Microfluidic system having an ion exchanger mixed-bed resin

Abstract

Disclosed is a microfluidic system having a housing and having at least one flow channel (20) formed within the housing, wherein at least one element (40) that has an ion exchanger mixed-bed resin is arranged in at least one sub-region of the flow channel (20), and at least the flow channel (20) is formed from a porous material, wherein the ion exchanger mixed-bed resin is intended, by way of its anion and cation exchanger properties, to reduce the ion concentration of a salt or of a contaminating compound of a fluid medium that has macromolecular compounds and / or cellular structures.

Description

[0001] Microfluidic system with ion exchange mixed bed resin

[0002] The invention relates to a microfluidic system with an ion exchange mixed bed resin, a method for producing a cartridge based on the system, the cartridge itself and a method for reducing an ion concentration of a salt or a contaminating compound in a fluid medium comprising macromolecular compounds and / or cellular structures.

[0003] In electrolyte systems, precise knowledge of the ions present and the precise and reproducible adjustment of ion concentrations are essential for adjusting, for example, the electrical conductivity, pH, and osmotic concentration of one or more electrolytes. These parameters therefore represent fundamental influencing factors in biological and chemical processes, such as experiments with DNA, proteins, and cells.

[0004] An ion concentration can be reduced, for example, through dilution steps. However, if high dilutions are required, a correspondingly high initial volume of diluent must be expected. This can lead to space constraints, among other things, because sufficient quantities of a suitable clean diluent must be stored upstream, and previously used reagents must be collected in waste compartments. Dilution has no selectivity for individual ion types, and the actual analyte is also diluted, possibly to below the detection limit of the detection method used. Furthermore, optimal mixing or homogenization must be ensured during dilution steps to avoid concentration gradients.

[0005] This represents a challenge, especially in microfluidic systems. For example, if the conductivity of 1 ml of physiological PBS solution is to be reduced from approximately 14,000 pS / cm to 1 pS / cm by dilution, the addition of 13,999 ml of DI water with a conductivity of approximately 1 pS / cm (dilution 1:14,000) is necessary, whereby it must be noted that the concentration of the analyte is also reduced by the same ratio.

[0006] Another option for adjusting the ion concentration is the use of dialysis filters. These exhibit a certain selectivity with respect to ion size, but their versatility is very limited. Dialysis filters are a diffusion-driven process that depends on the concentration gradient of the compartments separated by the dialysis membrane. Therefore, time is a limiting factor. This is especially the case in large sample volumes or systems with a large characteristic dimension L, because the diffusion time of a molecule scales with the square of L.

[0007] Furthermore, the lower limit of deionization is defined by the equilibration of the ion concentration in the compartments. The concentration gradient can be maintained by regularly using fresh liquids; however, the amount of pre-storable, fresh reagents is limited in miniaturized lab-on-chip systems. Furthermore, integration and handling pose challenges, as a microfluidic system specifically designed for this purpose is required. Use in miniaturized microfluidic systems further impairs efficacy due to the unfavorable surface-to-volume ratio. Use in disposable cartridges would further increase manufacturing costs and would not be economically viable.

[0008] If you want to accelerate the dialysis process and decouple it from concentration gradients, applying pressure to cause mixing is a logical option. Such processes come into play, for example, in seawater desalination plants. However, their integration and handling in lab-on-chip systems are even more difficult to implement. Furthermore, the membrane can become blocked, reducing the effectiveness of the deionization process. Furthermore, excessive pressure can destroy both the membrane and the sample. Extraction and precipitation methods are also commonly used in the deionization of solutions. These represent complex processes that are difficult to integrate and manage in microfluidic systems. Extraction methods, in particular, often involve the use of toxic and material-incompatible chemicals. Furthermore, these processes are rather undefined, which is reflected in their reproducibility.While precipitation methods allow the addition of specific anions and cations to specifically precipitate specific ions by forming an insoluble salt, this is particularly disadvantageous in microfluidic systems, as it can lead to blocking of the system. Adherence of the resulting solid phase to the system can thus negatively impact the process.

[0009] Furthermore, deionization processes using so-called “carbon nanotubes” have already been described.

[0010] Capacitive deionization (CDI) is another method for deionizing water, in which an electrical potential difference is generated by two electrodes. However, this method is not suitable for microfluidic systems intended as disposable products due to integration, handling, and cost. Furthermore, such systems have not yet been used for biological or chemical samples.

[0011] All state-of-the-art methods used for deionization processes have in common limited to non-existent compatibility with microfluidic systems as well as limitations due to limited possibilities for miniaturization or scaling.

[0012] In the deionization of tap water on a macroscopic scale (liter or kilogram), ion exchange mixed-bed resins are integrated into desalination cartridges, where tap water flows through them to deionize it. Once their ion exchange capacity is exhausted, the desalination cartridges can be replaced or regenerated. The ion exchange material usually consists of porous polystyrene beads, which can be functionalized with various ion exchange groups. These have an average diameter of approximately 0.6 mm, with each bead containing either an anion or

[0013] has a cation exchange function.

[0014] Anion exchange columns are also known for the purification of DNA-containing solutions. These bind the DNA contained in the solution to anion exchange gels, with the remaining solution passing through the anion exchange gel in a centrifugation step. The DNA bound to the anion exchanger can be washed and subsequently eluted from the column material. However, this specifically isolates the DNA from the solution, not the contaminating salts or ions.

[0015] Document DE 10 2008 000 369 A1 discloses the integration of a sample preparation system into a microfluidic device. The device may comprise a preparation substance on one side of a mass transfer membrane. The preparation substance may comprise an ion exchanger for desalting the sample, because an excessive salt concentration may be undesirable for a separation process following the preparation. The device may be configured to prepare a biological sample containing DNA, proteins, enzymes, cells, bacteria, or viruses.

[0016] WO 00 / 71243 A1 discloses the use of microfluidic systems that utilize microsphere matrices to detect target analytes. The target analyte can be a nucleic acid. A described device can comprise a separation module designed to separate impurities that interfere with the analysis of the target analyte. The separation module can contain ion exchange materials as separation media.

[0017] Document DE 102013201505 A1 discloses a device for extracting dry, pre-stored body fluids from a sample, a cartridge, and a method for extracting the body fluid. The device is designed as a lab-on-chip system and can include a filter or a purification device for the body fluid extracted from the sample. The purification device can be an ion exchanger.

[0018] DE 100 46 069 A1 describes a method and microfluidic elements for micropolynucleotide synthesis. The microfluidic elements used can include sections containing ion exchange resins, which enable the direct separation of products from reagents. An ion exchanger is provided to facilitate a separation process in the presence of polynucleotides.

[0019] The objective is to achieve a defined reduction in the concentration of ions and specific ion types in an electrolyte. The invention is intended to enable deionization for applications with limited process volumes, such as those used in microfluidic systems. The invention is intended to gently deionize fluid media containing macromolecular compounds and / or cellular structures, such as those found in biotechnology or chemistry.

[0020] This object is achieved by a microfluidic system according to claim 1, a method for producing a cartridge according to claim 11, a cartridge according to claim 14 and a method for reducing the ion concentration of a salt or a contaminating compound of a fluid medium comprising macromolecular compounds and / or cellular structures according to claim 15.

[0021] Further advantageous embodiments and refinements of the invention emerge from the dependent claims, the figures, and the exemplary embodiments. Embodiments of the invention can be advantageously combined with one another.

[0022] A first aspect of the invention relates to a microfluidic system having a housing and at least one flow channel formed within the housing, wherein at least one body comprising an ion exchange mixed bed resin is arranged in at least a partial region of the flow channel, and at least the flow channel is formed from a porous material, wherein the ion exchange mixed bed resin is provided by its anion and cation exchange properties for reducing the ion concentration of a salt or a contaminating compound of a fluid medium comprising macromolecular compounds and / or cellular structures.

[0023] The fluid medium can be, for example, a solution or a suspension. The fluid medium can, in particular, be a sample to be examined in which a specific analyte, such as a diagnostic marker, is to be detected. The macromolecular compounds can be, for example, nucleic acids and / or proteins.

[0024] The invention advantageously solves the above-described problem because the arrangement of an ion exchange mixed-bed resin enables a comparatively high ratio of deionization or ion binding surface area to total volume, thus reducing ion concentration in a space-saving manner. Another advantage is that a sample does not need to be diluted, thus eliminating the need to provide large volumes of diluent, thus saving space. Furthermore, the sensitivity of subsequent detection methods is not affected by excessive sample dilution.

[0025] The invention is also advantageous because no minimum ion concentration is required to establish equilibrium. A lower concentration limit can be set virtually arbitrarily and depends solely on the volume of the ion exchange mixed-bed resin (or the available ion exchange groups). Thus, ion concentrations comparable to those of deionized water can be achieved.

[0026] The selectivity or affinity of the ion exchange mixed-bed resin toward different ion types can advantageously be controlled by functionalizing the ion exchange mixed-bed resin with suitable surface groups. Changing the ratio of anion exchangers to cation exchangers can also further increase the selectivity. Furthermore, the invention advantageously enables gentle deionization of the fluid medium without impairing or destroying the actual analyte in the fluid medium. No aggressive chemicals or high pressures are required (e.g., for precipitation or extraction methods), which could degrade system components or contaminate and negatively impact subsequent process steps.

[0027] This allows the invention to be implemented without significant technical effort, enabling universal integration into microfluidic systems. Furthermore, the amount of mixed-bed resin used can be scaled to any size depending on the microfluidic system or the fluid to be deionized (conductivity and volume).

[0028] The term "deionization" is used here to mean the significant reduction of the ion concentration of a salt or contaminating compound in a fluid medium or solution. Ideally, this ion concentration is reduced to near zero. However, this term does not include the removal of macromolecular compounds (macromolecules) from the solution, which may also be present as ions and which are precisely the desired treatment, i.e., which are to be freed from salt ions and contaminating compounds. In particular, the terms "deionization" and "deionization" are used synonymously with "reduction" and "reduction" in reference to the ion concentration.

[0029] The body is preferably arranged in such a way that the fluid medium can flow around it as it flows through the flow channel. This advantageously enables the greatest possible contact between the surface of the body and the medium. In this way, ions from the medium are efficiently bound to the body. Advantageously, a number of bodies are arranged in the flow channel, thereby providing more surface area for interaction with ions in a sample. The body or bodies are provided, for example, in the form of small particles, e.g. as a sphere or beads. In a preferred embodiment, the bodies can also be so small that they are provided as a powder. Due to its larger surface area, this can further increase the efficiency of reducing the ion concentration. In addition, as a fine suspension, after being absorbed into a fluid, it can also be moved through the microfluidics.

[0030] Preferably, the body consists of a mixed-bed ion exchange resin. In other words, the body consists entirely of one material, namely the mixed-bed ion exchange resin, which is not mixed with any other materials. This advantageously provides a material from which the body(s) can be manufactured. This increases the efficiency of production and the efficiency of interaction with the ions in the fluid medium.

[0031] At least the flow channel of the system according to the invention is formed from a porous material, preferably a porous polymeric material. This is advantageous because the porous material can be passed through by the fluid medium and small ions such as ions of dissolved salts, whereas a body made of or containing an ion-exchange mixed-bed resin, as well as macromolecular compounds such as biomolecules such as proteins, nucleic acids, or cells, cannot pass through it, or can pass through it only slowly compared to salt ions. Pore sizes of 3000 to 5000 Daltons are therefore suitable to ensure this selective permeability. This offers a further important advantage, especially for a fluid medium containing an analyte in the form of a biomolecule such as a nucleic acid. Due to their charges, such biomolecules are also bound to ion-exchange mixed-bed resins, albeit significantly more slowly than small salt ions.The porous material of the flow channel allows deionization of the fluid medium without loss of charged biomolecules through binding of the biomolecules to the ion exchange mixed-bed resin. This is particularly advantageous when processing patient samples in diagnostics, since the sample material contained therein, in particular the desired diagnostic markers, is very limited, so that further loss of sample material could prevent the successful detection of the desired markers. In a preferred embodiment, the body is embedded in at least a portion of the material forming the flow channel. In other words, the body is immobilized in the material. The body can be introduced into designated cavities in the material and, for example, bonded to the material there. This can be carried out, for example, during the manufacturing process of the material, e.g.by incorporating it into the material during an injection molding process or by applying and pressing it into the still soft polymer.

[0032] In a preferred embodiment, polymeric porous material is arranged with the body in the flow channel such that the fluid medium can flow through it. The material is arranged transversely to the flow direction of the fluid medium in the flow channel. The material can be conceivable in the form of a precisely fitting porous frit (or a filter) arranged in the flow channel. The thickness of the frit can be chosen arbitrarily, with a greater thickness being associated with better deionization efficiency, since the ions dissolved in the fluid have more time to interact with the ion exchange material as they pass through the frit. The thickness is limited by the pressure that the microfluidic system can apply to move the fluid. In one embodiment, the body itself can be designed as a frit.

[0033] In a further preferred embodiment, the material with the body is arranged in the flow channel in such a way that the fluid medium can flow against it tangentially. Essentially, the inner surface of the flow channel is lined with the material. The material is then largely flowed against tangentially and no longer flows through completely, as is the case with the frit. Thus, it offers lower resistance. Furthermore, the efficiency of reducing the ion concentration can be improved by sufficiently long incubation times. In one embodiment, the body itself can form the lining material. Preferably, a film-like device made of a polymeric porous material is arranged in the region of the flow channel. Film-like here means that the device has a flat design and is significantly larger in height and width than in thickness.The foil-like device is referred to below as the foil. The foil can be made of the same material as the surroundings of the flow channel or of a different polymeric material.

[0034] Particularly advantageously, the foil is arranged transversely to the flow direction in the flow channel to capture particles made of or containing ion exchange mixed-bed resin in the fluid medium. The particles are stored in a carrier fluid and flushed into the system at the desired time. Contact of the particles with the fluid medium reduces the ion concentration in the medium. After passing through the foil, the medium contains fewer ions and no particles. The foil represents the effective reduction volume.

[0035] In a particularly preferred embodiment, the film is functionalized with ion exchange groups. The body or a number of bodies are arranged in the film. In an alternative embodiment, the ion exchange mixed-bed resin itself can also be provided as a film, i.e. in a thin, porous form. The formation of a film with bodies or of the body as a film is advantageous because it can be prefabricated as a single part and fitted into a specific microfluidic system. The film is then arranged within the flow channel like the carrier material described above, transverse to the flow direction, so that flow can pass through it alone or with another carrier material, or on an inner side of the flow channel. Here, too, the effective reduction volume corresponds to the film volume through which flow occurs or against which flow tangentially occurs.

[0036] In a further preferred embodiment, a first flow channel and a second flow channel are formed within the housing and are in fluid communication with one another. In the region of the fluid connection, a film is preferably arranged between the flow paths, forming a semi-permeable boundary between the first and second flow channels. Suitable embodiments of the film are those in which no bodies are integrated, which are then particularly suitable for capturing bodies from the fluid medium. Furthermore, suitable embodiments of the film are those which have bodies designed to bind salt ions from the fluid medium. The effective reduction volume corresponds to the volume of the film through which the material flows. As an alternative to using a film, the fluid connection can also be designed as a constriction between the two flow channels, where the bodies can be immobilized.In any case, the fluid medium is intended to be introduced into the first flow channel and discharged from the second flow channel with a significantly reduced ion concentration.

[0037] A second aspect of the invention relates to a method for producing a cartridge comprising a system according to the invention, comprising the steps:

[0038] - Providing a number of layers of a polymeric material which, depending on their planned position within the cartridge, have a shape such that they can form a flow channel within the housing, and at least the flow channel is formed from a porous material,

[0039] - Providing at least one body comprising an ion exchange mixed bed resin,

[0040] - arranging the layers and the body in such a way that a flow channel is formed and the body is located in at least a partial area of ​​the flow channel and cannot leave the flow channel,

[0041] - Joining the layers together.

[0042] Preferably, the body is provided with the layers that form the flow channel. The body can be integrated into the material, i.e., mixed into the material during the production of the corresponding layers, e.g., by an injection molding process, or can be embedded in the still-soft material. Alternatively, depressions, e.g., recesses in various geometric shapes, can be formed in the corresponding layers to accommodate the bodies.

[0043] Particularly preferably, a film made of a polymeric material is provided in the process. The film has been described above. The film can consist of the same polymeric material as the layers or a different polymeric material. The film can, for example, contain or consist of an ion exchange mixed-bed resin.

[0044] Preferably, the bodies are integrated into at least one area of ​​the film. In particular, bodies are selectively arranged in desired areas of the film. This advantageously saves material if the film is arranged between two flow channels and only has the bodies in the immediate flow path.

[0045] The film is preferably arranged in the flow channel perpendicular to the flow path of the fluid medium. Alternatively, the film can also be arranged along the flow channel. The film allows for the arrangement of bodies after the actual production of the cartridge, thus saving effort and allowing the cartridge to be manufactured from layers without integrating the bodies into the layers.

[0046] A third aspect of the invention relates to a cartridge for reducing the ion concentration of a salt or a contaminating compound in a fluid medium containing macromolecular compounds and / or cellular structures, produced by a method according to the second aspect of the invention. The advantages of the cartridge correspond to the advantages of the method according to the invention. The cartridge can be provided, for example, as a so-called lab-on-chip cartridge and used in the development of biological or molecular biological tests and methods.

[0047] A fourth aspect of the invention relates to a method for reducing the ion concentration of a salt or a contaminating compound of a fluid medium containing macromolecular compounds and / or cellular structures by means of a cartridge according to the invention, comprising the steps:

[0048] - Preparing the cartridge,

[0049] - Flushing the fluid medium into the flow channel,

[0050] - Incubation of the fluid medium in the flow channel,

[0051] - Discharge of the fluid medium from the flow channel for further use.

[0052] The method advantageously enables a reduction of the ion concentration of a salt or a contaminating compound in biological and chemical samples on the micro- and nanoliter scale.

[0053] Preferably, the desired level of reduction of the ion concentration of the fluid medium is controlled by the amount of ion exchange mixed-bed resin used and / or by the selection of the ion exchange groups in the ion exchange mixed-bed resin. In this way, a cartridge can advantageously be used for a specific fluid medium to be reduced. Furthermore, a cartridge can also be used according to a specific objective, e.g., if a particular purity of the fluid medium from salt ions is necessary for a specific application, or if, alternatively, certain ions are to be removed. Selective reduction can be controlled to a certain extent by processing different ion groups during the manufacturing process. Furthermore, the proportion of anion exchangers and cation exchangers in the mixed-bed resin can be adjusted.The surface area available for ion exchange is also crucial and can be adapted to the specific application.

[0054] In a further preferred embodiment of the process, the desired degree of reduction in the ion concentration of the fluid medium is controlled by the duration of the incubation of the fluid medium in the flow channel. If the fluid containing the ions is incubated statically with the mixed-bed resin, i.e., without establishing a flow, the reduction in the ion concentration is a purely diffusion-driven process. If the diffusion coefficients of the desired or undesired ions are known, the time factor can be used to further influence the selectivity of the process.

[0055] Non-selective binding of all ionic components to a mixed-bed resin is also possible, followed by a defined microfluidic addition of the desired ions. Alternatively, a deionized solution can be transported to pre-stored liquid or powdered ions, which are then reabsorbed into the fluid.

[0056] The invention is explained in more detail with reference to the figures. They show:

[0057] Figure 1 shows a cartridge according to an embodiment of the invention with a flow channel.

[0058] Figure 2 shows a cartridge according to an embodiment of the invention with two flow channels.

[0059] Figure 3 is a schematic representation of bodies made of ion exchange mixed bed resin.

[0060] Figure 4 is a schematic representation of an arrangement of the bodies according to Fig. 3 in a layer of the cartridge.

[0061] Figure 5 is a schematic representation of an arrangement of the bodies in the surface of a flow channel of the cartridge.

[0062] Figure 6 is a schematic representation of cavities in the surface of a flow channel in various forms.

[0063] Figure 7 is a schematic representation of a flow channel with a frit arranged therein with or made of ion exchange mixed bed resin.

[0064] Figure 8 is a schematic representation of a flow channel with bodies made of ion exchange mixed-bed resin arranged in the material of the flow channel formation. Figure 9 is a flow diagram of an embodiment of the method according to the invention for producing a cartridge.

[0065] Figure 10 shows a cartridge with two flow channels and a foil.

[0066] Figure 11 shows the production of a film functionalized with ion exchange mixed bed resin.

[0067] Figure 12 shows a cartridge with two flow channels and a film functionalized with ion exchange mixed bed resin.

[0068] Figure 13 shows a cartridge with a flow channel and a film functionalized with ion exchange mixed bed resin.

[0069] Figure 14 is a flow diagram of an embodiment of the method according to the invention for reducing an ion concentration by means of a cartridge.

[0070] Fig. 1 shows a cartridge 10 designed as a cartridge 11 with a flow channel 20. The cartridge 11 has four layers 30, namely a first layer 31, a second layer 32, a third layer 33, and a fourth layer 34. The flow channel 20 is formed by the second layer 32 and the third layer 33. The material of the layers 30 is in particular a porous polymer such as polycarbonate; other suitable polymeric materials can also be used. The pore size of the material should therefore be defined such that an ion exchange mixed-bed resin in powder form or as beads, as well as biomolecules such as proteins, nucleic acids, or cells, cannot pass into or through the material, or can only pass through it slowly compared to salt ions. Smaller molecules, such as dissolved salts, on the other hand, should be able to pass through the material. Pore ​​sizes of 3000 to 5000 Dalton are therefore suitable to ensure this selective permeability.This offers another important advantage, particularly for biomolecules such as nucleic acids. Due to their charges, these molecules are also bound to ion exchange mixed-bed resins, albeit significantly more slowly than small salt ions. Fig. 2 shows a cartridge 10 designed as a cartridge 12 with a first flow channel 21 and a second flow channel 22. The number of layers 30 in the layered structure corresponds to that of the cartridge 11 according to Fig. 1. In contrast to Fig. 1, in the cartridge 12, the first layer 31 and the third layer 33 each have different material thicknesses in sections, so that they enable the formation of the first flow channel 21 and the second flow channel 22 in the sections with lesser thickness. The first flow channel 21 and the second flow channel 22 are connected by a fluid connection 23. The fluid connection is provided by a tunnel in the second layer 32.The fluid connection 23 allows at least one flow of a liquid; it can be designed as a constriction so that bodies located in the liquid cannot pass through, or it can be provided for the arrangement of a film.

[0071] The cartridge 10 is intended to reduce the concentration of salt ions and / or ions of contaminating compounds in an ionic liquid. The ionic liquid can also be referred to as an ionic solution or a fluid medium and particularly comprises macromolecular compounds and / or cellular structures. To reduce the concentration of salt ions and / or ions of contaminating compounds in the ionic liquid, bodies 40 are used which comprise an ion exchange mixed-bed resin or, in a preferred embodiment, consist of the ion exchange mixed-bed resin. Fig. 3 shows two bodies 40, one being an anion exchange body and the other a cation exchange body, which are immobilized with the corresponding ions SO s and N , respectively. + Rs are functionalized, as well as the mobile counterions (Na +and CI'). The functionalization is stationary / immobilized and, together with the resin matrix, forms the framework of the bodies. Ion exchangers can be functionalized with a wide variety of ions. The counterions serve to ensure the ion exchange function. For the bodies to possess an ion exchange function, the functional groups must be loaded with (very) mobile ions. The cation exchanger must be loaded with a cation, and the anion exchanger with an anion. Anions and cations can also be functionalized on one body. The resin used as a support material is typically porous polystyrene, although other suitable polymers can also be used.

[0072] The bodies 40 are provided in an approximately spherical shape (preferably spherical) and have a diameter of 0.1 mm - 1.2 mm. The bodies 40 can also be further mechanically comminuted, e.g., by grinding, until they are powdered. This embodiment is particularly suitable for use in a suspension.

[0073] Fig. 4 shows an embodiment of the invention in which bodies 40 are embedded in a layer 30. Here, the bodies 40 are immobilized directly in the material of layer 30. The porous material of layer 30 has filtering properties. This arrangement can counteract the loss of charged biomolecules contained in an ionic liquid, since only small charged molecules can penetrate the filter material to interact with the mixed-bed resin, and the biomolecules, which are usually macromolecules, cannot bind to the mixed-bed resin. In other words, by packaging the bodies 40 in the porous material of layers 30, deionization of the ionic liquid can occur without loss of charged biomolecules through binding to the ion-exchange mixed-bed resin.

[0074] Fig. 5 shows an embodiment of the invention in which bodies 40 are arranged in the region of the surface of a layer 30. The bodies 40 can be embedded in the material of the layer 30, e.g. by being pressed into the still soft polymer material during the production of the layer 30. Alternatively, cavities 41, e.g. recesses or depressions, in which the bodies are arranged, can also be formed in the layer 30. Such cavities 41 can have various geometries, e.g. a rounded shape 42, a square shape 43, a triangular shape 44, a first trapezoidal shape 45 and a second trapezoidal shape 46 (Fig. 6). Fig. 7 shows a flow channel 20 in which an ion exchange filter designed as a frit 50 is arranged. The frit 50 is arranged transversely to the flow direction of an ionic liquid (indicated by the arrows) and fits precisely in the flow channel 20.In this way, the largest possible surface area is provided for ion exchange while simultaneously ensuring optimal flow through the polymer material. In one embodiment, the frit 50 comprises the same material as the layers 30 of the cartridge 10, i.e., a porous polymeric material, particularly polycarbonate, into which bodies 40 are embedded. In another embodiment, the frit 50 consists of the ion exchange mixed-bed resin, in other words, it is the body 40. The thickness of the frit 50 can be chosen arbitrarily, with a greater thickness correlating with higher efficiency, since the ions dissolved in the fluid can interact with the ion exchange material over a longer period of time as they pass through the frit 50. The thickness of the frit 50 is limited by the pressure that can be provided to the cartridge 10 to move the fluid. It is possible to arrange several frits 50 one behind the other in the flow channel 20.These can then be anion and cation exchange frits.

[0075] Fig. 8 shows a flow channel 20, the lower boundary of which is formed by layer 33 and the upper boundary by layer 32. Bodies 40 are arranged in the surface of layer 33. A corresponding arrangement can be provided as explained for Figs. 5 and 6. In this embodiment, an ionic liquid flows tangentially against these bodies (flow direction indicated by the arrows). Alternatively, lining layer 33 (or further layers 30 forming flow channel 20) with ion exchange mixed-bed resin is also possible.

[0076] Fig. 9 shows an embodiment of a method for producing a cartridge 10 in the form of a cartridge 12 with two flow channels using a flow diagram. In a first step S1, four layers 31, 32, 33, 34 made of porous polycarbonate (or another suitable polymeric material) are provided, which, depending on their planned position within the cartridge, have a shape that enables the formation of at least one flow channel and a housing. Specifically, the first layer 31 and the third layer 33 each have different material thicknesses in sections, so that they enable the formation of the first 21 and second flow channel 22 in the sections with lesser thickness. The second layer 32 has a tunnel that is provided for forming a fluid connection 23 between the first 21 and the second flow channel 22.

[0077] In a second step S2, a body 40 or a number of bodies 40 comprising an ion exchange mixed-bed resin are provided. In a preferred embodiment, the bodies 40 consist of the ion exchange mixed-bed resin. The bodies 40 can be easily integrated during assembly of the cartridge 10. If the bodies 40 are to be statically clamped in the desired flow channel 20 like a "sandwich," prior size selection, e.g., by sieving, is recommended. Static clamping of the bodies 40 can prevent slippage and possible blockage of the flow channels 20. Furthermore, the bodies 40 can be prevented from escaping from the cartridge structure, which could lead to problems during the assembly process using laser welding. This is particularly important because the bodies 40 could become electrostatically charged and shift from their intended installation position.Placement of the bodies 40 in the intended flow channel 20 can also be achieved by spreading the bodies 40 on a corresponding layer 30, whereby the bodies 40 are deposited in depressions in the layer 30. Areas that should remain free of bodies 40 can be covered or, during the introduction of the bodies 40, briefly provided with a negative of the corresponding layer 30. Superfluous bodies 40, which prevent a clean closure of the cartridge during the manufacturing process, can be removed, for example, by shaking, wiping, or using a blower.

[0078] In a third step S3, the layers 30 and the body(s) 40 are arranged with one another in such a way that a flow channel is formed and the bodies are located in at least a partial region of the flow channel and cannot escape from the flow channel.

[0079] In a fourth step S4, the layers 30 are joined together. Joining can be carried out, for example, by laser welding, gluing, or another suitable method.

[0080] In a further embodiment of the method, a film 60 is provided. The film 60 consists of a porous polymeric material, e.g., polycarbonate, polypropylene, polyethylene, polyvinyl chloride, or polyamide, and / or other polymers with glass transition temperatures comparable to that of polystyrene, from which the ion exchange mixed-bed resin of the bodies 40 is preferably made. The film 60 is integrated into the cartridge during its construction, specifically in such a way that it covers at least the tunnel of the second layer 32, so that a fluid medium, e.g., an ionic solution, always flows through.

[0081] In one embodiment, the film 60 is provided for intercepting bodies 40, also in powder form, that are flushed into a cartridge 12 with two flow channels 21, 22. These are pre-stored in a carrier liquid and flushed into the cartridge 12 at the desired time (Fig. 10A). Due to the flow of an ionic liquid conducted through the cartridge 12, the bodies 40 are intercepted by the film 60 at the fluid connection 23 (Fig. 10B). Direct pre-storage on the film 60 is also possible before an ionic liquid is conveyed over the ion exchange mixed-bed resin. The "filter cake" of ion exchange mixed-bed resin represents the effective volume for reducing the ion concentration of the ionic liquid.

[0082] The deionization capacity (also called total capacity) of an ion exchange mixed-bed resin system is typically specified in data sheets in equivalents per liter (eq / l). It refers to the number of active groups available relative to the valence of an ion to be bound (~ 6.02-10 23 per equivalent and valence = 1 , derived from the Avogadro constant), which can be found in one liter of resin mixture on one type of exchange resin grains. Generally, depending on the active group used, a distinction is made between strongly and weakly acidic cation exchange resins (Strongly Acidic Cation Exchange Resins or SACs and Weakly Acidic Cation Exchange Resins or WACs) as well as between strongly and weakly basic

[0083] Anion exchangers (Strongly Basic Anion Exchange Resins or SBAs and Weakly Basic Anion Exchange Resins or WBAs) are distinguished, each with different total capacities.

[0084] As an example, the deionization efficiency can be described using an ion exchange resin of the type Purolite MB 400 (data sheet https: / / www.prest.ro / wp-content / uploads / 2018 / 09 / Purolite-MB400.pdf). This is an ion exchange resin whose active groups in the cation exchanger are sulfonates (-SO3- and thus SACs, bound with H + as supplied) with a total capacity of 1.9 eq / l and in the anion exchanger quaternary ammonium ions (-N(CH3) 3+ and thus SBAs, bound with OH in the supplied form) with a total capacity of 1.3 eq / l (the volume ratio of cation to anion exchanger is 40% to 60%). The average mass density (bulk weight) of the resin mixture is 722.5 g / l. Polystyrene beads as polymer carriers have an average mass density of 1050 g / l and an average diameter of 0.6 mm.

[0085] Consequently, 1 ml of a 150 mM NaCl solution (which corresponds approximately to physiological conditions with a conductivity of approximately 14000 pS / cm at 20 °C and a sample volume typically processed in microfluidic systems) can be completely deionized with a mixed bed resin (MBH) volume of VMBH = 115.38 pl.

[0086] MBH volume for complete deionization of 1 ml of 150 mM NaCl solution:

[0087] Vci= (0.15 (mol / l) / 1.3 (eq / l))-1 ml=115.38 pl= VMBH

[0088] Here, it is assumed that the resin is unused (single-use) and that a deionization efficiency of 100% is present (the electrolyte comes into full contact with the MBH and saturation in the deionization reaction is present). The required MBH volume is thus sufficiently small (< 1 ml) to be relatively easily integrated into a microfluidic system. In comparison: To achieve an equivalent deionization result (i.e., equivalent electrical conductivity) by dilution, a

[0089] 13999 ml / 0, 11538 ml=1.21 -10 5 A larger volume of deionized water must be used or stored upstream in the microfluidic system. It should be noted that using a MBH does not reduce the analyte concentration.

[0090] On the other hand, the MBH volume is large enough to be reliably handled in series production. VMBH = 115.38 pl of ion exchange mixed-bed resin contains approximately

[0091] Nball = mMBH / rriball = VMBH*PMBH / (4 / 3'TT R 3 psphere)

[0092] = 115.38 mm 3 '722.5 pg / mm 3 / (4 / 3 TT- (0.3 mm) 3 - 1050 pg / mm 3 )

[0093] « 702

[0094] Body 40.

[0095] The film 60 can also be functionalized with ion exchange mixed-bed resin. Figure 11 illustrates the process of functionalizing the film 60 with bodies 40. The bodies 40 are incorporated into the porous polymer carrier film 60 via heated rollers 70. A functionalized film 61 is thereby produced. The above derivation of the required volume of the bodies 40 can be applied to a monolayer on an area of ​​the film 60 of approximately

[0096] AMBH = NKugei TT R 2 = 702 TT' (0.3 mm) 2 « 198.5 mm 2 Assuming that the beads are porous and thus fluidic, this corresponds to a carrier film 60 with effective dimensions of approximately 14 mm x 14 mm, which is entirely compatible with conventional microfluidic systems (credit card format). This space requirement can be further reduced by stacking multiple films 60 or MBH in a monolayer (2D) to form a multilayer system (3D). The spacing of the rolls 70 should be selected to produce a functionalized film 61 that is as stable as possible yet flexible. Values ​​for dges can therefore range, for example, between 10 and 1000 pm. The diameter of the resin beads dResin should be (slightly) larger than the thickness of the carrier film 60 dpoiie or the pore openings of their mesh, so that they do not simply fall through the carrier film 60, but can be stably welded to it.

[0097] The functionalized film 61 can then be integrated into the microfluidic cartridge 10 during construction. In a first embodiment, the film 61 is arranged in the same way as the unfunctionalized film 60 between the second and third layers in a cartridge 12, so that the ionic liquid flows through in any case and ions are bound by the ion exchange mixed-bed resin (Fig. 12).

[0098] In a second embodiment, the foil 61 is arranged with a cartridge 11 along the flow channel 20. The ionic liquid flows tangentially onto the foil 61 (Fig. 13).

[0099] The effective volume is based on the thickness of the film 61, which is multiplied by the effective area of ​​the film 61 through which the liquid flows. In other words, the effective volume for deionization refers to the location of the flow channel through which the ionic liquid flows (cartridge 12) or tangentially against it (cartridge 11) in order to reduce the ion concentration therein.

[0100] In Fig. 14, an embodiment of the method according to the invention for reducing an ion concentration in a fluid medium by means of a cartridge 10 is shown again as a flow diagram. In a first step S1, a cartridge 10 is provided. In a second step S2, an ionic liquid, e.g. a liquid with macromolecules in which salt ions are also dissolved, is flushed into the flow channel 20. In a third step S3, the ionic liquid is incubated in the flow channel 20 for a period of 10 minutes (or another suitable period of time). By adjusting the fluid flow, the ion exchanger and the ionic liquid can be incubated with one another for any desired length of time. The fluid medium is then discharged from the flow channel 20 for further use in a fourth step S4.

Claims

Patent claims 1. Microfluidic system with a housing and at least one flow channel (20) formed within the housing, wherein at least one body (40) comprising an ion exchange mixed-bed resin is arranged in at least one sub-region of the flow channel (20), and at least the flow channel (20) is formed from a porous material, wherein the ion exchange mixed-bed resin is provided by its anion and cation exchanger properties for reducing the ion concentration of a salt or a contaminating compound of a fluid medium comprising macromolecular compounds and / or cellular structures.

2. System according to claim 1, in which the body (40) is arranged such that it can be surrounded by the fluid medium when flowing through the flow channel (20).

3. System according to claim 1 or 2, wherein the body (40) consists of an ion exchange mixed bed resin.

4. System according to one of the preceding claims, wherein the body (40) is embedded at least in a part of the material that forms the flow channel (20).

5. System according to one of the preceding claims, in which polymeric porous material is arranged with the body (40) in the flow channel (20) such that it can be permeated by the fluid medium.

6. System according to one of the preceding claims, in which polymeric porous material is arranged with the body (40) in the flow channel (20) such that it can be tangentially flowed upon by the fluid medium.

7. System according to one of the preceding claims, in which a film (60, 61) made of a polymeric porous material is arranged in the area of ​​the flow channel (20).

8. System according to claim 7, wherein the film (61) is functionalized with ion exchanger groups.

9. System according to one of the preceding claims, in which a first flow channel (21 ) and a second flow channel (22) are formed within the housing, which are in fluid communication (23) with each other.

10. System according to claim 9, wherein the foil (60, 61 ) is arranged between the first flow channel (21 ) and the second flow channel (22).

11. Method for manufacturing a cartridge (10) comprising a system according to any one of claims 1-10, comprising the steps: - Providing a number of layers (30) of a polymeric material which, depending on their planned position within the cartridge (10), have a shape such that they can form a flow channel (20) within the housing, and at least the flow channel (20) is formed from a porous material, Providing at least one body (40) comprising an ion exchange mixed-bed resin, - Arranging the layers (30) and the body (40) together in such a way that a flow channel (20) is formed and the body (40) is located in at least one part of the flow channel (20) and cannot get out of the flow channel (20), - Joining the layers together. A method according to claim 11, wherein the body (40) is provided with the layers (30). A method according to claim 11 or 12, wherein a film (60, 61) made of a polymeric material is provided. A cartridge (10) for reducing the ion concentration of a salt or a contaminating compound in a fluid medium comprising macromolecular compounds and / or cellular structures, produced by a method according to any one of claims 11-13. A method for reducing the ion concentration of a salt or a contaminating compound in a fluid medium comprising macromolecular compounds and / or cellular structures using a cartridge (10) according to claim 14, comprising the steps of: - Providing the cartridge (10), - Flushing the fluid medium into the flow channel (20), - Incubation of the fluid medium in the flow channel (20), - Discharge of the fluid medium from the flow channel (20) for further use.

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