Microfluidic system with ion exchange mixed bed resins

Abstract

A microfluidic system is provided having a housing and at least one flow channel (20) formed within the housing, in which at least one body (40) having 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 to reduce the ion concentration of salts or contaminating compounds of a fluid medium containing macromolecular compounds and / or cellular structures by its anion and cation exchange properties.

Description

[0001] The present 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 the ion concentration of salts or contaminating compounds in a fluid medium containing macromolecular compounds and / or cellular structures.

[0002] In electrolyte systems, precise knowledge of the ions present therein and precise and reproducible regulation of the ion concentrations are essential, for example to adjust the conductivity, pH value and osmotic pressure of one or more electrolytes. These parameters represent fundamental influencing factors in biological and chemical processes, for example in experiments with DNA, proteins and cells.

[0003] For example, the ion concentration can be reduced by a dilution step. However, if a high dilution is required, a correspondingly high initial volume of diluent must be expected. This can lead to space problems, in particular, since a sufficient amount of the corresponding clean diluent must be stored in advance and the already used reagents must be collected in a waste compartment. The dilution is not selective for the individual ion types and the actual analytes are also co-diluted, optionally until below the detection limit of the detection method used. In addition, optimal mixing or homogenization must be ensured in the dilution step in order to avoid concentration gradients.

[0004] This is a challenge in microfluidic systems. For example, if the conductivity of 1 ml of physiological PBS solution is reduced from about 14,000 μS / cm to 1 μS / cm by dilution, 13,999 ml of deionized water with a conductivity of about 1 μS / cm (dilution 1:14,000) needs to be added, but it should be noted that the concentration of the analyte is reduced at the same ratio.

[0005] Another possible way to adjust the ion concentration is to use dialysis filters. They have a certain selectivity in terms of ion size, but their general applicability is very limited. The use of dialysis filters is 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 true in systems with large sample volumes or with a large characteristic size L, because the diffusion time of a molecule is proportional to the square of L.

[0006] Furthermore, the lower limit of deionization is defined by the equilibrium setting of the ion concentration in the compartment. The concentration gradient can be maintained by periodically using fresh liquid, but the amount of fresh reagent that can be pre-stored in a miniaturized chip lab system is limited. In addition, integrability and operation are also a challenge, as microfluidic systems designed specifically for this purpose are required. Use in miniaturized microfluidic systems also compromises effectiveness due to the unfavorable surface area to volume ratio. The use of disposable cartridges also increases production costs and is not economically viable.

[0007] If one wants to speed up the dialysis process and decouple the process from the concentration gradient, it makes sense to apply pressure to induce pressure mixing. Such processes play a role in seawater desalination plants, for example. However, integrability and operation in lab-on-a-chip systems are more difficult to achieve. In addition, the membrane may become clogged, which reduces the effectiveness of the deionization process. Furthermore, if the pressure is too high, the membrane and the sample may be destroyed.

[0008] Extraction and precipitation methods are also known for deionization of solutions. These are complex processes that are difficult to integrate and process in microfluidic systems. In particular in extraction methods, toxic and material-incompatible chemicals are often used. In addition, these processes are rather uncertain, which is reflected in their reproducibility. In precipitation methods, although certain anions and cations can be added in order to precipitate certain ions in a targeted manner by forming insoluble salts, this is particularly disadvantageous in microfluidic systems because the system may become clogged. Therefore, the adhesion of the resulting solid phase to the system can have a negative impact on the process.

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

[0010] Capacitive deionization (CDI) is another method for deionizing water, in which a potential difference is generated by two electrodes. However, this method is not suitable for microfluidic systems as disposable products in terms of integrability, operability and cost. In addition, such systems have not yet been used for biological or chemical samples.

[0011] All methods for deionization processes according to the prior art have in common limited or non-existent compatibility with microfluidic systems and are restricted by limited possibilities for miniaturization or scaling up.

[0012] In the deionization of tap water on a macro scale (liter or kilogram), the ion exchange mixed bed resin is integrated into the desalination filter cartridge, through which the tap water flows to deionize the tap water. If its ion exchange capacity is exhausted, the desalination filter cartridge can be replaced or regenerated. The ion exchange material here usually consists of porous polystyrene beads, which can be functionalized with a variety of ion exchange groups. The average diameter of these beads is about 0.6 mm, wherein each bead has an anion or cation exchange function.

[0013] Anion exchange columns are also known from the purification of DNA-containing solutions, which bind the DNA contained in the solution to an anion exchange gel, while the remaining solution is passed through the anion exchange gel in a centrifugation step. The DNA bound to the anion exchanger can be washed and then eluted again from the column material. However, in this case, the DNA is specifically separated from the solution, rather than contaminating salts or ions.

[0014] Publication DE 10 2008 000 369 A1 discloses the integration of sample preparation into a microfluidic device. The device can have a preparation substance on one side of a mass transfer membrane. The preparation substance can include an ion exchanger for desalting the sample, because too high a salt concentration may be undesirable for the separation process after preparation. The device can be configured to prepare biological samples containing DNA, protein, enzyme, cell, bacterium or virus.

[0015] Publication WO 00 / 71243 A1 discloses the use of a microfluidic system using a microbead matrix to detect a target analyte. The target analyte may be a nucleic acid. The described device may have a separation module designed to separate out impurities that affect the analysis of the target analyte. The separation module may contain an ion exchange material as a separation medium.

[0016] Publication DE 10 2013 201 505 A1 discloses a device for extracting dried body fluids pre-stored in a sample, a cartridge and a method for extracting body fluids. The device is designed as a chip lab system and can have a filter or a purification device for the body fluid extracted from the sample. The purification device can be an ion exchanger.

[0017] The publication DE 100 46 069 A1 describes a method and a microfluidic element for micropolynucleotide synthesis. The microfluidic element used can contain a part in which an ion exchange resin is present, which enables the product to be directly separated from the reagent. An ion exchanger is provided here to provide a separation process in the presence of a polynucleotide.

[0018] The aim is to reduce the concentration of ions and certain ion types in electrolytes in a specific way. The invention aims to enable deionization for applications with limited processing volumes, such as those operating in microfluidic systems. The invention aims to gently deionize fluid media containing macromolecular compounds and / or cellular structures, such as those found in biotechnology or chemistry.

[0019] 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 salts or contaminating compounds in a fluid medium containing macromolecular compounds and / or cell structures according to claim 15.

[0020] Further advantageous embodiments and configurations of the invention are apparent from the dependent claims, the drawings and the examples. Embodiments of the invention can be advantageously combined with one another.

[0021] A first aspect of the present invention relates to a microfluidic system having a housing and at least one flow channel formed in the housing, wherein at least one body having an ion exchange mixed bed resin is arranged in at least one sub-region of the flow channel, and at least the flow channel is formed of a porous material, wherein the ion exchange mixed bed resin is provided to reduce the ion concentration of salts or contaminating compounds of a fluid medium containing macromolecular compounds and / or cellular structures through its anion and cation exchange properties.

[0022] 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 compound can be, for example, a nucleic acid and / or a protein.

[0023] The invention advantageously achieves the above-mentioned objects, because the arrangement of the ion exchange mixed bed resin enables a relatively high ratio of deionization or ion binding surface area to total volume, which means that the ion concentration can be reduced in a space-saving manner. In addition, it is advantageous that the sample does not have to be diluted, so that large volumes of diluent do not have to be provided in a space-saving manner. In addition, the selectivity of the subsequent detection method will not be affected by excessive dilution of the sample.

[0024] Furthermore, the present invention is advantageous because no minimum ion concentration is required to establish equilibrium. The lower concentration limit can be set arbitrarily low to a certain extent and depends only on the volume of the ion exchange mixed bed resin (or available ion exchange groups). Thus, an ion concentration similar to that of deionized water can be achieved.

[0025] The selectivity or affinity of the ion exchange mixed bed resin for different ion types can be advantageously controlled by functionalizing the ion exchange mixed bed resin with appropriate surface groups. Changing the ratio of anion exchanger to cation exchanger can also further increase selectivity.

[0026] Furthermore, the present invention advantageously allows for gentle deionization of fluid media without damaging or destroying the actual analytes in the fluid media. There is no need to use corrosive chemicals or high pressures (such as precipitation or extraction methods), which may cause degradation of system components or contaminate and negatively impact subsequent process steps.

[0027] Therefore, the present invention can be realized without great technical effort and can be universally integrated into microfluidic systems. In addition, the amount of mixed bed resin used can be adjusted arbitrarily according to the size of the microfluidic system or the fluid to be deionized (conductivity and volume).

[0028] The term "deionization" as used herein means that the ion concentration of salts or contaminating compounds in a fluid medium or solution is significantly reduced. Ideally, the ion concentration is reduced to zero. However, the term does not include the removal of macromolecular compounds (macromolecules) from a solution, which may also exist as ions and are just what is desired, i.e., salt ions and contaminating compounds should be removed. In particular, the term "deionization" or "deionization" is synonymous with "reduction" or "reduction" of ion concentration.

[0029] Preferably, the main body is arranged so that the fluid medium can flow around it when flowing through the flow channel. Advantageously, the contact as large as possible between the main body surface and the medium is realized here. In this way, the ions from the medium are effectively bound to the main body. Advantageously, a plurality of main bodies are arranged in the flow channel, thereby providing more surface areas for interacting with the ions in the sample. The one or more main bodies are, for example, provided in the form of small particles, for example as balls or beads. In a preferred embodiment, the object can also have such a small size that they are provided in powder form. Due to its larger surface area, this can further improve the efficiency of reducing ion concentration. In addition, it can also be moved by microfluidics as a fine suspension after being absorbed in the fluid.

[0030] Preferably, the body is composed of an ion exchange mixed bed resin. In other words, the body is composed entirely of one material, the ion exchange mixed bed resin, which is not mixed with other materials. Thus, it is advantageous to provide a material from which one or more bodies can be made. This improves production efficiency and the efficiency of interaction with ions in the fluid medium.

[0031] At least the flow channel of the system according to the invention is formed by a porous material, preferably a porous polymer material. This is advantageous because the porous material can be passed through by the fluid medium and small ions (e.g. ions of dissolved salts), but cannot be passed through by the body consisting of or containing the ion exchange mixed bed resin and by macromolecular compounds (e.g. biomolecules, such as proteins, nucleic acids or cells) or can only be passed through slowly compared to the salt ions. Therefore, a pore size of 3000 to 5000 daltons is suitable for ensuring this selective permeability. In particular, in the case of a fluid medium with an analyte in the form of a biomolecule (e.g. nucleic acid), this provides another important advantage. Due to their charge, such biomolecules also bind to the ion exchange mixed bed resin, although much slower than small salt ions. By means of the porous material of the flow channel, deionization of the fluid medium is achieved by binding the biomolecules to the ion exchange mixed bed resin, but without losing the charged biomolecules. This is particularly advantageous when processing patient samples in diagnosis, because the sample material contained therein, in particular the diagnostic marker sought, is strictly limited so that further loss of the sample material may hinder the successful detection of the marker sought.

[0032] 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 fixed in the material. The body can be introduced into a predetermined cavity in the material and connected there, for example, to the material. This can be done, for example, during the production method of the material, for example by introducing it into the material during an injection molding method or by applying and pressing it into a still soft polymer.

[0033] In a preferred embodiment, a polymer porous material is arranged with a body in a flow channel so that a fluid medium can flow through. Here, the material is arranged transversely to the flow direction of the fluid medium in the flow channel. The material can be imagined as a form of a precisely matched porous glass frit (or filter) arranged in the flow channel. The thickness of the glass frit can be selected arbitrarily, wherein the higher the thickness, the higher the deionization efficiency, because the ions dissolved in the fluid have a longer time to interact with the ion exchange material when passing through the glass 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 glass frit.

[0034] In another preferred embodiment, the material is arranged with a body in the flow channel so that the fluid medium can flow through tangentially. Basically, the inner surface of the flow channel is lined with the material. In this case, the material is mostly flowed through tangentially and no longer completely flowed through like glass frit. Therefore, it provides a lower resistance. In addition, the efficiency of reducing the ion concentration can be improved by a sufficiently long incubation time. In one embodiment, the body itself can form the lining material.

[0035] Preferably, a membrane-like unit made of a polymer porous material is arranged in the region of the flow channel. Membrane-like means here that the unit has a flat design and the height and width are significantly greater than the thickness. The membrane-like unit is referred to as membrane for short hereinafter. The membrane can be provided by the same material as the surroundings of the flow channel or by a different polymer material.

[0036] Particularly advantageously, the membrane is arranged transversely to the flow direction in the flow channel in order to intercept bodies consisting of or containing ion exchange mixed bed resins present in the fluid medium. These bodies are stored in advance in a carrier liquid and are flushed into the system at the desired moment. By contacting the bodies with the fluid medium, the ion concentration in the medium is reduced. After passing through the membrane, the medium contains fewer ions and no bodies. The membrane here represents an effective volume reduction.

[0037] In a particularly preferred embodiment, the membrane is functionalized with ion exchange groups. The one or more bodies are arranged in the membrane. In an alternative embodiment, the ion exchange mixed bed resin itself can also be provided as a membrane, i.e. a thin porous form. It is advantageous to form a membrane with the body or to form the body as a membrane because it can be prefabricated and installed in a specific microfluidic system as a single component. Then, as with the above-mentioned carrier material, the membrane is arranged in the flow channel transversely to the flow direction so that it can be flowed through individually or with another carrier material, or on the inner side of the flow channel. Here, the effective reduction in volume also corresponds to the membrane volume through which the flow or tangential flow passes.

[0038] In another preferred embodiment, a first flow channel and a second flow channel are formed in the housing, which are fluidically connected to each other. In the region where the fluid is connected, a membrane is preferably arranged between the flow paths, which forms a semi-permeable boundary between the first flow channel and the second flow channel. The embodiment of a suitable membrane is one in which there is no integrated body, and is therefore particularly suitable for intercepting those of the body from a fluid medium. In addition, an embodiment with a membrane that is intended to combine the body of salt ions from the fluid medium is also suitable. Effectively reducing the volume corresponds to the membrane volume flowing through. As an alternative to using a membrane, the fluid connection can also be designed as a contraction between the two flow channels, and the body can be fixed at the contraction. In various cases, it is stipulated that the fluid medium is introduced into the first flow channel and is discharged from the second flow channel with a significantly reduced ion concentration.

[0039] A second aspect of the invention relates to a method for producing a cartridge comprising a system according to the invention, having the following steps:

[0040] - providing a plurality of layers made of polymer material which, according to their planned position in the cartridge, have a shape enabling the formation of flow channels in the housing and at least said flow channels being formed of a porous material,

[0041] - providing at least one body having an ion exchange mixed bed resin,

[0042] - the layers and the body are arranged relative to one another in such a way that a flow channel is formed and the body is located in at least a subregion of the flow channel and cannot come out of the flow channel,

[0043] - Joining the layers together.

[0044] Preferably, a body and a layer forming the flow channel are provided. The body can be integrated into the material, i.e. mixed into the material during the production of the corresponding layer, for example by injection molding, or sunk into the still soft material. Alternatively, a recess for accommodating the body, such as a notch of various geometric shapes, can be formed in the corresponding layer.

[0045] In the method, it is particularly preferred to provide a membrane made of a polymer material. The membrane has been described above. The membrane can consist of the same polymer material as the layers or contain different polymer materials. The membrane can, for example, contain an ion exchange mixed bed resin or consist of an ion exchange mixed bed resin.

[0046] The body is preferably integrated into at least one region of the membrane. In particular, the body is arranged in a targeted manner in a desired region of the membrane. If the membrane is arranged between two flow channels and has the body only in the immediately adjacent flow path, this advantageously saves material.

[0047] The membrane is preferably arranged in a flow channel transverse to the flow path of the fluid medium. Alternatively, the membrane can also be arranged along the flow channel. The membrane makes it possible to arrange the body after the actual manufacture of the tube, so that the tube can be made of layers in a cost-saving manner without integrating the body into the layers.

[0048] A third aspect of the invention relates to a cartridge for reducing the ion concentration of salts or contaminating compounds in a fluid medium containing macromolecular compounds and / or cell structures, which is produced by the inventive method of the second aspect of the invention. The advantages of this cartridge correspond to the advantages of the inventive method. This cartridge can be provided, for example, as a so-called lab-on-a-chip cartridge and used for the development of biological or molecular biological tests and methods.

[0049] A fourth aspect of the present invention relates to a method for reducing the ion concentration of salts or contaminating compounds in a fluid medium containing macromolecular compounds and / or cellular structures by means of the cartridge of the present invention, comprising the following steps:

[0050] - provide a cartridge,

[0051] - Flushing the fluid medium into the flow channel,

[0052] - incubation of the fluid medium in the flow channel,

[0053] - Removing the fluid medium from the flow channel for further use.

[0054] The method advantageously enables the reduction of ionic concentrations of salts or contaminating compounds in biological and chemical samples on a microliter and nanoliter scale.

[0055] Preferably, the desired level that reduces the ionic concentration of fluid medium is controlled by the amount of employed ion exchange mixed bed resin and / or by the selection of the ion exchange groups in the ion exchange mixed bed resin. In this way, the barrel can be advantageously used for specific fluid medium to be reduced. In addition, the barrel can also be used according to a specific purpose, for example if a specific application requires the special purity of a salt ion fluid medium, or if specific ions are to be removed. By handling different ionic groups in the manufacturing process, selectivity can be controlled to a certain extent to reduce. In addition, the ratio of anion exchanger and cation exchanger can be adjusted in the mixed bed resin. The surface that can be used for ion exchange is also of vital importance, and can be adjusted to be used for respective application situations.

[0056] In another preferred embodiment of the method, the desired level of reduction of the ion concentration of the fluid medium is controlled by the duration of incubation of the fluid medium in the flow channel. If the ion-containing fluid is incubated with the mixed bed resin statically, i.e., without regulating the flow rate, the reduction of 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 exert a further influence on the selectivity of the method.

[0057] It is also possible to bind all ionic components non-selectively to the mixed bed resin and then specifically microfluidically add the desired ions. Alternatively, it is also possible to deliver the deionized solution to the ions pre-stored in liquid or powder form in order to absorb them again into the fluid.

[0058] The present invention is explained in more detail with reference to the accompanying drawings, in which:

[0059] Figure 1 A cartridge having one flow channel according to one embodiment of the present invention is shown.

[0060] Figure 2 A cartridge having two flow channels according to one embodiment of the invention is shown.

[0061] Figure 3 A schematic diagram of a body made of ion exchange mixed bed resin is shown.

[0062] Figure 4 Shown according to Figure 3 Schematic diagram of the body being arranged in layers of a barrel.

[0063] Figure 5A schematic diagram showing the arrangement of the body in the surface of the flow channel of the cartridge.

[0064] Figure 6 Schematic diagrams showing cavities in the flow channel surface in different embodiments.

[0065] Figure 7 A schematic diagram of a flow channel in which a glass frit containing or made of an ion exchange mixed bed resin is arranged is shown.

[0066] Figure 8 A schematic diagram of a flow channel including a body made of an ion exchange mixed bed resin disposed in a flow channel forming material is shown.

[0067] Fig. 9 A flow chart of one embodiment of the method of the invention for producing a cartridge is shown.

[0068] Fig.10 A cartridge with two flow channels and one membrane is shown.

[0069] Fig.11 The production of membranes functionalized with ion exchange mixed bed resins is shown.

[0070] Fig.12 A cartridge with two flow channels and a membrane functionalized with an ion exchange mixed bed resin is shown.

[0071] Fig.13 A cartridge having one flow channel and one membrane functionalized with an ion exchange mixed bed resin is shown.

[0072] Fig.14 A flow chart of one embodiment of the method of the present invention for reducing ion concentration by a cartridge is shown.

[0073] exist Figure 11 shows a cartridge 10, which is 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 layer 30 is in particular a porous polymer, such as polycarbonate; other suitable polymer materials may also be used. Therefore, the pore size of the material should be limited so that the ion exchange mixed bed resin in the form of powder or beads and biomolecules (such as proteins, nucleic acids or cells) cannot or can only enter or pass through the material slowly compared to salt ions. On the contrary, smaller molecules (such as dissolved salts) should be able to pass through the material. Therefore, a pore size of 3000 to 5000 Daltons is suitable for ensuring this selective permeability. This provides another important advantage, in particular, for biomolecules such as nucleic acids. Due to their charge, these molecules also bind to the ion exchange mixed bed resin, although much slower than small salt ions.

[0074] Figure 2 A cartridge 10 is shown which is 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 Figure 1 The number of cartridges 11. Figure 1 Differently, in the cartridge 12, the first layer 31 and the third layer 33 each have different material thicknesses in sections, so that they can form the first flow channel 21 or the second flow channel 22 in the section with smaller 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 channel in the second layer 32. The fluid connection 23 at least enables the flow of the liquid; it can be designed as a constriction so that the body present in the liquid cannot pass through or be used to arrange the membrane.

[0075] The cartridge 10 is intended to reduce the concentration of salt ions and / or contaminating compound ions in the ionic liquid. The ionic liquid may also be referred to as an ionic solution or a fluid medium and has in particular a macromolecular compound and / or a cell structure. In order to reduce the concentration of salt ions and / or contaminating compound ions in the ionic liquid, a body 40 comprising or, in a preferred embodiment, consisting of an ion exchange mixed bed resin is used. Figure 3 In the figure, two bodies 40 are shown, one of which is an anion exchange body and the other is a cation exchange body, which are connected with the corresponding fixed ions SO3 - or N + R3 and the mobile counter ion (Na + and Cl -) functionalization. The functionalization is positionally fixed / fixed and forms the skeleton of the main body together with the resin matrix. Ion exchangers can be functionalized with various different ions. Counterions are used to ensure the ion exchange function. In order for the main body to have an ion exchange function, the functional groups must absolutely be loaded with (very) mobile ions. Cation exchangers must be loaded with cations and anion exchangers must be loaded with anions. Anions and cations on the main body can also be functionalized. The resin used as a carrier material is in particular porous polystyrene, but other suitable polymers can also be used.

[0076] The body 40 is provided in an approximately spherical shape (as spherical as possible) and has a diameter of 0.1 mm to 1.2 mm. The body 40 can also be further mechanically comminuted, for example by grinding, until they are in powder form. This embodiment is particularly suitable for use in suspensions.

[0077] Figure 4 An embodiment of the invention is shown in which the body 40 is embedded in the layer 30. Here, the body 40 is directly fixed in the material of the layer 30. The porous material of the layer 30 has filtering properties. By this arrangement, the loss of charged biomolecules contained in the ionic liquid can be offset, because only small charged molecules can penetrate into the filter material in order to interact with the mixed bed resin there, and the biomolecules, which are generally large molecules, cannot bind to the mixed bed resin. In other words, by encapsulating the body 40 in the porous material of the layer 30, the deionization of the ionic liquid can occur without the loss of charged biomolecules due to binding to the ion exchange mixed bed resin.

[0078] Figure 5 An embodiment of the invention is shown in which a body 40 is arranged in the surface region of a layer 30. The body 40 can be embedded in the material of the layer 30, for example by pressing it into the still soft polymer material during the production of the layer 30. Alternatively, a cavity 41, for example a notch or a recess, can also be formed in the layer 30, in which the body is arranged. Such a cavity 41 can have different geometric shapes, for example a rounded shape 42, a square 43, a triangle 44, a first trapezoid 45 and a second trapezoid 46 ( Figure 6 ).

[0079] Figure 7A flow channel 20 is shown in which an ion exchange filter designed as a glass frit 50 is arranged. The glass frit 50 is arranged transversely to the flow direction of the ionic liquid in the flow channel 20 (indicated by the arrow) in a precisely matched manner. In this way, a surface as large as possible is provided for ion exchange, while providing an optimal flow through of the polymer material. In one embodiment, the glass frit 50 has the same material as the layer 30 of the cartridge 10, i.e. a porous polymer material, in particular a polycarbonate, in which the body 40 is embedded. In another embodiment, the glass frit 50 consists of an ion exchange mixed bed resin, in other words, it is the body 40. The thickness of the glass frit 50 can be selected arbitrarily, wherein a larger thickness is associated with a higher efficiency, because the ions dissolved in the fluid can interact with the ion exchange material for a longer time when passing through the glass frit 50. The thickness of the glass frit 50 is limited by the pressure that can be provided to the cartridge 10 to move the fluid. A plurality of glass frits 50 can be arranged one after another in the flow channel 20. At this time, these can each be an anion and cation exchange glass frit.

[0080] Figure 8 A flow channel 20 is shown, the lower boundary of which is formed by the layer 33 and the upper boundary of which is formed by the layer 32. The body 40 is arranged in the surface of the layer 33. Figure 5 and Figure 6 A corresponding arrangement is provided as explained in . In this embodiment, they are flowed tangentially by the ionic liquid (flow direction indicated by the arrow). Alternatively, the layer 33 (or other layers 30 forming the flow channel 20) can also be lined with an ion exchange mixed bed resin.

[0081] Fig. 9 An embodiment of a method for producing a cartridge 10 is shown using a flow chart, which is a formation form of a cartridge 12 having two flow channels. In a first step S1, four layers 31, 32, 33, 34 made of porous polycarbonate (or other suitable polymer material) are provided, which have a shape that enables at least one flow channel and a shell to be formed according to their planned positions in the cartridge. Specifically, the first layer 31 and the third layer 33 each have different material thicknesses in sections, so that the first flow channel 21 or the second flow channel 22 can be formed in a section with a smaller thickness. The second layer 32 has a channel for forming a fluid connection 23 between the first flow channel 21 and the second flow channel 22.

[0082] In the second step S2, a main body 40 or a plurality of main bodies 40 containing an ion exchange mixed bed resin is provided. In a preferred embodiment, the main body 40 is composed of an ion exchange mixed bed resin. When assembling the cartridge 10, the main body 40 can be easily integrated. If you want to statically clamp the main body 40 in the desired flow channel 20 like a "sandwich", the pre-selection of the size is suitable, such as by screening. By statically clamping the main body 40, it is possible to prevent slipping and possible blockage of the flow channel 20. In addition, it is possible to prevent the main body 40 from leaking out of the cartridge structure, which may cause problems during the assembly process using laser welding. This is particularly important because the main body 40 becomes electrostatically charged and may be moved out of their intended installation position. The main body 40 can also be placed in the intended flow channel 20 by spreading the main body 40 on the corresponding layer 30, whereby the main body 40 reaches the recess in the layer 30. It should be kept that the area without the main body 40 can be covered or temporarily provided with the female mold of the corresponding layer 30 during the introduction of the main body 40. Excess body 40 that prevents the cartridge from being neatly closed during manufacture may be removed by shaking, wiping or blowing.

[0083] In a third step S3 , the layer 30 and the one or more bodies 40 are arranged with one another to form a flow channel, and the bodies are located in at least a sub-region of the flow channel and cannot come out of the flow channel.

[0084] In a fourth step S4, the layers 30 are bonded together. For example, the bonding may be performed by laser welding, gluing or other suitable methods.

[0085] In another embodiment of the method, a membrane 60 is provided. The membrane 60 consists of a porous polymer material, such as polycarbonate, polypropylene, polyethylene, polyvinyl chloride or polyamide and / or other polymers having a glass transition temperature comparable to polystyrene, which the ion exchange mixed bed resin of the body 40 preferably consists of. The membrane 60 is integrated into the cartridge when it is constructed, and in such a way that it covers at least the channels of the second layer 32, so that the fluid medium (i.e. the ionic solution) flows through in each case.

[0086] In one embodiment, the membrane 60 is intended to intercept the body 40 (ie in powder form) flushed into the cartridge 12 having two flow channels 21, 22. These are pre-stored in a carrier liquid and flushed into the cartridge 12 at the desired moment ( Fig.10 A). Due to the flow of the ionic liquid through the cartridge 12, the body 40 is intercepted by the membrane 60 at the fluid connection 23 ( Fig.10 B) It is also possible to store the ionic liquid directly on the membrane 60 and then pass it through the ion exchange mixed bed resin. The "filter cake" produced by the ion exchange mixed bed resin represents the effective volume for reducing the ion concentration of the ionic liquid.

[0087] The deionization capacity (also called total capacity) of an ion exchange mixed bed resin system is usually expressed in data sheets as equivalents per liter (eq / l). It refers to the number of active groups available relative to the valence (valency) of the ions to be bound in one liter of resin mixture of one type of exchange resin particles (approximately 6.02·10 23 Per equivalent, valence=1, derived from Avogadro's constant). In general, depending on the active groups used, a distinction is made between strongly acidic and weakly acidic cation exchange resins (strongly acidic cation exchange resins or SACs and weakly acidic cation exchange resins or WACs) and between strongly basic and weakly basic anion exchange resins (strongly basic anion exchange resins or SBAs and weakly basic anion exchange resins or WBAs), each of which has a different overall capacity.

[0088] For example, the deionization efficiency can be described using the Purolite MB 400 ion exchange mixed bed resin (data sheet https: / / www.prest.ro / wp-content / uploads / 2018 / 09 / Purolite-MB400.pdf). It is an ion exchange mixed bed resin whose active groups in the cation exchanger are sulfonate groups (-SO3- and hence SACs, in the supplied form with H + Combined), the total capacity is 1.9eq / l, the anion exchanger is a quaternary ammonium ion (-N(CH3) 3+ and therefore SBAs, in the form of supply with OH - The total capacity is 1.3 eq / l (the volume ratio of cation to anion exchanger is 40% to 60%). The average mass density (tapping density) of the resin mixture is 722.5 g / l. The average mass density of the polystyrene beads as the polymer support is 1050 g / l and the average diameter is 0.6 mm.

[0089] Thus, 1 ml of 150 mM NaCl solution (which roughly corresponds to physiological conditions with a conductivity of about 14000 μS / cm at 20°C and the sample volume typically processed in microfluidic systems) passes through (MBH) with a volume of V MBH = 115.38 μl of mixed bed resin was completely deionized.

[0090] Volume of fully deionized MBH for 1 ml of 150 mM NaCl solution:

[0091] V Cl =(0.15(mol / l) / 1.3(eq / l))·1ml=115.38μl=V MBH

[0092] It is assumed here that the resin is not used (disposable) and the deionization efficiency is 100% (the electrolyte is in full contact with the MBH and there is saturation of the deionization reaction).

[0093] Therefore, the required MBH volume is small enough (<1 ml) to be relatively easy to integrate into a microfluidic system. Comparison: To obtain equivalent deionization results (i.e. equivalent conductivity) by dilution, one must use 13999 ml / 0.11538 ml = 1.21 10 5 Larger volumes of deionized water or pre-storage in the microfluidic system. It should be noted that the use of MBH does not reduce the concentration of the analyte.

[0094] On the other hand, MBH is large enough to be reliably processed in series production. MBH = 115.38 μl of ion exchange mixed bed resin, there are about

[0095] N 球 =m MBH / m 球 =V MBH * MBH / (4 / 3·π·R 3 ·ρ 球 )

[0096] =115.38mm 3 722.5μg / mm 3 / (4 / 3·π·(0.3mm) 3 1050μg / mm 3 )

[0097] ≈702

[0098] 40 entities.

[0099] Membrane 60 may also be functionalized with an ion exchange mixed bed resin. Fig.11 4 is a diagram showing the process of functionalizing a membrane 60 with a body 40. The body 40 is incorporated into the porous polymer support membrane 60 by means of a heatable roller 70. A functionalized membrane 61 is produced. The above derivation of the necessary volume of the body 40 can be based on the area of ​​the membrane 60 in the case of a single layer, which is about

[0100] A MBH =N 球 π R 2 =702·π·(0.3mm) 2 ≈198.5mm 2

[0101] Assuming that the beads are porous and thus fluid flowable, this corresponds to a carrier membrane 60 with effective dimensions of about 14 mm x 14 mm, which is fully compatible with classical microfluidic systems (credit card format). This area requirement can be further reduced by stacking multiple membranes 60 or MBHs in a single layer (2D) to form a multilayer system (3D).

[0102] The roller spacing of the rollers 70 should be selected such that a functionalized membrane 61 which is as stable as possible but still soft is produced. 总 The value may therefore be, for example, 10 to 1000 μm. The diameter d of the resin beads 树脂 should be (slightly) larger than the thickness d of the carrier film 60 膜 Or the pore size of its mesh so that they do not easily fall through the carrier film 60 but can be stably welded thereto.

[0103] Then, when constructing the microfluidic cartridge 10, the functionalized membrane 61 can be integrated into the cartridge 10. In a first embodiment, the membrane 61 is arranged between the second and third layers in the cartridge 12 in the same manner as the non-functionalized membrane 60, so that the ionic liquid flows through in each case and the ions are bound by the ion exchange mixed bed resin ( Fig.12 ).

[0104] In a second embodiment, the membrane 61 is arranged along the flow channel 20 with the cartridge 11. Here, the ionic liquid flows tangentially through the membrane 61 ( Fig.13 ).

[0105] The effective volume is based on the thickness of membrane 61 multiplied by the effective flow-through or flow-through area of ​​membrane 61. In other words, the effective volume for deionization is based on the location of the flow channel through which the ionic liquid flows (cartridge 12) or tangentially (cartridge 11) to reduce the ion concentration therein.

[0106] exist Fig.14 In the embodiment of the present invention method for reducing the ion concentration in the fluid medium using the cartridge 10, a flow chart is again shown. In the first step S1, cartridge 10 is provided. In the second step S2, an ionic liquid (for example, a liquid with macromolecules in which salt ions are also dissolved) is flushed into the flow channel 20. In the third step S3, the ionic liquid is incubated in the flow channel 20 for a time period of 10 minutes (or another suitable time period). By regulating the fluid flow, the ion exchanger and the ionic liquid can be incubated together for any long time. Then, in the fourth step S4, the fluid medium is discharged from the flow channel 20 for further use.

Claims

1. A microfluidic system comprising a housing and at least one flow channel (20) formed in the housing, wherein at least one body (40) having 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 of a porous material, wherein the ion exchange mixed bed resin is provided to reduce the ion concentration of salts or contaminating compounds in a fluid medium containing macromolecular compounds and / or cell structures by its anion and cation exchange properties.

2. The system of claim 1, wherein the body (40) is arranged such that the fluid medium can flow around it when flowing through the flow channel (20).

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

4. A system according to any one of the preceding claims, wherein the body (40) is embedded in at least a portion of the material forming the flow channel (20).

5. System according to any of the preceding claims, wherein the polymer porous material is arranged with the body (40) in the flow channel (20) in such a way that the fluid medium can flow through it.

6. System according to any of the preceding claims, wherein the polymer porous material is arranged with the body (40) in the flow channel (20) in such a way that it can be flowed through tangentially by the fluid medium.

7. System according to any of the preceding claims, wherein a membrane (60, 61) made of a polymer porous material is arranged in the region of the flow channel (20).

8. The system according to claim 7, wherein the membrane (61) is functionalized with ion exchange groups.

9. The system according to any one of the preceding claims, wherein a first flow channel (21) and a second flow channel (22) are formed in the housing, the first flow channel (21) and the second flow channel (22) being in fluid communication (23) with each other.

10. The system of claim 9, wherein the membrane (60, 61) is arranged between the first flow channel (21) and the second flow channel (22).

11. Method for producing a cartridge (10) comprising a system according to any one of claims 1 to 10, comprising the following steps: - providing a plurality of layers (30) made of polymer material which, depending on their planned position in the cartridge (10), have a shape enabling the formation of a flow channel (20) in the housing and at least said flow channel (20) being formed of a porous material, - providing at least one body (40) having an ion exchange mixed bed resin, - the layer (30) and the body (40) are arranged relative to one another in such a way that a flow channel (20) is formed and the body (40) is located in at least one subregion of the flow channel (20) and cannot come out of the flow channel (20), - Joining the layers together.

12. The method according to claim 11, wherein the body (40) and the layer (30) are provided.

13. A method according to claim 11 or 12, wherein a membrane (60, 61) made of a polymer material is provided.

14. Cartridge (10) for reducing the ion concentration of salts or contaminating compounds of a fluid medium containing macromolecular compounds and / or cellular structures, produced by the method according to any one of claims 11-13.

15. A method for reducing the ion concentration of salts or contaminating compounds of a fluid medium containing macromolecular compounds and / or cellular structures by means of a cartridge (10) according to claim 14, comprising the following steps: - providing a cartridge (10), - flushing the fluid medium into the flow channel (20), - a warming fluid medium in the flow channel (20), - Removing the fluid medium from the flow channel (20) for further use.

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