conditioning and / or measurement steps is particularly advantageous for achieving consistent and reproducible results. Room temperature is defined as a temperature between 18°C ​​and 26°C. Active temperature control can advantageously compensate for temperature fluctuations in the external environment. This is especially beneficial in rooms where the temperature cannot be regulated or where the protein defect diagnostic device is exposed to warm exhaust air or cooling air from other devices.

[0082] An ATR element is a particularly well-established sensor element, allowing for the use of familiar specifications. A germanium or silicon single crystal is especially preferred for the ATR element, as its surface is particularly suitable for the application of a conditioning fluid. These single crystals are particularly well-suited for subsequent IR analysis, where the IR beam passes through the ATR element via total internal reflection.

[0083] Furthermore, the invention relates to a method for the surface treatment of a sensor element for protein defect detection, with a microfluidic device according to one of the aforementioned aspects, wherein the method comprises the following steps: a) Attaching a sensor element to the one-way fluid guide assembly such that the sensor element closes several interaction chambers on one side, wherein the sensor element has a surface to be treated which forms the previously open side of the interaction chambers; b) Introducing a linker-containing conditioning fluid into the interaction chambers while maintaining a preconditioned surface on the sensor element to which at least one linker is bound, to which an antibody can specifically bind; c) Extraction of the linker-containing conditioning fluid from the interaction chambers via the fluid channels; and d) optionally rinsing the interaction chambers with a rinsing fluid.

[0084] In particular, the surface of a sensor element to be treated can be preconditioned in the interaction chamber.

[0085] According to another aspect of the invention, it is provided that after step c) or d) the following steps are carried out: e) Introducing an antibody-containing conditioning fluid into the interaction chambers while maintaining an antibody-conditioned surface on the sensor element to which at least one antibody is covalently bound, to which a candidate biomarker can bind protein-specifically and conformationally independently; and f) Optionally, the interaction chambers can be rinsed with a rinsing fluid. In particular, conditioning with the antibodies can also take place in the interaction chamber in addition to preconditioning.

[0086] Another aspect of the invention provides that during step b) the linker-containing conditioning fluid flows along the surface to be treated and / or during step e) the antibody-containing conditioning fluid flows along the preconditioned surface of the sensor element, in particular bidirectionally.

[0087] The surface of the sensor element can be conditioned particularly efficiently by flowing the linker-containing or antibody-containing conditioning fluid along the surface. This is especially true because, while maintaining the same efficiency, a smaller volume of conditioning fluid and antibody-containing conditioning fluid is required without affecting the subsequent measurement.

[0088] Furthermore, it can be advantageous to determine and regulate the flow rate of the media flowing through the fluid channels, thereby increasing the measurement accuracy.

[0089] The invention further relates to a method for analyzing protein defects in a blood sample, with a protein defect diagnostic device according to one of the aforementioned aspects, wherein the method comprises the following steps: a) Introducing blood samples into the interaction chambers while maintaining a surface that is in a measurement-ready state; and b) Irradiation of the surface, which is in a state ready for measurement, with IR radiation, obtaining an IR spectrum.

[0090] The method according to the invention offers the advantage that conditioning, blood sample introduction, and surface irradiation can take place in a single interaction chamber without requiring separate devices. In particular, the interaction chamber is housed in a disposable fluid guide assembly, which can be discarded after surface irradiation in step b). This prevents cross-contamination with previous samples during the subsequent steps of conditioning, blood sample introduction, and measurement of the surface ready for measurement. This allows for a particularly low-contamination and simple process, eliminating the need to transfer the sensor element between different devices after each step.

[0091] Further features and advantages of the invention will become apparent from the following description and the accompanying drawings, to which reference is made. The drawings show: - Fig. 1 in a schematic representation a protein defect diagnostic device according to the invention with a microfluidic device according to the invention and an optical unit; - Fig. 2 in an isometric representation the protein defect diagnostic device according to the invention with the microfluidic device according to the invention made of Fig. 1; - Fig. 3 the fluid circuit diagram for the fluid flow of the microfluidic device from Fig. 2; - Fig. 4 in an isometric representation an embodiment of the one-way fluid guide assembly of the microfluidic device made of Fig. 2; - Fig. 5 in a side view the disposable fluid guide assembly made of Fig. 4, with the cutting planes AA and BB; - Fig. 6 in a top view the top of the disposable fluid guide assembly made of Fig. 4, with the cutting plane CC; - Fig. 7 in a bottom view the underside of the disposable fluid guide assembly from Fig. 4; - Fig. 8 in an isometric representation, detail B from Fig. 7, where detail B shows an enlarged view of the interaction chambers; - Fig. 9A a sectional view along the section plane AA from the Fig. 5 on the disposable fluid guide assembly, with the hatching omitted for clarity; - Fig. 9B a section view along the section plane BB from the Fig. 5 on the disposable fluid guide assembly, with the hatching omitted for clarity; - Fig. 10 an isometric section view along the section plane CC from Fig. 6 on the disposable fluid guide assembly, with details C, D and E; - Fig. 11 an enlarged isometric sectional view along the section plane CC of the left side of the one-way fluid guide assembly from Fig. 10, with detail F; - Fig. 12 an enlarged isometric sectional view along the section plane CC of the right side of the one-way fluid guide assembly from Fig. 10; - Fig. 13 an isometric sectional view of detail F from Fig. 11, where detail F shows an enlarged cross-sectional view of a throttle section; - Fig. 14 an isometric top view of detail A from Fig. 7, where detail A shows an enlarged underside view of the throttle section; - Fig. 15 an isometric top view of detail C from Fig. 10, where the detail shows a valve at an interface between fluid channel and sample channel, with the section plane DD; - Fig. 16A and Fig. 16B Sectional views along the section planes D1-D1 ( Fig. 16A) or D2-D2 ( Fig. 16B) from Fig. 15 of the valve from Fig. 15 as well Fig. 16C an isometric sectional view along the section plane D2-D2 from Fig. 15; - Fig. 17A and Fig. 17B each the details D and E from Fig. 10, where Detail D shows an enlarged view of a fluid channel valve and Detail E shows an enlarged view of a fluid channel valve and a flushing valve; - Fig. 18A and Fig. 18B each shows an isometric sectional view of two embodiments of the fluid channel valve from Fig. 17B; - Fig. 19 an isometric sectional view along the section plane BB from Fig. 5 on a sealing element and the underlying lower part; - Fig. 20 in a schematic flowchart the process steps for manufacturing the disposable fluid guide assembly from figure from the Fig. 4 to 19; - Fig. 21A and Fig. 21B each an isometric representation of a sensor element holder, with and without sensor element, with the section plane EE; - Fig. 22A and Fig. 22B each shows a frontal view of one of the two end faces of the sensor element holder from the Fig. 21A and Fig. 21B, with the cutting plane FF, - Fig. 22C a section view along the section plane EE from Fig. 21A; - Fig. 23 a section view along the section plane FF from Fig. 22A on the sensor element holder; - Fig. 24 an isometric representation of a combination of the one-way fluid guide assembly made of Fig. 4, as well as the sensor element holder with sensor element made of Fig. 21A, with the sectioning plane GG; - Fig. 25 a section view along the section plane GG from Fig. 24 of the combination of disposable fluid guide assembly and sensor element holder made of Fig. 24; - Fig. 26 a sectional view of the sensor element holder from Fig. 21A with a centering unit in an uncoupled state; - Fig. 27 a further sectional view of the sensor element holder according to the invention Fig. 21A and the centering unit from Fig. 26 in a coupled state; - Fig. 28 an isometric representation of a base block with centering elements as part of the centering unit from the Fig. 26 and Fig. 27, with the cutting plane HH; - Fig. 29 a section view along the section plane HH from Fig. 28, which shows the centering elements; - Fig. 30 an isometric representation of a container as a temperature control unit and centering unit for receiving the disposable fluid guide assembly made of Fig. 4, with sensor element blocks and fluid inlet blocks, with section plane II; - Fig. 31 a sectional view along section plane II from the Fig. 30 through the container; - Fig. 32 an isometric representation of a fluid inlet block made of Fig. 30, with the cutting plane JJ; - Fig. 33 a section view along the section plane JJ from Fig. 32 of the fluid inlet block, with the section plane KK; - Fig. 34 a section view along the section plane KK from Fig. 32; - Fig. 35 an isometric representation of a pneumatic unit with a drive unit; - Fig. 36 an isometric representation of the underside of the pneumatic unit Fig. 35; - Fig. 37 a schematic flowchart of the process steps for a process according to the invention for conditioning a sensor element for protein defect detection and for applying the sample to the sensor element; and - Fig. 38 a schematic flow diagram of the process steps for a method for guiding fluid over a sensor element surface for conditioning according to the invention and / or for applying blood samples.

[0092] Fig. Figure 1 shows a protein defect diagnostic device 10 for analyzing protein defects in a blood sample.

[0093] For this purpose, the protein defect diagnostic device 10 includes a microfluidic device 12 which is configured to condition a surface of a sensor element for protein defect detection and / or to apply a sample to a conditioned surface.

[0094] In the embodiment according to Fig. Figure 1 shows the protein defect diagnostic device 10 with the microfluidic device 12 configured to both condition the surface of a sensor element for protein defect detection and to apply a sample to the conditioned surface. It should be emphasized, however, that it is also possible to condition the surface in a device reduced to conditioning only, as shown in the figures, and to examine the blood sample for protein defects in a separate device similarly limited to the application and analysis of the blood sample.

[0095] The microfluidic device 12 comprises a pneumatic unit 14 and a first media dosing unit 16 as well as a second media dosing unit 18, wherein the pneumatic unit 14 can be reversibly coupled to the first and the second media dosing units 16, 18 and is configured to alternately apply overpressure or underpressure or ambient pressure to them.

[0096] A reversible coupling of any two components is in Fig. 1 highlighted with a double arrow.

[0097] Furthermore, the microfluidic device 12 comprises a first blood sample intake 20 and a second blood sample intake 22, each of which can be reversibly coupled to the pneumatic unit 14, so that the pneumatic unit 14 can alternately apply positive and negative pressure to the first blood sample intake 20 and the second blood sample intake 22.

[0098] Furthermore, the microfluidic device 12 has at least one interaction chamber 24 which is closed section by section by a sensor element 26 on one side.

[0099] The sensor element 26 is received in and attached to a sensor element holder 28, such that a surface 30 of the sensor element 26 closes off the interaction chamber 24 on one side (here the underside), i.e. section by section.

[0100] The interaction chamber 24 can be reversibly coupled to both the first and second media dosing units 16, 18 and the first and second blood sample receptacles 20, 22. In the coupled state, the interaction chamber 24 is fluidically connected to the first and second media dosing units and the first and second blood sample receptacles 20, 22, depending on the switching positions of some valves that will be presented below.

[0101] Consequently, the interaction chamber 24 provides a defined area within the microfluidic device 12 in which at least one conditioning fluid and / or sample fluid can interact with the surface 30 of the sensor element 26. Details regarding the conditioning fluid and sample fluid, as well as the surface 30 of the sensor element 26, are explained below.

[0102] Depending on the intended use of the protein defect diagnostic device 10, the microfluidic device 12 therefore has either all or only some of the aforementioned components. If, for example, the microfluidic device 12 is solely intended for conditioning the sensor element 26, then the first and second blood sample acquisition 20, 22 are omitted. In the interaction chamber 24, only the conditioning of the sensor element 26 then takes place.

[0103] If, on the other hand, the microfluidic device 12 is solely designed for the analysis of a blood sample for protein defect detection, then the first and second media dosing units 16, 18 are omitted. In the interaction chamber 24, only the sample application to the sensor element 26 then takes place.

[0104] In both of the aforementioned cases, the interaction chamber 24 and the pneumatic unit 14 remain in place.

[0105] However, as shown in the figures, a combination of the aforementioned configurations is also conceivable, such that the protein defect diagnostic device 10 with the microfluidic device 12 is configured to first perform a procedure for conditioning the sensor element 26 and subsequently a procedure for applying a sample fluid to the sensor element 26. For this purpose, the first and second media dosing units 16, 18 as well as the first and second blood sample intakes 20, 22 are provided.

[0106] Regardless of the above-mentioned embodiments of the microfluidic device 12, some of the aforementioned components can be at least partially integrated into a disposable fluid guide assembly 32, such as those found, for example, in the Fig. 4 to 8 are shown, although this is not to be understood as a limitation.

[0107] In the Fig. In the embodiment of the microfluidic device 12 shown in Figure 2, the first and second media dosing units 16, 18 are arranged outside the disposable fluid guide assembly 32, and the first and second blood sample receptacles 20, 22 are integrated into the disposable fluid guide assembly 32, with the interaction chamber 24 also being integrated into the disposable fluid guide assembly 32. This embodiment is described further below with reference to the Fig. 4 to 19 discussed in detail.

[0108] The protein defect diagnostic device 10 according to Fig. 1 also includes an optical unit 34 to analyze protein defects in a blood sample.

[0109] The optical unit 34 comprises an IR source 36 and an IR detector 38, both arranged in a common optical housing 40. The IR source 36 is configured to generate IR radiation, and the IR detector 40 is configured to measure the IR radiation generated by the IR source 36. Furthermore, the IR source 36 and the IR detector 38 are radiationally connected via a beam path 42 that passes through the interaction chamber 24.

[0110] Basically, the optical unit 34 is designed to direct an IR beam generated by the IR source 36 onto the sensor element 26 via the beam path 42 to the IR detector 40 in order to record an IR spectrum from the surface 30 of the sensor element 26.

[0111] To adjust the IR beam, several mirror elements 44 can be provided along the beam path 42, which reflect the IR beam from the optical housing 40 onto the surface 30 of the sensor element 26 and from there back into the optical housing 40 onto the IR detector 38.

[0112] Furthermore, the protein defect diagnostic device 10 includes a control unit 46 (see Fig. 2), with a control unit 48 and an evaluation unit 50, both of which are housed in a technical enclosure 52.

[0113] The controller 48 and the evaluation unit 50 are interconnected and each communicate with the pneumatic unit 14 via signal transmission in order to control the compressed air supply provided by the pneumatic unit 14. For this purpose, the evaluation unit 50 can receive specific signals from the pneumatic unit 14 in the form of parameters and / or measurement data, and based on these parameters and / or measurement data, the evaluation unit 50 transmits a control signal to the controller 48. Based on this control signal, the controller 48 can then control the pneumatic unit 14.

[0114] In particular, the evaluation unit 50 can receive signals from detection units that monitor at least one flow-relevant parameter in the one-way fluid guide assembly 32 and forward it to the evaluation unit 50. The flow-relevant parameter can be the flow direction of a fluid, the flow velocity of a fluid, the fluid volume per unit time, and the type of fluid, i.e., liquid or gaseous.

[0115] The control signal can, for example, be a signal to apply positive or negative pressure to the first and second media dosing units 16, 18 and the first and second blood sample intakes 20, 22.

[0116] What's next in Fig. As can be seen in Figure 2, the protein defect diagnostic device 10 further comprises a drive unit 54, which is configured to reversibly couple the pneumatic unit 14 with the disposable fluid guide assembly 32. Details of the drive unit 54 are explained below in the description.

[0117] The drive unit is a reversible linear drive that can be moved by motor or, as shown here, manually.

[0118] Furthermore, a centering unit 56 is provided in the protein defect diagnostic device 10, which can be reversibly coupled to the sensor element holder 28, so that the sensor element holder 28 can be aligned to the beam path 42, as shown in Fig. 2 shown. This is also further described below in connection with the Fig. Explained in sections 26 to 29.

[0119] Additionally, the protein defect diagnostic device 10, as described in Fig. As can be seen in Figure 2, a temperature control unit 58 is provided, which can be brought into contact with the rear of the sensor element holder 28 and is designed to temper the sensor element 26 to a predetermined temperature via the sensor element holder 28 when coupled. Details of the temperature control unit 58 are described below in connection with Fig. 31 explained.

[0120] The fluid flow diagram of a fluid guide in the microfluidic device 12 is explained in detail below. For this purpose, reference is made to... Fig. Reference is made to point 3, which is referenced below.

[0121] The fluid flow diagram of the fluid guidance system in Fig. Section 3 is divided into various sections, each corresponding to the aforementioned components. The fluid flow within the disposable fluid flow assembly 32 is shown in the center of the circuit diagram. The fluid flow for the first and second blood sample holders 20, 22 is integrated into the disposable fluid flow assembly 32. To the left of this is the fluid flow for the first media dosing unit 16, and to the right is the fluid flow for the second media dosing unit 18. The circuit for the compressed air within the pneumatic unit 14 is shown at the top of the circuit diagram.

[0122] The disposable fluid guide assembly 32 is in a coupled state with the first and second media dosing units 16, 18 and with the pneumatic unit 14.

[0123] First, the fluid guidance within the disposable fluid guidance assembly 32 will be discussed.

[0124] Within the one-way fluid guide assembly 32, several fluid channels, which will be explained in more detail below, are provided and can be switched via multiple valves. Unless otherwise stated, the valves described below are always shut-off valves, in this case diaphragm valves, which can be actuated by positive or negative pressure. In particular, the shut-off valves are designed to completely block or completely release the flow in a fluid channel or a fluid channel section.

[0125] The shut-off valves are specifically not designed to regulate the flow rate. Instead, the flow rate is controlled by the pneumatic unit 14 by applying positive or negative pressure to the first and second media dosing units 16, 18 and to the first and second blood sample intakes 20, 22.

[0126] In the one-way fluid guide assembly 32, the interaction chamber 24 is arranged centrally, with a first fluid opening 68 at a first end 66 of the interaction chamber 24 and a second fluid opening 72 at a second end 70 opposite it. A first fluid channel 74 opens at the first end 66 and is selectively connected to the interaction chamber 24 via at least one fluid channel valve 76. At the second end 70, a second fluid channel 78 opens and is connected to the interaction chamber 24 via a second fluid channel valve 80.

[0127] As in Fig. As shown in Figure 3, there can also be several interaction chambers 24, from which several first fluid channels 74 and second fluid channels 78 extend, with each interaction chamber 24 having only one first fluid channel 74 and only one second fluid channel 78 assigned to it.

[0128] In Fig. 3. Some lines, channels, valves, chambers, etc. are not all, but only examples of some, and are marked with reference symbols if they are units connected in parallel in terms of circuit technology, in order to improve clarity.

[0129] The fluid flow between the disposable fluid flow assembly 32 and the first media dosing unit 16 will now be discussed.

[0130] The circuit diagram of the fluid flow can also be seen to show that the first media metering unit 16 is selectively connected to the first fluid channel 74 (here all first fluid channels 74) at the first end 66 of the interaction chamber 24 via at least the associated fluid channel valve 76.

[0131] In more detail, the first media dosing unit 16 has a first media channel 88, in this case several first media channels 88, which can be reversibly coupled via an associated first media valve 90 either to the first fluid channel 74 or the several first fluid channels 74, whereby a fluidic connection exists in the coupled state.

[0132] As in Fig. As further shown in Figure 3, there can also be several first media channels 88 which can be reversibly coupled to the first fluid channel 74 or fluid channels 74 via first media valves 90, i.e. each media channel has its own media valve 90.

[0133] Furthermore, the first media dosing unit 16 has at least one first storage container 94 into which the first media channel 88 empties or from which the first media channel 88 extends.

[0134] For example, the first storage container 94 could be a liquid tank.

[0135] The first storage container 94 contains a conditioning fluid 96, wherein the conditioning fluid 96 is selected from the group consisting of distilled water, isopropanol, rinsing fluid, PDS, NaPi, MEA, antibody fluid, TBS, various linker fluids, such as linkers based on silanes or thiol ethers, and Tbd.

[0136] Preferably, a group of first storage containers 94 is provided, wherein at least one fluid channel, serving as a first media channel 88, extends from each storage container 94. For clarity, only some of the media channels 88 are designated with reference numerals. The media channels 88 also function as fluid channels.

[0137] Preferably, a different conditioning fluid 96 is arranged in each storage container 94, so that several of the conditioning fluids listed above can be provided.

[0138] More precisely, a section is provided between the first media channels 88 and the first storage tanks 94 in which the first media channels 88 are designed as first fluid lines 100 in the form of hoses or pipes (see also Fig. 2).

[0139] The first fluid line 100 can extend into its reservoir 94 and into the conditioning fluid 96 contained therein.

[0140] In addition, at least one first media control valve 104 in the pneumatic unit 14 is assigned to the first media dosing unit 16, which is designed to apply overpressure or underpressure to the first storage containers 94 in order to pump the conditioning fluid 96 contained therein into or out of the first storage containers 94.

[0141] For example, each first storage container 94 can be provided with a membrane (not shown here) that is gas-permeable but liquid-tight, so that the first media control valve 104 can couple to the membrane and apply overpressure or underpressure to the interior of the first storage container 94.

[0142] As in Fig. As further shown in Figure 3, the first media control valves 104 are provided to pressurize the first storage tanks 94 with overpressure or underpressure. In the circuit diagram shown in Fig. 3 a total of four media control valves 104 are provided, each of which is flow-connected to at least one first storage tank 94 via a first pneumatic line 108.

[0143] In this case, the first pneumatic lines 108 connect the first storage tanks 94 with the first media control valves 104.

[0144] For example, every first pneumatic line 108 can be a hose or a pipe designed to withstand overpressure or underpressure.

[0145] The first media dosing unit 16 further comprises a singular first media collection channel 112, in which the group of first media channels 92 after the media valves 90 are combined, and which can be reversibly coupled to the one-way fluid guide assembly 32 via a central media connection 114.

[0146] Furthermore, the central media connection 114 fluidically connects the first media collection channel 112 of the first media dosing unit 16 with a first distribution channel 116 provided in the disposable fluid guide assembly 32.

[0147] The first fluid channels 74 branch off from the first distribution channel 116. Therefore, the first distribution channel 116 is fluidically connected to the associated interaction chamber 24, and thus to all interaction chambers 24, via an associated first fluid channel valve 76.

[0148] One option provides that the fluid channels 74 or groups of these fluid channels 74 assigned to one end of the interaction chambers branch off from the common distribution channel 116 or several distribution channels, which leads to a central media connection 114. This also applies to the second fluid channels, which can likewise lead in groups to one or more common distribution channels.

[0149] The fluid flow of the second media dosing unit 18 will be discussed in more detail below.

[0150] The circuit diagram shows that the second media dosing unit 18 is selectively connected to the second fluid channel 78 at the second end 70 of each interaction chamber 24 via at least the respective second fluid channel valve 80.

[0151] The second media dosing unit 18 comprises at least one second, here several second storage containers 118, which are filled with conditioning fluid 96. Each second storage container 118 can be designed in the same way as the first storage container(s) 94 of the first media dosing unit 16.

[0152] As mentioned, several second storage containers 118 are provided, with each of the second storage containers 118 having an associated second media channel 122 leading into or extending away from them.

[0153] Preferably, each reservoir 118 contains a different conditioning fluid 96. However, the reservoirs 118 can initially be empty to receive conditioning fluid from the first reservoirs 94. It is not necessary for the same number of first and second reservoirs 94 and 118 to be provided. For example, there can be more first reservoirs 94 than second reservoirs 118, or vice versa.

[0154] The conditioning fluid is again preferably selected from the group consisting of distilled water, isopropanol, rinsing fluid, PDS, NaPi, MEA, antibody fluid, TBS, various linker fluids, such as linkers based on silanes or thiol ethers, as well as Tb.

[0155] In Fig. 3 Each second storage container 118 is assigned its own second media channel 122, which extends from the second storage container 118.

[0156] Each of the second media channels 122 can be reversibly coupled to its associated second fluid channel 78 via its own second media valve 126, with a fluidic connection existing between them in the coupled state. Alternatively, the media channel 122 can be reversibly coupled to groups of second fluid channels or all second fluid channels via at least one media valve 126.

[0157] The second media valves 126 can be designed, in particular, as solenoid valves, so-called Lorentz force valves, to adjust the flow rate from the second media channels 122 to the second fluid channels 78. In Lorentz force valves, permanent magnets generate a constant magnetic field. A coil in the valve housing moves within the magnetic field. This creates a constant force that moves a diaphragm.

[0158] As in Fig. As shown in Figure 3, every second media channel 122 can be reversibly coupled to every second fluid channel 78 via its second media valve 126.

[0159] More precisely, the second media channels 122 have a section to the second storage tanks 118, in which the second media channels 122 are designed as second fluid lines 128 in the form of hoses or pipes.

[0160] Furthermore, the second fluid lines 128 can also extend into the second storage containers 118 and into the conditioning fluid 96 contained therein.

[0161] The second media dosing unit 18 is assigned a second media control valve 132, each of which is reversibly coupled to the second storage tanks 118 via at least one pneumatic line 136 in order to pressurize them with negative or positive pressure. By applying negative or positive pressure, a conditioning fluid 96 stored in the second storage tanks 118 can be pumped out of or into them.

[0162] In the second media dosing unit 18, a second media collection channel 140 is also provided, in which the second media channels 122 merge. In contrast to the fluid guide in the first media dosing unit 16, the second media collection channel 140 splits again into second media channels 122 towards the one-way fluid guide assembly 32, which correspond to the number of second fluid channels 78 in the one-way fluid guide assembly 32 and are each equipped with a media valve.

[0163] As in Fig. As shown in Figure 3, the second media collection channel 140 can, for example, be designed in such a way that it changes the number of incoming and outgoing second media channels 120.

[0164] Furthermore, a section is provided between the second media channels 122, which branch off from the second media collection channel 140 towards the one-way fluid guide assembly, and the second fluid channels 78, in which the second media channels 122 are also designed as second fluid lines 128 (e.g. hoses or pipes).

[0165] As in Fig. As further shown in Figure 3, in this section the second fluid lines 128 (they thus form sections of the second media channels 122) can each be reversibly coupled to the second fluid channels 78 via a media connection 142.

[0166] In the area of ​​the media connections 142, a volume flow measuring unit 144 is provided for each fluid channel 78.

[0167] A bypass channel 148 is also provided between the first media dosing unit 16 and the second media dosing unit 18, which can be switched via a bypass valve 150. More precisely, the bypass channel 148 extends from the first media collection channel 112 to the second media collection channel 140 and connects the two fluidically.

[0168] The following describes, by way of example, a flow path of one of the conditioning fluids 96 between the first media dosing unit 16 and the second media dosing unit 18.

[0169] The conditioning fluid 96 is initially arranged in one of the first reservoirs 94. This reservoir can be pressurized via the associated first media control valve 104, so that the conditioning fluid 96 is pumped from the reservoir 94 and via the first fluid line 100 into its own first media channel 88, where the conditioning fluid 96 meets the first media valve 90.

[0170] After passing through the first media valve 90, the conditioning fluid 96 flows into the first media collection channel 112 and from there via the central media connection 114 into the one-way fluid guide assembly 32.

[0171] The conditioning fluid 96 enters the first distribution channel 116 of the disposable fluid guide assembly 32 via the central media connection.

[0172] Following the first distribution channel 116, the conditioning fluid 96 divides into the first fluid channels 74 with fluid channel valves 76. After passing through the first fluid channels 74, the conditioning fluid 96 flows into the respective interaction chambers 24 and from there out into the second fluid channels 78.

[0173] At the end of every second fluid channel 78, the conditioning fluid 96 passes through the second fluid channel valve 80 and exits the one-way fluid guide assembly 32 via the media connections 142. The conditioning fluid 96 then reaches the volume flow measuring unit 144 and the second fluid lines 128. After the second fluid lines 128, the conditioning fluid 96 passes through the second media collection channel 140.

[0174] Each conditioning fluid 96 has its own second reservoir 118, so that the appropriate media valve 126 is opened to allow the conditioning fluid 96 to enter its second reservoir 118.

[0175] While the conditioning fluid 96 traverses the flow path described above, the second reservoir 118 can be pressurized by the second media control valve 132, i.e., while the first reservoir 94 is pressurized. The flow path of the conditioning fluid 96 is then reversed. This requires only the second reservoir 118 and the first reservoir 94 to be pressurized accordingly.

[0176] Each conditioning fluid 96 can therefore be individually and reversibly pumped back and forth through all interaction chambers 24 by opening the corresponding valves between its reservoirs 94, 118.

[0177] The remaining channels and valves are explained in more detail below.

[0178] The disposable fluid guide assembly 32 is further equipped with a first flushing channel 152, which extends from outside the disposable fluid guide assembly 32 into it and is associated with the first fluid channels 74, each of the first fluid channels 74 being fluidically connected to the first flushing channel 152 via a first flushing valve 154. More precisely, the first flushing channel 152 opens at one end into a flushing reservoir 156 provided outside the disposable fluid guide assembly 32, in which at least one flushing fluid 158 is stored and which can be reversibly coupled to the disposable fluid guide assembly 32, and at its other end into the distribution channel 116.

[0179] The rinsing fluid 158 can be selected from the group consisting of water, buffer solution, in particular PBS solution and combinations thereof.

[0180] Furthermore, the disposable fluid guide assembly 32 is equipped with several second flushing channels 160 on the opposite side of the interaction chambers 24, which merge into a common flushing channel 162 within the disposable fluid guide assembly 32.

[0181] Each of the second fluid channels 78 is flow-connected to a second flushing channel 160 via a second flushing valve 164.

[0182] The common flushing channel 162 opens into a flushing container 166 located outside the disposable fluid guide assembly 32, in which a flushing fluid 158 is also stored or can be pumped into the flushing fluid from the flushing container 156 and pumped back into it.

[0183] The flushing reservoir 166 and the common flushing channel 162 are reversibly coupled to the one-way fluid guide assembly 32, wherein the second flushing valve 164 forms a flushing fluid interface 168 between a second flushing channel 160 and a second fluid channel 78. In particular, the second flushing valve 164 is designed as a two-way valve.

[0184] The first rinsing container 156 and the second rinsing container 166 are also reversibly coupled to the pneumatic unit 14, so that they can be alternately pressurized with overpressure or underpressure, so that the rinsing fluid 158 can be pumped back and forth between the rinsing fluid containers 158 and 166 via the first and second fluid channels 74, 78 and the interaction chambers 24.

[0185] Furthermore, a first disposal channel 170 is provided, which is assigned to the first media dosing unit 16. The first disposal channel 170 has a first valve-controlled outlet 172 leading to a first disposal container 174. In the fluid flow circuit diagram, the first disposal channel 170 is fluidically connected to the common first media collection channel 112, so that contaminated and / or used conditioning fluids 96 can be disposed of via this channel into the first disposal container 174.

[0186] In the second media dosing unit 18, a second disposal channel 176 is provided, which leads via a second valve-controlled outlet 178 to a second disposal container 180. The second disposal channel 176 is fluidically connected to the common second media collection channel 140, so that contaminated and / or used conditioning fluids 96 can also be disposed of via this channel into the second disposal container 180.

[0187] The one-way fluid guide assembly 32 is assigned a third disposal channel 182, which can be connected to a disposal container 186 via a third valve-controlled outlet 184. At its other end, the third disposal channel 182 opens into the first distribution channel 116, so that the latter is fluidically connected to the disposal container 186 via the disposal channel 182.

[0188] The third disposal container 186 is arranged outside the disposable fluid guide assembly 32 and can be reversibly coupled to it.

[0189] The fluid handling of the blood sample recordings 20 and 22 will be discussed in detail below.

[0190] Each of the blood sample recordings 20 is mixed with a blood sample from another person so that the blood samples of several people can be analyzed simultaneously.

[0191] The first blood sample acquisition units 20 are integrated into the disposable fluid guidance assembly 32.

[0192] The first blood sample intakes 20 are each fluidically connected to one of the first fluid channels 74 and thus to one of the interaction chambers 24 via their own first sample channel 188, with the respective first sample channel 188 originating from the blood sample intake 20.

[0193] Each first sample channel 188 is equipped with a first shut-off valve 190, so that the flow connection between blood sample intake 20 and its interaction chamber 24 can be switched.

[0194] Additionally, second blood sample intakes 22 are provided, which are also integrated into the disposable fluid guide assembly 32.

[0195] In particular, the second blood sample receptacles 22 are each fluidically connected to one of the second fluid channels 78 and thus to one of the interaction chambers 24 via a separate second sample channel 194, wherein the respective second sample channel 194 extends from or opens into the blood sample receptacle 22.

[0196] Every second sample channel 194 is equipped with an associated second shut-off valve 196, so that the flow connection between blood sample intake 22 and interaction chamber 24 can be switched.

[0197] Specifically, the first blood sample collection comprises 20 multiple first blood sample collection containers.

[0198] Accordingly, the second blood sample collection containers 22 are also (second) blood sample collection containers 204, which are identical in construction to the first blood sample collection containers 200.

[0199] The first blood sample collection containers 200 are reversibly coupled to a first blood sample control valve 208 of the pneumatic unit 14 and the second blood sample collection containers 204 to a second blood sample control valve 210, wherein the first and the second blood sample control valve 208, 210 are each configured to alternately apply positive and negative pressure to the first and second blood sample collection containers 200, 204, so that a blood sample 212 can be pumped back and forth between the first and second blood sample collection containers 200, 204 through the associated interaction chamber 24.

[0200] Blood sample 212 preferably consists of blood serum, blood or blood plasma.

[0201] In order to fluidically separate the conditioning fluid 96 from the blood sample 212, and to prevent mixing of the fluids and thus contamination of the blood sample 212, a first switchable interface 214 is provided between the first blood sample intake 20 and the interaction chamber 24, which is designed to fluidically separate the fluid flow of the conditioning fluid 96 and the blood sample 212.

[0202] More precisely, at the first interface 214, each first sample channel 188 from the first blood sample collection container 200 meets the first fluid channel 74, which leads into the first media dosing unit 16. A valve is therefore provided at each first interface 214, which fluidically separates the first sample channel 188 from the first fluid channel 74. Both channels 74 and 188 merge towards the interaction chamber 24 to form a common section 216 of the first fluid channel 74, which leads to the interaction chamber 74. The specific design of the first interface 214 is described below.

[0203] Furthermore, a second interface 222 is provided between every second blood sample intake 22 and the associated interaction chamber 24, which is designed to fluidically separate the fluid flow of the conditioning fluid 96 and the blood sample 212.

[0204] Therefore, a valve is provided at every second interface 222, which fluidically separates the second sample channel 194 from the second fluid channel 78. Both channels 78 and 194 merge towards the interaction chamber 24 to form a common section 224 of the second fluid channel 78. The specific design of the second interface 222 is described in detail below.

[0205] In order to apply negative or positive pressure to the first and second dosing units 16, 18, the first and second blood sample intakes 20, 22 and the first and second rinsing containers 156, 166, these are reversibly coupled to the pneumatic unit 14.

[0206] The pneumatic unit 14 is explained in detail below.

[0207] For the compressed air supply, a vacuum line 230, a pressure line 232 and a drive line 234 are provided in the pneumatic unit 14.

[0208] The vacuum line 230 is connected to a first pneumatic pump 236, and the pressure line 232 and the drive line 234 are jointly connected to a second pneumatic pump 238.

[0209] The first and second pneumatic pumps 236, 238 are designed to provide a vacuum or compressed air supply in the respective lines.

[0210] The overpressure line 232 has a higher pressure than the drive line 234. For example, the overpressure line 232 can be pressurized to approximately 1.5 bar relative to atmospheric pressure and the drive line 234 to approximately 0.3 bar relative to atmospheric pressure.

[0211] For adjusting the pressure, pressure regulators of the second pneumatic pump 238 can be connected downstream in the overpressure line 232 and the drive line 234.

[0212] Furthermore, each of the three strands 230, 232 and 234 is equipped with at least one manometer 240, so that the pressure in the respective strand can be monitored and, if necessary, readjusted.

[0213] Vacuum lines 242 are provided on the vacuum line 230, which lead into associated pilot valves 244, into which a pressure line 246 from the pressure line 232 also leads.

[0214] Depending on the switching state, the pilot valves 244 flow-wise connect the vacuum line 230 or the pressure line 232 with at least one associated, switchable valve in or outside the one-way fluid guide assembly 12, i.e. e.g. the aforementioned shut-off valves in the one-way fluid guide assembly 32.

[0215] In total, the first and second fluid channel valves 76, 80, the first and second shut-off valves 190, 196, the first flushing valve 154 and the second flushing valves 164 are each connected downstream of a pilot valve 244 and can be actuated via their pilot valve 244 with vacuum via the vacuum line 230 or with overpressure via the overpressure line 232, i.e., opened or closed.

[0216] To improve clarity, the following are included: Fig. 3 in the upper right corner symbolically represents a pilot valve 244 and a shut-off valve to be switched by it, so to speak as a placeholder for all pilot valves and their shut-off valves.

[0217] Further vacuum lines 242 branch off from the vacuum line 230 and, together with several drive line lines 248 branching off from the drive line 234, lead into several pilot control valves 250. Thus, each pilot control valve 250 is assigned one drive line 248 and one vacuum line 242.

[0218] From each pilot control actuator valve 250, a pneumatic line 251 extends to the respective actuator valves 104, 208, 210 and 128 to apply pressure or vacuum to them.

[0219] Furthermore, several silencer elements 252 are provided in the pneumatic unit 14.

[0220] The following explains how the interaction chamber 32 and the parts that define it are kept at a constant, predetermined temperature.

[0221] As explained above, the disposable fluid guide assembly 32 includes at least one interaction chamber 24, to which a temperature control unit 58 is assigned.

[0222] The temperature control unit 58 comprises a temperature control element 254, which is in physical contact with the interaction chamber 24, in particular with the sensor element 26 adjacent to the interaction chamber 24, thus transferring heat. Consequently, a thermally conductive connection 256 also exists between the temperature control element 254 and the temperature control unit 58, as shown in Fig. 3 is shown schematically.

[0223] The temperature control unit 58 is connected to a temperature control device 258 via a temperature control circuit 260 for heat transfer, the temperature control device 258 being configured to temper the temperature control unit 58 to a predetermined temperature via the temperature control circuit 260. In this respect, temperature control is achieved by means of a temperature control fluid circulating through the temperature control circuit 260. For example, the temperature control fluid can be a liquid such as water or a mixture of water with an antifreeze such as glycerin, ethylene glycol, ethanol, and / or propylene glycol.

[0224] The predetermined temperature can then be passed from the temperature control unit 58 via the heat transfer connection 256 to the temperature control element 254 and thus to the interaction chamber 24.

[0225] To monitor whether the predetermined temperature is present in the interaction chamber 24, the temperature control circuit 260 and the interaction chamber 24 are equipped with several cooling fluid temperature sensors 262. In particular, a sensor crystal temperature sensor 264 is provided, which monitors the temperature of the sensor element 26.

[0226] Furthermore, the temperature control unit 58 is connected to a compressed air supply via a compressed air connection 266, so that the temperature control circuit 260 can be easily dried and cleaned.

[0227] The Fig. Figure 4 shows a specific embodiment of the disposable fluid guide assembly 32 from the previous figures.

[0228] The disposable fluid guide assembly 32 has a lower part 268 which includes a plate-shaped section 270.

[0229] The plate-shaped section 270 has a fluid side 272 and a lower side 274 facing away from it. Furthermore, the plate-shaped section 270 has two end faces 276 and two longitudinal sides 278 connecting the two end faces 276.

[0230] In the embodiment according to Fig. 4 the plate-shaped section 270 has an essentially rectangular basic shape.

[0231] A projection 280 extends laterally outwards from each of the long sides 278. The projection 280 has a rectangular base shape and comprises (see Fig. 7) at each of its two corners a centering bore 282 and a centering element 283 in the form of a pin provided between the centering bores 282.

[0232] Furthermore, the disposable fluid guide assembly 32 (see Fig. 4 and Fig. 5) a top part 284 having a plate-shaped section 286, which is connected to a top 288 and a pneumatic side 290 facing away from it (see Fig. 5) is provided.

[0233] In the embodiment according to Fig. 4 The plate-shaped section 286 has a substantially rectangular basic shape, which corresponds to the shape of the plate-shaped section 270 of the lower part 268.

[0234] Between the top surface 288 and the pneumatic side 290, there are two end faces 292 at opposite ends, each connected by two longitudinal sides 294.

[0235] Analogous to the lower part 268, the upper part 284 also has two rectangular projections 296 extending laterally outwards, each with a centering bore 298 at its two corners. A centering element 283 is located centrally on the projection 296 between the two centering bores 298 (see Fig. 7) provided in the form of a recess.

[0236] As in Fig. As shown in Figure 5, the lower part 268, with its fluid side 272, points towards the pneumatic side 290 of the upper part 284a, so that the top 288 of the upper part 284 and the bottom 274 of the lower part 268 are freely accessible to the outside. In particular, the two plate-shaped sections 270, 286 lie congruently on top of each other.

[0237] Particularly preferred are the upper part 284 and the lower part 268 attached to one another, for example by gluing, welding or fastening them together section by section, as in the Fig. 4 and Fig. 5 is shown.

[0238] In the following figures, the lower part 268 and the upper part 284 are attached to each other via screw connections 300.

[0239] The outer contour of the upper and lower parts 168, 284 will first be explained in detail below.

[0240] The upper surface 288 of the upper part 284 has two rectangular, elongated recesses 302, each arranged perpendicular to the direction of extension of the first and second fluid channels 74, 78, in particular the first and second common sections 216, 224 of the first and second fluid channels 74, 78. In this case, one recess 302 is assigned to the first fluid channels 74 and the other recess 302 to the second fluid channels 78.

[0241] In the elongated recess 302, a plurality of sensor windows 306 are recessed, extending almost to the underlying first or second fluid channels 74, 78, in particular the common sections 216, 224 of the first or second fluid channels 74, 78.

[0242] Furthermore, the lower part 268 also has sensor windows 308 in the form of underside sensor windows 308 (see Fig. 7), extending from the underside 274 of the lower part 268 towards the upper side 288 of the upper part 284.

[0243] The upper and lower sensor windows 306, 308 are arranged opposite each other, so that the first and second fluid channels 74, 78, in particular the common sections 216, 224 of the first and second fluid channels 74, 78, of the one-way fluid guide assembly 32 run between the upper and lower sensor windows 306, 308.

[0244] Furthermore, the upper and lower sensor windows 306 and 308 are each designed to accommodate detection units. This is explained in more detail below.

[0245] As in Fig. As can be clearly seen in Figure 6, the upper surface 288 has several pneumatic channel openings 310, only some of which are marked with reference symbols to which pneumatic channels 311 are connected (see Figure 6). Fig. 11) connect, which run vertically and without interruption to the pneumatic side 290 of the upper part 284.

[0246] The pneumatic channel openings 310 are designed to couple reversibly with the pneumatic unit 14 in order to be subjected to overpressure or underpressure by it.

[0247] Fig. Figure 7 also shows that several media channel openings 312 are arranged on the underside 274, which can be reversibly coupled to the first or second media dosing unit 16, 18, so that a conditioning fluid 96 flowing in from the first or second media dosing unit 16, 18 can flow into the lower part 268 via the media channel openings 312.

[0248] In addition to the media channel openings 312, several outlet openings 313 are provided on the underside 274, which can be reversibly coupled to the first or second flushing container 156, 166 or to the third disposal container 186.

[0249] A block-shaped section 314 is provided in the center of the underside 274, projecting downwards from the underside 274 of the plate-shaped section 270. The block-shaped section 314 is in Fig. 8 shown in detail.

[0250] A base surface 316 is provided on the side of the block-shaped section 314, which faces away from the underside 274.

[0251] The base surface 316 has several elongated recesses in the form of interaction tracks 318, which extend across the base surface 316 and run parallel to each other, forming the interaction chambers 24 section by section. According to the present embodiment, a total of two pairs of interaction tracks 318 are provided, separated by longitudinal webs 319 (see Fig. 8) are objected to by each other.

[0252] The first and second fluid openings 68, 72 are provided at the opposite ends of the interaction paths 318.

[0253] Each interaction track 318, together with the fluid openings 68, 72, is enclosed in a frame-like manner by a sealing element 320, which projects beyond the base surface 316 and, together with the interaction track 318 and the surface 30 of a sensor element 26, defines the interaction chamber 24 (the sensor element 26 has been omitted for clarity). The sensor element presses with its surface 30 against the sealing elements 320 and closes the open side of the respective interaction chamber 24.

[0254] The sealing element 320 can in particular be designed as a sealing ring and is made of an elastic material.

[0255] Specifically, each of the two pairs of interaction tracks 318 is assigned an elongated double sealing ring which has the shape of the number eight, so that two interaction tracks 318 share one longitudinal side of the double sealing ring.

[0256] Furthermore, several sleeve-shaped alignment projections 322 are provided on the base surface 316. The alignment projections 322 allow the block-shaped section 314 to be aligned with a sensor element holder 28.

[0257] The block-shaped section 314 and the lower part 268 are manufactured together in one piece, which is not necessarily the case.

[0258] The inner part of the disposable fluid guide assembly 32 is explained in more detail below. This is particularly well illustrated in the Fig. 9A and Fig. 9B can be identified, each showing the unfolded disposable fluid guide assembly 32 along the section planes BB and AA, respectively. Fig. Figure 9A shows the fluid side 272 of the lower part 268 and Fig. 9B the pneumatic side 290 of the upper part 284. For clarity, a sealing element 330 was used (see Fig. 4) in the Fig. 9A and Fig. 9B omitted. This is in Fig. Figure 19 is shown schematically, which will be briefly discussed below.

[0259] Basically, the upper part 284 on the pneumatic side 290 and the lower part 268 on the fluid side 272 each have several fluid channels formed by grooves 326. The grooves 326 on the fluid side 272 can be associated with recesses 328 on the pneumatic side 290, which, together with a sealing element 330 arranged between the fluid side 272 and the pneumatic side 290, can act as valves.

[0260] The sealing element 330 is designed as a flat, profiled membrane that extends essentially completely over the fluid side 272.

[0261] More precisely (see Fig. 18) The sealing element 330 comprises a first membrane layer 332 and a second membrane layer 334 above it, wherein the first membrane layer 332 is arranged between the second membrane layer 334 and the fluid side 272.

[0262] Preferably, the first membrane layer 332 is thinner than the second membrane layer 334.

[0263] As in Fig. As further shown in Figure 19, the sealing element 330 has blood sample container recesses 336, so that a breakthrough through the first membrane layer 332 and the second membrane layer 334 is given.

[0264] In the area of ​​the recesses 328, the sealing element 330 is part of a diaphragm valve 338, so that the fluid channels adjacent to the recesses 328 and designed as grooves 326 can be switched.

[0265] The fluid-carrying grooves 326 are essentially arranged on the fluid side 272 of the lower part 268, as shown in Fig. Figure 9A shows that, more precisely, the fluid side has 272 different grooves 326, each with different geometries.

[0266] From above, the Fig. 9A has different grooves on the left and right sides of the fluid side 272. A dashed line symbolizes a central axis. The left and right sides essentially correspond to the fluid flow in the circuit diagram in Fig. 3. In this sense, the left side is assigned to the first fluid channels 74 and the right side to the second fluid channels 78, as discussed below.

[0267] On the left side, a wave-shaped groove 340 is provided, extending along or parallel to the end face 276 of the lower part 268. The beginning of the wave-shaped groove 340 is a dead end 339 and the other end represents an inlet opening 341 corresponding to the outlet opening 313.

[0268] The outlet opening 313 (see Fig. 7) on the underside 274 is fluidically connected to an inlet opening 341 via a bore (see Fig. 9A bottom left) connected on fluid side 272.

[0269] The wavy groove 340 has no direct connection to other grooves, but acts as a distribution channel.

[0270] The media inlet opening 345 on the fluid side 272 is fluidically connected to a media channel opening 312 (see Fig. 7) connected on the underside 274 and is spaced apart from the groove 340.

[0271] The groove 340 is spatially separated from the partially linear grooves 346.

[0272] Each groove 346 extends to the center of the fluid side 272 and opens into a fluid interaction chamber opening 348, which fluidically connects the linear groove 346 with the interaction chamber 24.

[0273] The grooves 346 run parallel to each other in sections.

[0274] On the right side of the fluid side 272, linear grooves 346 are visible, each extending from an associated media inlet opening 345 towards the center of the fluid side 272 and opening into a fluid interaction chamber opening 348, which fluidically connects the respective linear groove 346 with the associated interaction chamber 24. Thus, the right side has four inlets for the conditioning fluid 96.

[0275] A groove 346 on the left side is fluidically connected to a groove 346 on the right side via the respective interaction chamber 24.

[0276] Furthermore, each groove 346 on the right side is assigned an inlet opening 341, which lies between the fluid interaction chamber opening 348 and the media inlet opening 345.

[0277] In the fluid circuit diagram of Fig. 3. The wave-shaped groove 340 corresponds to the first distribution channel 116, and the linear grooves 346 on the left side correspond to the first fluid channels 74 and the first common section 216, as do the linear grooves 346 on the right side, which correspond to the second fluid channels 78 and the common section 224. The inlet openings 341 on the left side are assigned to the first flushing tank 156 and the third disposal tank 186, and the media inlet opening 345 to the central media connection 114. The inlet openings 341 on the right side are assigned to the second flushing tank 166.

[0278] In addition, the pneumatic side 290 has several recesses 328 which, together with the sealing element 330, form diaphragm valves 338. For the sake of simplicity, reference numerals are not provided for all valves, grooves, channels, openings, etc.

[0279] Each diaphragm valve 338 has a pneumatic channel 311 (see Fig. 10), which opens into the recesses 328 and extends through the upper part 284 to the pneumatic side 290.

[0280] The fluid flow of the conditioning fluid 96 and the blood sample 212 in the disposable fluid flow assembly 32 is explained in more detail below. For this purpose, reference is made to... Fig. 10, which shows an isometric cross-sectional view along the section plane CC and provides an insight into the one-way fluid guide assembly 32.

[0281] In principle, the flow paths for the conditioning fluid 96 within the disposable fluid guide assembly 32 differ on the left and right fluid sides 272. However, it is also conceivable that both sides have the same fluid guide for the conditioning fluid 96.

[0282] Unlike the fluid flow of the conditioning fluid 96, the fluid flow for the blood sample 212 is the same for the left and right sides. Therefore, the design of the fluid flow for the blood sample 212 will be discussed first.

[0283] As in Fig. As shown in Figure 11, the blood sample receptacle 20 has a blood sample receptacle 200, which is provided on the upper surface 288 of the upper part 284. This encloses a cavity 351 for receiving the blood sample 212.

[0284] As in Fig. As can be seen in Figure 10, the blood sample collection container 200 has a cavity 352 in the upper part 284, to which a cavity 354 in the lower part 268 is connected, and which form the common cavity 351.

[0285] Viewed from the top 288 of the upper part 284, the blood sample collection containers 200 merge into one another and form a kind of tower-like structure with an upper front 365.

[0286] In addition, each blood sample collection container 200 is provided with a sample inlet 366 on the common front side 365, through which a blood sample 212 can be introduced into the cavity 351.

[0287] Each sample inlet 366 is sealed liquid-tight by a membrane element 368, in particular a hydrophobic membrane. Specifically, the membrane element 368 is gas-permeable, allowing the cavity 351 in the blood sample receptacle 20 to be pressurized by the pneumatic unit 14 with either negative or positive pressure. Alternatively, instead of the membrane element 368, a cover is provided at the sample inlet 366, which can be opened to fill with the blood sample and then closed again.

[0288] As in Fig. As can be clearly seen in Figure 13, the cavity 354 in the lower part 268 has a bottom section 370, which is shaped as a trough that tapers conically downwards and opens into a central opening 372.

[0289] The blood sample 212 can enter an outlet line 374 via the central opening 372, which extends vertically downwards from the central opening 372 towards the underside 274.

[0290] A throttle channel 375 is connected to the outlet pipe 374 and extends through a throttle section 376.

[0291] A constriction 378 is provided in the throttle channel 375. This can be achieved, for example, by narrowing the cross-section of the throttle channel 375 in the area of ​​the throttle section 376 due to the constriction 378.

[0292] As demonstrated by Fig. 13 as well Fig. As can be clearly seen in Figure 14, the constriction 378 is created by a plate element 380, which is screwed to the lower part 268 from the underside 274 via several screw connections 382. As a result, the cross-section of the throttle channel 375 in the area of ​​the constriction 378 is reduced to a slot-like cross-section due to the plate element 380, thus effectively reducing the cross-section of the throttle channel 375. The throttle channel 375 is bounded downwards by the plate element 380 and from above by the underside 274 of the lower part 268.

[0293] Furthermore, the throttle channel 375 is fluidically connected to a sample riser line 384. In contrast to the constriction 378, the sample riser line 384 again has a cross-section typical for the one-way fluid guide assembly 32. The sample riser line 384 extends from the underside 274 to the fluid side 272 and terminates in a valve seat 386. This is particularly evident from the Fig. 15 and Fig. 16 to recognize.

[0294] The sample riser line 384, the throttle channel 375 and the outlet line 374 correspond to the first sample channel 188 according to the circuit diagram of the fluid flow. Fig. 3.

[0295] The valve seat 386, together with a sealing element 330 resting on the valve seat 386, forms a diaphragm valve 338, which is shown in the fluid flow diagram as follows: Fig. 3 corresponds to the first interface 214.

[0296] As in Fig. As can be clearly seen in Figure 15, a first fluid channel 74 coming from the left runs into the first interface 214 and meets a branch point 388.

[0297] From the junction 388, the first fluid channel 74 divides into two sub-channels 390, each of which runs around a sleeve-shaped extension 392 of the sample riser 384 and merge again at a subsequent junction 388 to form a common section 216, which in Fig. 15 runs to the right and is fluidically connected to the interaction chamber 24.

[0298] To ensure a particularly dead-space-free contour of the first interface 214, the valve seat 386 is provided with two wedge-shaped lugs 394, each of which is oriented towards the two branching points 388 where the two partial channels 390 merge again.

[0299] As in Fig. As can be seen particularly well in Figure 16A, the valve seat 386 has a concave shape between the wedge-shaped nose 394 and the opening of the sample riser line 384. In this respect, the wedge-shaped nose 394 is a protrusion.

[0300] The section of the valve seat 386 that annularly surrounds the opening of the sample riser 384 is taller than either of the two wedge-shaped protrusions 394. However, it is also conceivable that the wedge-shaped protrusion 394 is shorter, provided that a depression exists between the wedge-shaped protrusion 394 and the opening of the sample riser 384. Such a depression is particularly advantageous to prevent the diaphragm from sagging in the region of the branch 388. In particular, the wedge-shaped protrusion 394 provides support for the diaphragm, thus advantageously eliminating the need for a further support in the form of a column or projection in the region of the branch 388. This allows the diaphragm to seal against the valve seat 386 in the unactuated state, and also enables an unimpeded flow of volume along the partial channels 216 in this state.

[0301] Furthermore, as in the Fig. 16B and Fig. Figure 16C shows that on the pneumatic side 290 of the upper part 284 in the area of ​​the recess 328 an anchoring point 396 in the form of a recess 398 is provided, into which the sealing element 330 can engage via a membrane projection 400.

[0302] Preferably, the anchoring point 396 is annular and completely surrounds the recess 328 of the first interface 214.

[0303] The Fig. Figures 16A to 16C show the diaphragm valve 338 in an unactuated state, in which the sealing element 330 rests on the valve seat 386 and thus seals the sample riser line 384 fluid-tight.

[0304] Opposite the sample riser 384, a pneumatic channel 311 is provided, which fluidly connects the recess 328 to the top surface 288 of the upper part 284. In the actuated state, a vacuum is applied via the pneumatic channel 311, so that the sealing element 330 is drawn upwards towards the top surface 288 into the recess 328, thereby opening the sample riser 384, which is then fluidly connected to the sub-channels 390.

[0305] The fluid interaction chamber opening 348 connects to the common section 216 and leads into an interaction chamber line 402 (see Fig. 10 and Fig. 12) leads to.

[0306] The interaction chamber line 402 extends as a straight channel through the lower part 268 and through the block-shaped section 314, and opens into the interaction chamber 24 via the fluid opening 68 or 72. The interaction chamber line 402 widens at the fluid opening 68 or 72 towards the interaction chamber 24, forming a conical section 406 (see Fig. 10), which is opposite the interaction pathways 318.

[0307] The above description of the first blood sample collection 20 applies analogously to the second blood sample collection 22; in this respect, reference is made to the above description.

[0308] The flow path 410 of the blood sample is explained in more detail below. Flow path 410 is indicated by the dashed line in the Fig. 11 and Fig. 12 shown.

[0309] First, the membrane element 368 or the lid is removed from the sample inlet 366 and the blood sample 212 is placed into the blood sample receptacle 20. For example, the blood sample 212 can be pipetted into the sample inlet 366 by hand.

[0310] The sample inlet 366 is then closed again by the membrane element 368. This can then be reversibly coupled to the pneumatic unit 14, so that the blood sample 212 located in the blood sample receptacle 20 can be pressurized with positive or negative pressure. To move the blood sample 212, positive pressure is applied to the first blood sample receptacle 20 and negative pressure to the second blood sample receptacle 22. However, positive pressure can also be applied to only the first blood sample receptacle 20.

[0311] Due to the applied overpressure in the blood sample collection unit 20 (see Fig. 11) The blood sample 212 is forced into the central opening 372. From there, the blood sample 212 flows via the outlet line 374 and along the throttle section 376 through the throttle channel 375 into the sample rise line 384. The throttle section 376 ensures that the applied pressure increases, so that a higher pressure can be applied to the blood sample intake 20 to move the blood sample 212. Increased pressure is advantageous because, due to the small volume of blood sample 212, very low pressures would be necessary for transport, which would be difficult to control.

[0312] From the sample riser line 384, the blood sample 212 enters the section of the interface 214. This is closed by the diaphragm valve 338. By applying a vacuum on the pneumatic side 290 in the pneumatic channel 311, which corresponds to and is opposite the sample riser line 384, the first diaphragm layer 332 is lifted from the valve seat 386 and pressed against the ceiling of the recess 328, so that the sample riser line 384 is fluidically connected to the sub-channels 390.

[0313] The blood sample 212 can then flow via the sleeve-shaped extension and the wedge-shaped nose 394 through the branching point 388 into the first common section 216 of the fluid channel 74 and further via the common section designated as interaction chamber line 402 into the interaction chamber 24.

[0314] From the interaction chamber 24, the blood sample 212 takes the same path to the blood sample receptacle 22 as described above for the first blood sample receptacle 20. Reference is therefore made to the explanation above.

[0315] As already mentioned above, Fig. As shown in Figure 10, the fluid flow of the conditioning fluid 96 differs between the left and right sides of the disposable fluid flow assembly 32. Therefore, the fluid flow for the conditioning fluid 96 will first be explained for the left side. For this purpose, see Figure 10. Fig. 11. Referenced.

[0316] From the media channel opening 312 on the underside 274, a media riser 414 extends and terminates in the media entry opening 345 (see Fig. 17A), which is opposite a recess 328 on the pneumatic side 290.

[0317] Opposite the media riser 414, a pneumatic channel 311 is arranged, which is fluidically separated from the media riser 414 by the sealing element 330, in particular the first membrane layer 332, wherein the sealing element 330 is shown in the for clarity Fig. Number 11 was omitted.

[0318] The sealing element 330 also forms a diaphragm valve 338 here, which is the first fluid channel valve 76 in the circuit diagram of the fluid guidance according to Fig. 3 is.

[0319] An enlarged view of the corresponding second fluid channel valve 80 on the right side of the one-way fluid guide assembly 32 is shown in the Fig. 18A and Fig. 18B shown, which has the same design as the first fluid channel valve 76.

[0320] The design and function of the fluid channel valve 76 are explained below using the second fluid channel valve 80 as an example, with reference to Fig. Reference is made to 18A, which shows an enlarged view of the second fluid channel valve 80. Fig. 17B shows.

[0321] In the unactuated state of the second fluid channel valve 80, the media riser 414 is spatially separated from the second fluid channel 78 in the plane of the fluid side 272 by a partition. In particular, the first diaphragm layer 332 lies flat against this partition and thereby covers the media inlet opening 345 of the media riser 414 as well as the second fluid channel 78.

[0322] To create a fluidic connection between the media riser 414 and the second media channel 78, the recess 328 is a trough- or box-shaped recess 416 which, when viewed from the top 288, covers the media riser 414 and an initial section of the second fluid channel 78. Actuation of the second fluid channel valve 80 causes the first diaphragm layer 332 to be lifted towards the recess 416, thereby creating a fluidic connection between the initial section of the second fluid channel 78 and the media inlet opening 345.

[0323] As in Fig. As further shown in Figure 18A, in addition to the first membrane layer 332, a second membrane layer 334 is provided, which is arranged above the first membrane layer 332 and faces the upper surface 284. Furthermore, the second membrane layer 334 is cut out in the area of ​​the box-shaped recess 416, so that only the first membrane layer 332 rests on the opening of the second fluid channel 78 and the opening of the media riser 414 when not actuated.

[0324] The above explanation applies equally to the first fluid channel valve 76, as in Fig. 17A and Fig. 18B shown. Unlike the Fig. 18A and Fig. 17B, ​​is the media riser 414 in Fig. 17A is fluidically connected via the recess 416 to the first distribution channel 116, 340 when the first fluid channel valve 76 is in an open state. In contrast to Fig. 18A, is in Fig. Figure 18B provides only a first membrane layer 334. This can be held on the pneumatic side 290 of the upper part 284 via an anchoring point 396 in the form of a recess 398, whereby the sealing element 334 can engage in the recess 398 via a membrane projection 400. However, two membrane layers 332 and 334 can also be provided, as shown in Fig. 18A is shown.

[0325] The flow path 412 of the conditioning fluid 96 is explained in detail below. The conditioning fluid 96 can enter or exit the disposable fluid guide assembly 32 from both the left and the right via the media channel openings 312. It is assumed below that the conditioning fluid 96 enters the disposable fluid guide assembly 32 from the right side.

[0326] The conditioning fluid 96 reaches the second fluid channel valve 80 via the media channel opening 312 and the media riser line 414. When the second fluid channel valve 80 is open, the conditioning fluid 96 flows from the media riser line 414 into the second fluid channel 78.

[0327] From there, the conditioning fluid 96 flows via the two sub-channels 390 of the flushing fluid interface 168 to the second interface 222 (see Fig. 12) to.

[0328] At the second interface 222, the conditioning fluid 96 splits again into the two sub-channels 390 and rejoins towards the second common section 224. Via the fluid interaction chamber opening 348, it enters the interaction chamber line 402 and flows on to the interaction chamber 24.

[0329] From there (see Fig. 11) the conditioning fluid 96 re-enters the next interaction chamber line 402 upwards towards the top 288 and thus enters the first common section 216.

[0330] The conditioning fluid 96 flows along the first common section 216 to the first interface 214.

[0331] There, the conditioning fluid 96 is divided according to the two sub-channels 390 and merges again in the first fluid channel 74 and further downstream meets the first fluid channel valve 76.

[0332] When the first fluid channel valve 76 is open, the conditioning fluid 96 flows into the first distribution channel 116. From there, it encounters another first fluid channel valve 76 and flows through this into the media riser 414 and exits the one-way fluid guide assembly 32 via the media channel opening 312. Naturally, the flow path 412 of the conditioning fluid 96 can also be reversed.

[0333] Furthermore, in Fig. Figure 17B shows the flushing fluid interface 168 to the left of the second fluid channel valve 80. The flushing fluid interface 168 has the same design as the first interface 214 described above, except that instead of the sample riser line 384, a flushing fluid riser line 418 is provided, which corresponds to the second flushing channel 160.

[0334] Fig. Figure 20 shows a schematic flowchart of the steps of a procedure for manufacturing the disposable fluid guide assembly 32.

[0335] In a first step S1, the lower part 268 is injection molded. Preferably, the lower part 268 is made of COC, because the material is fluid-repellent, so that no samples can adhere to the surface.

[0336] Optionally, the plate element 380 for the throttle section 376 can be injection molded and then attached to the underside 274 of the lower part 268, so that the throttle channel 375 is sealed fluid-tight. Preferably, the plate element is also made of COC. Particularly preferably, the plate element 380 can be welded to the underside 274, especially by laser welding.

[0337] Subsequently, the upper part 284 is injection molded in a second step using S2. Preferably, the upper part 284 is made of COC.

[0338] The sealing element 330 is then arranged between the lower part 268 and the upper part 284 (S3).

[0339] Finally, the upper and lower parts 268, 284 are fluidically connected to each other by clamping the sealing element 330 (S4).

[0340] It is particularly preferred that the upper and lower parts 268, 284 are welded together, especially by laser welding.

[0341] The mounting of the sensor element is described below. the Fig. 21-23 explained. In Fig. 21 A Two sensor elements 30 are attached to the common sensor element holder 28. The sensor element holder 28 has a plate-shaped body 420 (see Fig. 21A) with an essentially rectangular basic shape.

[0342] The plate-shaped body 420 comprises a front side 422, a rear side 424 facing away from it, and two longitudinal sides 426 between the front side 422 and the rear side 424, each connecting two end faces 428.

[0343] In each of the longitudinal sides 426, a prestressing mechanism 432 is held in the wall.

[0344] In the middle between the two preload mechanisms 426 are perpendicular to the direction of movement R V The pre-tensioning mechanism 432 provides stop elements 434 spaced apart, against which the sensor elements 30 are clamped. The direction of movement R V is in Fig. 22C shown.

[0345] In particular, the stop elements 434 are designed as projections in the form of longitudinal ribs, each of which has an extension direction perpendicular to the direction of movement R. V of the preloading mechanism 432.

[0346] As in Fig. As can be seen in 21A, the pre-tensioning mechanism 432 is located centrally between the stop elements 434 in its direction of movement.

[0347] In particular, at least the two stop elements 434 can each be integrated in one piece into the sensor element holder 28.

[0348] Furthermore, the plate-shaped body 420 has recesses 436 on its front side 422 forming recesses for the sensor elements 26. The stop elements 434 project from the bottom 438 of the recesses.

[0349] The recordings 436 are in particular one perpendicular to the direction of movement R V continuous depressions running along the pre-tensioning mechanism 432.

[0350] Each pre-tensioning mechanism 432 is designed to act laterally in the direction of the two stop elements 434 and thus to clamp a sensor element 26 arranged in the receptacle 436 laterally against the stop element 434 in a loss-proof manner.

[0351] The pretensioning mechanisms 432 are designed symmetrically to a mirror plane 437, so that on each of the longitudinal sides 426 adjacent to the front 422 there is a pretensioning mechanism 432 and an associated receptacle 436, wherein the mirror plane 437 passes through the stop elements 434.

[0352] As in Fig. As can be seen in Figure 21B, the base 438 of each depression is provided with several steps 440, each having an upward-facing contact section. The contact sections are designed as flat surfaces. Grooves 444 extend between the steps 440.

[0353] More precisely, the recess comprises a lateral contact section 441, designed as a shoulder 440, on each of its lateral edges, on which the sensor element 26 can rest flat against its edge. At least one central contact section 443, running parallel to the lateral contact sections 441, is provided between the lateral contact sections 441, and the sensor element 26 also rests on this central contact section.

[0354] In a coupled state of sensor element 26 and sensor element holder 28, an air-filled reflection channel 445 is located between the adjacent contact sections 441, 443 (see Fig. 21A and Fig. 22A).

[0355] As in the Fig. 21A, Fig. 22A and Fig. As can be seen particularly well in 25, each sensor element 26 forms two reflection channels 445 in the area of ​​the grooves 444 in each recording 436. Each reflection channel 445 has an inlet opening 446, which corresponds to a first end face 428, and an outlet opening 447, which corresponds to the opposite second end face 426 of the sensor element holder 28.

[0356] The pre-tensioning mechanism 432 is explained in more detail below.

[0357] Each pre-tensioning mechanism 432 is assigned a clamping element 448.

[0358] The clamping element 448 comprises a guide section 450 in the form of a block, which fits into a corresponding recess 454 (see Fig. 23) is embedded in one of the longitudinal sides 426. The pre-tensioning mechanism 432 is guided linearly in the plate-shaped body 420 by the guide section 450. The recess 454 is located in the direction of movement R. vthe preloading mechanism 432 is longer than the block, so that it moves along the direction of movement R v the preloading mechanism 432 can be guided linearly.

[0359] A guide web 456 projects upwards from the guide section 450, extending along the direction of movement R. v of the pre-tensioning mechanism 432. In particular, the guide web 456 and the guide section 450 merge seamlessly into one another.

[0360] As in Fig. As shown in Figure 22C, the guide rib 456 extends through the recess in the sensor element holder to the respective receptacle 436.

[0361] The guide rib 456 has a contact nose 460 aligned towards the stop element 434 (see Fig. 21B) with a flat end face, which has chamfered flanks on both sides. The flat end of the contact nose 460 presses against the end face of the sensor element 26 to securely clamp it in the receptacle 436.

[0362] To adjust the preload, the preload mechanism 432 is further equipped with an adjusting screw 468, which can be screwed into a threaded bore 476 in the plate-shaped body 420 to varying depths in order to move the preload mechanism 432.

[0363] Furthermore, a spring 482 is provided in an enlarged bore in the guide section 450, which actuates the adjusting screw 468 and thus the preloading mechanism 432 against the direction of movement R. v preloading mechanism 432.

[0364] To the side of the adjusting screw 468 (see Fig. 23) Each clamping element 448 has two lateral openings 484 for receiving guide pins 486, which are pressed into the plate-shaped body 420 and serve as linear guides.

[0365] The clamping element 448 is made of a softer material (e.g., plastic) than the plate-shaped body 420, the stop elements 434, and the sensor element 26.

[0366] Furthermore, a through hole 491 is located in the plate-shaped body 420 (see Fig. 23) provided.

[0367] The sensor element 26 is a crystal block. This has an essentially rectangular base shape and a sensor element back 494 (see Fig. 22A) and two adjacent side surfaces 496, which terminate at the surface 30 of the sensor element 26. Beveled end faces 498 are provided between the surface 30 of the sensor element 26 and the rear side 494 of the sensor element.

[0368] The angle between the rear of the sensor element 494 and the beveled front face is particularly preferred to be approximately 45 degrees.

[0369] In Fig. Figure 22A further shows that the crystal block is placed in the sensor element holder 28 with its sensor element back 494 onto the contact sections 441 and 443. A side surface 496 of the crystal block rests against the end face of the contact nose 460. Tightening the adjusting screw 468 causes a linear advance of the clamping element 448 towards the stop elements 434, so that the crystal block is clamped in the receptacle 436 between the stop element 434 and the clamping element 448.

[0370] Furthermore, as e.g. in Fig. As shown in Figure 21B, a notch 500 is provided in the plate-shaped body 420 in the area around the exit opening 447 and the inlet opening 446, so that the beveled end faces 498 towards the rear 424 are not covered by the base 438 or the receiver 436. As a result, an IR beam can strike the beveled end face 498 freely and almost perpendicularly.

[0371] The sensor element holder 28 together with the sensor elements 26 contained therein can be brought into engagement with the disposable fluid guide assembly 32, in particular with the base surface 316 of the block-shaped section 314.

[0372] The coupled state of sensor element holder 28 with the sensor element 26 contained therein and the disposable fluid guide assembly 32 is in Fig. 24 shown.

[0373] For this purpose, the sensor element holder 28 is placed with its front side 422 onto the section of the base surface 316 surrounding the interaction paths 318 in a planar position and is held in place by means of the upper recesses 502 provided on the front side 422 of the sensor element holder 28 (see Fig. 21B) aligned to the block-shaped section 314 by its sleeve-shaped, projecting alignment projections (see Fig. 8) penetrate the recesses 502 precisely. Screws 600 then protrude through the central holes of the alignment projections 322 and are screwed into internal threads in the block-shaped section 314 to press the sensor elements 26 against the block-shaped section 314 and to close the interaction chambers 24 that were previously open on this side.

[0374] To ensure that the sensor element holder 28 is mounted in the installation position on the disposable fluid guide assembly 32 in a way that prevents confusion and is precisely positioned, for example an alignment projection 322 and a recess 502 are larger in diameter than the others.

[0375] The sensor element holder 28, attached to the disposable fluid guide assembly 32 and containing the sensor element 26, can then be coupled to the optical unit 34 of the protein defect diagnostic device 10. For this purpose, the sensor element holder 28 with the sensor element 26 contained therein must be aligned in the beam path 42 to record an IR spectrum from the surface. This alignment is performed by the aforementioned centering unit 56, which will be explained in more detail below.

[0376] In order for the sensor element holder 28 to interact with the centering unit 56, the sensor element holder 28 is provided with an underside alignment geometry in the form of an elongated hole 606 and a round hole 608, which are subsequently described using the Fig. 26 - 30 will be discussed in more detail.

[0377] The centering unit 56 has a contact side in the form of the base 616 (see Fig. 27) which can be reversibly coupled to the sensor element holder 28 and on which the sensor element holder 28 rests with its rear side 424. This is exemplified in the Fig. 26 and Fig. 27 shown.

[0378] Furthermore, in the Fig. 26 and Fig. 27 It can be clearly seen that the centering unit 56 has the shape of a container 612. Preferably, the container 612 is made of a thermally conductive material, preferably a metallic material or an alloy.

[0379] The term "container" in the context of the receptacle for a part of the disposable fluid guide assembly 32, including sensor element holder 28 and sensor element 26, means that a receptacle for these parts is formed to allow heat input or output from multiple sides. This does not require a closed or fluid-tight container, but rather a base 616 and one or more side walls 618 for heat transfer. Optionally, the base 616 and side wall or side walls 618 can also be in contact with the sensor element holder 28 and the disposable fluid guide assembly 32. However, if the block-shaped section 314 is surrounded on all sides by the container 612, heat transfer is maximized.

[0380] The container 612 has a central recess 614, which is defined by a bottom 616, a container opening opposite the bottom 616 and four side walls 618.

[0381] The floor 616 is closed, surrounded in a frame-like manner by the four side walls 618.

[0382] Preferably, the shape of the central recess 614 corresponds to the shape of the cross-section of the block-shaped section 314 and / or the sensor element holder 28 in order to accommodate them without a large lateral gap. In the present case, the central recess 614 therefore has a rectangular basic shape.

[0383] As in Fig. As shown in Figure 27, the sensor element holder 28, which is equipped with the sensor element 26, can be inserted into the central recess 614 together with the block-like section 314, so that the rear side 424 rests flat on the base 616. The base 616 forms the contact surface of the centering unit 56.

[0384] To align the sensor element holder 28 in the beam path 42, the centering unit 56 has two centering elements. These are located closer to the Fig. 28 and Fig. 29 explained.

[0385] The centering elements are designed as spring-loaded guide pins 622, which are guided in an associated through-hole 624 in the base 616 of the container 612.

[0386] As in Fig. As shown in Figure 28, the guide pins 622 are not anchored in the container 612, but in a base block 626 which is located below the container 612 and supports it.

[0387] The base block 626 has an essentially U-shaped profile, with two feet 625 and a shelf 627 on which the container 612 can be attached. The guide pins 622 are also anchored in the shelf 627. The base block 626 can, for example, be attached to a base plate (not shown here) via its two feet 625.

[0388] Each of the two guide pins 622 has a conical end 628 that faces away from the base block 626 and projects into the central recess 614 of the container 612.

[0389] The conical end 628 is followed by a shaft 630 (see Fig. 27) which extends laterally through the through-hole 624 in the base 616 of the container 612, fitting precisely, and terminates in a centering recess on the contact surface of the base block 626, where it is anchored. Alternatively, the guide pins 622 can also be conically shaped over the entire area in which they project into the sensor element holder 28.

[0390] The centering recess is associated with a preloading mechanism 634 with springs 642 to axially preload the guide pins 622 upwards. To accommodate the springs 642, the guide pins 622 have a widened shaft section which is mounted in the base block 626.

[0391] The guide pins 622 can spring back in the axial direction to such an extent that the rear side 424 of the sensor element holder 28 abuts the base 616.

[0392] Centering via the centering unit 56 can be carried out as follows (see Fig. 27). The sensor element holder 28 is first attached to the disposable fluid guide assembly 32 and can then be inserted into the central recess 614 with its rear side 424 facing forward, whereby one guide pin 622 engages in the elongated hole 606 and another guide pin 622 engages in the round hole 608. This aligns the sensor element holder 28 in the xy-plane. For alignment along the z-axis and perpendicular to the z-axis, the sensor element holder 28 is pressed further towards the base 616, whereby the guide pins 622 yield and guide the sensor element holder 28 to the base 616, where its rear side 424 comes into contact with it. This aligns the sensor element holder 28 along the z-axis and perpendicular to it. The elongated hole 606 has an oval contour or is chamfered to allow the guide pin 622 to engage more effectively.

[0393] Furthermore, container 612 is equipped with two beam path shafts 645 (see Fig. 27 and Fig. 28) provided which extend through two side walls 618, are arranged opposite each other and open into the central recess 614.

[0394] Consequently, the underside alignment geometry and the centering elements are coordinated in such a way that the inlet opening 446 and the outlet opening 447 each point in the direction of one of the two beam path shafts 645.

[0395] Furthermore, the beam path channels 645 each open at their end facing away from the recess 614 onto the base block 626, wherein the base block 626 also contains beam path channels 645 corresponding to the beam path channels 645 in the container 612, which connect to them. These also extend essentially completely through the base block 626. The beam path channels 645 are designed to receive the beam path 42 and guide it from the optical unit 34, which is usually located below the base block 626, via the beam path channels 645 into the recess 614, into the sensor element 26, and back out again.

[0396] Typically, the two beam path shafts 645 extend at a 45° angle to a plane in which the bottom 616 of the container 612 lies, so that the beam path has a right angle to the beveled front face 498.

[0397] Furthermore, a leakage protection unit (not shown here) can be provided, with a collection basin (not shown here) that at least partially, preferably completely, surrounds the container 612 and a sensor (not shown here) for detecting fluid in the collection basin, which is connected to the control unit 48, which is designed to output a signal when fluid escapes.

[0398] Furthermore, container 612 (see Fig. 30) Two media connection blocks 646, each of which is received in a separate receiving opening 648 in the container 612. As mentioned, the media connection blocks 646 serve to quickly and reliably reversibly couple the conditioning fluid-carrying channels in the disposable fluid guide assembly 32 with the storage containers 94 and the disposal containers 174.

[0399] The receiving openings 648 for the media connection blocks 646 have an elongated, box-shaped form and are provided on two opposite sides of the container 612. The two media connection blocks 646 are described in more detail below.

[0400] Furthermore, the container 612 has two receiving openings 650 for sensor element blocks 652, as shown in Fig. 30 is shown.

[0401] The receiving openings 650 for sensor element blocks 652 have an elongated, box-shaped form and are provided on opposite sides of the recess 614. In particular, a receiving opening 650 for sensor element blocks 652 is arranged between a receiving opening 648 for media connection blocks 646 and the central recess 614.

[0402] In particular, the two sensor element blocks 652 can each be detection units 653 equipped with optical sensors 651.

[0403] The detection units 653 are designed to monitor the fluid flow without contact adjacent to the ends 66, 70 of the interaction chamber 24.

[0404] For example, the detection unit 653 can be a source for generating radiation with specific wavelengths with which the fluid channels of the disposable fluid guide assembly 32 can be irradiated, or it can be a detector 684 that can detect radiation with specific wavelengths.

[0405] On the side of one of the two openings 650 facing away from the recess 614, a cable duct 654 is provided, extending to the outer contour of the container 612 and connecting it to the opening 650. Cables can be laid in the cable ducts 654 to connect the sensor element blocks 652 to the control unit 46, in particular the evaluation unit 50 and the control unit 48, for signal transmission.

[0406] Furthermore, the two receiving openings 650 are each limited on one side facing the receiving openings 648 by a wall 656, so that the sensor element blocks 652 are securely positioned.

[0407] Above this, on the bottom 616 of the container 612, there is a thermal sensor element 660 projecting from the bottom 616, axially prestressed and resiliently mounted (see Fig. 31) ordered.

[0408] In the coupled state, the thermosensor element 660 extends into the through-hole 491 in the sensor element holder 28 to detect the temperature of the sensor element back 494 of the sensor element 26.

[0409] The following describes the media connection blocks 646 based on the Fig. 32 to 34 are explained in more detail.

[0410] Each media connection block 646 has a block-shaped housing 686, with a top 688 and a bottom 690 arranged opposite it.

[0411] Between the top surface 688 and the bottom surface 690, end faces 692 extend at opposite ends, each connected to the other via two longitudinal sides 694.

[0412] The media connection block 646 is inserted into the receiving opening 648 with the underside 690 facing forward, so that the top side 688 is exposed.

[0413] On the upper surface 688, several first media inlet openings 698 are provided, only some of which are labeled, as well as several second media inlet openings 700, wherein the several first media inlet openings 698 are assigned to one longitudinal side 694 and the several second media inlet openings 700 to the other longitudinal side 694. More precisely, the several first media inlet openings 698 and the several second media inlet openings 700 each lie on a straight line.

[0414] The first media inlet openings 698 and the second media inlet openings 700 of the upper surface 688, each arranged in a row, are designed to be reversibly coupled to the media risers 414 of the one-way fluid guide assembly 32.

[0415] The first media inlet openings 698 are each fluidically connected to openings 698' on one longitudinal side 694 and the second media inlet openings 700 are each connected to openings 700' on the other longitudinal side 694 via L-shaped media channel sections 702 (see in particular Fig. 34).

[0416] The first openings 698' and the second openings 700' on the longitudinal sides 694 are designed to be reversibly coupled to the first or second fluid lines 100, 128 of the first and second media dosing units 16, 18, whereby a fluidic connection exists in the coupled state.

[0417] The present design features eight primary media inlet openings 698 and three secondary media inlet openings 700 on the top surface 688 and on one longitudinal side 694. The number can, of course, be varied.

[0418] Furthermore, the upper surface 688 can have a flushing fluid connection 704 which is fluidically connected via an L-shaped flushing fluid channel section 706 to a flushing fluid connection 704' on the longitudinal side 694.

[0419] Furthermore, two disposal channel connections 708 are provided on the top 688, each of which is fluidically connected via an L-shaped disposal channel section 710 to a disposal channel connection 708' on the longitudinal sides 694.

[0420] Advantageously, the media connection block 646 described above can be used for both the left and right sides of the disposable fluid guide assembly 32, since a single component provides two different flow paths through the multiple first and second media inlet openings 698, 700. In other words, depending on the application, either the first media inlet openings 698 or the second media inlet opening 700 connects to the media risers 414 of the disposable fluid guide assembly 32 and to the fluid lines 100, 128 of the first and second media metering units 16, 18.

[0421] Furthermore, on the top side there is 688 (see Fig. 33) A sealing element 712 in the form of a planar, elastic membrane is provided, which has a plurality of recesses that correspond to the underlying media inlet openings 698, 700 on the top surface 688. The sealing element 712 is designed to seal the fluidic connection when coupled with the media risers 414 of the one-way fluid guide assembly 32 by clamping the sealing element 712 planarly between the top surface 696 and the bottom surface 274 of the lower part 268 and elastically deforming it.

[0422] Furthermore, the media connection block 646 has 688 alignment geometries 718 on its upper side, which are aligned with counter-alignment geometries 720 (see Fig. 36) can be brought into engagement with the disposable fluid guide assembly 32 in order to align themselves with the disposable fluid guide assembly 32.

[0423] The alignment and counter-alignment geometries 718, 720 can, for example, be corresponding pins and openings that interlock when coupled.

[0424] The media connection block 646 is equipped at both its opposite ends on the underside 690 with an anchor pin 722, which is inserted into corresponding holes with interference in the area of ​​the receiving opening 648.

[0425] Optionally, the anchor pins 722 can be assigned a locking mechanism provided in the receiving opening 648, so that the receiving openings 648 can be reversibly coupled to the media connection blocks 646. This allows the media connection blocks 646 to be easily removed from the receiving openings 648 and cleaned.

[0426] Furthermore, the media connection blocks 646 are springable and / or tiltable in several spatial directions to the rear 424 of the sensor element holder 28 and are in particular spring-loaded and compliant.

[0427] The spring-loaded mounting is achieved by a first pair of springs 724, which support the underside 690 against the top of the associated receiving opening 648.

[0428] Furthermore, several second springs 726 are provided, particularly between the first pair of springs 724. These multiple second springs 726 are also assigned to the underside 690, but extend almost completely into the block-shaped housing 686. As a result, only a portion of the group of second springs 726 protrudes from the underside 690. A gimbal suspension is simulated via the springs 724 and 726.

[0429] The following section discusses the temperature control unit 58 in detail. This unit is particularly well-suited for use in... Fig. 31 to recognize.

[0430] The temperature control unit 58 comprises the temperature control element 254, which can be brought into surface contact with the rear surface 424 of the sensor element holder 28. The temperature control unit 58 is designed to bring the sensor element 26 to a predetermined temperature in a coupled state of sensor element holder 28, sensor element 26 and temperature control element 254.

[0431] The predetermined temperature is preferably room temperature. Room temperature is understood to be a temperature between 17°C and 26°C.

[0432] Particularly preferred, as shown in the present case, is the tempering element 254 in the entirety or sections of the container 612. This allows for a particularly compact design of the protein defect diagnostic device 10.

[0433] In the coupled state between the disposable fluid guide assembly 32 and the temperature control element 254, the interaction chamber 24 together with the sensor element holder 28 and the sensor element 26 can be received in the recess 614, so that the rear side 424 of the sensor element holder 28 rests on the bottom 616 of the container 612, in particular wherein the side walls 618 of the disposable fluid guide assembly 32 and / or the sensor element holder 28 abut side walls 618 of the container 612 or are only minimally removed from them.

[0434] Consequently, the block-like section 314 projecting from the underside 274 of the lower part 268 is completely incorporated into the container 612.

[0435] As in Fig. As shown in Figure 31, the temperature control element 254 comprises at least one temperature control channel 728 inside the container 612, which passes through one or more side walls 618 and / or the bottom 616 of the container 612.

[0436] Particularly preferred are several temperature control channels extending through the container 612. For this purpose, the container 612 has an inlet 732 and an outlet 734, between which the one or more temperature control channels 728 extend within the container 612.

[0437] In other words, the temperature control channels 728 completely surround the circumference of the recess 614, ensuring particularly uniform temperature control. Since the temperature control channels 728 extend almost completely through the interior of the container, the media connection blocks 646 are also advantageously temperature controlled.

[0438] A temperature control fluid (not shown) flows in the temperature control channel 728, having been introduced into it by the temperature control device 258. The temperature control device 258 tempers the temperature control fluid to the predetermined temperature or to a temperature slightly higher or lower than the predetermined temperature to compensate for temperature losses during transport.

[0439] The temperature control device 258 is located outside the container 612 and is fluidically coupled to the inlet 732 and the outlet 734, thus creating the aforementioned temperature control circuit 260. In this circuit, the temperature control fluid is introduced from the temperature control device 258 into the inlet 732 of the container 612. There, it flows through the temperature control channels 728, thereby temperature-controlling the container 612. This allows the container to bring the sensor element holder 28, and thus also the sensor element 26, to the predetermined temperature, since these are connected in a heat-transferring manner when coupled.

[0440] The pneumatic unit 14 will be discussed in detail below. This will include a discussion of the... Fig. 35 and Fig. 36 referred.

[0441] Specifically, the pneumatic unit 14 is designed as a pneumatic connection block 758, which has a bottom surface 760 facing the disposable fluid guide assembly 32 and a top surface 762 facing away from it.

[0442] The top surface 762 is equipped with several pneumatic units 764 which are fluidically coupled to pump inlets 766 provided on the top surface 762.

[0443] As in Fig. As can be seen from figure 36, the underside 760 has a media dosing interface 768 at opposite ends, which is provided with an elastic sealing membrane 770, to which pump outlets 772 open, which are flow-connected to the pump inlets 766 on the top side 762 and of which only some are marked with reference numerals.

[0444] The sealing membrane 770 therefore has recesses corresponding to the pump outlets 772.

[0445] Each media dosing interface 768 is designed to be coupled in a coupled state with the disposable fluid guide assembly 32 to the pneumatic channel openings 310 of the pneumatic channels 311 in order to apply positive or negative pressure to the pneumatic channels 311.

[0446] In particular, each media dosing interface 768 is designed as an elongated, rectangular projection which has a rib-shaped contact surface 774 on its opposite longitudinal sides, against which the rib-shaped structure of the outside of the sample receiving containers 200, 204 can be supported in the coupled state. Consequently, in the coupled state, the disposable fluid guide assembly 32 is held in a slip-proof manner in the pneumatic connection block 758.

[0447] Furthermore, the underside 760 of the pneumatic connection block 758 is equipped with a detection unit 653 in the form of a sensor unit 776, which is provided with several sensors 777.

[0448] The sensors 777 can be either sources and / or detectors that interact with corresponding sources and / or detectors in the sensor element blocks 652. In the coupled state, a beam path exists between the two, through which optical signals can be sent and received. The free exchange of optical signals is ensured by the sensor windows 306, 308, which allow a beam path perpendicular through the one-way fluid guide assembly 32 and make other fluid channels adjacent to the sensor windows 306, 308 optically accessible for the beam path.

[0449] In addition, the underside 760 is provided with alignment geometries, for example in the form of guide pins 780, with which the pneumatic connection block 758 can be aligned to the disposable fluid guide assembly 32.

[0450] In addition to the media dosing interfaces 768, a blood sample intake interface 784 is provided, which is shaped as a recess.

[0451] The blood sample collection containers 202 and 204 can engage in the recess to be supported in a slip-proof manner.

[0452] The pneumatic connection block 758 is further coupled to a drive assembly 788 belonging to the surface 30 of the sensor element 26 (see Fig. 35), which is designed for the linear displacement of the pneumatic connection block 758 and thus for the rapid fluidic coupling and uncoupling and thus replacement of the disposable fluid guide assembly 32.

[0453] The drive assembly 788 includes a drive, e.g., a crank 790, to which a spindle 792 is non-rotatably connected. The spindle 792 passes through a threaded nut 796, which is attached to a drive block 798 that has a drive surface 800 on its underside for contact with the pneumatic connection block 758.

[0454] The drive block 798 is guided linearly in the base block 662 via rods 804.

[0455] To put the protein defect diagnostic device 10 into operation, the sensor element holder 28 and thus the disposable fluid guide assembly 32 are first aligned by the centering unit 56.

[0456] When the disposable fluid guide assembly 32 is placed on top and pressed down, the two movable media connection blocks 646 align themselves with the disposable fluid guide assembly 32. Subsequently, by actuating the crank 790, the pneumatic connection block 758 can be guided downwards along the centering rods 804 towards the container 612 until the underside 760 of the pneumatic connection block 758 rests against the top 288 of the disposable fluid guide assembly 32. The pneumatic connection block 758 also aligns itself with the disposable fluid guide assembly 32. This means that the entire device aligns itself with the position of the optical unit 34.

[0457] Overall, a positive connection is created between the media connection blocks 646 and the disposable fluid guide assembly 32, which is clamped between the media connection blocks 646 and the pneumatic connection block 758. This clamping achieves a fluidic connection between the disposable fluid guide assembly 32 and the pneumatic connection block 758, as well as a fluidic connection between the media connection blocks 646 and the disposable fluid guide assembly 32.

[0458] Furthermore, the disposable fluid guide assembly 32, in particular the sensor element holder 28, is finally aligned in the beam path 42. The protein defect diagnostic device 10 is in an operational state, so that either the surface 30 of the sensor element 26 can be conditioned and / or brought into contact with a blood sample. In addition, an IR spectrum can now be recorded from the surface 30 of the sensor element 26 via the optical unit 34.

[0459] A hydraulically or purely electrically operated drive assembly 788 is also conceivable.

[0460] Fig. Figure 37 shows a schematic flow diagram of the process steps for conditioning a sensor element for protein defect diagnosis and for applying a blood sample to a sensor element for protein defect diagnosis and for analyzing protein defects in a blood sample.

[0461] The procedural steps are explained in more detail below.

[0462] First, a sensor element is attached to the one-way fluid guide assembly, such that the sensor element closes several interaction chambers on one side, the sensor element having a surface to be treated which forms the previously open side of the interaction chamber (step S5).

[0463] Subsequently, a linker-containing conditioning fluid is introduced into the interaction chambers below a preconditioned surface on the sensor element, to which at least one linker is bound, to which antibodies can specifically bind (step S6).

[0464] Next, the linker-containing conditioning fluid is passed through the fluid channels from the interaction chamber (step S7).

[0465] Alternatively, the interaction chamber can be rinsed with a rinsing fluid (step S8), which serves to clean and vent it.

[0466] Optionally, the interaction chamber can be kept in contact with a fluid until an antibody-containing conditioning fluid is introduced. This fluid can be, for example, a buffer fluid to prevent the interaction chamber from running dry. This can be achieved by leaving a residual fluid, such as a buffer fluid, in the interaction chamber after each process step. This residual fluid can then be displaced by the antibody-containing conditioning fluid, thus keeping the interaction chamber continuously moist.

[0467] The antibody-containing conditioning fluid is then introduced into the interaction chamber below an antibody-conditioned surface on the sensor element, to which at least one antibody is bound, to which a candidate biomarker can bind protein-specifically and conformationally independently (step S9).

[0468] Optionally, the interaction chamber can be rinsed with a rinsing fluid after the previous step (step S10). Subsequently, further corresponding steps can be carried out with other conditioning fluids to condition the surface of the sensor element.

[0469] Optionally, the interaction chamber can be kept in contact with a fluid until a blood sample is introduced. This fluid can also be, for example, a buffer fluid to prevent the interaction chamber from running dry. This can be achieved by leaving a residual amount of fluid in the interaction chamber after each procedure step. This residual fluid can then be displaced by the blood sample, thus keeping the interaction chamber moist until the sample is applied.

[0470] Following this, the blood sample is placed in the interaction chamber below a surface that is in a ready-to-measure state (step S11).

[0471] Finally, the surface, which is in a state ready for measurement, is irradiated with IR radiation below an IR spectrum (step S12).

[0472] In Fig. Figure 38 shows another schematic flowchart illustrating the procedural steps for analyzing protein defects in a blood sample. The individual procedural steps are explained in detail below.

[0473] In the first step, a conditioning fluid is guided from the first fluid channel through the interaction chamber into the second fluid channel (step S13).

[0474] The conditioning fluid is then returned along the second fluid channel through the interaction chamber to the first fluid channel (step S14).

[0475] Steps S13 and S14 can be repeated for a predetermined duration or until a predetermined number of cycles is reached.

[0476] Subsequently, a blood sample can be guided along a first flow direction from a first sample collection point through the interaction chamber to the second blood sample collection point (step S15).

[0477] Alternatively, the fluid flow of the blood sample can be measured along the first flow direction, whereby a flow reversal opposite to the first flow direction is initiated upon detection of an air front or an irregularity in the fluid flow.

[0478] The blood sample can then be guided from the second sample intake through the interaction chamber to the first sample intake along a second flow direction that runs opposite to the first flow direction (S16).

[0479] Optionally, the blood sample flow can be measured along the second flow direction. Upon detection of an air front or an irregularity in the fluid flow, a flow reversal opposite to the second flow direction is initiated. Preferably, the flow reversal is initiated when the respective container from which the fluid flow originates is completely empty. This can be determined in particular by detecting the air front, as this indicates that the respective fluid-conveying container is completely empty. This ensures particularly precise control over the fluid flow. By initiating the flow reversal, it is advantageously possible to prevent air bubbles from entering the interaction chamber right from the initial filling stage.

[0480] Steps S15 and S16 can be repeated for a predetermined number of cycles or for a predetermined time period.

[0481] Finally, the surface of the sensor element is irradiated with IR radiation to obtain an IR spectrum (step S17).

[0482] Alternatively, steps S15 and S16 can be performed during step S17.

[0483] In particular, the surface of the sensor element can be tempered, especially to room temperature, during at least one of the steps S15 - S17.

[0484] The surface of the sensor element can also be tempered, in particular to room temperature, during at least one of the steps S15 - S17, preferably all steps S15 - S17. QUOTES INCLUDED IN THE DESCRIPTION

[0000] This list of documents cited by the applicant was automatically generated and is included solely for the reader's convenience. The list is not part of the German patent or utility model application. The DPMA accepts no liability for any errors or omissions. Cited patent literature

[0000] US 2020 / 0 141 866 A1

[0008]

Claims

[1] Microfluidic device (12) for applying a blood sample to a sensor element (26) for a protein defect diagnosis and / or for conditioning a sensor element (26) for a protein defect diagnosis, comprising a disposable fluid guide assembly (32) having a plurality of interaction chambers (24) which are delimited in sections by a sensor element (26) for protein defect detection, wherein a first (74) and a second fluid channel (78) open into the interaction chambers (24) at one end (66) and at the opposite end (70), wherein the fluid channels (74, 78) are switchable by valves (76, 80) integrated into the disposable fluid guide assembly (32), and the disposable fluid guide assembly (32) further comprises pneumatic channels (311) which control the integrated valves (76, 80), a bracket (28) for mechanically securing the disposable fluid guide assembly (32), and a pneumatic unit (14) with a plurality of drive valves (104, 132, 208, 210), the pneumatic unit having freely ending pump outlets (772) for reversible coupling to the one-way fluid guide assembly (32). [2] Microfluidic device (12) according to claim 1, characterized by that the microfluidic device (12) has a first media dosing unit (16) which can be reversibly coupled to the first fluid channels (74), and a second media dosing unit (18) which can be reversibly coupled to the second fluid channels (78). [3] Microfluidic device (12) according to claim 2, characterized by that the first media dosing unit (16) has a plurality of first storage containers (94) for conditioning fluids (96) and the second media dosing unit (18) has a plurality of second storage containers (118) for conditioning fluids (96), wherein from each of the plurality of first storage containers (94) extends a fluid channel serving as a media channel (88), which can be reversibly coupled via at least one media valve (90) selectively to groups of first fluid channels (74) or to all first fluid channels (74), and wherein from each of the plurality of second storage containers (118) extends a fluid channel serving as a media channel (122), which can be reversibly coupled via at least one media valve (126) selectively to groups of second fluid channels (78) or to all second fluid channels (78), in particular wherein each media channel (122) is provided with its own media valve (126). [4] Microfluidic device (12) according to claim 3, characterized bythat the media channels (88) of the first media metering unit (16) combine to form a common media collection channel (112) which can be reversibly coupled to at least one central media connection (114) on the disposable fluid guide assembly (32), and / or that the media channels (122) of the second media metering unit (18) combine to form a common media collection channel (140) which can be selectively connected to groups of or all of the second fluid channels (78) via valves. [5] Microfluidic device (12) according to claim 4, characterized by that at least one disposal channel (170) provided with an outlet valve (172) branches off from the at least one common media collection channel (112), which opens into a disposal container (174) for waste medium. [6] Microfluidic device according to one of claims 3 to 5, characterized bythat at least one drive valve (104) is assigned to the plurality of first storage containers (94) for conditioning fluids (96), and at least one drive valve (132) is assigned to the plurality of second storage containers (118) for conditioning fluids (96), in order to subject each storage container (94, 118) of the plurality of first and second storage containers (94, 118) for conditioning fluids (96) to overpressure and underpressure or overpressure and ambient pressure via its assigned drive valve (104, 132), in particular wherein the drive valves (104, 132) of the assigned interaction chamber (24) are alternately controlled such that one storage container (94, 118) is subjected to overpressure and the other to underpressure or ambient pressure. [7] Microfluidic device (12) according to one of claims 2 to 6, characterized by that the microfluidic device (12) has at least one of the following features: - the first media dosing unit (16) and the second media dosing unit (18) are fluidly connected to one another via a bypass channel (148) provided outside the one-way fluid guide assembly (32), wherein the bypass channel (148) has at least one shut-off valve (150); and - the microfluidic device (12) further comprises a volume flow measuring (144) and control unit (48) which is assigned to the first or second fluid channels (74, 78) and is arranged in particular between the first fluid channels (74) and the first media dosing unit (16) or the second fluid channels (78) and the second media dosing unit (18) in order to control, in particular to adjust, the volume flow in the fluid channels (74, 78). [8] Microfluidic device (12) according to one of claims 2 to 7, characterized bythat the disposable fluid guide assembly (32) has a top side (288) and a bottom side (274) and the pneumatic unit (14) rests on the top side (288) and is connected there to the fluid channels (74, 78) and the first media dosing unit (16) and the second media dosing unit (18) rests on the bottom side (274) and is connected to the media channels (88, 122), in particular wherein the disposable fluid guide assembly (32) is clamped between a pneumatic connection block (758) of the pneumatic unit (14) and media connection blocks (646) of the media dosing unit (16, 18) [9] Microfluidic device (12) according to one of the preceding claims, characterized by that the valves (76, 80) on the one-way fluid guide assembly (32) are designed as diaphragm valves which can be reversibly coupled to the pneumatic unit (14), wherein the pneumatic unit (14) is further configured to actuate each diaphragm valve. [10] Microfluidic device (12) according to one of the preceding claims, characterized by in that the microfluidic device (12) has a first blood sample receptacle (20) with a group of first blood sample receptacles (200) which merge into the associated first fluid channels (74) via first sample channels (188), and a second blood sample receptacle (22) with a group of second blood sample receptacles (204) which merge into the associated second fluid channels (78) via second sample channels (194), so that each interaction chamber (24) can only be fluidically connected to its own first and second blood sample receptacles (200, 204). [11] Microfluidic device (12) according to claim 10, characterized by that each sample channel (188, 194) is provided with its own shut-off valve (190, 196) in order to pump the blood sample (212) to the interaction chamber (24) when the valve (190, 196) is open. [12] Microfluidic device (12) according to claim 11, characterized by in that the plurality of first blood sample containers (200) and the plurality of second blood sample containers (204) are each assigned a separate connection to the pneumatic unit (14), which can be switched via at least one control valve (208, 210) such that each blood sample container (200, 204) can be subjected to overpressure and underpressure or overpressure and ambient pressure via the at least one control valve (208, 210), in particular wherein the blood sample containers (200, 204) of an interaction chamber (24) are alternately controlled such that one blood sample container (200, 204) is subjected to overpressure and the other to underpressure or ambient pressure. [13] Microfluidic device (12) according to claim 12, characterized byin that each of the plurality of first and / or second blood sample receptacles (200, 204) is provided with a membrane element (368) which covers a sample inlet (366) on the blood sample receptacle (200, 204) in a liquid-tight, resealable manner, wherein the membrane element (368) is designed in particular as a hydrophobic, gas-permeable membrane film which can be reversibly coupled to the at least one control valve (208, 210) assigned to the blood sample receptacle (200, 204) in order to subject the blood sample receptacle (200, 204) to overpressure and underpressure or to overpressure and ambient pressure via the membrane element (368). [14] Microfluidic device (12) according to one of claims 10 to 13, characterized by that the first blood sample receptacle (20) and the second blood sample receptacle (22) are formed integrally with the disposable fluid guide assembly (32). [15] Microfluidic device (12) according to one of claims 10 to 14, as far as dependent on claim 3, characterized by in that the sample channels (188, 194) are each combined into associated media channels (88, 122) at an interface (214, 222) to form a common fluid channel (216, 224) of an interaction chamber (24), wherein a diaphragm valve is located at the interface (214, 222) which controls the inflow of blood or medium into the common fluid channel (216, 224). [16] Microfluidic device (32) according to one of the preceding claims, characterized bythat two flushing fluid containers (156, 166) are provided, each of which is assigned to the fluid channels (74, 78) at one end (66, 70) of the interaction chambers (24), and that each channel (74, 78) can be individually fluidically connected to a flushing fluid container (156, 166) via a valve (154, 164), wherein the flushing fluid containers (156, 166) are coupled to the pneumatic unit (14) in such a way that the pneumatic unit can pump flushing fluid back and forth through the fluid channels (74, 78) and the interaction chambers (24) between the flushing fluid containers (156, 166) by alternately applying pressure and negative pressure or ambient pressure to the flushing fluid containers (156, 166). [17] A protein defect diagnostic device (10) comprising a microfluidic device (12) according to any one of claims 1 to 16, wherein the protein defect diagnostic device (10) comprises a sensor element (26) which closes interaction chambers (24) with its surface-treated upper side (30) on the underside, and an optical unit (34) which has an IR source (36), an IR detector (38) and a beam path (42) connecting the IR source (36) and the IR detector (38) through the interaction chambers (24), wherein the optical unit (34) is configured to guide the IR radiation generated by the IR source (36) via the sensor element (26) to the IR detector (38) via the beam path (42) in order to record an IR spectrum from the surface (30) of the sensor element (26). [18] Protein defect diagnostic device (10) according to claim 17, characterized by that the protein defect diagnostic device (10) has at least one of the following features: - a temperature control unit (58) which is designed to control the temperature of the sensor element (26) to a predetermined temperature, wherein the temperature control unit (58) in particular comprises a cooling and / or heating element (254) which is connected to the sensor element (26) in a heat-transferring manner, in particular wherein the cooling and / or heating element (254) has at least one cooling and / or heating channel (728) which is connected to an external temperature control device (258) via a temperature control circuit (260); - the sensor element (26) is an ATR element, in particular a germanium single crystal or a silicon single crystal. [19] A method for conditioning a sensor element (26) for protein defect detection, comprising a microfluidic device (12) according to any one of claims 1 to 16, the method comprising the following steps: a) attaching a sensor element (26) to the disposable fluid guide assembly (32) such that the sensor element (26) closes a plurality of interaction chambers (24) on one side, wherein the sensor element (26) has a surface (30) to be treated which forms the previously open side of the interaction chambers (24); b) introducing a linker-containing conditioning fluid (96) into the interaction chambers (24) to obtain a preconditioned surface (30) on the sensor element (26) to which at least one linker is bound, to which an antibody can specifically bind; c) discharging the linker-containing conditioning fluid (96) from the interaction chambers (24) via the fluid channels (74, 78); and d) optionally flushing the interaction chambers (24) with a flushing fluid (158). [20] A conditioning method according to claim 19, characterized by that after step c) or d) the following steps are carried out: e) introducing an antibody-containing conditioning fluid (96) into the interaction chambers (24) to obtain an antibody-conditioned surface (30) on the sensor element (26) to which at least one antibody is covalently bound, to which a candidate biomarker protein can bind specifically and conformation-independently; and f) optionally flushing the interaction chambers (24) with a flushing fluid (158). [21] A conditioning method according to claim 19 or 20, characterized by that during step b) the linker-containing conditioning fluid (96) flows along the surface (30) to be treated and / or during step e) the antibody-containing conditioning fluid (96) flows along the preconditioned surface (30) of the sensor element (26), in particular flows bidirectionally. [22] A conditioning method according to any one of claims 19 to 21, characterized bythat the flow rate of the media flowing through the fluid channels (96) is determined and regulated. [23] A method for analyzing protein defects in a blood sample (212), using a protein defect diagnostic device (10) according to any one of claims 17 and 18, the method comprising the following steps: a) introducing blood samples (212) into the interaction chambers (24) while maintaining a surface (30) that is in a measurement-ready state; and b) irradiating the surface (30), which is in a ready-to-measure state, with IR radiation to obtain an IR spectrum.

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