[go: up one dir, main page]

WO2025003467A1 - Vanne synchronisée - Google Patents

Vanne synchronisée Download PDF

Info

Publication number
WO2025003467A1
WO2025003467A1 PCT/EP2024/068360 EP2024068360W WO2025003467A1 WO 2025003467 A1 WO2025003467 A1 WO 2025003467A1 EP 2024068360 W EP2024068360 W EP 2024068360W WO 2025003467 A1 WO2025003467 A1 WO 2025003467A1
Authority
WO
WIPO (PCT)
Prior art keywords
liquid
microfluidic device
fluid conduit
membrane
chamber
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.)
Pending
Application number
PCT/EP2024/068360
Other languages
English (en)
Inventor
Jeroen Lammertyn
Dries VLOEMANS
Francesco DAL DOSSO
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.)
Katholieke Universiteit Leuven
Original Assignee
Katholieke Universiteit Leuven
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 Katholieke Universiteit Leuven filed Critical Katholieke Universiteit Leuven
Publication of WO2025003467A1 publication Critical patent/WO2025003467A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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
    • B01L3/502723—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
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502738—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by integrated valves
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K99/0001—Microvalves
    • F16K99/0003—Constructional types of microvalves; Details of the cutting-off member
    • F16K99/0032—Constructional types of microvalves; Details of the cutting-off member using phase transition or influencing viscosity
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0605—Metering of fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • 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
    • B01L2300/00—Additional constructional details
    • B01L2300/16—Surface properties and coatings
    • B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
    • 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
    • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
    • 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
    • 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

Definitions

  • the present invention relates to a microfluidic device comprising a vent, which opens upon dissolution of an air-impermeable and water-soluble membrane.
  • the invention further relates to the use of the device of the invention for liquid partitioning.
  • the same device When the same device is used to both collect the sample (e.g., via microneedles) directly from a living organism (e.g., human body, animal or plant) and further process it downstream in the system, it is necessary to decouple the extracted sample liquid from the unlimited sample source (e.g., represented by the body bloodstream) in the living organism.
  • a living organism e.g., human body, animal or plant
  • the filtered and unfiltered liquid sample fractions e.g., plasma and blood cell fractions during plasmapheresis
  • various types of microfluidic valving methods such as mechanical valves with moving elements, valving via heating and the like exist.
  • most of these valves are very complex which make them too expensive for usage in disposable microfluidic systems and/or require user intervention to decouple fluidically the isolated volume of liquid from the larger liquid volume it is isolated from.
  • US2016/279634 discloses a microfluidic device comprising an inlet and a capillary channel, i.e., fluid conduit, in connection therewith.
  • a dissolvable valve is provided comprising a dissolvable membrane having a first side oriented towards the capillary channel, and capillary means connected to the second side of the dissolvable membrane such that when the membrane is dissolved by the liquid, liquid is transported through the valve to the second side of the membrane by capillary action.
  • AU2014280043 discloses a microfluidic device comprising a sacrificial valve, e.g., water-soluble membrane, whose opening is triggered by the opening of a second valve, causing a retraction of a fluid spacer thus bringing liquid into contact with the dissolvable valve membrane.
  • a sacrificial valve e.g., water-soluble membrane
  • the present invention relates to a microfluidic device comprising, a. an inlet for liquid; b. a fluid conduit in fluid connection with the inlet; c. a first air-impermeable and water-soluble membrane that (i) is closing a first opening in a wall of the fluid conduit, (ii) is positioned to dissolve upon circulation of liquid through the fluid conduit, and (iii) has a first side oriented toward an inside of the fluid conduit; d. a vent that is in fluid connection with the other side of the first air-impermeable and water-soluble membrane and wherein said vent comprises means to prevent liquid flow through the first opening, while allowing circulation of air therethrough; e. means for increasing hydraulic resistance to liquid flow, located downstream of the inlet and upstream of the first opening; and, f. an outlet, located downstream of the opening, and in fluid connection therewith.
  • the device of the invention further comprises, a pump, downstream of, and in fluid connection with, the outlet..
  • the microfluidic device comprises, a. an inlet for liquid; b. a fluid conduit in fluid connection with the inlet; c. a first air-impermeable and water-soluble membrane that (i) is closing a first opening in the wall of the fluid conduit, (ii) is positioned to dissolve upon circulation of liquid through the fluid conduit, and (iii) has a first side oriented toward the inside of the fluid conduit; d.
  • vent that is in fluid connection with the other side of the first air-impermeable and water-soluble membrane so that when the first membrane is opened by dissolution in liquid flowing through the fluid conduit, air can flow through the vent inside the fluid conduit and wherein said vent comprises means to prevent liquid flow through the first opening, while allowing circulation of air therethrough; e. means for increasing hydraulic resistance to liquid flow, located downstream of the inlet and upstream of the first opening, and configured so that when the first membrane is open, the intake of air from the vent can overcome the surface tension of the liquid passing through the fluid conduit and thereby partition said liquid; and, f. a pump configured to draw in liquid through the fluid conduit.
  • said walls of the fluid conduit define said inside.
  • the means for increasing hydraulic resistance to liquid flow comprises, a geometric flow resistance, a porous filtration element, a thermal expansion valve, a hydrogel swelling valve, a hydrophobic flow resistance, a plunger valve, a rotating valve, a pressure valve or a combination thereof.
  • the means for increasing hydraulic resistance to liquid flow comprise, or consist of, a geometric flow resistance, a porous filtration element, a thermal expansion valve, a hydrogel swelling valve, a hydrophobic flow resistance or a combination thereof.
  • the means for increasing hydraulic resistance to liquid flow comprise a filter.
  • said filter is a plasma separation membrane.
  • the means for increasing hydraulic resistance to liquid flow comprise a single, or an array of, hollow microneedle(s).
  • the means to prevent liquid flow through the first opening, while allowing circulation of air therethrough comprise, or consists of, hydrophobic porous material.
  • the means for increasing hydraulic resistance to liquid flow comprise: a. a first chamber in fluid connection with the inlet and with the fluid conduit; b. a second air-impermeable and water-soluble membrane that (i) is closing an opening in a wall of the first chamber, (ii) is positioned to dissolve upon circulation of liquid through the first chamber, and (iii) has a first side oriented toward an inside of the first chamber; c. a second chamber that (i) is filled with a hydrophilic porous material, (ii) is in fluid connection with the other side of the second membrane and, (iii) comprises a trapped volume of gas in the pore of the hydrophilic porous material, and, d. a geometric restriction in the fluid connections upstream and downstream of the first chamber.
  • the dissolution speed (e.g., in water) of said second membrane is adjusted to avoid fluid communication between the first chamber and second chamber before opening of the first membrane.
  • the means for increasing hydraulic resistance to liquid flow comprise: a. a first chamber in fluid connection with the inlet [106] and with the fluid conduit; b. a second air-impermeable and water-soluble membrane that (i) is closing an opening in a wall of the first chamber, (ii) is positioned to dissolve upon circulation of liquid through the first chamber, and (iii) has a first side oriented toward an inside of the first chamber; c.
  • a second chamber that (i) is filled with a hydrophilic porous material, (ii) is in fluid connection with the other side of the second membrane so that when the second membrane is opened by dissolution in liquid flowing through the first chamber, part of that liquid is absorbed by the hydrophilic porous material, expelling the trapped volume of gas in the pores of the hydrophilic porous material towards the first chamber [114] resulting the formation of a gas bubble therein; and, d. a geometric restriction in the fluid connections upstream and downstream of the first chamber configured to trap into said first chamber the gas bubble formed by capillary filling of the second chamber after opening of the second membrane; and wherein the dissolution speed of said second membrane is adjusted to avoid fluid communication between the first chamber and second chamber before opening of the first membrane.
  • the pump is a capillary pump.
  • the present invention further relates to the use of the microfluidic device of the invention, to partition a volume of aqueous liquid.
  • the invention also relates to a method to partition a volume of aqueous liquid comprising the steps of a. drawing in aqueous liquid through the fluid conduit of the microfluidic device according to the invention; and, b. partitioning said aqueous liquid.
  • the step of partitioning the aqueous liquid does not require any user intervention to open and/or close valves nor the use of valves fitted with actuators.
  • FIG. 1 panel A is a drawing of an exemplary embodiment of the fluid conduit [101]
  • Panel B is a drawing of an exemplary embodiment of the microfluidic device.
  • FIG. 2 illustrates fluid flows in exemplary embodiments of the device and fluid conduit shown in FIG. 1 during operation, before (panels A, i and ii) and after (panels B, iii and iv) the opening of the membrane [102], Solid arrows represent liquid flows. Dashed arrows represent air flows. Solid T- shaped lines shows blocking of fluid flows. References to individual elements of the device and fluid conduit are identical to that in FIG. 1.
  • Panels i to vii are drawings illustrating fluid flows in an exemplary embodiment of a device and fluid conduit comprising a plasma separation membrane [107] during operation.
  • Solid arrows represent liquid flows.
  • Dashed arrows represent air flows.
  • Solid T-shaped lines shows blocking of fluid flows.
  • FIG. 4 Panels i to v are drawings illustrating fluid flows in an exemplary embodiment of a device and fluid conduit wherein an array of hollow microneedles [111] is used. Solid arrows represent liquid flows. Dashed arrows represent air flows. Solid T-shaped lines shows blocking of fluid flows.
  • FIG. 5 Panels i to ix are drawings illustrating fluid flows in an exemplary embodiment of a device and fluid conduit wherein the second valve of the invention is used as a mean [105] for increasing hydraulic resistance to liquid flow during operation.
  • Solid arrows represent liquid flows.
  • Dashed arrows represent air flows.
  • Solid T-shaped lines shows blocking of fluid flows.
  • the inventors have developed a first valve comprising a dissolvable membrane separating a liquid conduit from a vent.
  • the first valve when incorporated within a microfluidic device comprising, upstream of said valve, means for increasing hydraulic resistance to liquid flow, allows to split off a discrete liquid volume from an upstream liquid source.
  • the present invention relates to a microfluidic device.
  • the microfluidic device comprises a fluid conduit [101] with an opening [112] in the wall of said fluid conduit [101],
  • the fluid conduit [101] may comprise walls that define an inner compartment or inside.
  • the fluid conduit [101] is selected from the group consisting of a channel, a duct, a chamber and combinations thereof.
  • the fluid conduit (e.g., a chamber, a channel and/or a duct) comprises two parts defined by the location of the opening [112], the upstream part [101a] and the downstream part [101b],
  • the microfluidic device comprises a vent [104],
  • the vent [104] is in fluid connection with the opening [112], When the opening [112] is open, both the upstream part [101a] and the downstream part [101b] of the fluid conduit [112] are connected via the vent [104] to the outside environment.
  • the opening [112] when the opening [112] is open, air can circulate between the inside of the fluid conduit [101] and the outside environment via the opening [112] and the vent [104],
  • the inside of the fluid conduit [101] and the vent [104] are separated by an air-impermeable water-dissolvable membrane [102],
  • the air-impermeable water-dissolvable membrane [102] is closing the opening [112] in the wall of the fluid conduit [101],
  • the air-impermeable water-dissolvable membrane [102] is positioned to dissolve upon circulation of (aqueous) liquid through the fluid conduit [101],
  • the air- impermeable water-dissolvable membrane [102] has a first side oriented toward the inside of the fluid conduit [101],
  • the other side of the membrane [102] is connected to the outside environment of the device through the vent [104],
  • the vent [104] is in fluid connection with the other side of the air-impermeable water-d
  • the vent [104] comprises, between the outside environment and the membrane [102], (e.g., flanking the side of the membrane [102] oriented toward the vent [104]) means to prevent liquid outflow through the opening [112], while allowing circulation of air therethrough, such as an air-permeable, hydrophobic porous material [103],
  • said means to prevent liquid outflow through the opening [112], while allowing circulation of air therethrough is an air-permeable liquid barrier.
  • Example of air-permeable liquid barrier that may be used in the context of the invention include, without being limited to, porous material configured to prevent entry of liquid therein, geometric restriction, surface coating and combinations thereof.
  • FIG. 1A illustrates an exemplary embodiment of such a fluid conduit.
  • the device further comprises, upstream of the opening [112] and/or in fluid connection therewith, means [105] for increasing hydraulic resistance to liquid flow and an inlet [106] for liquid.
  • the means [105] for increasing hydraulic resistance to liquid flow are located between the inlet [106] and the opening [112].
  • the device comprises downstream of the opening and/or in fluid connection therewith, an outlet [119], Downstream of the opening [112], the fluid conduit [101] may be connected via the outlet [119], to further means for liquid processing (e.g., volume metering, sample dilution, sample incubation, sample splitting, readout, among many more) and/or to a pump [108], acting as driving source for the liquid manipulation inside the microfluidic device.
  • the pump [108] is downstream of and/or in fluid connection with the outlet. In one embodiment, the pump is configured to draw in liquid through the fluid conduit.
  • This pump [108] can either be active (e.g., peristaltic pump, pressure pump, syringe pump, ...) or, preferably, passive in nature (e.g., capillary pump).
  • FIG. IB illustrates an exemplary embodiment of such a device.
  • upstream and downstream are used herein in reference to position along the liquid flow from the inlet to towards the outlet of the microfluidic device of the invention.
  • a being “upstream” with respect to B typically means that A is, along the liquid flow, closer to the inlet than B.
  • a being “downstream” with respect to B typically means that A is, along the liquid flow, closer to the outlet than B.
  • APpump downstream negative pressure gradient
  • the membrane [102] dissolves into the sample liquid [109],
  • the dissolution time of the membrane [102] can be tuned by adjusting the thickness (e.g., a couple of pm to several hundreds of pm), material type (e.g., polyvinyl alcohol) and composition (e.g., mixture percentage of used chemicals, molecular weight of used chemicals) of the membrane.
  • the intake of air through the vent [104], the opening [112] and subsequently, the downstream part of the fluid conduit [101b] splits the sample liquid into an upstream [109a] and downstream [109b] fraction.
  • the hydraulic flow resistance Rc generated by the means [105] for increasing hydraulic resistance to liquid flow in the upstream part of the microfluidic device must be large enough to force air flow being pulled from the ambient environment through the vent [104], the opening [112] and then into the fluid conduit [101], and thus overcome the liquid cohesion originating from the surface tension of the sample liquid [109] in the fluid conduit [101], More specifically, the pressure drop ( c) generated by the means [105] for increasing the hydraulic resistance to liquid flow in the upstream part of the microfluidic device, must be large enough to force the intake of air from the ambient environment through the vent [104], the opening [112] and then into the fluid conduit [101], and thus overcome the liquid cohesion originating from the surface tension (APv) of the sample liquid [109] in the fluid conduit [101], jzis equal to the pressure difference over the liquid-air interface of the sample liquid [109] at the opening [112] in the main
  • the pressure drop (APc) generated by the means [105] for increasing the hydraulic resistance to liquid flow in the upstream part of the microfluidic network can be calculated using the electronic analogy for fluidic systems (Eq. (2)): where, Rc, resembles the hydraulic resistance to liquid flow for a given flow rate, Q, of the sample liquid [109] through the microfluidic channel. It is within the reach of the skilled artisan to tune (e.g., by changing the channel geometry, surface properties, etc.) the means [105] for increasing the hydraulic resistance so that APc > APv- Consequently, upon opening of the membrane [102] by dissolution, the intake of air from the ambient environment is favored over the intake of additional liquid from the upstream microfluidic network.
  • downstream sample liquid fraction [109b] can be further manipulated in the downstream part of the microfluidic device, where depending on the application, additional fluid operations may be performed (e.g., volume metering, sample dilution, sample incubation, sample splitting, readout, among many more).
  • FIG. 2A-B illustrates an exemplary embodiment of a microfluidic device before (panel A) and after (panel B) dissolution of the membrane [102],
  • the microfluidic device comprises, a. an inlet [106] for liquid; b. a fluid conduit [101] in fluid connection with the inlet [106]; c. a first air-impermeable and water-soluble membrane [102] that (i) is closing a first opening [112] in the wall of the fluid conduit [101], (ii) is positioned to dissolve upon circulation of liquid through the fluid conduit [101], and (iii) has a first side oriented toward the inside of the fluid conduit [101]; d.
  • vent [104] that is in fluid connection with the other side of the first membrane [102] so that when the first membrane [102] is opened by dissolution in liquid flowing through the fluid conduit [101], air can flow through the vent [104] inside the fluid conduit [101] and wherein said vent [104] comprises means to prevent liquid flow through the first opening [112], while allowing circulation of air therethrough; e. means [105] for increasing hydraulic resistance to liquid flow, located downstream of the inlet [106] and upstream of the first opening [112], and configured so that when the first membrane [102] is open, the intake of air from the vent [104] can overcome the surface tension of the liquid passing through the fluid conduit [101] and thereby partition said liquid; and, f. a pump [108] configured to draw in liquid through the fluid conduit [101],
  • the microfluidic device comprises a. an inlet [106] for liquid; b. a fluid conduit [101] in fluid connection with the inlet [106], preferably a fluid conduit [101] in fluid connection with the inlet [106] and wherein said fluid conduit [101] comprises walls that define an inside; c. a first air-impermeable and water-soluble membrane [102] that (i) is closing a first opening [112] in the wall of the fluid conduit [101], (ii) is positioned to dissolve upon circulation of liquid through the fluid conduit [101], and (iii) has a first side oriented toward the inside of the fluid conduit [101]; d.
  • vent [104] that is in fluid connection with the other side of the first air-impermeable and water-soluble membrane [102] and wherein said vent [104] comprises means to prevent liquid flow through the first opening [112], while allowing circulation of air therethrough; e. means [105] for increasing hydraulic resistance to liquid flow, located downstream of the inlet [106] and upstream of the first opening [112]; f. an outlet [119], located downstream of the opening [112] and in fluid connection therewith; and, g. a pump [108], downstream of, and in fluid connection with, the outlet [119], Preferably, the pump is configured to draw in liquid through the fluid conduit [101],
  • the means to prevent liquid flow through the opening [112], while allowing circulation of air therethrough prevents outflow of the sample liquid [109] outside of the microfluidic device through the vent [104]
  • the opening of the membrane [102] establishes a gas-permeable fluidic connection between the fluid conduit [101] and the vent [104] and the hydraulic resistance generated by the means [105] for increasing hydraulic resistance to liquid flow in the upstream part of the microfluidic device forces the intake of air from the vent [104] into the fluid conduit [101],
  • the introduced flow resistance allows to break up the cohesive forces (i.e., surface tension) that keep the sample liquid [109] in the fluid conduit [101] together.
  • the sample liquid [109] is separated in two liquid plugs.
  • the volume of sample liquid [109] entering the downstream part of the fluid conduit [101b] before splitting can be adjusted by tuning the dissolution speed (i.e., by adjusting film thickness, material type and composition) of the membrane [102] and/or the volumetric flow rate at which the sample liquid [109] is manipulated through the fluidic conduit [101],
  • the microfluidic device of the invention comprises means [105] for increasing hydraulic resistance to liquid flow, located upstream of the opening [112],
  • said means [105] for increasing hydraulic resistance to liquid flow are configured so that when the membrane [102] is open, the intake of air from the vent [104] can overcome the surface tension of the liquid passing through the fluid conduit [101] and thereby partition said liquid.
  • the means [105] for increasing hydraulic resistance to liquid flow is configured so as to generate upstream of the opening [112], a pressure drop ( Pc) superior to the surface tension (zl/Y) of the liquid [109, 110b] in the fluid conduit [101],
  • Examples of means [105] for increasing hydraulic resistance to liquid flow include, without being limited to, plunger valves, rotating valves, pressure valves and thermal expansion valves, hydrogel swelling valves, geometric flow resistors (i.e., channel restriction, microneedles), hydrophobic flow resistors and porous filtration elements (i.e., filter).
  • plunger valves rotating valves
  • pressure valves and thermal expansion valves hydrogel swelling valves
  • geometric flow resistors i.e., channel restriction, microneedles
  • hydrophobic flow resistors i.e., porous filtration elements
  • porous filtration elements i.e., filter
  • the means [105] for increasing hydraulic resistance to liquid flow comprise, or consist of, a geometric flow resistance (e.g., hollow microneedles), a porous filtration element (e.g., a plasma separation membrane), a thermal expansion valve, a hydrogel swelling valve, a hydrophobic flow resistance, a plunger valve, a rotating valve, a pressure valve or a combination thereof.
  • the means [105] for increasing hydraulic resistance to liquid flow comprise, or consist of, a geometric flow resistance (e.g., hollow microneedles), a porous filtration element (e.g., a plasma separation membrane), a thermal expansion valve, a hydrogel swelling valve, a hydrophobic flow resistance or a combination thereof.
  • the means [105] for increasing hydraulic resistance to liquid flow comprise, or consist of, a filter.
  • said filter is a plasma separation membrane [107],
  • the dissolution speed of the membrane [102] is configured to avoid the entry of blood cells in the downstream part of the fluid conduit [101b],
  • plasma separation membrane examples include without being limited to Whatman Fusion 5, Whatman MFI, VividTM GF, VividTM GX, VividTM GR.
  • the means [105] for increasing hydraulic resistance to liquid flow comprise, or consist of, a single, or an array of, hollow microneedles [111].
  • the inlet [106] is the opening(s) of the single, or array of, hollow microneedle(s) [111].
  • the present invention also relates to a second valve that may be used in the microfluidic device of the invention as a mean [105] for increasing hydraulic resistance to liquid flow.
  • the second valve comprises, a. first chamber [114] comprising an inlet for liquid and an outlet for liquid; b. an air-impermeable and water-soluble membrane [118] that (i) is closing an opening [115] in the wall of the first chamber [114], (ii) is positioned to dissolve upon circulation of liquid through the first chamber [114], and (iii) has a first side oriented toward the inside of the first chamber [114]; c.
  • a second chamber [116] that (i) is filled with a hydrophilic porous material [117], (ii) is in fluid connection with the other side of the second membrane [118] and/or (iii) comprises a trapped volume of gas in the pores of the hydrophilic porous material; and, d. a geometric restriction at the inlet and at the outlet of the first chamber [114],
  • the first chamber [114] comprises walls defining an inside.
  • the second chamber is configured so that when the second membrane [118] is opened by dissolution in liquid flowing through the first chamber [114], part of the liquid is absorbed by the hydrophilic porous material [117], The trapped volume of gas in the pores of the hydrophilic porous material [117] is thereby expelled toward the first chamber [114], resulting in the formation of a gas bubble therein.
  • FIG. 5i illustrates an exemplary embodiment of a microfluidic device comprising such a second valve.
  • the second chamber [116] is configured to trap gas in the pores of the hydrophilic porous material [117] before the opening of the second membrane [118], In other words, the second chamber [116] comprises a trapped volume of gas in the pores of the hydrophilic porous material [117],
  • the dissolution speed of the membrane [118] is adjusted to avoid fluid communication between the first chamber [114] and second chamber [116] before air circulation between the vent [104] and the fluid conduit [101] becomes possible (i.e. opening of the first membrane [102]).
  • the volume of gas trapped in the hydrophilic porous material [117] is configured to form in the first chamber [114] a gas bubble sufficiently large to be trapped by the geometric restrictions at the inlet and outlet of the first chamber [114],
  • hydrophilic porous material examples include without being limited to, (nitro)cellulose paper, glass-fiber paper and capillary microstructures (e.g., array of micropillars).
  • the microfluidic device of the invention comprises means to prevent liquid flow through the opening [112], while allowing circulation of air therethrough.
  • the means to prevent liquid outflow through the opening [112], while allowing circulation of air therethrough is an air-permeable liquid barrier.
  • the means to prevent liquid outflow through the opening [112] and/or the air-permeable liquid barrier is selected from the group consisting of, porous material configured to prevent entry of liquid therein (such as hydrophobic porous material), geometric restriction, surface coating and combinations thereof.
  • the means to prevent liquid flow through the opening [112], while allowing circulation of air therethrough comprise, or consist of, hydrophobic porous material [103],
  • hydrophobic porous material examples include, without being limited to filter paper with inherent hydrophobic properties or filter paper that is treated hydrophobically, hydrophobic polymer membranes (e.g., comprising or composed of, polytetrafluorethylene, polyvinylidene fluoride, and/or polypropylene).
  • the microfluidic device of the invention comprises an air-impermeable and water soluble membrane [102] and, in embodiment wherein the microfluidic device comprises the second valve of the invention, a second air-impermeable and water-soluble membrane [118],
  • the air-impermeable and water-soluble membrane(s) may be dissolved by aqueous liquid, including, without being limited to (aqueous) biological fluids such as (whole) blood, serum or plasma.
  • Examples of material that can be used in the context of the invention for the air-impermeable and water-soluble membrane(s) include, without being limited to, polyvinyl alcohol (PVA), dissolvable polysaccharides, gelatin and the like.
  • PVA polyvinyl alcohol
  • dissolvable polysaccharides examples include, without being limited to, gelatin and the like.
  • the air-impermeable and water-soluble membrane(s) comprise a substance to be released into the liquid circulating in the fluid conduit [101].
  • Example of material that may be included in the air-impermeable and water-soluble membrane(s) of the invention include, without being limited to blood anticoagulant reagents, (such as Ethylenediaminetetraacetic acid, heparin, sodium citrate, citrate, sodium fluoride), DNA and/or RNA stabilizing reagents, cell lysis and viral inactivation reagents, assay reagents, micro and/or nanoparticles and compounds to be used as internal control and/or calibration means.
  • blood anticoagulant reagents such as Ethylenediaminetetraacetic acid, heparin, sodium citrate, citrate, sodium fluoride
  • DNA and/or RNA stabilizing reagents DNA and/or RNA stabilizing reagents
  • cell lysis and viral inactivation reagents cell lysis and viral in
  • the present invention further relates to the use of the microfluidic device of the invention to partition a volume of aqueous liquid.
  • the present invention also relates to a method to partition a volume of aqueous liquid comprising the steps of: a. drawing in aqueous liquid through the fluid conduit [101] of the microfluidic device of the invention; and, b. partitioning said volume of liquid.
  • step b of the method of the invention does not require any user intervention to open and/or close valves nor the use of valves fitted with actuators.
  • the use and/or the method of the invention exclude substantial physical interventions on the human or animal body which require professional medical expertise to be carried out and/or which entail a substantial health risk and/or do not necessitate the presence of a human or animal body.
  • Example 1 Device with a filtration membrane
  • the means [105] for increasing hydraulic resistance to liquid flow comprises a porous filter that is integrated into the upstream part of the microfluidic device.
  • a porous filter that is integrated into the upstream part of the microfluidic device.
  • Such microfluidic devices with an integrated filter are, in particular, interesting for applications that require the separation/removal of specific compounds such as cells, cell debris, nucleic acids, proteins and other contaminating (bio)chemicals from the sample liquid which can induce unwanted bias in downstream (bio)analytical processes.
  • This typically requires the sample to be sent through a filter, typically, consisting of a porous substrate (e.g., untreated/treated nitrocellulose, glass fiber, asymmetric polysulfone, . . .) or packed column with microparti cles/beads.
  • the filter introduces a hydraulic resistance, which in combination with the downstream vent allows to split off a discrete liquid plug from the filtered sample liquid.
  • FIG. 3 An example of such a microfluidic device is illustrated in FIG. 3, where a plasma separation membrane is being used to retain blood cells from whole blood and only allows the plasma fraction to be sent to the downstream part of the microfluidic device.
  • FIG. 3 i to vii A detailed description of the different steps of operation is given in FIG. 3 i to vii:
  • a volume of whole blood [110] is applied to the inlet [106] of the microfluidic device, which is in fluid communication with the plasma separation membrane [107],
  • This can be a venous blood sample stabilized with anticoagulants (i.e., heparin, K2EDTA, K3EDTA, sodium citrate, among others), a stabilized capillary blood sample with anticoagulants or a nonstabilized capillary blood sample.
  • the blood sample When making contact with the plasma separation membrane, the blood sample is absorbed through capillary forces. During the wicking process, the blood cells are retained in the upstream part of the porous substrate (top part in case of vertical filtration membranes) of the plasma separation membrane [107] resulting in the separation of blood cells [110a] and plasma fraction [110b], The separation of the blood cells [110a] and plasma fractions [110b] inside the plasma separation membrane [107] can be driven solely through capillary forces or an additional external pressure gradient can be used to pull the whole blood sample through the porous membrane and drive the plasma separation. (iii-iv) Once the plasma separation membrane [107] is fully saturated, the plasma fraction is aspirated into the fluid conduit [101]and the dissolvable membrane [102] begins to reconstitute in the plasma fraction [110b],
  • the hydrophobic porous material [103] prevents outflow of the plasma fraction [110b] outside of the microfluidic device through the vent [104]
  • the opening of the membrane [102] establishes the connection between the fluid conduit [101] and the vent [104] after which the hydraulic resistance of the plasma separation membrane [107] in the upstream part of the microfluidic device forces the intake of air from the vent [104] into the fluid conduit [101],
  • the introduced flow resistance by the upstream plasma separation membrane [107] allows to break up the cohesive forces that keep the plasma fraction [110b] in the fluid conduit [101] together.
  • the plasma fraction [110b] located in the downstream part of the fluid conduit [101b] becomes a discrete plasma fraction volume that is completely separated from the upstream part.
  • Example 2 Device with hollow microneedle
  • the means [105] for increasing hydraulic resistance to liquid flow comprises a single or multiple hollow microneedle(s) [111].
  • Such microfluidic device with one or multiple integrated hollow microneedle(s) are, in particular, interesting for applications where it is desired to extract a sample liquid (e.g., capillary blood, interstitial fluid) [109] directly from a living organism (e.g., human body, animal or plant) and further process it in the device.
  • a sample liquid e.g., capillary blood, interstitial fluid
  • a living organism e.g., human body, animal or plant
  • a discrete sample volume is required and, therefore, it is necessary to decouple the extracted sample liquid from the unlimited sample source (e.g., represented by the body bloodstream) in the patient.
  • the small diameter of the lumen [113] inside the hollow microneedle(s) [111] induces a hydraulic flow resistance, which in combination with the vent [104] allows to split off a discrete liquid plug and then decouple fluidically the microfluidic device from the sample source.
  • a hydraulic flow resistance which in combination with the vent [104] allows to split off a discrete liquid plug and then decouple fluidically the microfluidic device from the sample source.
  • FIG. 1 A detailed description of all the different steps of the operation of a device with integrated hollow microneedles as means [105] for increasing hydraulic resistance to liquid flow is illustrated in FIG.
  • sample liquid e.g., capillary blood or interstitial fluid
  • the sample liquid is aspirated from the sample source, through the inlet [106] and lumen of the hollow microneedles, into the fluid conduit [101] of the microfluidic device by a microfluidic pump.
  • the hydrophobic porous material [103] prevents outflow of the sample liquid [109] outside of the microfluidic device through the vent [104],
  • the opening of the membrane [102] establishes the air connection between the fluid conduit [101] and the vent [104] after which the hydraulic resistance of the hollow microneedle(s) [111] in the upstream part of the microfluidic device forces the intake of air from the vent [104] into the fluid conduit [101],
  • the introduced flow resistance by the upstream hollow microneedle(s) [111] allows to break up the cohesive forces that keep the sample liquid [109] in the fluid conduit [101] together.
  • the sample liquid [109b] located in the downstream part of the fluid conduit [101b] becomes a discrete sample liquid volume that is completely separated from the upstream part [109a],
  • Example 3 Device with a trapped-sas valve
  • the means [105] for increasing hydraulic resistance to liquid flow comprises a valve comprising a chamber containing trapped gas behind a dissolvable membrane that, after letting through a certain amount of liquid, will increase the hydraulic flow resistance by entrapping a gas bubble in the liquid path.
  • the valve is located upstream vent [104] and downstream of the inlet [106] and comprises a first chamber [114], in fluid connection with the (upstream) inlet [106] and the (downstream) fluid conduit [101],
  • the first chamber [114] is separated from an adjacent second chamber [116] containing porous hydrophilic material [117] (e.g., filter paper) by another dissolvable membrane [118],
  • the dissolvable membrane [118] dissolves by reconstituting into the sample liquid [109]
  • the dissolution time of the dissolvable membrane [118] can be tuned by adjusting the thickness (e.g., a couple of pm to several hundreds of pm), material type (i.e., polyvinyl alcohol) and composition (i.e., mixture percentage of used chemicals, molecular weight of used chemicals) of the used membrane.
  • the valve is able to increase the flow resistance within the microfluidic device after a certain time - determined by the second membrane [118] dissolution speed and/or the volumetric flow rate of the liquid, without the need for user intervention. This is particularly interesting in microfluidic systems, where no upstream hydraulic resistance is present.
  • Sample liquid [109] is aspirated toward the first chamber [114] (e.g. by a microfluidic pump).
  • the dissolvable membrane [118] forms a physical barrier between the first chamber [114] and the second chamber [116] containing a hydrophilic porous substrate [117], the sample liquid [109] will be able to flow toward the fluid conduit [101], Upon filling of the fluid conduit [101] with the sample liquid [109], the dissolvable membrane [102] reconstitutes in the sample liquid [109],
  • the dissolving time of the dissolvable membranes [118, 102] can be customized to specific windows by adjusting the thickness (e.g., a couple of pm to several hundreds of pm), material type (i.e., polyvinyl alcohol) and composition (z.e., mixture percentage of used chemicals, molecular weight of used chemicals) of the used membrane.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Engineering & Computer Science (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Mechanical Engineering (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)

Abstract

La présente invention concerne un dispositif microfluidique comprenant (i) un évent [104], qui s'ouvre lors de la dissolution d'une membrane imperméable à l'air et hydrosoluble [102] et (ii) des moyens [105] permettant d'augmenter la résistance hydraulique au flux de liquide situé en amont dudit évent [104]. L'invention concerne en outre l'utilisation du dispositif de l'invention permettant de séparer un volume de liquide et un procédé de séparation d'un volume de liquide.
PCT/EP2024/068360 2023-06-29 2024-06-28 Vanne synchronisée Pending WO2025003467A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP23182489 2023-06-29
EP23182489.7 2023-06-29

Publications (1)

Publication Number Publication Date
WO2025003467A1 true WO2025003467A1 (fr) 2025-01-02

Family

ID=87060357

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2024/068360 Pending WO2025003467A1 (fr) 2023-06-29 2024-06-28 Vanne synchronisée

Country Status (1)

Country Link
WO (1) WO2025003467A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2014280043A1 (en) 2013-06-14 2016-01-07 Dublin City University Microfluidic device
US20160279634A1 (en) 2013-09-30 2016-09-29 Göran Stemme A microfluidic device, use and methods
WO2018197337A1 (fr) * 2017-04-24 2018-11-01 miDiagnostics NV Agencement de dosage dans un système de fluide entrainé par force capillaire et son procédé

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2014280043A1 (en) 2013-06-14 2016-01-07 Dublin City University Microfluidic device
US20160279634A1 (en) 2013-09-30 2016-09-29 Göran Stemme A microfluidic device, use and methods
WO2018197337A1 (fr) * 2017-04-24 2018-11-01 miDiagnostics NV Agencement de dosage dans un système de fluide entrainé par force capillaire et son procédé

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HAUSER JANOSCH ET AL: "A microfluidic device for TEM sample preparation", LAB ON A CHIP, vol. 20, no. 22, 10 November 2020 (2020-11-10), UK, pages 4186 - 4193, XP055919484, ISSN: 1473-0197, DOI: 10.1039/D0LC00724B *

Similar Documents

Publication Publication Date Title
US10865437B2 (en) Processing particle-containing samples
JP5624629B2 (ja) 粒子を濾過するためのシステム及び方法
EP2533044B1 (fr) Séparation de plasma avec une membrane microporeuse
JP6782998B2 (ja) 装置
CN102782472B (zh) 样品制备装置和方法
CN106573201B (zh) 毛细管压力重置机构及应用
US9561505B2 (en) Sample preparation devices and systems
JP2007518978A (ja) 血漿用オンデマンドチューブ
TWI678522B (zh) 檢體萃取及製備裝置
EP3782730B1 (fr) Dispositif de filtration en profondeur pour la séparation de phases d'échantillon
US20180200677A1 (en) Hemolysis-free blood plasma separation
CN105722576A (zh) 用于获取血浆的过滤介质以及相关的过滤装置和方法
IL167305A (en) Implementation of microfluidic components in a microfluidic system
DE102013210818B3 (de) Fluidhandhabungsvorrichtung und Verfahren zum Prozessieren einer Flüssigkeit unter Verwendung einer Diffusionsbarriere
CN113167785B (zh) 微流体装置
WO2025003467A1 (fr) Vanne synchronisée
Vo et al. Engineering an extremely high flow rate micropump and integrating with an inertial microfluidics for rapid and efficient blood plasma extraction from fingertip blood with lancets
EP3987007B1 (fr) Globules rouges pour l'administration de médicaments
US11391652B2 (en) Device for preparing a calibrated volume of blood plasma
EP4480580A1 (fr) Dispositif fluidique
EP4609168A1 (fr) Dispositifs et procédés pour la manipulation et la concentration de particules et de grandes molécules dans un bout-filtre jetable
Kim et al. Multi-DNA extraction chip based on an aluminum oxide membrane integrated into a PDMS microfluidic structure
HK40081265A (en) Liquid to liquid biological particle concentrator with disposable fluid path
TR2021012577A2 (tr) Mi̇kroparçacik ve hücreleri̇n özkütleleri̇ne bağli ayriştirilmasi i̇çi̇n vakumla entegre edi̇lmi̇ş santri̇füjlenebi̇len mi̇kroakişkan yonga
NZ600343B (en) Plasma separation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24735654

Country of ref document: EP

Kind code of ref document: A1