WO2020064332A1 - Système microfluidique, dispositif d'analyse pour analyser un échantillon et procédé de manipulation d'un volume de fluide - Google Patents

Système microfluidique, dispositif d'analyse pour analyser un échantillon et procédé de manipulation d'un volume de fluide Download PDF

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Publication number
WO2020064332A1
WO2020064332A1 PCT/EP2019/074218 EP2019074218W WO2020064332A1 WO 2020064332 A1 WO2020064332 A1 WO 2020064332A1 EP 2019074218 W EP2019074218 W EP 2019074218W WO 2020064332 A1 WO2020064332 A1 WO 2020064332A1
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WIPO (PCT)
Prior art keywords
chamber
fluid
sample
fluid volume
channels
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PCT/EP2019/074218
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German (de)
English (en)
Inventor
Hannah Bott
Tino Frank
Original Assignee
Robert Bosch Gmbh
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Publication of WO2020064332A1 publication Critical patent/WO2020064332A1/fr

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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
    • B01L3/502723—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
    • B01L2200/0684—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
    • B01L2300/04—Closures and closing means
    • B01L2300/046—Function or devices integrated in the closure
    • B01L2300/048—Function or devices integrated in the closure enabling gas exchange, e.g. vents
    • 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
    • B01L2300/0877—Flow 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
    • B01L2400/08—Regulating or influencing the flow resistance
    • B01L2400/084—Passive control of flow resistance
    • B01L2400/086—Passive control of flow resistance using baffles or other fixed flow obstructions
    • 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

Definitions

  • the invention relates to a microfluidic system, an analysis apparatus for analyzing a sample with a corresponding microfluidic system and a method for handling a volume of fluid.
  • Microfluidic systems allow the analysis of small sample quantities with high sensitivity. Automation, miniaturization and
  • a major challenge in the processing of microfluidic systems is the air-free filling and the removal of gas inclusions, such as air bubbles that arise during operation.
  • gas inclusions such as air bubbles that arise during operation.
  • PDMS polydimethylsiloxane
  • air bubbles can easily be removed by the material itself. The fluid is compressed slightly and the resulting pressure pushes the gases through the PDMS, leaving fluids in liquid form. This is a special material property of PDMS.
  • PDMS is not a suitable material for the user market because it is difficult to process this polymer. Therefore, in the
  • Mass production systems often made from airtight polymers. To run bubble-free processes, gas-permeable membranes often have to be integrated or complex filling processes have to be carried out.
  • Air bubbles are undesirable in a system in that they affect the planned fluid flow and the process can no longer run ideally. In Optofluidic systems lead to interference of the evaluation. If temperature is actively supplied, this process is influenced by bubbles and their different heat coefficient.
  • fluids should have dissolved a defined amount of gas.
  • a 5% saturation of C0 2 or a certain amount of 0 2 is necessary to control aerobic growth of prokaryotes. This saturation is usually achieved by flowing the corresponding gas into the target fluid. This creates air bubbles that cannot escape in a microfluidic unit that is usually made of airtight polymers. Air bubbles in a flow system can also lead to unwanted lysis of mammalian cells.
  • the point-of-care analysis of a sample should include a quick sample analysis, without complicated and time-consuming work steps that would have to be carried out by trained personnel in central laboratories. This can be achieved using a lab-on-chip (LoC) system.
  • LoC lab-on-chip
  • LoC systems are used for various applications.
  • the various problems can be processed and different processes can be programmed.
  • the possible applications of a LoC system differ in the workflows and processes, "on chip”, but also in sample collection and preparation in the "macro world".
  • a microfluidic system comprising a chamber and at least two channels, each in the
  • Chamber open wherein the chamber in the region of an upper side of the chamber has an opening through which at least part of an interior of the chamber is in direct exchange with an atmosphere.
  • the solution presented here advantageously allows a dynamic process for the active removal of air bubbles and gas exchange from a microfluidic system.
  • the process or the system can be used, for example, for filling and / or during a microfluidic process.
  • a central aspect of the solution presented here is in particular a microfluidic chamber, which allows flow and up to
  • Atmosphere is open.
  • air bubbles can advantageously be released into the atmosphere, while the bubble-free fluid can be passed on to a further fluidic system connected to the microfluidic system.
  • the solution presented here contributes in particular to the fluidic enabling and implementation of complex, microfluidic sample input and preparation at the point of care.
  • the proposed solution enables in particular the multiple submission of materials and / or a fluidic, sample-specific integration into a universal LoC (lab-on-chip) platform.
  • the concepts described can, for example, be combined in modules and can offer individual solutions for a universal LoC platform.
  • the processes described here generally take place entirely in the world-to-chip interface, i.e. in the
  • the microfluidic system is, in particular, a system for a (microfluidic) analysis apparatus for analyzing a sample or a system which (for analysis purposes) can be connected to an analysis apparatus (in particular an analysis device of an analysis apparatus).
  • the system and / or the chamber in particular form a so-called world-to-chip interface for a particularly universal LoC (lab-on-chip) platform.
  • the system can in particular be an (exchangeable) input system which can be connected to an analysis device, for example in order to introduce a sample that has been preprocessed (prepared) in the input system into the analysis device.
  • the system preferably has a (universal or standardized) interface. This interface is in particular set up in such a way that it corresponds to a sample interface of an analysis apparatus (in particular an analysis device of an analysis apparatus).
  • the channels of the system can open in the interface of the system.
  • the microfluidic system can be formed, for example, in the manner of a plug and / or chip that has the chamber and the channels. Furthermore, this plug or chip generally has an interface via which it (in particular its channels) can be connected to a (microfluidic)
  • Analysis system (such as formed by the analysis apparatus) can be connected.
  • This plug and / or chip is used in particular for sample input into the (microfluidic) analysis system and / or for pre-processing the sample in the chamber (if the plug / chip is connected to the analysis system).
  • the microfluidic system can be formed as a unit. In other words, this means in particular that at least the chamber and the two channels can be made integrally or in one piece.
  • the system can, for example, be cast or built up in layers, in particular printed three-dimensionally.
  • a non-air-permeable polymer is preferably proposed, e.g. B.
  • microfluidic system and / or the chamber are preferred.
  • the chamber is preferably an input chamber, particularly preferably a sample input chamber.
  • the chamber relates to a microfluidic chamber for dynamic sample entry and / or sample preparation on the world-to-chip interface of a LoC platform.
  • the atmosphere can in particular be an earth's atmosphere. In other words, this means in particular that the chamber can be open to the surroundings. Alternatively or cumulatively, the atmosphere can be specifically enriched with a certain gas
  • Gas composition for example, an earth's atmosphere with increased CO 2 content.
  • At least one of the two channels opens into the chamber in the region of a chamber floor. This advantageously contributes to the fact that the interior of the chamber can be used as completely as possible.
  • the channels preferably open into mutually opposite sections of a chamber wall.
  • each channel is preferably (exactly) assigned to a subspace or reservoir within the chamber.
  • At least one of the two channels extends at least partially along a chamber wall of the chamber.
  • the channels can extend through a body of the system so that they (again) behind a chamber wall
  • valves in the channels can be used to determine the direction of flow and / or the
  • At least one separating element is arranged in the chamber, which divides the chamber into at least two subspaces.
  • the subspaces are in particular at least partially separated from one another and / or preferably (directly) connected to one another in the region of the opening.
  • the latter can be achieved, for example, in that the separating element does not extend completely from a chamber floor to a chamber ceiling or the opening.
  • the chamber can also be referred to as a “poly chamber”.
  • the chamber can consist of independent partial volumes. These can, for example, be processed independently of one another and / or by adding an additional defined limit volume to a complete one
  • Chamber volume can be combined. If, for example, a trough (in the middle) is formed in a large chamber, which is open to the atmosphere, the addition of samples is made possible particularly advantageously by the outside world.
  • the partition element is preferably a partition wall.
  • the partition can in particular have a ramp on at least one side.
  • the separating element can comprise an overhang. The overhang can partially overlap a partition assigned to it (in the vertical direction).
  • the separating element is preferably set up in such a way that it
  • At least two separating elements are preferably provided, which subdivide the interior of the chamber into at least three (adjacent) subspaces.
  • the outer subspaces are preferably (directly) connected to one of the channels.
  • the at least one separating element can also contribute to the fact that multi-stage and / or dynamic processes can also be carried out in the system.
  • An example of such a multi-step process is an alkaline lysis.
  • a (microfluidic) analysis apparatus for analyzing a sample with a microfluidic system presented here.
  • the analysis apparatus is, in particular, a LoC (lab-on-chip) platform or a LoC analysis device.
  • the analysis apparatus can provide a fluid system, in particular fluid supply for the microfluidic system, via which, for example, (certain) fluid (s) can be introduced or discharged into the chamber via at least one of the channels.
  • the analysis apparatus can, for example, have a universal sample interface, via which the analysis apparatus can be connected to the (exchangeable) system proposed here.
  • the (exchangeable) system can, for example, be designed for specific samples and / or allow preprocessing of the sample.
  • Fluid volume proposed comprising at least the following steps:
  • steps a), b) and c) is usually the case for a regular operating procedure.
  • steps a), b) and c) can also be carried out at least partially in parallel or even simultaneously.
  • the system presented here and / or the analysis apparatus presented here are preferably set up to carry out the method presented here. The method can be carried out, for example, by means of the system presented here and / or the analysis apparatus presented here.
  • the system and / or the method are preferably used for (active)
  • Air bubble removal from the fluid volume and / or for (active) gas saturation of the fluid volume Air bubble removal from the fluid volume and / or for (active) gas saturation of the fluid volume.
  • An (active) removal of air bubbles from the fluid volume and / or a (active) saturation of the fluid volume with gas preferably takes place.
  • the processes of removal and / or saturation preferably take place during steps a) and / or b).
  • the fluid volume is a sample that is at least partially introduced into the chamber via the opening in step a).
  • the opening is sufficiently large that a sample can thereby be introduced into the chamber.
  • the sample can be, for example, a liquid sample or a sample, in particular dissolved in a liquid.
  • a simple sample entry usually only requires the application of a solution.
  • samples are often complex, multi-component fluids. This can be, for example, a suspension such as blood, urine, respiratory condensate or cerebrospinal fluid.
  • the examination of the corresponding target component (s) often consists of several process steps. To date, these steps can only be integrated in a microfluidic network adjoining the input chamber, and therefore generally require a redesign of the entire analysis unit for different samples.
  • the solution proposed here allows, in particular, a universal platform (analysis apparatus) to be used for various applications. In particular via a universal sample interface, the analysis apparatus can be connected to the system proposed here, which can be designed for specific samples and in particular allows preprocessing of the sample.
  • At least a part of the fluid volume be moved back and forth through the channels in the chamber by means of a fluid movement.
  • this can also be referred to as a pendulum movement.
  • Fluid volume is repeatedly discharged from the chamber by means of a fluid movement through the channels and is re-introduced into the chamber.
  • this can also be referred to in particular as a circulating or circular flow.
  • volume of fluid in the chamber is saturated with a gas.
  • This can advantageously contribute to a cell culture medium with physiological saturate essential gases such as 0 2 and / or CO2.
  • Fluid volume can be particularly relevant in this context
  • At least two fluid volumes be introduced into the chamber and initially
  • Reservoirs or subspaces advantageously enable lysis processes, which can include several steps.
  • At least two fluid volumes are mixed with one another in the chamber.
  • one of the fluid volumes can be sub-layered until, for example, it can reach the other of the fluid volumes via a separating element.
  • a particular advantage can also be seen in the fact that the mixing processes which are carried out in the chamber can be carried out with a connection to the atmosphere. This advantageously reduces the
  • At least one fluid volume kept in the chamber be under-layered with fluid.
  • a fluid volume held ready in the chamber can be overlaid with a fluid.
  • a solid reagent be kept ready in the chamber. This advantageously allows a three-stage lysis to be carried out in the chamber.
  • volume of fluid in the chamber is flushed with fluid which is separate from the fluid volume.
  • This advantageously allows active cooling of the fluid volume that has been flushed.
  • the cooling can advantageously serve to prevent the failure of heat-sensitive components, which can, for example, advantageously improve an ultrasound effect.
  • particles be sedimented from the fluid volume.
  • blood cells can be sedimented from serum.
  • the settling of the blood cells in the chamber can also advantageously be magnetically reinforced.
  • a solid substance be sub-layered in the chamber in order to dissolve it in the fluid volume.
  • a particularly advantageous functionality of the process described here can be achieved in particular in cooperation with a higher-level control of an analysis apparatus.
  • the fluidics of the analysis apparatus can be used to introduce fluid flows into the channels or to withdraw them from the channels.
  • Fig. 1 an exemplary embodiment of a proposed here
  • microfluidic system 2: another exemplary embodiment of a microfluidic system proposed here,
  • Fig. 4 an exemplary operation of a proposed here
  • FIG. 1 schematically shows an exemplary embodiment of a microfluidic system 1 proposed here.
  • the microfluidic system 1 has a chamber 2 and at least two channels 3, 4, which each open into the chamber 2.
  • the chamber 2 has an opening 6 in the area of an upper side 5 of the chamber 2, through which at least part of an interior 7 of the chamber 2 is in direct exchange with an atmosphere 8.
  • Fig. La shows schematically a section through the system 1, which in a
  • FIG. Lb schematically illustrates a section through the system 1, which lies in a (horizontal) x-y plane.
  • the sectional view according to FIG. 1 a also shows that one of the two channels 3, 4 opens into the chamber 2 in the region of a chamber bottom 9.
  • both channels 3, 4 open in the area of the chamber bottom 9.
  • the sectional view according to FIG. 1b also illustrates that at least one of the two channels 3, 4 is at least partially along one
  • Chamber wall 10 of the chamber 2 can extend.
  • both channels 3, 4 even extend at least partially along the chamber wall 10.
  • FIGS. 1 a An exemplary basic geometry of the system 1, in particular the chamber 2, is shown in FIGS.
  • FIG. 1 a shows, for example, that at least one, in particular for the processes also described here
  • Chamber 2 is provided, which is open to the atmosphere 8 upwards.
  • channels 3, 4 lead to chamber 2, which can connect them to the remaining part of a microfluidic device, not shown here.
  • the chamber 2 can be controlled, for example, with a fluidic system.
  • FIG. 1b shows, by way of example, that the two (supply) channels 3, 4 can advantageously enable a circular flow as close as possible to the (atmosphere) chamber 2.
  • the opening 5 to the atmosphere 8 can also be used, for example, to bring material into a microfluidic unit or an apparatus.
  • the solution presented here can thus be used, for example, when entering the sample, but also as desired during the overall fluidic process.
  • FIG. 2 schematically shows a further exemplary embodiment of a microfluidic system 1 proposed here.
  • the reference numerals are used uniformly, so that the previous explanations relating to FIG. 1 can be referred to in full.
  • the separating element 11 can be arranged in the chamber 2, which divides the chamber 2 into at least two Sub-rooms 12, 13 divided.
  • the separating element 11 here has, for example, a separating element height 21.
  • the separating element 11 is formed here, for example, in the manner of a partition.
  • the chamber 2 shows an example of the basic concept of a system 1 proposed here with a chamber 2.
  • the chamber 2 generally has two or more subspaces and can thus also be referred to as a so-called poly chamber.
  • the chamber 2 is divided into two subspaces 12, 13 which are still open at the top and which are separated by a separating element 11
  • Separating element height 21 are separated from each other and are each connected to a channel 3, 4 with a fluid system or a fluid system (not shown here). In other words, this can also be described in such a way that an entire chamber 2 is divided into two chambers 12, 13 which are open at the top and which are separated by a dividing wall 11 with a height of 21 and are each equipped with a feed channel 3, 4 for fluidics.
  • the (total) chamber 2 is open to the atmosphere 8. This opening 6 is used in particular to add a sample from the outside and functions here, for example, as the so-called “world-to-chip interface”. Became the primary
  • the entire system 1 which can also be described as a microfluidic unit, can be transferred to a processing station (not shown here in more detail), and a procedure also described here, in particular for sample preparation and sample collection ( automated).
  • FIG. 3 schematically shows an exemplary sequence of a method proposed here.
  • the method is used to handle a volume of fluid 14.
  • the sequence of steps a), b) and c) illustrated with blocks 110, 120 and 130 generally arises during a regular operating sequence.
  • steps a), b) and c) can also be carried out at least partially in parallel or even simultaneously.
  • the fluid volume 14 is introduced into a chamber 2 of a microfluidic system 1, so that the fluid volume 14 in at least part of an interior 7 of the chamber 2 via an opening 6 in the area of an upper side 5 of the chamber 2 in direct exchange with an atmosphere 8 arrives.
  • fluid 15, 17 is introduced into chamber 2 via at least one of two channels 3, 4, which each open into chamber 2.
  • fluid 14, 15, 17 is discharged from chamber 2 via at least one of the two channels 3, 4.
  • Fig. 4 shows schematically an exemplary operation of one here
  • FIG. 3 shows an example of an advantageous concept for removing bubbles that can be carried out by means of the system 1.
  • the fluid 14 with the (air) bubbles 22 is conducted to the chamber 2, which is open to the atmosphere 8. Due to the much lower density, the bubbles 22 still rise above and can pass into the atmosphere 8. In moving fluid, i.e. if the river flows, the ascent of the bladder can also be promoted.
  • FIG. 5 schematically shows a further exemplary mode of operation of a microfluidic system 1 proposed here.
  • the reference numerals are used uniformly, so that the preceding explanations, in particular relating to FIGS. 1 to 3, can be referred to in full.
  • the fluid volume 14 can be a sample that was at least partially introduced into the chamber via the opening 6.
  • the sample is in this
  • the fluid volume 14 is surrounded here by way of example with a working fluid 15 (or transport fluid) which has no tendency to interact with the fluid volume 14 to mix. This advantageously allows fluid transport or handling (or handling) of the sample.
  • FIG. 5 also shows by way of example how bubbles 22 can advantageously be removed from a limited volume 14, which is located in a two-phase system (with the (fluid) phases 14 and 15).
  • a limited, aqueous volume 14 is enclosed in an oil phase 15.
  • the water plug 14 is preferably in the Chamber 2 oscillated back and forth so that the rise of the bubbles 22 can be promoted and the bubbles 22 can pass into the atmosphere 8 as quickly as possible.
  • FIG. 6 schematically shows a further exemplary mode of operation of a microfluidic system 1 proposed here.
  • the reference numerals are used uniformly, so that the preceding explanations, in particular relating to FIGS. 1 to 3, can be referred to in full.
  • FIG. 6 shows an advantageous embodiment in which the chamber 2 has been supplemented with a geometric element, which is formed here, for example, with the separating element 11 (in this case a cuboid elevation), which the
  • Atmospheric exchange surface can be transported. If this geometric element 11 is missing, the flow lines are generally coplanar with the x-y plane or invariant in the z direction (cf. FIG. 1). Due to the geometric element 11, the flow lines are advantageously also variant in the z-direction and the bubbles 22 are actively buoyed by the flow 14.
  • FIG. 7 schematically shows a further exemplary mode of operation of a microfluidic system 1 proposed here.
  • the reference numerals are used uniformly, so that the preceding explanations, in particular with regard to FIGS. 1 to 3, can be referred to in full.
  • FIG. 7 a shows, by way of example, that and how the fluid volume 14 can be repeatedly discharged from the chamber 2 by means of a fluid movement through the channels 3, 4 and re-introduced into the chamber 2.
  • FIG. 7b illustrates by way of example that and how at least a part of the fluid volume 14 can be moved back and forth in the chamber 2 by means of a fluid movement through the channels 3, 4.
  • FIG. 7 thus shows, by way of example, different types in which mode the flow can be conducted through the chamber 2.
  • a circular flow is shown in FIG. 7a.
  • the fluid - as a whole or in
  • FIG. 8 schematically shows a further exemplary mode of operation of a microfluidic system 1 proposed here.
  • the reference numerals are used uniformly, so that the preceding explanations, in particular with respect to FIGS. 1 to 3, can be referred to in full. 8 illustrates by way of example that and how the fluid volume 14 in the chamber 2 can be saturated with a gas 16.
  • FIG. 8 shows an example of how a fluid 14 can be saturated with a gas 16 - in the specific case 5% CO 2 - for example.
  • the space (surrounding the system 1 8) which has now been described as atmosphere 8 is saturated with 5% CO 2 .
  • this can also be described in such a way that the (surrounding system 1)
  • Atmosphere 8 is enriched accordingly with C0 2 .
  • the upper space of chamber 2 or the area of chamber 2 that is not filled with fluid 14 forms a larger gas volume with the corresponding composition.
  • FIG. 8c schematically shows a further exemplary mode of operation of a microfluidic system 1 proposed here.
  • the reference numerals are used uniformly, so that the preceding explanations, in particular with respect to FIGS. 1 to 3, can be referred to in full.
  • FIG. 9 illustrates in a further example that and how the fluid volume 14 in the chamber 2 can be saturated with a gas 16.
  • the saturation of the medium in the chamber 2 can also be achieved, for example, by actively flowing gas 16 into the medium 14 in the chamber 2. This can create air bubbles.
  • the gas flow can be stopped and, for example, a method for bubble removal, such as a short oscillation (shaking) or setting a circular flow, which is also proposed here and described above in particular in connection with FIG. 7, can be carried out .
  • FIG. 10 schematically shows a further exemplary mode of operation of a microfluidic system 1 proposed here.
  • the reference numerals are used uniformly, so that the preceding explanations, in particular with respect to FIGS. 1 to 3, can be referred to in full.
  • FIG. 10 illustrates by way of example that and how at least two fluid volumes 14, 17 can be introduced into the chamber 2 and initially kept separate from one another in the chamber 2. Furthermore, FIG. 10 illustrates by way of example that and how at least two fluid volumes 14, 17 can be mixed with one another in the chamber 2.
  • FIG. 10 shows an example of a sequence for
  • FIG. 10 a illustrates that the volumes 14, 17 to be mixed have been stored upstream in subspace 12 and subspace 13 or have been presented by the user as a sample.
  • FIG. 10 b illustrates that the volume in the partial space 12 is now increased by a further volume via the inlet to the partial space 12 formed with the channel 3, wherein the additional volume can be the same fluid with which the volume 17 is formed is or a different fluid.
  • the volume in subspace 12 reaches the fill level, which corresponds to the height 21 of the connecting channel or the separating element 11 (cf. FIG. 2) and is thereby transferred into subspace 13 and merges with volume 14 to form a total volume .
  • FIG. 7b An intermixing of the volumes mentioned is illustrated in FIG.
  • the volumes thus mixed can (together) be drawn into a fluid system (not shown here) for analysis, for example through channel 4.
  • Mixing takes place, for example, by diffusion.
  • Mixing by diffusion is a generally quick process in microfludic processes.
  • mixing can also be achieved by means of a pendulum flow - repeated movement of the liquid back and forth (cf. FIG. 7b).
  • FIG. 11 schematically shows another exemplary mode of operation of a microfluidic system 1 proposed here.
  • the reference numerals are used uniformly, so that the preceding statements, in particular with respect to FIGS. 1 to 3, can be referred to in full.
  • FIG. 11 illustrates by way of example that and how at least one fluid volume 17 kept in the chamber 2 can be sub-layered with fluid 15.
  • FIG. 11 illustrates by way of example that and how at least one fluid volume 17 kept in the chamber 2 can be sub-layered with fluid 15.
  • FIG. 11 a a sample 14 is entered into subspace 13, and a buffer 17 is upstream in subspace 12.
  • Fig. 11b it is illustrated that the with the Channel 3 formed inlet to sub-space 12, a liquid 15 with a slow flow is now pumped in to underlay the buffer 17.
  • the undercoating liquid 15 does not mix with the buffer 17 (in the case of an aqueous buffer, for example, an oil can be undercoated) and lifts it up to the level of the connecting channel or the separating element (cf. FIG. 2).
  • sample 14 and buffer 17 mix and can be drawn in for analysis in a fluid system not shown here, for example via channel 4. Mixing can again be carried out, for example, as in the method according to FIG. 10.
  • FIG. 12 schematically shows a further exemplary mode of operation of a microfluidic system 1 proposed here.
  • the reference numerals are used uniformly, so that the preceding statements, in particular with respect to FIGS. 1 to 3, can be referred to in full.
  • FIG. 12 illustrates by way of example that and how a solid reagent 18 can be kept available in the chamber 2.
  • the underlaying principle for a (sample entry) chamber 2 with three reservoirs or subspaces 12, 13, 23 is shown in FIG. 12.
  • the three subspaces 12, 13, 23 lie next to one another and are separated from one another at least in sections by two separating elements (cf. FIG. 2).
  • the two separating elements each have, for example, a partition and an overhang.
  • a liquid reagent 17 is upstream in subspace 12 and a solid reagent 18 in subspace 23.
  • the sample 14 is entered into the subspace 13.
  • the upstream liquid reagent 17 is then raised in the subspace 12 by layering it with a liquid 15 from the fluid (not shown here) (for example, a fluid of a chip not shown here) and transferred into the subspace 13.
  • a liquid 15 from the fluid for example, a fluid of a chip not shown here
  • Fig. 12c that is liquid reagent 17 is mixed in subspace 13 with sample 14 and the resulting substance is transferred into subspace 23 by further sub-layers.
  • the sample 14 and the reagents 17, 18 are now mixed in the subspace 12 and can be drawn into the fluidics (of the chip) for analysis.
  • This principle enables, for example, a 3-stage lysis in the
  • the components of the lysis can be stored independently of one another until the time of use and can then be added in the required order.
  • An example of a 3-component lysis includes the following steps and reagents: First, the cells to be analyzed are placed in the middle reservoir or subspace 13, which contains distilled water to break up the cell membrane. Potassium hydroxide (KOH) is then transferred from the left reservoir or sub-space 12 to sub-space 13 by the underlaying principle and is used to remove lipid residues in the sample liquid. Finally, the sample is transferred to the right reservoir or partial space 23, in which hydrochloric acid (HCl) is stored upstream for neutralization, using the underlayer principle.
  • KOH potassium hydroxide
  • HCl hydrochloric acid
  • FIG. 13 schematically shows a further exemplary mode of operation of a microfluidic system 1 proposed here.
  • the reference numerals are used uniformly, so that the preceding statements, in particular with respect to FIGS. 1 to 3, can be referred to in full.
  • FIG. 13 illustrates by way of example that and how the fluid volume 14 in the chamber 2 can be flushed with fluid 15, which is separated from the fluid volume 14.
  • FIG. 13 illustrates in particular how a sample 14 can be cooled in a (sample entry) chamber 2 with three reservoirs or partial spaces 12, 13, 23 during an ultrasound treatment.
  • the two outer reservoirs or the subspaces 12 and 23, which adjoin the sample reservoir or the central subspace 13 are filled with a cooling liquid 15 (cf. FIG. 13b) and then the action of the sonotrode (indicated here in FIG. 13c) started.
  • the cooling advantageously prevents the precipitation of heat-sensitive components, which can improve the ultrasound effect.
  • the cooling liquid 15 is then removed from the (sample entry) chamber 2 (for example via the channels 2, 4; cf. FIG. 13d) and the sample 14 can be passed through, for example the underlaying principle described above can be drawn into a fluid system.
  • FIG. 14 schematically shows a further exemplary mode of operation of a microfluidic system 1 proposed here.
  • the reference numerals are used uniformly, so that the preceding statements, in particular with respect to FIGS. 1 to 3, can be referred to in full.
  • 14 illustrates by way of example that and how particles 19 can be sedimented from the fluid volume 14. 14 is one
  • sample entry chamber 2 with three reservoirs or subspaces 12, 13, 23, but shown without an overhang.
  • This can be used, for example, to sediment particles 19 from a sample liquid 14.
  • the sample 14, 19 is entered into the intermediate reservoir or the subspace 13 (see FIG. 14a).
  • the particles 19 settle in the subspace 13 (cf. FIG. 14b).
  • the sample liquid 14 is overlaid with a dilution substance 15 (see FIG. 14c) and by diffusion the sample liquid 14 is distributed over all reservoirs or subspaces 12, 13, 23 (see FIG. 14d).
  • the diluted sample liquid can then be drawn into a fluid system without particles, for example via channel 4.
  • blood cells can be sedimented from serum using this principle.
  • the settling of the blood cells in the chamber can e.g. be magnetically amplified.
  • FIG. 15 schematically shows another exemplary mode of operation of a microfluidic system 1 proposed here.
  • the reference numerals are used uniformly, so that the preceding statements, in particular with respect to FIGS. 1 to 3, can be referred to in full.
  • 15 illustrates by way of example that and how a solid substance 20 can be sub-layered in the chamber 2 in order to dissolve it in the fluid volume 14. 14 shows one in this connection
  • substance 20 in the form of a so-called “bead” and for its dissolving process in sample 14.
  • the solid substance 20 is preferably stored in a subspace 12 separate from the sample 14 and can thus be transferred to the sample 14 and dissolved at a defined point in time. This is advantageous if the sample 14 is initially other reagents such as. B. a lysis buffer should be fed. That the subspaces 12 and 13 at least
  • separating element 11 separating sections from one another advantageously has the shape of a ramp.
  • the sequence is structured, for example, as follows:
  • the solid substance 20 is stored in the subspace 12, the sample 14 is input into the subspace 13.
  • 15 b illustrates that a liquid phase 15, which does not dissolve and raise the solid substance 20 (e.g. an oil), is pumped from a fluid system (not shown here) into the subspace 12, for example, via the channel 3.
  • a fluid system not shown here
  • 15d illustrates that the solid substance 20, as soon as it comes into contact with the sample 14, is dissolved therein.
  • This is an exemplary advantage in the bead dissolving process in contrast to the dissolving of the beads on chip. Air pockets and foam formation can advantageously be avoided.
  • Air bubbles, in particular from the fluid with the sample material, can be avoided.
  • Air bubbles can be removed by a dynamic process.
  • the process is a universal process based on a universal geometry, which can be integrated into any microfluidic processes on a universally designed microfluidic analysis unit.
  • the process can also be used to saturate a fluid with a gas. This is of particular interest if, for example, a cell culture medium is to be saturated with physiological essential gases such as 0 2 or C0 2 . • The process serves as the basis for the cultivation of cells on a microfluidic platform.
  • the described invention can be applied to an already existing LoC platform. This results in further fluidic possibilities without having to adapt the core of the fluidics.
  • Sample entry chamber can be by insert or directly in the
  • the volumes can be processed separately as well as combined with one another.
  • connection also allows a flow through the
  • the samples can be drawn into the fluidics via various input lines.
  • the described processes of the invention can also be used to integrate chambers into the sample input which have no direct connection to the fluidics.
  • the sample is drawn in through flow or with the help of an underlaying principle.
  • Sample entry chamber performed with connection to the atmosphere can be. This reduces the likelihood of air bubbles forming in the fluidic system.
  • a lyophilisate can be stored upstream and in the sample entry chamber
  • the input of the sample can be standardized for many samples

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Abstract

L'invention concerne un système microfluidique, une unité d'analyse pour analyser un échantillon et un procédé de manipulation d'un volume de fluide. Le système microfluidique (1) comprend une chambre (2) et au moins deux canaux (3, 4) qui débouchent chacun dans la chambre (2), la chambre (2) présentant une ouverture (6) dans la zone d'un côté supérieur (5) de la chambre (2), par laquelle au moins une partie d'un espace intérieur (7) de la chambre (2) est en échange direct avec une atmosphère (8).
PCT/EP2019/074218 2018-09-25 2019-09-11 Système microfluidique, dispositif d'analyse pour analyser un échantillon et procédé de manipulation d'un volume de fluide WO2020064332A1 (fr)

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DE102018216308.1A DE102018216308A1 (de) 2018-09-25 2018-09-25 Mikrofluidisches System, Analyseapparat zur Analyse einer Probe und Verfahren zur Handhabung eines Fluidvolumens

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DE102021201146A1 (de) 2021-02-08 2022-08-11 Robert Bosch Gesellschaft mit beschränkter Haftung Vorrichtung und Verfahren zur Separation von Blutplasma aus Vollblut

Citations (3)

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US20040181343A1 (en) * 2002-11-01 2004-09-16 Cellectricon Ab Computer program products and systems for rapidly changing the solution environment around sensors
US20060234298A1 (en) * 2002-02-12 2006-10-19 Cellectricon Ab Systems and methods for rapidly changing the solution environment around sensors
US20160051981A1 (en) * 2012-07-23 2016-02-25 Tasso, Inc. Methods, Systems, and Devices Relating to Open Microfluidic Channels

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WO2014039514A2 (fr) * 2012-09-05 2014-03-13 President And Fellows Of Harvard College Élimination de bulles dans des systèmes microfluidiques
WO2015188171A1 (fr) * 2014-06-06 2015-12-10 Berkeley Lights, Inc. Isolation de structures microfluidiques et piégeage de bulles

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Publication number Priority date Publication date Assignee Title
US20060234298A1 (en) * 2002-02-12 2006-10-19 Cellectricon Ab Systems and methods for rapidly changing the solution environment around sensors
US20040181343A1 (en) * 2002-11-01 2004-09-16 Cellectricon Ab Computer program products and systems for rapidly changing the solution environment around sensors
US20160051981A1 (en) * 2012-07-23 2016-02-25 Tasso, Inc. Methods, Systems, and Devices Relating to Open Microfluidic Channels

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