Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
  • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
  • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
  • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
  • B01L3/502769—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
  • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
  • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
  • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
  • B01L3/502723—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by venting arrangements
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
  • B01L2200/06—Fluid handling related problems
  • B01L2200/0605—Metering of fluids
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
  • B01L2200/06—Fluid handling related problems
  • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
  • B01L2200/0663—Stretching or orienting elongated molecules or particles
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
  • B01L2200/06—Fluid handling related problems
  • B01L2200/0673—Handling of plugs of fluid surrounded by immiscible fluid
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
  • B01L2200/06—Fluid handling related problems
  • B01L2200/0684—Venting, avoiding backpressure, avoid gas bubbles
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
  • B01L2200/16—Reagents, handling or storing thereof
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2300/00—Additional constructional details
  • B01L2300/08—Geometry, shape and general structure
  • B01L2300/0809—Geometry, shape and general structure rectangular shaped
  • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2300/00—Additional constructional details
  • B01L2300/08—Geometry, shape and general structure
  • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
  • B01L2300/087—Multiple sequential chambers
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2400/00—Moving or stopping fluids
  • B01L2400/04—Moving fluids with specific forces or mechanical means
  • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
  • B01L2400/0469—Buoyancy
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2400/00—Moving or stopping fluids
  • B01L2400/04—Moving fluids with specific forces or mechanical means
  • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
  • B01L2400/0481—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure squeezing of channels or chambers
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
  • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
  • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
  • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
  • B01L3/502738—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by integrated valves
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L7/00—Heating or cooling apparatus; Heat insulating devices
  • B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
  • B01L7/525—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples with physical movement of samples between temperature zones

Definitions

• Microfluidic systems allow the analysis of small sample volumes with high sensitivity. Automation, miniaturization and parallelization of procedures allow a reduction of manual steps and can therefore help to avoid errors. Miniaturization of microfluidic systems also allows laboratory processes to be carried out directly at the sample, so that no general laboratory environment is needed.
• microfluidic applications may also be referred to as "lab-on-chip”. This field of application of microfluidics is also referred to as “point-of-care (PoC)".
• PoC point-of-care
• a particular challenge for microfluidic systems is the transfer of macroscopic samples into the microfluidic environment.
• microfluidically limited sample solutions can be moved without loss in a microfluidic device with a microfluidic chamber and channel system using the described method.
• a limited sample (For example, cell lysate from a few cells, cfDNA material, cytokine enrichment) from a sample input chamber into a chamber to perform a
• Detection method e.g., PCR are transferred bubble and lossless.
• Sample addition may allow rare material (e.g., cell-free DNA,
• circulating cancer cells, secreted cytokines, lysate from a few cells) in a small volume of a microfluidic device are enriched and thus presented in a high concentration.
• Sample entry chamber must not be in the same location of the microfluidic device in the described method, in which a
• the sample may instead be transported within the microfluidic device by the described method. Such transport often occurs in the prior art in an aqueous solution by laminar flow. However, this may result in material being deposited on the channel walls or thinned by more liquid or diffusion. Furthermore, through a contact surface to the outside world and / or by a lack of possibility for prewetting the chamber air into the system, which can lead to disturbing bubbles for subsequent processes.
• microfluidic refers here primarily to the order of magnitude of the microfluidic device.
• the microfluidic device is characterized in that physical phenomena that are generally associated with microtechnology are relevant in the fluidic channels and chambers arranged therein. These include, for example, capillary effects, effects (especially mechanical effects) associated with
• thermophoresis and electrophoresis. These phenomena are usually dominant in microfluidics over effects such as gravity.
• the microfluidic device can also be characterized in that it is made at least partially by a layer-by-layer process and that channels are arranged between layers of the layer structure.
• Microfluidic may also be characterized via the cross-sections within the device which serve to guide the fluid. Typical are, for example, cross sections in the range of 100 pm [microns] times 100 pm up to 800 pm times 800 pm. Also much smaller cross sections, for example in the range of 1 mhh to 20 mhh [microns], in particular in the range of 3 mhh to 10 mhh are possible.
• the microfluidic device may in particular be a so-called “lab on a chip” or a “point-of-care” system (PoC).
• a “lab on a chip” is designed and set up to perform biochemical processes. That means functionalities of a
• the microfluidic device may e.g. As channels, reaction chambers, upstream reagents, valves, pumps and / or Aktuations-, detection and
• the microfluidic device can make it possible to process biochemical processes fully automatically. This can z. B. Tests on liquid samples are performed. Such tests can z. B. find application in medicine.
• the microfluidic device may also be referred to as a microfluidic cartridge.
• biochemical processes can be carried out in the microfluidic device.
• the samples may also be admixed with additional substances which trigger, accelerate and / or facilitate biochemical reactions.
• a first medium can be transported from a first location of the microfluidic device to a second location of the microfluidic device.
• step a) of the described method at least a first medium is provided at a first location of the microfluidic device.
• the first medium is preferably a liquid, in particular an aqueous solution.
• the first medium may be a sample to be examined.
• provisioning is meant in particular that the at least one first medium is brought to the first location of the microfluidic device, for example by filling the at least one first medium through an opening in the microfluidic device.
• Provision also includes, for example, the microfluidic device already contained the at least one first medium before the beginning of the described method. So for example, a microfluidic device can be obtained from a supplier in which the at least one first medium is already arranged upstream in a chamber. It is also possible for the at least one first medium in step a) to be obtained by combining several substances and provided in this respect.
• a solvent may be preceded in the microfluidic device. When a sample is added to the microfluidic device, the solvent may be added to the sample. The solution of the sample in the solvent may be the first medium.
• step b) of the described method the at least one first medium from the first location to a second location of the microfluidic
• the at least one first medium of at least one second medium is enclosed in such a way that the at least one first medium only to the at least one second medium and to
• Fluidbegrenz the microfluidic device or only adjacent to the at least one second medium.
• the at least one first medium and the at least one second medium are not miscible with each other.
• step b) the transport of the first medium takes place through the microfluidic device.
• the at least one first medium can be protected particularly well.
• the at least one first medium of the at least one second medium is preferably enclosed in such a way that the at least one first medium adjoins only the at least one second medium and optionally additionally fluid boundaries of the microfluidic device.
• Microfluidic device for example, which limits a channel or a chamber of the microfluidic device.
• Media such as the at least one first medium and the at least one second medium can, within the microfluidic device in particular within the
• Fluid boundaries are present and moving.
• the fluid boundaries may have a material such as glass and / or plastic on the fluid to be limited.
• the at least one first medium can in particular be prevented from coming into contact with other substances in step b). This can be achieved by the at least one first medium, insofar as it is not in contact with a fluid boundary, being in contact only with the at least one second medium. Characterized in that the at least one first medium and the at least one second medium are not miscible with each other, the at least one first medium can be transported without change by contact with the second medium.
• the at least one second medium can in particular be understood as an aid for the transport of the at least one first medium. After transport, the at least one first medium and the at least one second medium can be separated from one another.
• the at least one second medium is preferably an oil. It is also preferred that the at least one second medium is an organic substance.
• the at least one first medium is polar and the at least one second medium is nonpolar.
• water as the first medium and oil as the second medium.
• water can be added with classical attributes such as Tween, Triton-X, BSA and / or calcium for the first medium.
• inert mineral oils, silicone oils and / or fluorinated oils can be used as possible second media.
• a defined volume of an aqueous phase (as the at least one first medium) in an oil phase (as the at least one second medium) can be trapped and moved in a controlled manner.
• an analyte present in the aqueous phase can be present in a limited, small amount and can be processed without loss and dilution in the microfluidic device.
• the at least one first medium in particular an aqueous volume
• the at least one first medium can be enclosed in such a way that, for example, a limited analyte in the at least one first medium does not dilute by deposition or diffusion. It is thus in particular a loss-free transport of Limited sample materials (as the first medium) possible.
• a lysate produced locally in a microfluidic small volume may be transported from a few cells from an input chamber to another location in the microfluidic device for biochemical processing.
• Lossless transport of limited material such as DNA, proteins, and / or single cells may allow for a design of a microfluidic processing unit, for example, where a heater or optical units are provided at a location other than a trial input. This may allow a particularly universal design of the microfluidic device.
• a wetting of fluid boundaries ie in particular of channel walls and / or chamber walls
• a thin layer of the second medium can deposit on the fluid boundaries.
• this thin layer may have the advantage that no DNA is bound to the polycarbonate (or to the layer of the second medium) as material of the fluid boundary. This may contribute to a lossless transport of DNA in the at least one first medium.
• the microfluidic device preferably comprises a one-way flow system which enables a diagnosis in the manner of point-of-care.
• the components of the microfluidic device can thereby in a
• Polycarbonate injection molded part are manufactured.
• a predeterminable volume of the at least one first medium is provided in a chamber of the microfluidic device, wherein the chamber has at least one connection, and wherein the predeterminable volume of the at least one first medium in the chamber is separated and is measured by the at least one port is flowed around with the at least one second medium outside the chamber.
• the at least one first medium may in particular be a sample to be analyzed.
• the desired amount of the at least one first medium according to the present embodiment can be separated and measured.
• the chamber of the microfluidic device considered in this embodiment can be filled, in particular via the at least one connection, with the at least one first medium. If the chamber is completely filled with the at least one first medium, the volume of the at least one first medium corresponds to the (preferably known) volume of the chamber.
• a demarcation between the volume within the chamber and outside the chamber, especially in the region of the at least one port, can be problematic. It may therefore be unclear where exactly the boundary of the chamber passes through the at least one connection.
• this limit can be determined by the at least one second medium.
• the at least one connection is designed in such a way that a flow of the at least one second medium (with preferably fixed parameters, such as, for example, a flow velocity) flows around the at least one connection in a reproducible manner.
• a reproducible recirculation there results an interface between the at least one first medium and the at least one second medium, which is located in particular in the region of the at least one connection.
• a plurality of first media are provided in step a), wherein the plurality of first media according to step b) are transported such that the plurality of first media are mixed in a chamber of the microfluidic device.
• the plurality of first media may be components of a substance to be analyzed.
• the plurality of first media may remain separated from one another, for example, until an analysis is to be carried out.
• a reaction between the plurality of first mediums may be prevented until the analysis is performed.
• the two-phase technology in which the at least one first medium and the at least one second medium are used
• Such mixing can therefore be carried out sufficiently fast, in particular, if the volumes to be mixed are sufficiently small.
• At least a portion of the at least one first medium and / or at least a portion of the at least one second medium in step b) are transported at least temporarily by peristaltic pumping.
• peristaltic pumping is meant here a pump which promotes a fluid by means of peristalsis.
• a typical peristaltic pump is a peristaltic pump, also called peristaltic pump.
• Peristaltic pumps are displacement pumps in which the medium to be pumped is pushed through a channel by an external mechanical deformation.
• Microfluidic peristaltic pumps may be constructed by a plurality of valves. Frequently used microfluidic valves include a channel which is closable by a movement of the channel wall due to an electrical force or a magnetic force. Such valves produce an (internal) volume change of the channel. If such valves in one
• Series connection are arranged along a channel can be achieved by a suitable control of the valves that a peristaltic of the channel occurs, which causes a promotion of the liquid.
• a peristaltic pump has the advantage that it requires no (other) pumping elements in addition to the valves (for example mechanically or electrically operating pump chambers). It is sufficient that the majority of the valves is provided.
• peristaltic pumping it is preferred that there is the possibility of an (automatic) valve circuit, according to which the valves are automatically controlled in a suitable order for the promotion.
• dynamic volume adjustment can be achieved. That is in particular in a two-phase system (comprising the at least one first medium and the at least one second medium) particularly well possible.
• a two-phase system comprising the at least one first medium and the at least one second medium
• the volumes would be predetermined by fixed geometries of the chambers.
• the chamber geometry only forms an upper limit of the possible volume. Since an aqueous and an oil phase do not mix, the inert oil can compensate for the volume not needed by the aqueous phase. This may allow additional dynamic component and volume adjustment within the microfluidic device.
• the method further comprises at least the following method step, which is carried out before, during or after step b):
• Gas inclusions can occur especially in the form of gas bubbles in the
• Gas inclusions may be particularly disadvantageous because of these volumes can be determined only inaccurate and / or because it can cause reactions between the gas and in particular the at least one first medium.
• gas inclusions can be removed.
• the gas may be, in particular, air.
• the gas can be a product of chemical reactions.
• the at least one gas inclusion can be removed in particular by transporting a medium.
• a medium enclosing the at least one gas inclusion can thus be replaced by the microfluidic one
• the at least one gas inclusion can be removed, in particular, insofar as the gas is passed out of the microfluidic device or that the gas is introduced into at least one part of the microfluidic device other part of the microfluidic device is passed, wherein the gas is less harmful or disturbing in the latter part.
• the at least one gas inclusion can also be removed by removing a gas dissolved in the at least one first medium (that is to say a substance which is present in gaseous form under normal conditions) from the at least one first medium.
• a two-phase system comprising the at least one first medium and the at least one second medium
• many oils which are preferably used as the at least one second medium
• water the preferably as an essential component, the at least one first medium is used. Therefore, it can be achieved that dissolved in water gases in the
• gas containment can also be removed by quasi-phase extraction.
• Removal of the at least one gas inclusion may be achieved, in particular, in the preferred embodiment of the method in which the microfluidic device is oriented, at least during a portion of step c), such that one side of a portion from which the at least one gas inclusion is removed a horizontal plane is tilted.
• the microfluidic device is oriented during the entire step c) in such a way that one side of a section from which the at least one gas inclusion is removed is tilted relative to a horizontal plane.
• the microfluidic device is oriented such that the side of the portion from which the at least one gas inclusion is removed is tilted with respect to the horizontal plane by an angle in the range of 20 ° to 45 °, in particular by 30 °.
• a temperature of a fluid in which the at least one gas inclusion is enclosed is changed in step c).
• the at least one gas inclusion in step c) is removed by transport of the at least one first medium and / or the at least one second medium.
• At least one second medium for removing the at least one gas inclusion may be particularly advantageous in that the at least one first medium and / or the at least one second medium are present anyway in the microfluidic device or that these medium are moved anyway by the described method ,
• a shuttle polymerase chain reaction [shuttle PCR] is carried out, wherein the at least one first medium is a reaction medium of the shuttle polymerase chain reaction.
• PCR is a method of amplifying DNA using the enzyme DNA polymerase.
• a PCR can in particular under
• Chambers with different temperature is transported. So a temperature change can be done very quickly.
• the described method may in particular provide the advantage that a shuttle PCR can be defined, bubble-free and carried out without loss.
• a single-phase system on the other hand, there would be the risk that residues of the reaction medium could remain in a channel and / or air could enter the reaction chamber.
• a microfluidic device is provided, which is intended and arranged for carrying out the method described.
• Microfluidic device applicable and transferable.
• Fig. La to ld four schematic representations of microfluidic
• Fig. 5 a schematic representation of a microfluidic
• Fig. 7a to 7f schematic representations of a microfluidic
• Multi-valve device differently connected for peristaltic pumping in six consecutive times
• 13a to 13d are schematic representations of a microfluidic
• FIG. 14 shows a schematic illustration of a method for operating a microfluidic device according to one of the exemplary embodiments from the previous figures.
• a liquid phase as the first medium 2 between two oil phases as the second Medium 3 can be included.
• the first medium 2 can be presented in particular with a defined volume.
• the volume of the first medium 2 can be determined by the fixed and precisely producible geometry of the microfluidic device 1. In this form, therefore, a defined concentration of the first medium 2, in particular if I it is an analyte, are submitted.
• the first medium 2 In order to move the volume of the first medium 2 without the analyte diluting therein by diffusion, the first medium 2 is trapped between the second medium 3 (shown here by two oil phases). Since oil and water do not mix, there is no dilution of the first medium 2 by diffusion. This can enable a loss-free microfluidic transport of a defined volume of the first medium 2 through a first channel 5 or out of a first chamber 4.
• the first chamber 4 is connected via a first connection 25 to a first channel 5 and via a second connection 26 to a second channel 6.
• the first medium 2 and the second medium 3 are surrounded by fluid boundaries 24.
• the first medium 2 may be arranged upstream in the first chamber 4 (FIG. 1 a) and transported through the first connection 25 from the latter into the first channel 5 (FIG. 1 b). In the further course of the first channel 5, the first medium 2 can be enclosed between the second medium 3 (FIG. 1c).
• Fig. Id another situation is shown, in which the first medium 2 is enclosed in a first chamber 4 of the microfluidic device 1.
• FIGS. 2 a to 2 c and 3 a to 3 e show two embodiments of a microfluidic device, with which a defined volume of an aqueous phase as the first medium 2 can be brought between two inert oil phases as the second medium 3.
• a first chamber 4 of known volume is arranged between a first channel 5 and a second channel 6 parallel to the first channel 5.
• the first chamber 4 is connected via a first connection 25 to a first channel 5 and via a second connection 26 to a second channel 6.
• Fluid control for example, by using valves or a
• the flow can be in different directions and Channel compositions are set (for example, as a flow only in the channels 5, 6 or as a flow from the second channel 6 through the first chamber 4 in the first channel 5).
• the first chamber 4 (FIG. 2 a) initially filled with a second medium 3 is flowed through with an aqueous phase as the first medium 2 and the flow is stopped so that the first
• Chamber 4 is completely filled with the first medium 2 (Fig. 2b).
• the adjacent channels 5, 6, but not the first chamber 4, are then flushed with oil as the second medium 3, so that the first chamber 4 is surrounded by two oil-filled channels 5, 6 (FIG. 2c).
• a flow from the second channel 6 through the first chamber 4 in the first channel 5 can be adjusted.
• the three phases ie the second medium 3 in the second channel 6, the first medium 2 in the first chamber 4 and the second medium 3 in the first channel 5) move laminarly without mixing.
• the first chamber 4 only adjoins (via a first connection 25) a first channel 5 and not a first channel 5 and a second channel 6 as in the first embodiment
• a portion of the first chamber 4 is open or (as shown) through a gas-permeable membrane 7 of the
• the gas-permeable membrane 7 can
• sample entry area in particular be used as a sample entry area, in particular for applications in which only small amounts of a sample are introduced into the microfluidic device.
• Fig. 3a is also shown that in the first chamber 4, a sample. 8
• the first channel 5 is first filled with oil as the second medium 3 in order to vent the entire system.
• the first chamber 4 is then filled with a liquid phase as the first medium 2 (FIG. 3b).
• the first channel 5 is again flowed through with oil as the second medium 3 and thus the first chamber 4 is completely closed (FIG. 3c).
• the first medium 2 can then again be enclosed between an oil phase as a second medium 3, by the first
• Chamber 4 is pumped out via the first channel 5 ( Figure 3d) until the first chamber 4 is empty ( Figure 3e).
• FIGS. 4 a to 4 e A further exemplary embodiment of a microfluidic device 1 with which a defined volume of an aqueous phase as the first medium 2 can be brought between two inert oil phases as the second medium 3 is shown in FIGS. 4 a to 4 e.
• two partial volumes of the first medium 2 are removed from the first chamber 4 in succession.
• the starting point shown in Fig. 4a corresponds largely to the representation in Fig. 2c.
• FIGS. 4a to 4e thus show that a two-phase system (with first medium 2 and second medium 3) can also be utilized in order to fill a microfluidic chamber only partially bubble-free with an aqueous phase (as first medium 2).
• the residual volume of the chamber can be compensated accordingly with an inert oil phase (as the second medium 3). This can be a dynamic adaptation of
• FIG. 5 shows a state from the exemplary embodiment from FIGS. 4a to 4e, in which the first chamber 4 is partially filled with the first medium 2 and partly with the second medium 3.
• FIGS. 6a to 6f show an exemplary embodiment of a microfluidic device
• the first medium 2 is half filled in a first chamber 4 with a defined volume (Fig. 6a).
• the first chamber 4 is connected via a first connection 25 to a first channel 5 and via a second connection 26 to a second channel 6.
• the feeding first channel 5 is then completely filled with oil as the second medium 3 again (FIGS. 6b and 6c).
• the first channel 5 is filled with the further first medium 9 (FIG. 6d).
• the first chamber 4 is filled (preferably slowly), so that the whole of the first chamber 4 with the two first media 2, 9 in the correct ratio is filled.
• the first channel 5 is then filled again with the second medium 3, so that the two first media 2, 9 are again enclosed in the first chamber 4 by the second medium 3 in the channels 5, 6 (FIG. 6e).
• Diffusion can mix the two first media 2, 9 in the first chamber 4 quickly, especially if the respective volumes are small.
• the result is shown in Fig. 6f, in which in the first chamber 4, a mixture 10 of the two first media 2, 9 is present.
• the mixing process can be accelerated by a temperature change. If desired, (bio) chemical reactions can also be carried out during mixing.
• Chamber geometries may allow for mixing with different ratios between the first media 2, 9.
• FIGS. 7a to 7f show how fluids in a linear or circular channel system of a microfluidic device can be moved by means of valves at a controlled speed. Valves in the microfluidic
• Devices can not only be used to open and close microfluidic paths, but can also be used as peristaltic pumps.
• a desired microfluidic pathway which may be linear or circular and shown here as a linear first channel 5
• the valves form a peristaltic pump by serially opening and closing.
• 7a to 7f show the principle using the example of three adjacent valves 11, 12, 13.
• a circle indicates an open valve, while a cross indicates a closed valve.
• the valve status can also be displayed digitally, for example by setting a "1" to "open” and a "0" to "closed”.
• valves 11, 12, 13 do not have to be placed next to one another, but can be arranged arbitrarily along the first channel 5. This has the advantage that no special pump valves need to be placed, but already existing valves 11, 12, 13 can be used.
• the flow speed can be in one determined interval by means of a duration of a pause between successive valve positions.
• FIGS. 9a to 9d show how the embodiment according to FIGS. 2a to 2c can be realized by a peristaltic pump in a multi-chamber system (comprising a first chamber 4, a second chamber 14 and a third chamber 15).
• the microfluidic device 1 is completely filled with an oil phase as the second medium 3 (FIG. 9a). This does not necessarily have to be done by peristaltic pumping.
• a fifth valve 18 and a sixth valve 19 are closed between the chambers 4, 14, 15 and a first channel 5 (FIG. 9b).
• a laterally to the chambers 4, 14, 15 arranged channel 5 is then at least partially filled with the first medium 2.
• the fifth valve 18 and the six valve 19 are opened to the chambers 4, 14, 15 and it is so long with the valves 11, 12, 13 pumped peristaltically until the first chamber 4 completely with the first medium 2 is filled ( Figures 9c and 9d).
• the pump can be coupled to an optical feedback system and automatically stopped when fully charged. Alternatively, even a trapped aqueous plug with the chamber volume can be introduced into the first chamber 4. If the first chamber 4 is completely filled, the fifth valve 18 is closed to the first chamber 4 and the first channel 5 again completely flushed with the second medium 3 (by opening a fourth valve 17), so that only the first medium 2 in the first chamber 4 remains (Figure 9d).
• FIGS. 10 a to 10 d show how a two-phase system (with a first medium 2 and a second medium 3) can be used to remove gas inclusions 16 in the first medium 2.
• Gas inclusions 16, such as perturbing bubbles, are removed by a temperature gradient in this design.
• three microfluidic chambers 4, 14, 15 are arranged one behind the other and connected to each other by means of a respective small channel.
• Each of the three chambers 4, 14, 15 is individually heated.
• the first chamber 4 is set to the highest temperature and the second chamber 14 and the third chamber 15 to a deeper. In this case, the heated gas inclusions 16 move from the first medium 2 into the colder second medium 3. If the gravitational force continues to act along the chamber geometry (as shown), the
• Chamber 4 is present, wherein the second chamber 14 and the third chamber 15 are filled with the second medium 3.
• a gas phase can form.
• the temperature can then be raised again in the second medium 3 to ensure that the gas settles at the top.
• the phase system can be displaced in each case by one chamber, the first medium 2 then being located, for example, in the second chamber 14 and the bubble-free second medium 3 in the third chamber 15.
• the blister-containing first chamber 4 is then eliminated from the chamber system.
• the first chamber 4 can be closed or refilled with the second medium 3.
• FIG. 11 shows how an inclination of the microfluidic device 1 and thermally different zones for the removal of gas inclusions 16 according to FIGS. 10a to 10d can be utilized.
• the gravity does not have to work completely. Instead, an inclination (eg of 30 °) is possible.
• FIG. 11 shows a horizontal plane 21 and an angle 22 between the horizontal plane 21 and a side 23 of the microfluidic device 1 from FIGS. 10a to 10d.
• the three-chamber system shown in FIGS. 10a to 10d may be oriented such that the first chamber 4 is located below the first medium 2 (ci in FIG. 11).
• Each chamber 4, 14, 15 is then in its own thermal zone (Ti, T 2 , T 3 ). Gravity may cause the light gas to move from the gas enclosure 16 to the upper end of the third chamber 15 by heating (C3 in FIG. 11).
• FIGS. 12a to 12c show an embodiment in which a gas enclosure 16 as in FIGS. 10a to 10d and 11 can be removed.
• FIGS. 12a to 12c it is assumed that the gas inclusion 16 according to the
• FIGS. 10a to 10d has been removed from the first medium 2 with the aid of the conditions from FIG. 11 (FIG. 12a).
• a second medium 3 is pushed from below through the three chambers 4, 14, 15 until the first medium 2 has been completely displaced from the first chamber 4 into the second chamber 14 , In this case, the gas inclusion 16 is displaced from the third chamber 15 into the first channel 5 (FIG. 12b). Subsequently, through
• the gas from the microfluidic device first be discharged, leaving a completely bubble-free microfluidic
• Figs. 13a to 13d show how with a two-phase system
• the microfluidic device 1 can be designed in particular according to FIGS. 7a to 7f, 10a to 10d and 11.
• three valves 11, 12, 13 are preferably provided which form a peristaltic pump.
• the PCR reaction mixture (as the first medium 2) is preferably introduced bubble-free in the first chamber 4, while the second chamber 14 and the third chamber 15 and the first channel 5 are filled with the second medium 3 (Fig. 13a).
• the chambers 4, 14, 15 are set to the appropriate temperatures required for the PCR.
• the first medium 2 as a PCR mixture can then be used for respective times in the corresponding chambers 4,
• Figures 13b to 13d shows how to shuttle back and forth between two temperatures (commuted, engl., "Shuttled”).
• FIG. 14 shows a method for operating a microfluidic device 1 according to one of the exemplary embodiments from the previous figures. The method comprises the following steps:
• the method preferably comprises the following (dashed line) method step, which is carried out before, during or after step b):
• step c) is performed after step b).

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• 2018
  • 2018-01-15 DE DE102018200518.4A patent/DE102018200518B4/de active Active
  • 2018-12-19 EP EP18845400.3A patent/EP3740315A1/de active Pending
  • 2018-12-19 WO PCT/EP2018/085927 patent/WO2019137775A1/de unknown
  • 2018-12-19 CN CN201880086506.5A patent/CN111565847B/zh active Active
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