EP3393661A1 - Dispositif microfluidique, et procédé de production ainsi que procédé de fonctionnement d'un dispositif microfluidique - Google Patents

Dispositif microfluidique, et procédé de production ainsi que procédé de fonctionnement d'un dispositif microfluidique

Info

Publication number
EP3393661A1
EP3393661A1 EP16808605.6A EP16808605A EP3393661A1 EP 3393661 A1 EP3393661 A1 EP 3393661A1 EP 16808605 A EP16808605 A EP 16808605A EP 3393661 A1 EP3393661 A1 EP 3393661A1
Authority
EP
European Patent Office
Prior art keywords
fluid chamber
opening
fluid
chamber
substrate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP16808605.6A
Other languages
German (de)
English (en)
Other versions
EP3393661B1 (fr
Inventor
Thomas BRETTSCHNEIDER
Jochen Rupp
Daniel Czurratis
Christian Dorrer
Karsten Seidl
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Robert Bosch GmbH
Original Assignee
Robert Bosch GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Robert Bosch GmbH filed Critical Robert Bosch GmbH
Publication of EP3393661A1 publication Critical patent/EP3393661A1/fr
Application granted granted Critical
Publication of EP3393661B1 publication Critical patent/EP3393661B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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
    • B01L3/50273—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 the means or forces applied to move the fluids
    • 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
    • B01L2200/12—Specific details about manufacturing devices
    • 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
    • B01L2300/041—Connecting closures to device or container
    • B01L2300/044—Connecting closures to device or container pierceable, e.g. films, membranes
    • 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
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0672—Integrated piercing tool
    • 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
    • B01L2300/0887—Laminated structure
    • 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
    • B01L2300/12—Specific details about materials
    • B01L2300/123—Flexible; Elastomeric
    • 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
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0633—Valves, specific forms thereof with moving parts
    • B01L2400/0655—Valves, specific forms thereof with moving parts pinch valves
    • 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
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0677—Valves, specific forms thereof phase change valves; Meltable, freezing, dissolvable plugs; Destructible barriers
    • B01L2400/0683—Valves, specific forms thereof phase change valves; Meltable, freezing, dissolvable plugs; Destructible barriers mechanically breaking a wall or membrane within a channel or chamber

Definitions

  • Microfluidic device method for manufacturing and method for operating a microfluidic device
  • the invention is based on a device or a method according to the preamble of the independent claims.
  • microfluidic devices liquids are provided or transported on a chip.
  • Such microfluidic devices can be used, for example, in so-called lab-on-a-chip systems (LOCs), in which the entire functionality of a macroscopic laboratory is accommodated on, for example, a credit card-sized plastic substrate (LOC cartridge) and complex biological, diagnostic, chemical or physical processes can be miniaturized.
  • LOCs lab-on-a-chip systems
  • Many LoC systems require a variety of fluids, such as liquid reagents, such as: As saline solutions, ethanol-containing solutions, aqueous solutions, detergents or dry reagents, such as lyophilisates, salts, etc., which are required for a variety of diagnostic applications.
  • These reagents can either be manually pipetted onto the LOC cartridge or pre-stored on the cartridge. The latter brings advantages in terms of automation, contamination risks, user-friendliness and transportability of LOC systems.
  • WO 2014/090610 Al describes a concept in which liquids are stored in tubular bags, so-called stickpacks.
  • the stickpacks are integrated into the LOC system, where they can be opened and emptied via a deflection of a flexible membrane. Disclosure of the invention
  • An advantage of the described microfluidic device is that liquids, such as reagents and moisture-sensitive dry reagents for LOC applications stored for a long time stable and if necessary on a
  • a mechanical element such as a stamp, a stamp unit, or a plunger can be provided.
  • a microfluidic device comprising: a chamber substrate having a fluid chamber for receiving a fluid; a lid substrate having a punch opening, the punch opening being disposed opposite to a fluid chamber opening of the fluid chamber; a flexible membrane sandwiched between the chamber substrate and the
  • Cover substrate is arranged and the punch opening and the
  • Spans fluid chamber opening Spans fluid chamber opening; and a punch unit configured to retract into the fluid chamber through the punch opening to deflect the membrane into the fluid chamber to allow the fluid to flow out of the fluid chamber when the fluid is received in the fluid chamber.
  • the chamber and lid substrate may be a polymeric substrate of high barrier plastics.
  • the Membrane is designed to be deflected at a pressure on the membrane.
  • the membrane is highly flexible and tear-resistant in one embodiment.
  • the membrane is configured to retract to its original position upon a withdrawal of the pressure. Especially with a large deflection of the
  • Membrane can also lead to a plastic deformation, which is not necessarily the function in the way.
  • An imagined mechanical stamping unit of the microfluidic device enables reliable reagent release. Since a high force can be safely applied to the example containing a fluid fluid chamber, the fluid can, for example, in a blister or behind a
  • Barrier film are stored with a particularly strong layer structure, which allows safe and long-term stable storage of the fluid.
  • the presented membrane has the advantage that the stamp unit can always remain separated from the fluid and thus due to the hygienic
  • the fluid chamber may, for example, have a volume less than 30 ml, 20 ml, 10 ml, 5 ml, 1 ml or less than 0.1 ml.
  • a mechanically movable punch unit has the advantage that the release of the reagents does not necessarily have to be gravity-driven.
  • the stamp unit can displace the volume of reagent through the membrane into other chambers or channels, wherein the entire structure can be arbitrarily aligned, for example at 0 ° inclination, but also under, for example, 30 °, 45 ° or 60 ° tilt. This offers advantages in handling and processing of the LOC cartridge.
  • the fluid may be received in the fluid chamber and held in the fluid chamber by a barrier film closing the fluid chamber.
  • the barrier film may be formed to be opened by the stamp unit, for example, a channel or a
  • Fluidic transfer chamber to connect with the fluid chamber.
  • the fluid such as a reagent
  • the fluid can be stored safely in the fluid chamber and can be released selectively only when required by introducing the stamp unit into the barrier film.
  • the fluid can be arranged in an insertion container, which is received by the fluid chamber, wherein the
  • the insert container may be flexible or plastically shaped.
  • the insert may be formed so that it can be accommodated accurately in the fluid chamber, the material of the insert can thereby a higher
  • the fluid may also be arranged in a blister which is received by the fluid chamber, wherein the blister is a volume of the fluid chamber in the
  • a blister can be formed from one or more sealing films whose edges can be connected by tight sealing seams and a cost-effective alternative for one
  • a blister of an elastic material can be selected from
  • the diameter of the punch opening can be any diameter of the punch opening.
  • a stamp tip of the stamp unit can advantageously be formed so that the fluid is displaced in the fluid chamber in the direction of a channel.
  • a simple method is to stamp the stamp with a defined one
  • Feed rate typically 1 mm / min to 50 mm / min
  • the stamp unit moves in the first step until the first tear of the barrier film.
  • the stamp unit retracts a few millimeters to allow the reagent to escape through the resulting cracks.
  • the stamp unit moves to the bottom of the fluid chamber for a complete displacement of the liquid in the
  • Stamp unit conceivable to allow optimal and efficient reagents release in the rearrangement chamber.
  • the device may have a channel which extends on a chamber substrate side facing the membrane and is fluidly connected to the fluid chamber.
  • the channel can open into the fluid chamber.
  • Rearrangement chamber be arranged for safe collection of the fluid.
  • another fluid may be upstream, for mixing with the fluid after the release of the fluid can be determined.
  • such a rearrangement chamber can also open directly into the fluid chamber.
  • the diameter of the punch opening may be smaller than half the diameter of the fluid chamber opening.
  • the punch opening may be arranged adjacent to the channel. A relatively small one
  • Stamp opening can accommodate a correspondingly small stamp unit, which in turn can make room for example, a further punch opening and / or for a vent on the side of the fluid chamber opening available.
  • the channel can be arranged at a certain angle of inclination of the device so that the fluid can flow off or be sucked off in a gravity-directed direction.
  • the vent opening can be arranged, for example, over the die opening, from where
  • an inflow of ambient air through the vent opening can promote the outflow of the fluid.
  • the channel may have a channel extension and the lid substrate a
  • vent opening which opens into the channel extension, wherein the punch opening can be arranged between the vent opening and the channel, wherein the membrane does not span the vent opening.
  • An imaginary vent opening above the channel with connection to the channel can favor, for example, due to an established connection to the ambient air, a drainage of the fluid through the channel.
  • the lid substrate may have a vent opening which fits into the
  • Fluid chamber opens, the punch opening between the
  • Vent and the channel can be arranged, wherein the membrane can span the vent.
  • the apparatus may further comprise a further punch unit adapted to retract into the fluid chamber through the vent opening to deflect the diaphragm into the fluid chamber to allow inflow of further fluid into the fluid chamber.
  • a proposed approach allows the opening of a fluid chamber sealed by the barrier film, for example, and / or the opening of a blister disposed in the fluid chamber at two different locations. The approach is also the basic requirement for a possibly additional air duct with connection to the vent and the
  • Fluid chamber which can allow an inflow of another fluid into the fluid chamber.
  • Chamber substrate and the membrane, an intermediate substrate is arranged, which has a die opening continuing further punch opening and a vent opening continuing further vent opening and is formed to produce a transverse to the vent opening and opening into the further vent opening air duct.
  • the air duct may extend in a direction facing away from the channel.
  • An imaginary air duct can create a negative pressure in the
  • the channel can run between the membrane and the intermediate substrate and open into the punch opening. This approach allows a favorable arrangement of the channel when an intermediate substrate is placed in the device.
  • a diameter of the fluid chamber opening may be the punch opening
  • the fluid chamber may have a second punch opening which corresponds to a diameter of the further vent opening.
  • the chamber substrate can be formed more stable.
  • a possibly arranged barrier film for closing the fluid chamber may, according to this embodiment, for example be glued along an inside of the fluid chamber facing the fluid chamber opening side and / or arranged between the chamber substrate and the intermediate substrate. If the barrier film between the
  • Chamber substrate and the intermediate substrate is arranged, the
  • a fluid chamber bottom opposite the fluid chamber opening may be formed by a further barrier film. Due to the above-described increased stability of the chamber substrate on the fluid chamber opening side, the opposite fluid chamber bottom of the chamber substrate can only be formed by the further barrier film.
  • the chamber substrate may for example be previously filled by the side of the fluid chamber floor and
  • Barrier film in the direction of the punch movement be balanced.
  • the formation of an air path during active suction of the fluid is completely excluded, since the bottom of the fluidic chamber over the entire surface with the
  • a method for manufacturing a microfluidic device comprises the following steps:
  • Fluid chamber opening of the fluid chamber arranged punch opening; Disposing a flexible membrane between the chamber substrate and the lid substrate, the membrane spanning the die opening and the fluid chamber;
  • a method of operating a said microfluidic device comprises the following step:
  • FIG. 1 is a schematic cross-sectional view of a microfluidic device according to an embodiment
  • FIG. 2 is a cross-sectional view of a microfluidic device according to an embodiment
  • 3 is a cross-sectional view of a microfluidic device according to an embodiment
  • 4 is a cross-sectional view of a microfluidic device according to an embodiment
  • FIG. 5 is a cross-sectional view of a microfluidic device with insertion container according to an embodiment
  • FIG. 6 is a perspective view of a chamber substrate having a plurality of fluid chambers according to an embodiment
  • FIG. 7 is a cross-sectional view of a microfluidic device with a vent opening according to one embodiment
  • FIG. 8 is a cross-sectional view of a microfluidic device with a vent opening according to one embodiment
  • FIG. 9 is a cross-sectional view of a microfluidic device with an intermediate substrate and a further stamping device according to a
  • FIG. 10 is a cross-sectional view of a microfluidic device with an intermediate substrate and a further stamping device according to a
  • FIG. 11 is a cross-sectional view of a microfluidic device with a further barrier film according to an exemplary embodiment
  • FIG. 12 is a cross-sectional view of a microfluidic device with a further barrier film according to an embodiment
  • FIG. 13 is a cross-sectional view of a microfluidic device with a further barrier film according to an exemplary embodiment
  • 14 shows a cross-sectional view of a microfluidic device with a further barrier film according to an exemplary embodiment
  • 15 is a perspective view of a device having a plurality of fluid chambers according to an embodiment
  • 16 is a flowchart of a method of manufacturing a
  • microfluidic device according to an embodiment
  • 17 is a flowchart of a method for operating a
  • Microfluidic device according to one embodiment.
  • the following description of favorable embodiments of the present invention are for the in the various figures.
  • FIG. 1 shows a schematic cross section of a microfluidic device 100 according to one exemplary embodiment.
  • the device 100 comprises a chamber substrate 105 with a fluid chamber 110 and a cover substrate 115 arranged adjacent to the chamber substrate 105.
  • the cover substrate 115 is disposed between the chamber substrate 105 and a stamp unit 120
  • the lid substrate 115 has a punch opening 125 and the fluid chamber 110 has a fluid chamber opening 130. Between the
  • Chamber substrate 105 and the cover substrate 115 a flexible membrane 135 is arranged, which spans the fluid chamber opening 130 and the adjacent arranged punch opening 125.
  • a flexible membrane 135 is arranged, which spans the fluid chamber opening 130 and the adjacent arranged punch opening 125.
  • a facing side of the membrane 135 optionally extends a channel 140 which is fluidly connected to the fluid chamber 110.
  • the channel 140 extends on a side of the cover substrate 115 facing the membrane 135. The channel is then penetrated via a through hole in the cover
  • Membrane 135 fluidly connected to the fluid chamber 110.
  • the diameter of the punch opening 125 in this variant is advantageously smaller than the diameter of the fluid chamber opening 130, so that the channel 140 in the
  • the stamp unit 120 is shaped to retract into the fluid chamber 110 through the lid substrate 115.
  • the stamp unit 120 according to this exemplary embodiment has, on a side facing the cover substrate 115, a rounded stamp tip which corresponds to an internal geometry of the fluid chamber 110. As the stamp unit 120 retracts into the fluid chamber, the diaphragm 135 is deflected from the rounded punch tip of the stamp unit 120 into the fluid chamber 110.
  • the stamp unit 120 is made of the
  • Fluid chamber moves back, takes the diaphragm 135 according to a
  • Embodiment its original position, which is shown in Fig. 1, a again.
  • the membrane 135 remains at least partially deformed after retraction of the stamp unit 120.
  • a fluid may be contained in a blister in the fluid chamber 110.
  • the fluid may also be filled directly into the fluid chamber, wherein the fluid chamber opening 130 may then be closed by a barrier film, so that the fluid can not flow into the channel 140.
  • the fluid may alternatively be accommodated in an insert container accommodated in the fluid chamber 110, wherein the insert container may be closed by the barrier film.
  • the microfluidic device 100 is shown in FIG. 1 in a position with a 0 ° inclination.
  • FIG. 2 shows a schematic cross section of a microfluidic device 100 according to one exemplary embodiment. This may be the microfluidic device 100 described with reference to FIG. 1, with which
  • Device 100 has a transfer chamber 210 with a valve 215.
  • the fluid 205 is received directly in the fluid chamber 110 according to this embodiment, the barrier film 200 closing the fluid chamber opening, whereby the fluid 205 is securely held in the fluid chamber 110.
  • the fluid 205 does not completely fill the fluid chamber 110, it may be another content such as gas or air in the fluid chamber 110 may be arranged.
  • the fluid 205 may also be received in a blister disposed in the fluid chamber 110.
  • the rearrangement chamber 210 is according to this embodiment with the
  • Channel 140 is connected, wherein the channel 140 between the fluid chamber 110 and the rearrangement chamber 210 is arranged.
  • the rearrangement chamber 210 is arranged below the fluid chamber 205 according to this embodiment.
  • the rearrangement chamber 210 has the valve 215 on a side facing away from the fluid chamber 110.
  • the LOC system 100 in the form of the microfluidic device 100 can consist of polymer-based multilayer structures in the form of the chamber substrate 105 and the cover substrate 115.
  • Cover substrate 115 comprise polymer-based substrates in which cavities in the form of fluid chamber 205 and / or channel 140 are arranged.
  • a storage of liquids 205, hereinafter referred to as fluids 205, with small volumes below 1 ml is only conditionally possible in the fluid chamber 110 of the chamber substrate 105, since most plastics do not have sufficient barrier properties for long-term stable storage (PC, PA, US Pat. PS, PMMA).
  • the fluid 205 such as a reagent
  • Valves 215, and when needed (on-demand) can be provided, which implies additional requirements for storage concepts. Therefore, in order to store the fluid 205 in a stable manner, according to this embodiment, a separate container, such as a blister pack or a tubular bag in the form of the blister, can be accommodated in the fluid chamber 110, whereby the
  • Chamber substrate 105 is not limited in its choice of materials. This implies requirements on the manufacturing process due to handling and pick-and-place processes.
  • the chamber substrate 105 is made of plastics having high barrier properties, such as COP, COC, PP, PE or PET, allowing for safe fluid or reagent pre-storage in the chamber substrate 105 allows.
  • a concept based on such plastics can be integrated directly into the material system of the fluid chamber 110 or through a joining process
  • bonding, welding, or clamping fluidly connected to the fluid chamber 110.
  • the device 100 shown has, according to one exemplary embodiment, a polymer layer structure consisting of at least two polymer substrates, namely the chamber substrate 105 and the cover substrate 115, which are separated by the flexible membrane 135.
  • an upstream fluid 205 is arranged, for example in the blister, in a sealed injection-molded insert container or in an opening in the form of the one which is closed by the or more barrier films 200
  • Fluid chamber 110 within the chamber substrate 105 At least one punch unit 120, for example a plunger is used, which can penetrate through at least one opening in the form of the punch opening 125 in the lid substrate 115 by relative movement in the LOC in the form of the fluid chamber 110 , 3 shows a schematic cross section of a microfluidic device
  • stamp unit 120 is inserted into the stamp opening and the barrier film 200 is opened by the stamp unit 120.
  • the flexible membrane 135 is deflected by the stamp unit 120 without tearing.
  • the barrier film 200 is caused by the
  • Stamp unit 120 exerted a force, which leads to the tearing of a sealing foil of the arranged for example in the fluid chamber 110 blister and / or the barrier film 135.
  • FIG. 4 shows a schematic cross section of a microfluidic device 100 according to one exemplary embodiment. This may be the device 100 described with reference to FIG. 3, with the difference that according to this embodiment, the stamp unit 120 is completely in the Fluid chamber 110 is inserted and the fluid 205 is displaced into the rearrangement chamber 210.
  • the fluid 205 is either in a supply chamber 210, previously referred to as rearrangement chamber 210, displaced or
  • Predetermined breaking points in, for example, the barrier film by z Predetermined breaking points in, for example, the barrier film by z.
  • the stamp unit 120 safely very large forces on the barrier film or the sealing film. It eliminates an associated additional manufacturing step.
  • barrier films can be used, which have a strong layer structure and / or are formed very thick, for. B. by PP and metal layers, in particular
  • the stamping unit 120 advantageously does not come into contact with the upstream fluid 205 during the entire release process.
  • the flexible membrane 135 enables complete separation from the mechanical actuation mechanism in the form of the stamp unit 120 and the fluid 125 in the fluid chamber 110 a
  • Actuator be installed and need not together with the example used blister or insert in the form of
  • Disposal container be disposed of. As a result, both the costs for the device 100 and the costs for a drive unit remain low, since this requires no additional mechanism in order to grip a punch unit 120 accommodated on the device 100.
  • the chamber substrate 105 may be made of plastics having high barrier properties, e.g. B. PP,
  • PE polystyrene
  • COC polystyrene
  • COP polystyrene
  • additional coatings such as Al, AI203, SiO, the requirements for long-term storage of fluids such as 205
  • the chamber substrate 105 is connected to the flexible
  • the cover substrate 135 has at least one opening in the form of the punch opening 125. For the release of the fluid 205, the stamp unit 120 moves through the
  • Stamp opening 125 deflects the flexible membrane 135 without this breaks, and breaks up the barrier film.
  • the fluid 205 is displaced via the transfer channel in the form of the channel 140 into the rearrangement chamber 210 and is ready for further microfluidic processes.
  • the fluid 205 may be sucked when opening the valve 215 by a negative pressure in a behind it located microfluidic network.
  • the flexible membrane 135 allows a complete fluidic separation between the fluidics in the
  • Chamber substrate 105 with all participating fluids 205 and the mechanical
  • stamp unit 120 is preferably formed so that it displaces as large a volume as possible from the fluid chamber 110, without sealing at the edges of the fluid chamber 110 so that the fluid 205 no longer enters the rearrangement chamber 210. This is best achieved if the shape of the stamp unit 120 is the inverse of the
  • Fluid chamber 110 corresponds to, but for example, a few hundred
  • punch unit 120 For punch unit 120, according to an alternative exemplary embodiment, any desired geometries, dimensions and shapes are conceivable
  • FIG. 5 shows a schematic cross section of a microfluidic device 100 with insertion container 500 according to one exemplary embodiment. This may be the device 100 described with reference to FIG. 2, with the difference that, according to this exemplary embodiment, the insert container 500 having a cavity 505 is received by the fluid chamber 110. The fluid 205 is disposed in the cavity 505 of the loading container 500.
  • the fluid chamber 110 has a rectangular shaped cross-section to accommodate the insertion tray 500, which also has a rectangular cross-section according to this embodiment.
  • the insert container 500 can be inserted with a precise fit or approximately exact fit into the fluid chamber 110. Due to the separate insert container, the channel 140 or the wall between the fluid chamber 110 and the rearrangement chamber 210 can be completely eliminated in an advantageous and space-saving embodiment.
  • the fluid chamber 110 and the rearrangement chamber 210 are combined into one chamber, or in other words, the rearrangement chamber 210 and the inserter bin 500, also referred to as an inserter, are not separated.
  • the wall between the fluid chamber 110 and the rearrangement chamber 210 may be reduced to a small indentation, as a ridge for holding the insert container 500 in the fluid chamber 110, or forming the channel 140
  • Insert container 500 integrated into the chamber substrate 105.
  • the insert container 500 ideally has higher barrier properties than the surrounding chamber substrate 105.
  • This insert container 500 contains the fluid 205 and is sealed to the barrier film 200.
  • the release of the fluid 205 is identical, as described in the preceding figures.
  • the material selection of the chamber substrate 105 remains independent of the requirements of the long-term stable reagent pre-storage according to this embodiment.
  • the insert container 500 can be glued, clamped, welded or integrated by other joining methods.
  • the loading container 500 may also be easily inserted into a suitably shaped receiving chamber in the form of the fluid chamber 110 in the Chamber substrate 105 has been inserted.
  • properly formed it is meant here that the fluid chamber 110 closely encloses the loading container 500. This has the advantage that the dead volume of the structure is minimized and slipping of the loading container 500 is avoided.
  • the loading container 500 has according to this embodiment, the cavity 505 for receiving the fluid 205, but according to an alternative embodiment, also have a plurality of such cavities 505, the z. B. each filled with different fluids 205. These cavities 505 may be arranged in the form of a bar or only in certain places, for. B. at the top, comb-like with each other. This has the advantage that in the fluid chamber 110 separating elements, for. As walls, may be arranged between the various fluids 205, which can reliably prevent mixing of the fluids 205. Furthermore, the deflection of the flexible membrane 135 by the movable plunger unit causes the fluidic path to be sealed at the connection recesses 605 shown in FIG. 6 in order to be able to reliably prevent mixing of the fluids 205 stored in separate fluid chambers 110 after their release.
  • FIG. 6 shows a perspective view of a chamber substrate 105 with a plurality of fluid chambers 110 according to one exemplary embodiment. This may be the chamber substrate 105 described with reference to FIG. 5, with the difference that no fluid in the cavities 505 of FIG.
  • the chamber substrate 105 has four fluid chambers 110 arranged next to one another.
  • the number of fluid chambers 110 is merely exemplary, so that more or fewer than four fluid chambers 110 may be provided.
  • Below the fluid chambers 110 four rearrangement chambers 210 are arranged according to this embodiment.
  • Insert container 500 is formed according to this embodiment as a four cavities 505 comprehensive insert container 500, wherein one of the cavities 505 is received in each case in one of the four fluid chambers 110. According to this embodiment, the insertion tray 500 in a
  • Rearrangement chambers 210 remote area between the cavities 505th three connecting webs 600 on.
  • the chamber substrate 105 has in the region corresponding to the connecting webs 600 three connecting recesses 605 for receiving the connecting webs 600.
  • 7 shows a cross section of a microfluidic device 100 with a
  • Vent opening 700 according to one embodiment. This may be the device 100 described with reference to FIG. 3, with the difference that the punch opening 125 is smaller than in FIG. 3 and arranged in the region of the channel 140, and that the channel 140 has a
  • the channel extension 705 extends according to this embodiment in a direction away from the channel 140, the punch opening 125 is arranged between the channel extension 705 and the channel 140.
  • Channel extension 705 is also disposed between the fluid chamber 110 and the diaphragm 135.
  • the channel extension 705 extends according to this
  • the vent opening 700 extends on a side facing away from the stamp opening 100 side
  • Fluid chamber 110 according to this embodiment in parallel to the
  • a blister is embedded in the chamber substrate 105 in such a way that two sealed sealing areas 715 of the blister rest on a surface provided in the chamber substrate 105 and can be glued there, for example.
  • the lid substrate 115 has the vent opening 700, under which the membrane 135 is opened on.
  • the punch opening 125 is closed by the membrane 135.
  • Stamp unit 120 may enter the assembly through die opening 125
  • FIG. 8 shows a cross-section of a microfluidic device 100 with a vent opening 700 according to one exemplary embodiment.
  • This can be the device 100 described with reference to FIG. 7, with the difference that the stamp unit 120 according to this exemplary embodiment is led out of the device 100 again, as a result of which the diaphragm 135 in the region of the stamp opening 125 is retracted and the fluid 205 flows into the channel 140.
  • FIG. 9 shows a cross-section of a microfluidic device 100 with an intermediate substrate 900 and a further stamp unit 905 according to one exemplary embodiment. This may be the device 100 described with reference to FIG. 7, with the difference that the channel 140 has no channel extension and the vent opening 700 is arranged in a region of the height 710.
  • the intermediate substrate 900 is between the
  • Chamber substrate 105 and the lid substrate 115 arranged.
  • Intermediate substrate 900 has a further vent opening 910 and a further punch opening 915.
  • the further punch opening 915 continues the punch opening 125 and the further vent opening 910 continues the vent opening 700.
  • the intermediate substrate 900 is formed to be one in the other
  • Venting channel 910 opening air duct 920 to form.
  • the air channel 920 is arranged transversely to the further venting channel 910 on a side of the membrane 135 facing the fluid chamber 110.
  • the air duct 920 extends in a direction away from the punch opening 125.
  • Stamp unit 905 is according to this embodiment by the
  • the further stamping device 905 opens according to this embodiment, the barrier film 200 and / or the sealing film of the example recorded blister in a region in which the fluid 205 is not arranged in the position shown in Fig. 9. According to this Embodiment, the two sealing areas 715 between the
  • Chamber substrate 105 and the intermediate substrate 900 arranged.
  • a second plunger in the form of the further stamp unit 905 is used to push a second opening into the barrier film 200 and / or the sealing film of a blister. Since blisters are not completely filled due to their production, it is particularly advantageous to make the second opening at a location of the stickpack, ie the blister, behind which there is air or gas.
  • This embodiment has the particular advantage that the blister can be ventilated via the air duct 920 and thus a particularly high emptying efficiency is achieved.
  • the fluid 205 is directly in the
  • Fluid chamber 110 upstream, which is sealed by the barrier film 200 which is sealed by the barrier film 200.
  • the arrangement is chosen so that the barrier film 200 in the
  • Sealing areas 715 is connected flat with the chamber substrate 105.
  • An example polymeric sealing layer of the barrier film 200 has
  • Air duct 920 ensures. It is also particularly advantageous to design the further stamping unit 905 so that it penetrates the barrier film 200 in front of the stamping unit 120. In this way, it is ensured that any overpressure occurring within the fluid chamber 110 can escape before the stamp unit 120 penetrates. With different execution The stamp units 120, 905 can continue to be a simultaneous actuation.
  • FIG. 10 shows a cross-section of a microfluidic device 100 with an intermediate substrate 900 and a further stamp unit 905 according to one
  • Embodiment. may be the device 100 described with reference to FIG. 9, with the difference that the stamping device 120 and the further stamping device 905 according to this embodiment are led out of the device 100 again, whereby the membrane 135 in the region of the stamp opening 125 and is withdrawn in the region of the vent opening 700, whereby the fluid 205 flows into the channel 140 and another fluid flows from the environment of the device 100 through the air channel 920 into the fluid chamber 110.
  • This embodiment has the particular advantage that after tearing the barrier film and retracting the
  • stamping units the reagent can be actively sucked through the channel 140, at the same time the risk of the formation of an air path up to the vent 700 (as in FIG 7 and FIG 8) is reduced to a minimum.
  • the emergence of an air path for venting 700 would in the worst case, an active suction of the released reagent is no longer possible.
  • FIG. 11 shows a cross-section of a microfluidic device 100 with a further barrier foil 1100 according to one exemplary embodiment. This may be the device 100 described with reference to FIG. 9, with the difference that the fluid chamber bottom is formed by the further barrier foil 1100, and that the fluid chamber 110 has a second punch opening 1105.
  • the fluid chamber opening 130 according to this embodiment has a diameter corresponding to the die opening 125.
  • Fluid chamber opening 130 is arranged on a side of fluid chamber 110 facing channel 140.
  • the second fluid chamber opening 1105 has a diameter corresponding to the vent opening 700.
  • Fluid chamber opening 1105 is fluidly connected to the further vent opening 910.
  • the fluid chamber 110 has a rectangular cross section.
  • the chamber substrate 105 according to this embodiment extends over the punch opening side including the fluid chamber opening 130 and the second punch opening 1105.
  • the Barrier film 200 is according to this embodiment between the
  • the barrier film 200 spans the fluid chamber opening 130 and the second punch opening 1105.
  • the barrier film 200 according to this exemplary embodiment is in the region of the fluid chamber opening 130 and in the region of the second one
  • the chamber substrate 105 is sealed on both sides with the barrier films 200, 1100. The sealed on both sides
  • Chamber substrate 105 with integrated fluid 205 is attached via a joining step, for example by gluing and / or welding and / or clamping on the multi-layer structure of the device 100 that the punch opening 125 and the vent opening 700 on an axis with the openings in the form of the fluid chamber opening 130th and the second fluid chamber opening 1105.
  • a joining step for example by gluing and / or welding and / or clamping on the multi-layer structure of the device 100 that the punch opening 125 and the vent opening 700 on an axis with the openings in the form of the fluid chamber opening 130th and the second fluid chamber opening 1105.
  • the mechanical stamp devices 120, 905 can be moved back and the fluid 205 ready to be actively attracted, for example, in the fluidic channel 140.
  • FIG. 12 shows a cross-section of a microfluidic device 100 with the further barrier foil 1100 according to one exemplary embodiment.
  • This may be the device 100 described with reference to FIG. 11, with which Difference in that the stamping device 120 and the further stamping device 905 are again led out of the device 100 according to this embodiment, whereby the diaphragm 135 in the region of the punch opening 125 and in the region of the vent opening 700 is retracted, whereby the fluid 205 flows into the channel 140 and the further fluid from the environment of the device 100 flows through the air channel 920 into the fluid chamber 110.
  • FIG. 13 shows a cross section of a microfluidic device 100 with the further barrier foil 1100 according to one exemplary embodiment.
  • This may be the device 100 described with reference to FIG. 11, with the difference that the barrier film 200 according to this exemplary embodiment is arranged on an inner side of the fluid chamber 110 such that it spans the fluid chamber opening 130 and the second fluid chamber opening 1105.
  • the barrier film 200 is according to this embodiment by the
  • Stamp unit 120 and the other stamp unit 905 opened.
  • the barrier film 200 is sealed on the inside of the fluid chamber 110, so that no air path between the channel 140 and the air channel 920 can form here as well.
  • the chamber substrate 105 is directly connected to the multi-layer structure of the device 100, that is the
  • the barrier film 200 may according to an alternative embodiment in the
  • Chamber substrate 105 in the region of the fluid chamber opening 130 and the second fluid chamber opening 1105 be sunk locally.
  • the required polymer substrates ie the starting material, and the required structures in the polymer substrates can be produced for example by milling, injection molding, hot stamping, deep drawing and / or laser structuring.
  • Materials for the chamber substrate 105 and the lid substrate 115 may be thermoplastics, e.g. PC, PA, PS, PP, PE, PMMA, COP, COC.
  • Materials for the tray 500 may be thermoplastics, for. PC, PA, PS, PP, PE, PMMA, COP, COC and / or glass.
  • Materials for the stamping device 120 and the further stamping device 905 may include thermoplastics, for. PC, PA, PS, PP, PE, PMMA, COP, COC, and / or metals such as steel or brass, as well as elastomers.
  • Coatings of reservoirs such as fluid chamber 110, may be made with Al, Al 2 O 3, SiO 2.
  • Materials for membrane 135 may be elastomer, thermoplastic elastomer (TPU, TPS), thermoplastics, or heat sealable films.
  • barrier film 200 and sealing film can be commercially available
  • Polymer composite films are used from polymeric sealing and protective layers, for. As PE, PP, PA, PET and as a barrier layer, as a rule
  • the thickness of the chamber substrate 105 and the cover substrate 115 can be from 0.5 to
  • the thickness of the membrane 135 may be 5 to 300 ⁇ .
  • a thickness of the membrane 135 In a multilayer structure of the barrier films 200, a thickness of the
  • Barrier layer (i.d. R. Alu) 5 ⁇ to 500 ⁇ , a thickness of the polymer layer 5 ⁇ to 500 ⁇ , a thickness of the protective layer 5 ⁇ to 500 ⁇ and an elastic layer on the sealing film 50 ⁇ amount to 2 mm.
  • the volume of the blister can be 100 to 10000 ⁇ . Cuboid shapes, cylindrical shapes, cubic shapes and any other suitable shapes and geometries are suitable as forms for the stamp devices 120, 905.
  • FIG. 14 shows a cross section of a microfluidic device 100 with the further barrier foil 1100 according to one exemplary embodiment. This may be the device 100 described with reference to FIG. 12, with the difference that the barrier film 200 according to this exemplary embodiment is arranged on the inside of the fluid chamber 110.
  • FIG. 15 shows a perspective view of a device 100 with a plurality of fluid chambers 110 according to one exemplary embodiment. This may be one of the devices 100 described with reference to FIGS. 11 to 14. According to this exemplary embodiment, the chamber substrate 105 has four fluid chambers 110 arranged adjacent to one another.
  • FIG. 16 shows a flowchart of a method 1600 for producing a microfluidic device according to an exemplary embodiment. This may be one of the devices described with reference to FIGS. 1 to 5.
  • a chamber substrate having a fluid chamber for receiving a fluid is provided.
  • a flexible membrane is placed between the chamber substrate and the lid substrate, with the membrane spanning the die opening and the fluid chamber.
  • a channel extending on a side of the membrane facing the chamber substrate is produced which is fluidically connected to the fluid chamber.
  • Generation 1620 may be performed at a suitable time of the method, for example, prior to the step of providing 1610 the lid substrate, so that in the providing step 1610, the lid substrate having the channel may already be provided.
  • a stamp unit is arranged to be formed is to retract into the fluid chamber through the die opening to deflect the membrane into the fluid chamber to allow the fluid to flow out of the fluid chamber into the channel when the fluid in the fluid chamber
  • FIG. 17 shows a flowchart of a method 1700 for operating a microfluidic device according to one exemplary embodiment. This may be one of the devices described with reference to FIGS. 1 to 5.
  • a stamper unit is retracted into the fluid chamber through the stamper opening to deflect the membrane into the fluid chamber to allow the fluid to flow out of the fluid chamber into the channel when the fluid is received in the fluid chamber.
  • the force is exerted by a stamp unit which is actuated in an optional step 1710. The actuation can be done, for example, using a mechanical or
  • electromechanical actuator are executed.
  • an exemplary embodiment comprises a "and / or" link between a first feature and a second feature, then this is to be read so that the embodiment according to one embodiment, both the first feature and the second feature and according to another embodiment either only first feature or only the second feature.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
  • Micromachines (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)
  • Reciprocating Pumps (AREA)

Abstract

L'invention concerne un dispositif microfluidique (100). Le dispositif (100) comporte un substrat de chambre (105) comprenant une chambre à fluide (110) destinée à contenir un fluide, un substrat supérieur (115) doté d'une ouverture à poinçon (125), l'ouverture à poinçon (125) étant disposée en regard d'une ouverture (130) de la chambre à fluide (110), une membrane souple (135) qui est disposée entre le substrat de chambre (105) et le substrat supérieur (115) et qui recouvre l'ouverture à poinçon (125) et l'ouverture de chambre à fluide (130), ainsi qu'une unité poinçon (125) qui est conçue pour entrer à travers l'ouverture à poinçon (125) dans la chambre à fluide (110), afin de dévier la membrane (135) dans la chambre à fluide (110), afin de permettre un écoulement du fluide hors de la chambre à fluide (110) lorsque le fluide est contenu dans la chambre à fluide (110).
EP16808605.6A 2015-12-22 2016-12-06 Dispositif microfluidique et procédé de fonctionnement d'un dispositif microfluidique Active EP3393661B1 (fr)

Applications Claiming Priority (2)

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DE102015226417.3A DE102015226417A1 (de) 2015-12-22 2015-12-22 Mikrofluidische Vorrichtung, Verfahren zum Herstellen und Verfahren zum Betreiben einer mikrofluidischen Vorrichtung
PCT/EP2016/079866 WO2017108387A1 (fr) 2015-12-22 2016-12-06 Dispositif microfluidique, et procédé de production ainsi que procédé de fonctionnement d'un dispositif microfluidique

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EP3393661A1 true EP3393661A1 (fr) 2018-10-31
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EP (1) EP3393661B1 (fr)
KR (1) KR20180093254A (fr)
CN (1) CN108472648B (fr)
DE (1) DE102015226417A1 (fr)
ES (1) ES2766528T3 (fr)
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DE102017206489A1 (de) * 2017-04-18 2018-10-18 Robert Bosch Gmbh Vorrichtung und Verfahren für ein mikrofluidisches System zum Analysieren einer Probe
DE102018206066A1 (de) 2018-04-20 2019-10-24 Robert Bosch Gmbh Vorrichtung zum Ankoppeln einer Kartusche für ein Chiplabor-Analysegerät, Chiplabor-Analysegerät und Verfahren zum Ankoppeln einer Kartusche für ein Chiplabor-Analysegerät
ES2928249T3 (es) * 2018-09-11 2022-11-16 Hoffmann La Roche Cartucho con envase para líquido
CN111203291B (zh) * 2020-04-18 2020-07-31 博奥生物集团有限公司 一种液体存储控释装置以及生物检测芯片
EP3912721A1 (fr) * 2020-05-22 2021-11-24 Thinxxs Microtechnology Ag Cellule d'écoulement comprenant un dispositif de blocage à rupture
CN114100702B (zh) * 2020-08-27 2023-05-30 京东方科技集团股份有限公司 一种检测芯片及其制备方法、使用方法、检测装置
EP4129481A1 (fr) 2021-08-06 2023-02-08 Microliquid SL Soupape monolithique normalement fermée pour applications microfluidiques
DE102022207706A1 (de) 2022-07-27 2024-02-01 Robert Bosch Gesellschaft mit beschränkter Haftung Analysegerät zum Analysieren einer in einer Kartusche enthaltenen Probe und Verfahren zum Betreiben eines Analysegerätes

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CA2610875A1 (fr) 2005-06-06 2006-12-14 Decision Biomarkers, Inc. Epreuves fondees sur des agencements d'ecoulement liquide
US8741230B2 (en) * 2006-03-24 2014-06-03 Theranos, Inc. Systems and methods of sample processing and fluid control in a fluidic system
CN102105227B (zh) * 2008-06-19 2013-11-06 贝林格尔英格海姆米克罗帕茨有限责任公司 定量供应流体的容器
DE102009045685A1 (de) * 2009-10-14 2011-04-21 Robert Bosch Gmbh Mikrofluidischer Chip
DE102010001412A1 (de) 2010-02-01 2011-08-04 Robert Bosch GmbH, 70469 Mikrofluidisches Bauelement zur Handhabung eines Fluids und mikrofluidischer Chip
DE102012212650A1 (de) * 2012-07-19 2014-01-23 Robert Bosch Gmbh Mikrofluidische Lagerungsvorrichtung zum Vorlagern eines Fluids, Verfahren zu dessen Herstellung und eine Verwendung derselben
DE102012222719A1 (de) * 2012-12-11 2014-06-12 Robert Bosch Gmbh Folienbeutel zum Bevorraten eines Fluids und Vorrichtung zum Bereitstellen eines Fluids
EP2905079A1 (fr) * 2014-02-10 2015-08-12 Robert Bosch Gmbh Dispositif de stockage préalable d'un fluide dans un système micro-fluidique, procédé de fonctionnement et procédé de fabrication d'un tel dispositif

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CN108472648B (zh) 2020-12-22
ES2766528T3 (es) 2020-06-12
WO2017108387A1 (fr) 2017-06-29
US11065621B2 (en) 2021-07-20
US20210162403A1 (en) 2021-06-03
DE102015226417A1 (de) 2017-06-22
EP3393661B1 (fr) 2019-11-06
CN108472648A (zh) 2018-08-31
KR20180093254A (ko) 2018-08-21

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