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WO2025003168A1 - Dispositif de manipulation de liquide - Google Patents

Dispositif de manipulation de liquide Download PDF

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Publication number
WO2025003168A1
WO2025003168A1 PCT/EP2024/067864 EP2024067864W WO2025003168A1 WO 2025003168 A1 WO2025003168 A1 WO 2025003168A1 EP 2024067864 W EP2024067864 W EP 2024067864W WO 2025003168 A1 WO2025003168 A1 WO 2025003168A1
Authority
WO
WIPO (PCT)
Prior art keywords
liquid
liquid storage
chamber
handling device
fluidic
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/EP2024/067864
Other languages
English (en)
Inventor
Richard Luxton
Jimish PATEL
Peter DEAL
Nuno REIS
Darius HITICAS
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.)
Osler Diagnostics Ltd
Original Assignee
Osler Diagnostics Ltd
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 Osler Diagnostics Ltd filed Critical Osler Diagnostics Ltd
Publication of WO2025003168A1 publication Critical patent/WO2025003168A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/50273—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
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • B01L2200/027—Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic 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
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0642—Filling fluids into wells by specific techniques
    • 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
    • B01L2200/0689—Sealing
    • 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
    • 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
    • B01L2400/0478—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure pistons
    • 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
    • B01L2400/04—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
    • 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
    • B01L3/502715—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 interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • 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

Definitions

  • the present disclosure relates to liquid handling devices, liquid handling systems and methods of moving liquids in liquid handling devices.
  • Point-of-care diagnostic devices are typically used for carrying out diagnostic tests, such as immunoassays, on a biological sample (such as whole blood, blood serum or blood plasma).
  • a biological sample such as whole blood, blood serum or blood plasma.
  • the biological sample needs to be transferred to the diagnostic device.
  • the diagnostic device is subsequently inserted into an analyser device (or instrument), which controls the movement of fluids (e.g. biological samples, reagents, buffer solutions, etc.) within the diagnostic device and conducts measurements of biomarkers, in order to conduct the diagnostic test.
  • fluids e.g. biological samples, reagents, buffer solutions, etc.
  • Point-of-care detection brings a diagnostic test conveniently and immediately to a patient, allowing better and faster clinical decisions to be made.
  • integration of diagnostic tests into a point- of-care device or system is challenging. Preparation of a sample for an immunoassay may require mixing of multiple solutions and reagents, with precise control of volumes and mixing times. Further, the device is ideally automated to obviate the need for a medical professional to be present.
  • a liquid handling device comprising: a fluidic layer comprising: a plurality of channels; and an opening in a surface of the fluidic layer, wherein the opening extends through at least part of the thickness of the fluidic layer to one of the plurality of channels; a rigid layer comprising an actuatable portion; and a liquid storage capsule positioned between the fluidic layer and the actuatable portion, wherein the liquid storage capsule comprises: a body defining a volume in which a liquid is stored, the body comprising a first deformable portion, a main liquid storage portion, and a restriction connecting the first deformable portion to the main liquid storage portion; and a sealing layer configured to seal the volume; wherein the liquid storage capsule is positioned over the opening such that a portion of the sealing layer covers the opening; wherein the actuatable portion comprises a protrusion extending towards the liquid storage capsule, wherein the actuatable portion is actuatable from a first position, in which the protru
  • the protrusion may be unable to pass into the opening.
  • the liquid storage capsule may be positioned over the opening such that the first deformable portion and the restriction are at least partly positioned over the opening.
  • the opening may have an obround shape.
  • the first deformable portion may comprise a first region and a second region, wherein a first distance between the first region and the sealing layer is greater than a second distance between the second region and the sealing layer.
  • the first region and the second region may be concentric, such that the first region surrounds the second region.
  • a width of the opening may be less than a width of the protrusion.
  • the protrusion may comprise an end that engages the first deformable portion of the liquid storage capsule.
  • the end of the protrusion may be flat.
  • the end of the protrusion may have a cross-section with a major sector shape.
  • the protrusion may comprise a groove defining a cross-section of the end of the protrusion.
  • the groove may be aligned with the restriction of the liquid storage capsule.
  • the groove may define the major sector shape of the cross-section of the end of the protrusion.
  • the cross-section of the end of the protrusion may include one or more outwardly extending projecting ribs.
  • the one or more outwardly extending projecting ribs may extend from a curved portion of the major sector shape.
  • the protrusion may be a first protrusion and the actuatable portion may comprise a second protrusion extending towards the liquid storage capsule.
  • the body of the liquid storage capsule may comprise a second deformable portion.
  • the opening may be a first opening and the fluidic layer may comprise a second opening that extends through at least part of the thickness of the fluidic layer to one of the plurality of channels.
  • the portion of the sealing layer may be a first portion of the sealing layer, and the liquid storage capsule may be positioned over the second opening such that a second portion of the sealing layer covers the second opening.
  • the second protrusion may not deform the second deformable portion.
  • the second protrusion may deform the second deformable portion into contact with the second portion of the sealing layer to cause rupture of the second portion of the sealing layer.
  • the liquid storage capsule may be a first liquid storage capsule and the liquid handling device may comprise a second liquid storage capsule.
  • the second liquid storage capsule may comprise: a body defining a volume in which a liquid is stored, the body comprising a first deformable portion and a second deformable portion; and a sealing layer configured to seal the volume.
  • the actuatable portion may comprise: a third protrusion extending towards the first deformable portion of the second liquid storage capsule; and a fourth protrusion extending towards the second deformable portion of the second liquid storage capsule.
  • the fluidic layer may comprise: a third opening that extends through at least part of the thickness of the fluidic layer to one of the plurality of channels; and a fourth opening that extends through at least part of the thickness of the fluidic layer to one of the plurality of channels.
  • the second liquid storage capsule may be positioned over the third opening and the fourth opening such that a first portion of the sealing layer of the second liquid storage capsule covers the third opening and a second portion of the sealing layer of the second liquid storage capsule covers the fourth opening.
  • the third protrusion may not deform the first deformable portion of the body of the second liquid storage capsule and the fourth protrusion may not deform the second deformable portion of the body of the second liquid storage capsule.
  • the third protrusion may deforms the first deformable portion of the body of the second liquid storage capsule into contact with the first portion of the sealing layer of the second liquid storage capsule to cause rupture of the first portion of the sealing layer of the second liquid storage capsule.
  • the fourth protrusion may deform the second deformable portion of the body of the second liquid storage capsule into contact with the second portion of the sealing layer of the second liquid storage capsule to cause rupture of the second portion of the sealing layer of the second liquid storage capsule.
  • a liquid handling device comprising: a fluidic layer comprising: a plurality of channels; and an opening in a surface of the fluidic layer, wherein the opening extends through at least part of the thickness of the fluidic layer to one of the plurality of channels; a rigid layer comprising an actuatable portion; and a liquid storage capsule positioned between the fluidic layer and the actuatable portion, wherein the liquid storage capsule comprises: a body defining a volume in which a liquid is stored; and a sealing layer configured to seal the volume; wherein the liquid storage capsule is positioned over the opening such that a portion of the sealing layer covers the opening; wherein the actuatable portion comprises a protrusion extending towards the liquid storage capsule, wherein the actuatable portion is actuatable from a first position, in which the protrusion does not deform the body, to a second position, in which the protrusion deforms the body into contact with the portion of the sealing layer to cause rupture
  • the opening may have an obround shape.
  • the body of the liquid storage capsule may comprise a first deformable portion configured to be deformed by the protrusion when the actuatable portion is in the second position.
  • the body may further comprise a main liquid storage portion and a restriction connecting the first deformable portion to the main liquid storage portion, wherein the liquid storage capsule is positioned over the opening such that the first deformable portion and the restriction are at least partly positioned over the opening.
  • the first deformable portion may comprise a first region and a second region, wherein a first distance between the first region and the sealing layer is greater than a second distance between the second region and the sealing layer.
  • the first region and the second region are concentric, such that the first region surrounds the second region.
  • a width of the opening may be less than a width of the protrusion.
  • the protrusion may comprise an end that engages the first deformable portion of the liquid storage capsule.
  • the end of the protrusion may be flat.
  • the end of the protrusion may have a cross-section with a major sector shape.
  • the protrusion may comprise a groove defining a cross-section of the end of the protrusion.
  • the groove may be aligned with the restriction of the liquid storage capsule.
  • the groove may define the major sector shape of the cross-section of the end of the protrusion.
  • the cross-section of the end of the protrusion may include one or more outwardly extending projecting ribs.
  • the one or more outwardly extending projecting ribs may extend from a curved portion of the major sector shape.
  • the protrusion may be a first protrusion and the actuatable portion may comprise a second protrusion extending towards the liquid storage capsule.
  • the opening may be a first opening and the fluidic layer may comprise a second opening that extends through at least part of the thickness of the fluidic layer to one of the plurality of channels.
  • the portion of the sealing layer may be a first portion of the sealing layer, and the liquid storage capsule may be positioned over the second opening such that a second portion of the sealing layer covers the second opening.
  • the second protrusion In the first position, the second protrusion may not deform the body of the liquid storage capsule. In the second position, the second protrusion may deform the body into contact with the second portion of the sealing layer to cause rupture of the second portion of the sealing layer.
  • the liquid storage capsule may be a first liquid storage capsule and the liquid handling device may comprise a second liquid storage capsule, the second liquid storage capsule comprising: a body defining a volume in which a liquid is stored; and a sealing layer configured to seal the volume.
  • the actuatable portion may comprise: a third protrusion extending towards the second liquid storage capsule; and a fourth protrusion extending towards the second liquid storage capsule.
  • the fluidic layer may comprise: a third opening that extends through at least part of the thickness of the fluidic layer to one of the plurality of channels; and a fourth opening that extends through at least part of the thickness of the fluidic layer to one of the plurality of channels.
  • the second liquid storage capsule may be positioned over the third opening and the fourth opening such that a first portion of the sealing layer of the second liquid storage capsule covers the third opening and a second portion of the sealing layer of the second liquid storage capsule covers the fourth opening.
  • the third protrusion may not deform the body of the second liquid storage capsule and the fourth protrusion may not deform the body of the second liquid storage capsule.
  • the third protrusion may deform the body of the second liquid storage capsule into contact with the first portion of the sealing layer of the second liquid storage capsule to cause rupture of the first portion of the sealing layer of the second liquid storage capsule.
  • the fourth protrusion may deform the body of the second liquid storage capsule into contact with the second portion of the sealing layer of the second liquid storage capsule to cause rupture of the second portion of the sealing layer of the second liquid storage capsule.
  • a liquid handling device comprising: a fluidic layer comprising a chamber, wherein the chamber comprises: an opening at an upper end of the chamber; and a sealing layer configured to seal the opening of the chamber; wherein the chamber comprises one or more protrusions, wherein each of the one or more protrusions extends from an inner wall of the chamber; wherein when a reagent ball is housed in the chamber, the one or more protrusions prevent the reagent ball from contacting the sealing layer.
  • the opening may be configured to permit the reagent ball to be inserted into the chamber.
  • the one or more protrusions may be resiliently deformable.
  • the fluidic layer is formed of a thermoplastic elastomer.
  • Each of the one or more protrusions may extend from the inner wall of the chamber at the upper end of the chamber.
  • the opening may be defined in part by each of the one or more protrusions.
  • the fluidic layer may comprise a projection extending from an upper surface of the fluidic layer, wherein the projection defines, in part, the chamber.
  • the chamber may further comprise: a fluid inlet located below the one or more protrusions; and an air outlet located in the inner wall; wherein a first maximum distance between the air outlet and the upper end base is less than or equal to a second maximum distance between the one or more protrusions and the upper end.
  • Each of the one or more protrusions may comprise: a first protrusion portion extending from the inner wall of the chamber; and a second protrusion portion extending from a distal end of the first protrusion portion, wherein the second protrusion portion extends away from the upper end ofthe chamber.
  • a liquid handling device comprising: a first liquid storage container and a second liquid storage container, wherein each of the first and second liquid storage containers is configured to be opened by creating an inlet and an outlet in the liquid storage container; and a fluidic layer, comprising: a network of channels; and a pneumatic port configured to receive a positive pressure; wherein the network of channels comprises: a first liquid storage container inlet channel configured to provide a fluidic connection between the pneumatic port and the inlet in the first liquid storage container when the first liquid storage container is opened; and a second liquid storage container inlet channel configured to provide a fluidic connection between the pneumatic port and the inlet in the second liquid storage container when the second liquid storage container is opened.
  • the liquid handling device may further comprise: a first liquid storage container valve configured to control the flow of liquid from the outlet of the first liquid storage container; and a second liquid storage container valve configured to control the flow of liquid from the outlet of the second liquid storage container.
  • the network of channels further may comprise: a first liquid storage container outlet channel configured to be in fluidic communication with the outlet in the first liquid storage container when the first liquid storage container is opened, wherein the first liquid storage container valve is on the first liquid storage container outlet channel.
  • the network of channels may further comprise: a second liquid storage container outlet channel configured to be in fluidic communication with the outlet in the second liquid storage container when the second liquid storage container is opened, wherein the second liquid storage container valve is on the second liquid storage container outlet channel.
  • the liquid handling device may further comprise a well, wherein the well is defined at least partially by an opening extending through at least part of the thickness of the fluidic layer, wherein the well is in fluidic communication with the pneumatic port, the first liquid storage container inlet channel and the second liquid storage container inlet channel.
  • the opening, the first liquid storage container inlet channel and the second liquid storage container inlet channel may each be provided in an upper surface of the fluidic layer.
  • a depth of the opening may be greater than a depth of the first and second liquid storage container inlet channels.
  • the liquid handling device may further comprise a lower part, the lower part comprising a trough in an upper surface of the lower part.
  • the fluidic layer may be positioned on top of the lower part.
  • the well may be defined at least partially by the opening in the fluidic layer and the trough in the lower part.
  • the opening in the fluidic layer may extend through the thickness of the fluidic layer.
  • the pneumatic port may extend through the thickness of the fluidic layer, wherein the pneumatic port is in fluidic communication with the trough via a connector channel in the lower part.
  • the well may comprise an absorbent material.
  • Each of the first liquid storage container inlet channel and the second liquid storage container inlet channel may comprise: one or more first channel regions; and a second channel region, wherein a first depth of the one or more first channel regions is less than a second depth of the second channel region.
  • the second depth may be equal to the thickness of the fluidic layer.
  • a first width of the one or more first channel regions may be less than a second width of the second channel region.
  • the liquid handling device may further comprise a third liquid storage container, wherein the third liquid storage container is configured to be opened by creating an inlet and an outlet in the liquid storage container, and wherein the network of channels further comprises a third liquid storage container inlet channel configured to provide a fluidic connection between the pneumatic port and the inlet in the third liquid storage container when the third liquid storage container is opened.
  • the pneumatic port may be a first pneumatic port.
  • the liquid handling device may further comprise a second pneumatic port configured to be placed in fluidic communication with the outlet in the first liquid storage container.
  • the second pneumatic port may be configured to be placed in fluidic communication with the outlet in the second liquid storage container.
  • the liquid handling device may further comprise a third pneumatic port configured to be placed in fluidic communication with the outlet in the second liquid storage container.
  • a method of controlling liquid flow in a liquid handling device comprising: creating an inlet and an outlet in a first liquid storage container of the liquid handling device to create a fluidic connection between a pneumatic port of the liquid handling device and the inlet in the first liquid storage container; creating an inlet and an outlet in a second liquid storage container of the liquid handling device to create a fluidic connection between the pneumatic port and the inlet in the second liquid storage container; dispensing liquid from the outlet in the first liquid storage container by applying a positive pressure via the pneumatic port; and dispense liquid from the outlet in the second liquid storage container by applying a positive pressure via the pneumatic port.
  • Dispensing liquid from the outlet in the first liquid storage container may comprise opening a first liquid storage container valve configured to control the flow of liquid from the outlet in the first liquid storage container.
  • Dispensing liquid from the outlet in the second liquid storage container may comprise opening a second liquid storage container valve configured to control the flow of liquid from the outlet in the second liquid storage container.
  • the method may further comprise: creating an inlet and an outlet in a third liquid storage container of the liquid handling device to create a fluidic connection between the pneumatic port and the inlet of the third liquid storage container; and dispensing liquid from the outlet in the third liquid storage container by applying a positive pressure via the pneumatic port.
  • the pneumatic port may be a first pneumatic port.
  • the liquid handling device may comprise a second pneumatic port.
  • Dispensing liquid from the outlet in the first liquid storage container may comprise: opening one or more valves of the liquid handling device to create a fluidic connection between the outlet in the first liquid storage container and the second pneumatic port; and venting the second pneumatic port during application of the positive pressure via the first pneumatic port.
  • Dispensing liquid from the outlet in the second liquid storage container may comprise: opening one or more valves of the liquid handling device to create a fluidic connection between the outlet in the second liquid storage container and the second pneumatic port; and venting the second pneumatic port during application of the positive pressure via the first pneumatic port.
  • the liquid handling device may comprise a third pneumatic port.
  • Dispensing liquid from the outlet in the second liquid storage container may comprise: opening one or more valves of the liquid handling device to create a fluidic connection between the outlet in the second liquid storage container and the third pneumatic port; and venting the third pneumatic port during application of the positive pressure via the first pneumatic port.
  • a liquid handling device comprising: a first chamber in fluidic communication with a second chamber; a first pneumatic port in fluidic communication with one of the first chamber and the second chamber; a second pneumatic port in fluidic communication with the other one of the first chamber and the second chamber; a chamber inlet conduit configured to permit liquid to flow into the first chamber; a chamber outlet conduit configured to permit liquid to flow out of the second chamber; and a third pneumatic port in fluidic communication with a first liquid reagent capsule, wherein when the first liquid reagent capsule is opened, the first liquid reagent capsule is in selective fluidic communication with the first chamber or the second chamber.
  • selective fluidic communication between A and B means that A can be placed in fluidic communication with B by opening one or more valves in order to provide a fluidic connection between A and B through components of a fluidic network.
  • Liquid flow through the chamber inlet conduit may be controlled using a chamber inlet valve.
  • Liquid flow through the chamber outlet conduit may be controlled using a chamber outlet valve.
  • Liquid flow from the first liquid reagent capsule may be controlled using a first liquid reagent capsule valve.
  • the first pneumatic port may be in permanent fluidic communication with the first chamber.
  • the second pneumatic port may be in permanent fluidic communication with the second chamber.
  • the liquid handling device may further comprise: a first flow cell in fluidic communication with the second chamber via the chamber outlet conduit; a second flow cell in fluidic communication with the first flow cell; and a bypass conduit configured to permit liquid to bypass the second flow cell after flowing through the first flow cell. Liquid flow through the bypass conduit may be controlled using a bypass conduit valve.
  • the first flow cell is in fluidic communication with a waste chamber via a first flow cell outlet conduit. Liquid flow into the waste chamber via the first flow cell outlet conduit may be controlled using the bypass conduit valve.
  • the waste chamber may be permanently vented.
  • the second flow cell may be in fluidic communication with the waste chamber via a second flow cell outlet conduit. Liquid flow into the waste chamber via the second flow cell outlet conduit may be controlled using a second flow cell outlet valve.
  • the third pneumatic port may be in fluidic communication with a second liquid reagent capsule. Liquid flow from the second liquid reagent capsule may be controlled using a second liquid reagent capsule valve. When the second liquid reagent capsule is opened, the second liquid reagent capsule may be in selective fluidic communication with the second flow cell.
  • the second liquid reagent capsule When the second liquid reagent capsule is opened, the second liquid reagent capsule may be in fluidic communication with the second flow cell via the second flow cell outlet conduit.
  • the third pneumatic port may be in fluidic communication with a third liquid reagent capsule. Liquid flow from the third liquid reagent capsule may be controlled using a third liquid reagent capsule valve. When the third liquid reagent capsule is opened, the third liquid reagent capsule may be in selective fluidic communication with the first chamber. Additionally or alternatively, when the third liquid reagent capsule is opened, the third liquid reagent capsule may be in selective fluidic communication with the first flow cell.
  • the liquid handling device may further comprise a sample inlet chamber in fluidic communication with the chamber inlet conduit. Liquid flow from the sample inlet chamber may be controlled using a sample inlet valve.
  • the sample inlet chamber may be permanently vented.
  • the liquid handling device may further comprise a sample flow cell in fluidic communication with the sample inlet chamber via a sample flow cell inlet conduit. Liquid flow into the sample flow cell may be controlled using a sample flow cell valve.
  • the sample flow cell may be in fluidic communication with a sample flow cell waste chamber via a sample flow cell outlet conduit. Liquid flow into the sample flow cell waste chamber may be controlled using the sample flow cell valve.
  • the sample flow cell waste chamber may be in fluidic communication with the second pneumatic port.
  • the liquid handling device may further comprise a third chamber, wherein the third chamber is in fluidic communication with the first pneumatic port.
  • the first pneumatic port may be in permanent fluidic communication with the third chamber.
  • Liquid flow into the third chamber may be controlled using a third chamber valve.
  • the third chamber may be in fluidic communication with the first liquid reagent capsule.
  • the third chamber may house a dry reagent.
  • the first liquid reagent capsule may be in fluidic communication with the first chamber via a priming conduit. Liquid flow through the priming conduit may be controlled using a priming conduit valve.
  • the priming conduit may be in fluidic communication with the sample flow cell inlet conduit via the priming conduit valve.
  • the third pneumatic port may be in fluidic communication with an air/wash supply conduit. Air flow through the air/wash supply conduit may be controlled using an air supply valve. The air/wash supply conduit may be in fluidic communication with the chamber outlet conduit.
  • One or more of the first chamber and the second chamber may house a dry reagent.
  • a method of metering liquid in a channel of a liquid handling device comprising: applying a first pressure to move a first liquid from a first chamber through a first fluidic path including two junctions; applying a second pressure to move a fluid through a second fluidic path including a portion of the first fluidic path between the two junctions, such that the fluid displaces a volume of the first liquid between the two junctions.
  • the first pressure may be applied using a first pneumatic port of the liquid handling device, wherein the first pneumatic port is in selective fluidic communication with the first chamber.
  • the second pressure may be applied using a second pneumatic port of the liquid handling device, wherein the second pneumatic port is in selective fluidic communication with the second chamber.
  • the second pressure may be applied to dispense the fluid and the first liquid to a third chamber.
  • the first pressure may be applied to aspirate the first liquid from the first chamber through the first fluidic path.
  • the first chamber may be permanently vented.
  • the first pressure may be applied to dispense the first liquid from the first chamber through the first fluidic path.
  • the fluid may be a second liquid.
  • the second pressure may be applied to dispense the second liquid from a second chamber through the second fluidic path.
  • the fluid may be air.
  • the second pressure may be applied to supply air through an air supply conduit to the second fluidic path.
  • the method may further comprise metering multiple volumes of the first liquid by repeating, one or more times, the steps of: applying the first pressure to move the first liquid from the first chamber through the first fluidic path including the two junctions; applying the second pressure to move the fluid through the second fluidic path including the portion of the first fluidic path between the two junctions, such that the fluid displaces a volume of the first liquid between the two junctions.
  • a method of priming a fluidic circuit of a liquid handling device comprising: applying a first pressure to move liquid from a chamber into a first channel; continuing to apply the first pressure to move the liquid until a liquid front of the liquid has moved beyond a junction on the first channel, wherein the junction connects the first channel to a second channel; and applying a second pressure to move liquid from the chamber into the second channel via the first channel and the junction.
  • Applying the first pressure may comprise applying a negative pressure to move the liquid.
  • the chamber may be permanently vented.
  • Applying the second pressure may comprise applying a negative pressure to move the liquid.
  • Applying the first pressure may comprise applying a negative pressure to a first pneumatic port of the liquid handling device.
  • Applying the second pressure may comprise applying a negative pressure to a second pneumatic port of the liquid handling device.
  • Applying the second pressure may comprise applying a positive pressure to move the liquid. Applying the second pressure may comprise applying a positive pressure to the first pneumatic port of the liquid handling device. Applying the second pressure may comprise applying a positive pressure to the first pneumatic port of the liquid handling device while venting a third pneumatic port of the liquid handling device.
  • a method of diluting a sample using a liquid handling device comprising: applying a negative pressure to aspirate a volume of a first liquid into a first flow cell of the liquid handling device; applying a negative pressure to aspirate a volume of the first liquid into a first chamber of the liquid handling device; applying a positive pressure to dispense a volume of a second liquid into the first chamber; repeating, one or more times, the steps of: applying a positive pressure to dispense the first liquid and the second liquid from the first chamber to the second chamber; and applying a negative pressure to aspirate the first liquid and the second liquid from the second chamber to the first chamber; applying a positive pressure to move a mixture comprising the first liquid and the second liquid from the first chamber or the second chamber to the second flow cell.
  • the method may further comprise measuring a detection signal in the first flow cell.
  • the method may further comprise measuring a detection signal in the second flow cell.
  • the volume of the first liquid aspirated into the first chamber may be a metered volume of the first liquid.
  • the volume of the second liquid dispensed into the first chamber may be a metered volume of the second liquid.
  • a method of resuspending dry reagents using a liquid handling device comprising: applying a first pressure to transfer a metered volume of a first liquid into a first chamber to resuspend one or more first dry reagents, wherein resuspending the one or more first dry reagents forms a first reagent; applying a second pressure to transfer a metered volume of the first liquid into a second chamber to resuspend one or more second dry reagents, wherein resuspending the one or more second dry reagents forms a second reagent; applying a third pressure to move the first reagent through at least one flow cell; applying a fourth pressure to move the second reagent through the at least one flow cell; and measuring a detection signal in the at least one flow cell.
  • the volume of the first liquid transferred into the first chamber may be a metered volume of the first liquid.
  • the volume of the first liquid transferred into the second chamber may be a metered volume of the first liquid.
  • FIG. 1 is an isometric view of a liquid handling device.
  • FIG. 2 is an isometric view of the liquid handling device shown in FIG. 1 with a label of the liquid handling device having been removed.
  • FIG. 3 is an exploded view showing the components of the liquid handling device in FIG. 1 .
  • FIG. 4 is an exploded view of components shown in FIG. 3 that are assembled in a first assembly stage.
  • FIG. 5 is an exploded view of components shown in FIG. 3 that are assembled in a second assembly stage.
  • FIG. 6 is an exploded view of components shown in FIG. 3 that are assembled in a third assembly stage.
  • FIG. 7 is a top view of the liquid handling device shown in FIG. 1 with a label of the liquid handling device having been removed.
  • FIG. 8 is a top view showing liquid storage capsules attached to a fluidic layer of the liquid handling device shown in FIG. 1.
  • FIG. 9A is an exploded view showing components of the liquid storage capsules shown in FIG. 8 according to a first example.
  • FIG. 9B is an exploded view showing components of the liquid storage capsules shown in FIG. 8 according to a second example.
  • FIG. 10 is an isometric view of a first part of the liquid handling device shown in FIG. 1.
  • FIG. 11 is a top view of the first part shown in FIG. 10.
  • FIG. 12 is an underside view of the first part shown in FIG. 10.
  • FIG. 13 is a section view through line A-A in FIG. 12.
  • FIG. 14 is a top view of the liquid handling device shown in FIG. 1.
  • FIG. 15 is a section view through line P-P in FIG. 14.
  • FIG. 16 is a section view through line Q-Q in FIG. 14.
  • FIG. 17 is an enlarged section view of region R shown in FIG. 15.
  • FIG. 18 is a top view showing the liquid storage capsules and fluidic layer of the liquid handling device shown in FIG. 1 , where the liquid storage capsules and fluidic layer are shown as partially transparent.
  • FIG. 19 is a top view showing protrusions of an actuatable portion of the first part shown in FIG. 10 overlaid on FIG. 18.
  • FIG. 20 is a section view through line H-H in FIG. 7.
  • FIG. 21 is an enlarged section view of region S shown in FIG. 20.
  • FIG. 22 is a schematic diagram showing a protrusion, a deformable portion of a liquid storage capsule, and an opening in a fluidic layer.
  • FIG. 23 is an isometric view of a second part of the liquid handling device shown in FIG. 1 .
  • FIG. 24 is a top view of the second part shown in FIG. 23.
  • FIG. 25 is an exploded view of certain components shown in FIG. 3.
  • FIG. 26 is a top view of a fluidic layer of the liquid handling device shown in FIG. 1 .
  • FIG. 27 is a bottom view of the fluidic layer shown in FIG. 26.
  • FIG. 28 is a schematic diagram of a fluidic network defined by channels in the fluidic layer shown in FIGS. 26 and 27.
  • FIG. 29 is a further schematic diagram of the fluidic network shown in FIG. 28
  • FIG. 30 is a side view of the fluidic layer shown in FIG. 26.
  • FIG. 31 is a section view through the fluidic layer shown in FIG. 26.
  • FIG. 32 a top view of the components shown in FIG. 25 when assembled.
  • FIG. 33 is a section view through line Z-Z in FIG. 32.
  • FIG. 34 is an enlarged section view of region T shown in FIG. 33.
  • FIG. 35 is a flowchart of a method of controlling liquid flow in a liquid handling device.
  • FIG. 36 is a flowchart of a method of metering liquid in a channel of a liquid handling device.
  • FIG. 37 is a flowchart of a method of priming a fluidic circuit of a liquid handling device.
  • FIG. 38 is a flowchart of a method of diluting a sample using a liquid handling device.
  • FIG. 39 is a flowchart of a method of resuspending dry reagents using a liquid handling device.
  • FIG. 40 is a flowchart of a method of carrying out a first assay using the liquid handling device shown in FIG. 1.
  • FIG. 41 is a flowchart of a method of carrying out a second assay using the liquid handling device shown in FIG. 1.
  • FIG. 42 is a flowchart of a method of carrying out a third assay using the liquid handling device shown in FIG. 1.
  • FIG. 43 is a flowchart of a method of carrying out a fourth assay using the liquid handling device shown in FIG. 1.
  • microfluidic cartridge is intended to refer to a device with conduits having a width or depth of less than 1 mm. It will further be appreciated that the implementations described herein are not limited to microfluidics, and are applicable to liquid handling devices, of various sizes, that are used for various purposes.
  • FIG. 1 is an isometric view of a liquid handling device in the form of a diagnostic cartridge 100 (e.g. a microfluidic cartridge), while FIG. 2 shows an isometric view of the cartridge 100 with a label 110 of the cartridge removed.
  • the cartridge 100 comprises a number of components, as seen from the exploded view shown in FIG. 3.
  • the cartridge 100 comprises a first part 200 and a second part 500, each of which is formed of a rigid material.
  • the first part 200 is an upper part and the second part 500 is a lower part.
  • the first part 200 and the second part 500 define a housing of the cartridge 100.
  • the first part 200 comprises a rigid face 250 that defines an upper surface of the cartridge 100.
  • the second part 500 comprises a rigid face 570 (as shown for example in FIG. 15) that defines a lower surface of the cartridge 100.
  • first part 200 further comprises side walls 252 that are joined to the rigid face 250
  • second part 500 further comprises side walls 572 joined to the rigid face 570.
  • the side walls 252 of the first part 200 and the side walls 572 of the second part 500 cooperate to define the side walls of the cartridge 100.
  • the cartridge 100 further comprises a fluidic layer 300 disposed within the housing defined by the first part 200 and the second part 500.
  • the fluidic layer 300 is disposed between the rigid face 250 of the first part 200 and the rigid face 570 of the second part 500. Therefore, the fluidic layer 300 is disposed between a first rigid layer in the form of the rigid face 250, and a second rigid layer in the form of the rigid face 570.
  • the fluidic layer 300 is formed of an elastomeric material, such as a thermoplastic elastomer (TPE), for example, a silicon-based TPE or styrene-ethylene- butylene-styrene (SEBS); polydimethylsiloxane (PDMS); or liquid silicone rubber (LSR).
  • TPE thermoplastic elastomer
  • SEBS silicon-based TPE
  • SEBS styrene-ethylene- butylene-styrene
  • PDMS polydimethylsiloxane
  • LSR liquid silicone rubber
  • a first surface 308 of the fluidic layer 300 comprises a plurality of valve regions 302 (shown, for example, in FIGS. 25 and 26).
  • the cartridge 100 is received in an analyser device that comprises actuators that apply forces to the valve regions 302 of the fluidic layer 300, to close one or more conduits 600 (best shown in FIGS. 16 and 21 ) within the cartridge 100.
  • the properties of the material used for the fluidic layer 300 are dependent on the available force that can be applied to the valve regions 302 of the fluidic layer 300 by the actuators. Two properties of importance are the hardness of the material, and the relaxation time of the material (i.e. the time for the material to return to its original form following deformation). Examples of suitable materials include the elastomeric materials listed above.
  • the fluidic layer 300 may be a medical-grade material, to prevent reaction of the fluidic layer 300 with the reagents used in the diagnostic test or assay.
  • the fluidic layer 300 comprises a network of channels 304 (shown in FIGS. 26 and 27), some of which are provided in the first surface 308, and others of which are provided in a second surface 310 of the fluidic layer 300 that is opposite to the first surface 308.
  • the cartridge 100 also comprises a fluidic network comprising a plurality of conduits 600, which are defined at least in part by the network of channels 304 in the fluidic layer 300.
  • the conduits 600 are defined by: (i) the network of channels 304 in the fluidic layer 300; (ii) a first sealing layer 400 (shown in FIG. 3) that is configured to seal the channels 304 in the second surface 310 of the fluidic layer 300; and (Hi) a second sealing layer 410 configured to seal the channels 304 in the first surface 308 of the fluidic layer.
  • Providing channels 304 in an elastomeric fluidic layer 300 provides improved sealing of the fluidic layer, irrespective of the bonding process used to seal the network of channels 304 (e.g. pressuresensitive adhesive tape, laser welding, etc.). This is because the elastomeric fluidic layer 300 acts as a compliant layer when it is being sealed against another layer (e.g. sealing layer 400).
  • using an elastomeric material for the fluidic layer 300 means that the channels 304 can be compressed in order to close respective conduits 600. This means that a single layer can be utilised to implement the channels 304 and valves (i.e. valve regions 302), thereby providing a simple cartridge construction.
  • the cartridge 100 further comprises: a label 110 arranged to cover at least a portion of the rigid face 250 of the first part 200; a plurality of liquid storage capsules 120 that are disposed within the cartridge 100 between the fluidic layer 300 and the first face 250; sealing tapes 130a and 130b arranged to seal chambers 332 in the fluidic layer (with the chambers 332 being best shown in FIG.
  • a sealing tape 180 for attaching the liquid storage capsules 120 to the second sealing layer 410; a sensor strip 150 comprising a plurality of sensors, each sensor in fluidic communication with a respective measurement chamber 610 defined by a corresponding aperture 454 in the first sealing layer 400; and a plurality of absorbent waste pads 160, each arranged to fit within a corresponding waste chamber 508a, 508b or trough 514a, 514b provided in the second part 500 (with the waste chambers 508 and troughs 514 being best shown in FIG. 24).
  • the first part 200 comprises a receptacle in the form of a cylinder 202, which is configured to receive a portion of a liquid storage container such as a blood collection tube (e.g. a Vacutainer (RTM) blood collection tube manufactured by Becton, Dickinson and Company of Franklin Lakes, NJ, USA).
  • a blood collection tube typically contains a volume of liquid (e.g. blood), and a headspace that includes a volume of gas.
  • the cylinder 202 may be as described in PCT/EP2022/087658, the entire contents of which are hereby incorporated by reference, and the cartridge may further comprise an actuatable liquid extraction mechanism as described PCT/EP2022/087658.
  • the actuatable liquid extraction mechanism may be any of the actuatable liquid extraction mechanisms described in PCT/EP2022/071433, the entire contents of which are hereby incorporated by reference.
  • FIG. 3 also shows the arrangement of the plurality of liquid storage capsules 120 within the cartridge 100.
  • the liquid storage capsules 120 are sealed to the fluidic layer 300 using a sealing tape 180.
  • each liquid storage capsule 120 comprises an inlet chamber 122, a main chamber 124 (also referred to herein as a “liquid storage chamber”) storing a liquid such as a liquid reagent, and an outlet chamber 126.
  • a sealing layer 136 e.g. a sealing foil is used to seal the chambers 122, 124, 126 of each liquid storage capsule 120.
  • the capsule 120 also includes a first restriction 123 between the inlet chamber 122 and the liquid storage chamber 124, and a second restriction 125 between the liquid storage chamber 124 and the outlet chamber 126.
  • Each of the first and second restrictions 123, 125 is provided in the form of a neck (or narrowed region) between the liquid storage chamber 124 and the inlet/outlet chamber.
  • the inlet chamber 122 is in fluidic communication with the liquid storage chamber 124 via the first restriction 123.
  • the outlet chamber 126 is in fluidic communication with the liquid storage chamber 124 via the second restriction 125.
  • the liquid storage capsules 120 may be as described in PCT/EP2022/058804, the entire contents of which are hereby incorporated by reference.
  • the liquid storage capsules 120 shown in FIG. 3 comprise one larger liquid storage capsule (i..e a first liquid storage capsule 120a) and two smaller liquid storage capsules (i.e. a second liquid storage capsule 120b and a third liquid storage capsule 120c).
  • Each of the smaller liquid storage capsules 120b, 120c is arranged perpendicular to the larger liquid storage capsule 120a, such that the smaller liquid storage capsules 120b, 120c are parallel to each other.
  • each of the liquid storage capsules 120 is positioned over two openings 350 in the fluidic layer 300.
  • the material of the liquid storage capsule 120 is deformed into each of the openings 350.
  • the deformation of the liquid storage capsule 120 into the openings 350 causes rupture of the sealing layer (e.g. foil) used to seal the capsule 120.
  • FIG. 4 shows a first assembly stage of the cartridge 100. Firstly, the absorbent waste pads 160 are located in the waste chambers 508 and troughs 514 provided in the second part 500. Next, the sensor strip 150 is positioned at one end of the second part 500. A fluidic layer assembly (comprising the fluidic layer 300, the first sealing layer 400 and the second sealing layer 410) is then positioned within the second part 500.
  • FIG. 5 shows a second assembly stage, in which the liquid reagent capsules 120 and sealing tape 180 are attached to the fluidic layer assembly such that the liquid reagent capsules 120 are positioned over openings 350 in the fluidic layer 300.
  • FIG. 6 shows a third assembly stage, in which the first part 200 is coupled to the second part 500 to form the cartridge housing.
  • FIG. 7 is a top view of the cartridge 100 with the label 110 removed.
  • the first part 200 comprises an actuatable portion 240 (e.g. an actuatable platform).
  • the actuatable portion 240 is positioned over the liquid storage capsules 120.
  • the actuatable portion 240 is actuatable from a first position, in which the actuatable portion 240 does not deform the liquid storage capsules 120, to a second position, in which the actuatable portion 240 deforms the liquid storage capsules 120.
  • the actuatable portion 240 is actuatable relative to the rigid face 250 of the first part 200, and is actuatable in a direction normal to the rigid face 250 of the first part 200.
  • the actuatable portion 240 is rigid.
  • the actuatable portion 240 is U-shaped, such that it can be deformed towards each of the liquid storage capsules 120.
  • the U-shape of the actuatable portion 240 also allows the actuatable portion 240 to pass around a projection 330 (also shown in FIG. 25) that extends from the first surface 308 of the fluidic layer 300 and a pneumatic port 312 in the fluidic layer 300.
  • the sealing tape 180 also includes an indent 182 that allows the chambers 332 and pneumatic ports 312 to protrude through the sealing tape 180.
  • FIG. 9A shows the liquid storage capsules 120 in more detail.
  • each liquid storage capsule 120 includes a capsule body 134 that defines the shape of the liquid storage chamber 124, the inlet chamber 122, the outlet chamber 126 and the first and second restrictions 123, 125.
  • the capsule body 134 includes an aperture via which the capsule 120 is filled, as best shown in FIG. 9B.
  • the capsule 120 further comprises a sealing layer 136 that seals the aperture, as shown in FIG. 9B.
  • the sealing layer 136 is attached to the sealing tape 180.
  • the sealing tape 180 includes a first set of openings 184 that have the same size and shape as the openings 350 in the fluidic layer 300 over which the liquid storage capsules 120 are positioned. The size and shape of these openings 350 (and corresponding first set of openings 184 in the sealing tape 180) are described further below.
  • FIG. 9A also shows that the sealing tape 180 includes a second set of openings 186, which allow access to the valve regions 302 defined by the fluidic layer 300.
  • the inlet chamber 122 and the outlet chamber 126 each comprise first region 127a, 127b and a second region 128a, 128b (also referred to herein as a “recess”) in a top surface of the chamber 122, 126.
  • the first region 127 and the second region 128 are concentric, such that the first region 127 surrounds the second region 128.
  • the distance between the first region 127 and the sealing layer 136 is greater than the distance between the second region 128 and the sealing layer 136.
  • the second region 128 provides a recess in the top surface of the chamber 122, 126, wherein the recess is surrounded by the first region 127 of the chamber 122, 126.
  • FIG. 9B shows an alternative construction of the liquid storage capsules, in which a single part 134a defines the capsule bodies 134 of all three liquid storage capsules 120.
  • the apertures in the liquid storage capsules 120 are sealed using a single sealing layer 136a.
  • the single sealing layer 136a includes openings 138 that allow access to the valve regions 302 defined by the fluidic layer 300.
  • FIG. 10 is an isometric top view of the first part 200.
  • the top surface (i.e. exterior surface) of the actuatable portion 240 is flat (or includes a plurality of flat regions).
  • the flat surface of the actuatable portion 240 allows the actuatable portion 240 to be easily moved from the first position to the second position, without requiring a particular shape of actuator to move the actuatable portion 240.
  • the first part 200 includes a plurality of resiliently deformable members 246 (in the example shown in FIGS. 10 and 11 , four resiliently deformable members 246 are shown).
  • Providing a plurality of resiliently deformable members 246 allows the actuatable portion 240 to be actuated in a vertical direction, meaning that the actuatable portion 240 is parallel to a base (i.e. the sealing layer) of each liquid storage capsule 120 when the actuatable portion 240 is in the first portion and when the actuatable portion 240 is in the second position.
  • Vertical movement of the actuatable portion 240 allows substantially the same force to be applied to the recesses 128 of a particular liquid storage capsule 120.
  • a first one of the resiliently deformable members 246 is connected to a first edge 256a of the actuatable portion 240; a second one of the resiliently deformable members 246 is connected to a second edge 256b of the actuatable portion 240 that is opposite to the first edge 256a; a third one of the resiliently deformable members 246 is also connected to the first edge 256a of the actuatable portion 240, but spaced apart from the connection point of the first one of the resiliently deformable members 246; and a fourth one of the resiliently deformable members 246 is connected to a third edge 256c of the actuatable portion 240 that is also opposite to the first edge 256a.
  • the underside of the actuatable portion 240 comprises three pairs of protrusions 242 (shown in section view in FIG. 13). Each pair of protrusions 242 extends towards the liquid storage capsules 120 and is aligned with the inlet chamber 122 and outlet chamber 126 of one of the liquid storage capsules 120. When the actuatable portion 240 is moved to the second position, one of each pair of protrusions 242 deforms the inlet chamber 122, while the other one of the pair of protrusions deforms the outlet chamber 126.
  • the actuatable portion 240 when the actuatable portion is moved from the first position to the second position, the deformation of the inlet chamber 122 and the outlet chamber 126 by the protrusions 242 forces the recesses 128 (defined by the capsule body 134) into contact with the sealing layer 136.
  • the force applied to the sealing layer 136 by the recesses 128 is high enough to cause rupture of the sealing layer 136.
  • the rupture of the sealing layer 136 provides an inlet (in the sealing layer 136) to the inlet chamber 122, and an outlet (in the sealing layer 136) from the outlet chamber 126.
  • the liquid storage capsules 120 may not include recesses 128, in which case the protrusions 242 may deform a portion of the inlet and outlet chambers 122, 126 (e.g. a flat or domed upper surface of the inlet and outlet chambers 122, 126) of each liquid storage capsule 120 so that a portion of the capsule body 134 is forced into contact with the sealing layer 136.
  • the protrusions 242 are sized and shaped so that they cannot pass into the openings 350 in the fluidic layer that are covered by the liquid storage capsules 120. This means that downward displacement of the protrusions 242 is limited by the second sealing layer 410 and the first surface 308 of the fluidic layer 300. Consequently, the protrusions 242 cannot be forced through both the capsule body 134 and the sealing layer 136.
  • the openings 350 that are covered by the liquid storage capsules 120 are positioned so that the inlet chamber 122 and the restriction 123 of a liquid storage capsule 120 are at least partly positioned over one opening 350 while the outlet chamber 126 and the restriction 125 are at least partly positioned over another opening 350.
  • the protrusions 242 deform the inlet chamber 122 and the outlet chamber 126, but do not deform the restrictions 123, 125. Therefore, even if the recesses 128 are forced into the openings 350, part of the opening remains unblocked because it is positioned below one of the restrictions 123, 125.
  • Positioning each restriction 123, 125 partially over one of the openings 350 also means that the fluidic layer 300 provides less reaction force when a force is applied to the top of the restriction 123, 125, reducing the likelihood of the restriction 123, 125 becoming crushed during actuation of the actuatable portion 240.
  • the protrusion 242 and the liquid storage capsule 120 are sized and positioned in relation to each other such that when the actuatable portion 240 is in the second position, the protrusions 242 do not deform the restrictions 123, 125. Consequently, the risk of blockage within the liquid storage capsule 120 is reduced.
  • each of the protrusions 242 comprises a groove 243 that defines a crosssection of the end of the protrusion 242.
  • the groove 243 of each protrusion 242 is aligned with a corresponding restriction 123, 125 of a liquid storage capsule 120.
  • FIG. 19 shows that four of the protrusions 242 have an end cross-section with a major sector shape, while the other two protrusions 242 have an end cross-section with a trapezoid shape having the groove 243 in the longer parallel edge of the trapezoid.
  • Providing the groove 243 in the end cross-section of each protrusion 242 reduces the risk of the protrusion 242 deforming the restriction 123, 125 of the liquid storage capsule 120 when deforming the inlet chamber 122 and the outlet chamber 126.
  • the end crosssection also includes a plurality of outwardly extending projecting ribs 245 that extend from a curved portion of the major sector shape.
  • the outwardly extending projecting ribs 245 serve to maximise the overall width of the protrusions 242 (thereby preventing the protrusions 242 from passing into the openings 350), while minimising the overall cross-sectional area of the end of the protrusions 242 (because the larger the area of the end of the protrusion 242, the higher the force needed to deform the capsule body 134).
  • the perimeter of the trapezoid prevents the protrusion 242 from passing into the openings 350.
  • the trapezoid-shaped protrusions 242 may also be provided with outwardly extending projecting ribs 245.
  • FIG. 13 is a cross-section through the first part 200, showing the resiliently deformable members 246 in more detail.
  • the underside of the actuatable portion 240 also includes concave regions 244.
  • the actuatable portion 240 includes three concave regions, which can be seen in FIGS. 16 and 17.
  • Each concave region 244 is provided between two of the protrusions 242.
  • Each concave region 244 is configured to accommodate the main chamber 124 of its corresponding liquid storage capsule 120 when the actuatable portion 240 is in the second position. This means that the main chamber 124 is not deformed by the actuatable portion 240 when the actuatable portion 240 is in the second position.
  • FIG. 13 also shows the resiliently deformable members 246 that couple the actuatable portion 240 to the first part 200.
  • the resiliently deformable members 246 are configured to bias the actuatable portion 240 away from the second position (i.e. towards the first position). The resiliently deformable members 246 therefore force the actuatable portion away from engagement with the inlet and outlet chambers 122, 126 of the liquid storage capsules 120.
  • Each resiliently deformable member 246 has a curved (specifically, U-shaped) profile, which allows the resiliently deformable member 246 to undergo elastic deformation during movement of the actuatable portion 240 to the second position.
  • the resiliently deformable members 246 are formed of the same material as the actuatable portion 240 and the first part 200. In other words, the resiliently deformable members 246 are integral with the first part 200 and the actuatable portion 240, and are each provided in the form of a resilient living hinge. This allows the manufacture of the first part 200, including the actuatable portion 240 and the resiliently deformable members 246, to be simplified (e.g. produced by injection moulding).
  • FIGS. 11 and 12 also show that the rigid face 250 includes a plurality of apertures 254.
  • the plurality of apertures 254 includes apertures 254a that are aligned with the valve regions 302 of the fluidic layer 300, an aperture 254b aligned with a first pneumatic port 312a of the fluidic layer 300, and an aperture 254c that provides an opening for a second pneumatic port 312b and a third pneumatic port 312c of the fluidic layer 300, along with the projection 330 extending from the first surface 308 of the fluidic layer 300 (as shown, for example, in FIG. 25).
  • the ports 312 and projection 330 are described with reference to FIG. 30.
  • the apertures 254a in the rigid face 250 allow the valve regions 302 of the fluidic layer 300 to be accessed by an external valve actuator.
  • the apertures 254b and 254c allow the pneumatic ports 312 of the fluidic layer 300 to be accessed by an external pneumatic actuator.
  • FIGS. 15 to 17 show the alignment of the protrusions 242 with the inlet and outlet chambers 122, 126 of the liquid storage capsules 120, when the actuatable portion 240 is in the first position. It will be appreciated that when a force is applied to the actuatable portion 240 to move the actuatable portion 240 towards its second position, the protrusions 242 engage the inlet and outlet chambers 122, 126 and cause deformation of the inlet chamber 122 and the outlet chamber 126 of the liquid storage capsule 120 to force the recesses 128 into contact with the sealing layer 136.
  • the portion of the sealing layer 136 at the underside of the inlet chamber 122 is deformed into the first one of the openings 350, and the portion of the sealing layer 136 at the underside of the outlet chamber 126 is deformed into the second one of the openings 350.
  • the deformation of the inlet chamber 122 and the outlet chamber 126 causes rupturing of the material at the underside of the inlet chamber 122 and the outlet chamber 126, meaning that an opening is created in each of the inlet chamber 122 and the outlet chamber 126.
  • the top surface of the capsules 120 is formed of a material that is capable of plastic deformation, in order to allow for deformation of the recesses 128.
  • FIGS. 15 and 17 show one of the concave regions 244 that accommodates a main chamber 124 of the second liquid storage capsule 120b.
  • FIGS. 15 and 17 also show that the second liquid storage capsule 120b and the openings 350 it covers are sized and positioned with respect to one another so that the inlet chamber 122 and the restriction 123 of the second liquid storage capsule 120b are partially positioned over one of the openings 350, while the outlet chamber 126 and the restriction 125 are partially positioned over another one of the openings 350.
  • FIG. 16 shows the concave region 244 that accommodates the main chamber 124 of the first liquid storage capsule 120a, which can also be seen in FIG. 15.
  • first liquid storage capsule 120a and the openings 350 it covers are sized and positioned with respect to one another so that the inlet chamber 122 and the restriction 123 of the first liquid storage capsule 120a are partially positioned over one of the openings 350, while the outlet chamber 126 and the restriction 125 are partially positioned over another one of the openings 350.
  • FIG. 18 shows, in partially transparent view, the positioning of the liquid storage capsules 120 with respect to the openings 350 in the fluidic layer 300.
  • the openings 350 and the liquid storage capsules 120 are sized and positioned with respect to one another so that each opening 350 extends partially beneath one of the restrictions 123, 125 of one of the liquid storage capsules 120.
  • each of the openings 350 and the liquid storage capsules 120 are sized and positioned with respect to one another so, for each liquid storage capsule 120, the inlet chamber 122 and the restriction 123 of the liquid storage capsule 120 are partially positioned over a first opening 350 covered by the liquid storage capsule 120, while the outlet chamber 126 and the restriction 125 of each liquid storage capsule 120 are partially positioned over a second opening 350 covered by the liquid storage capsule 120.
  • FIG. 18 also shows that each of the openings 350 has an obround shape. The obround shape allows the openings 350 to extend beneath the inlet or outlet chamber 122, 126 and adjoining restriction 123, 125, while minimising the width of the openings 350.
  • a circular opening extending beneath the inlet or outlet chamber and adjoining restriction would be large enough to prevent blockage of the opening by the capsule body 134 (specifically, the recess 128), but may not prevent the protrusion 242 from puncturing both the capsule body 134 and the sealing layer 136 of the liquid storage capsule 120.
  • FIG. 19 shows that the width of each opening 350 (i.e. the width of the obround shape) is less than the width of the corresponding protrusion 242 that is aligned with the opening 350.
  • the footprint of each protrusion 242 extends outside of the footprint of the corresponding opening 350 with which it is aligned.
  • the perimeter of each protrusion 242 extends outside the perimeter of the corresponding opening 350 with which it is aligned. This means that, as shown in FIG. 19, each protrusion 242 is unable to pass into the corresponding opening 350 with which it is aligned.
  • each protrusion 242 also shows the alignment of the groove 243 of each protrusion 242 with the restriction 123, 125 that partially covers the opening 350 with which the protrusion 242 is aligned.
  • the groove 243 of each protrusion 242 is aligned with a centreline passing through (i) the recess 128 of the inlet or outlet chamber 122, 126 with which the protrusion 242 is aligned, and (ii) the restriction 123, 125 adjoining the inlet or outlet chamber 122, 126 with which the protrusion 242 is aligned.
  • FIG. 20 is a cross-section through the inlet chambers 124 of each of the smaller liquid storage capsules 120b, 120c.
  • the width of each of the protrusions 242 is greater than the width of the corresponding opening 350 with which it is aligned, meaning that no part of the protrusions 242 can pass into the corresponding opening 350 with which it is aligned.
  • FIGS. 20 and 21 show that the end of each protrusion 242 is flat. Providing a flat end of each protrusion 242 means that no part of the protrusion 242 can pass into the opening 350 with which the protrusion 242 is aligned. The flat end of the protrusions 242 also reduces the risk of puncturing the capsule body 134 when deforming the inlet and outlet chambers 122, 126 of the liquid storage capsules 120.
  • FIG. 22 schematically shows a protrusion 242, an inlet or outlet chamber 122, 126 of a liquid storage chamber 120, and an opening 350 from the same position as shown in FIGS. 20 and 21 (i.e. looking through the width of the opening 350). Three distances are indicated in FIG. 22.
  • a first distance, indicated as ‘O’, is the clearance between the inlet or outlet chamber 122, 126 (specifically, the first region 127 of the inlet or outlet chamber 122, 126) and the end of the protrusion 242.
  • a second distance, indicated as ‘DT is the displacement of the capsule body 134 (specifically, the recess 128 of the inlet or outlet chamber 122, 126) without piercing the sealing layer 126 after the protrusion contacts the first region 127 of the inlet or outlet chamber 122, 126.
  • a third distance, indicated as ‘D2’ is the displacement of the capsule body 134 (specifically, the recess 128 of the inlet or outlet chamber 122, 126) during piercing of the sealing layer 126. It can be seen from FIG. 22 that D2 is limited by the protrusion 242 being unable to pass into the opening 350, reducing the risk of the protrusion 242 puncturing the capsule body 134.
  • the distances C and D1 are implemented in order to prevent early piercing of the liquid storage capsules 120 during manufacturing and handling.
  • the width of the protrusion 242 is also greater than the width of the second portion 128 (or recess), reducing the likelihood of the protrusion 242 passing into the recess 128, and thereby reducing the likelihood of the protrusion 242 piercing the both the capsule body 134 and the sealing layer 136.
  • FIG. 23 shows an isometric view of the second part 500
  • FIG. 24 shows a top view of the second part 500
  • the second part 500 includes a sample waste chamber defined by a first well 504 in the upper surface of the second part 500.
  • the sample waste chamber receives excess sample during receipt of the sample in the cartridge 100.
  • the sample waste chamber is in fluidic communication with a permanent vent 506, provided in the form of a hole in the second part 500. Accordingly, a sample inlet chamber 236 in the first part 200 (shown in FIG. 12), which receives the sample, is permanently vented via the permanent vent 506.
  • the second part 500 further comprises two further waste chambers (first waste chamber 508a and second waste chamber 508b), each of which is provided in the form of two recesses in the interior surface of the rigid face 570.
  • the first waste chamber 508 is in fluidic communication with a first trough 514a in the interior surface of the rigid face 570.
  • the second waste chamber is in fluidic communication with the first well 504, and is therefore permanently vented via the permanent vent 506.
  • the second part 500 further comprises a first trough 514a in the form of a circular depression in the interior surface of the rigid face 570, a second trough 514b in the form of a circular depression in the interior surface of the rigid face 570, and a third trough 514c in the form of a circular depression with integral finger in the interior surface of the rigid face 570.
  • Each of the troughs 514 provides a fluidic connection between a pneumatic port 312 in the fluidic layer 300 and one or more channels 304 of the fluidic layer 300, as described in more detail below. Specifically, as described with reference to FIG. 26, a number of the channels 304 are fluidically connected to the troughs 514, via holes in the sealing layer 400.
  • the second part 500 further comprises a first pneumatic port support region 516a, provided adjacent to the first trough 514a, a second pneumatic port support region 516b, provided adjacent to the second trough 514b, and a third pneumatic port support region 516c, provided adjacent to the third trough 514c.
  • Each of the pneumatic port supports 516 is disposed beneath a corresponding pneumatic port 312 of the fluidic layer 300, when the cartridge 100 is assembled.
  • the first pneumatic port support region 516a comprises a connector channel 518a that connects the first pneumatic port 312a to the first trough 514a.
  • the second pneumatic port support region 516b comprises a connector channel 518b that connects the second pneumatic port 312b to the second trough 514b.
  • the third pneumatic port support region 516c comprises a connector channel 518c that connects the third pneumatic port 312c to the third trough 514c.
  • the port support regions 516 are in contact with the underside of the sealing layer 400 used to seal the channels 304 in the second surface 310 of the fluidic layer 300. This means that, when a force is applied to the pneumatic ports 312 of the fluidic layer 300, the contact between the sealing layer 400 and the port supports 516 provides a reaction force against the applied force, thereby preventing downward deformation of the sealing layer 400. This helps the pneumatic ports 312 to form a seal with a pneumatic actuator.
  • the troughs 514 in the second part 500 prevent liquid from reaching the pneumatic ports 312, which connect to pneumatic actuators of the analyser device. Accordingly, the troughs 514 prevent liquid from reaching the analyser device, particularly during aspiration of liquid. Such liquid could potentially contaminate or damage the analyser device.
  • the pneumatic pressure is supplied via the connector channel 518 of the port support 516.
  • the connector channel 518 is disposed above the base of the trough 514, meaning that any liquid drawn from the channels 304 in the fluidic layer 300 pools in the bottom of the trough 514 and does not reach the connector channel 518. Therefore, any liquid drawn from the channels 304 in the fluidic layer 300 is not drawn through the connector channel 518 and into the analyser via the pneumatic port 312.
  • the fluidic communication between the first waste chamber 508a and the first trough 514a allows the venting state of the waste chambers 508 to be controlled via the first pneumatic port 312a (i.e. by either venting or not venting the first pneumatic port 312a using the analyser in which the cartridge 100 is received).
  • the second part 500 also comprises a plurality of valve support regions 524 (indicated by dashed circle lines in FIG. 24). In the example shown in FIGS. 23 and 24, twelve valve support regions 524 are shown. Each of the valve support regions 524 is aligned with a corresponding valve region 302 in the fluidic layer 300. Each of the valve support regions 524 contacts the underside of the sealing layer 400 used to seal the channels 304 in the second surface 310 of the fluidic layer 300. This means that, when a force is applied to a valve region 302 of the fluidic layer 300 by an actuator of the analyser, the valve region 302 is compressed between the actuator and the corresponding valve support region 524. The waste chambers 508a, 508b do not, therefore, extend beneath the valve regions 302 of the fluidic layer 300.
  • the second part 500 further comprises a plurality of capsule support regions 526 (again indicated by dashed square lines in FIG. 24).
  • a plurality of capsule support regions 526 (again indicated by dashed square lines in FIG. 24).
  • six capsule support regions 526 are shown.
  • Each of the capsule support regions 526 is aligned with a corresponding opening 350 in the fluidic layer 300 that is aligned with an inlet chamber 122 or outlet chamber 126 of one of the plurality of capsules 120.
  • Each of the capsule support regions 526 contacts the underside of the sealing layer 400 used to seal the channels 304 in the second surface 310 of the fluidic layer 300.
  • FIG. 25 is an exploded view showing the fluidic layer 300, first sealing layer 400, and second sealing layer 410.
  • the first sealing layer 400 is arranged to seal the channels 304 in the second surface 310 of the fluidic layer 300, while the second sealing layer 410 is arranged to seal the channels 304 in the first surface 308 of the fluidic layer 300.
  • FIG. 25 shows the plurality of valve regions 302 of the cartridge, each of which is provided in the form of a depression in the fluidic layer 300.
  • the fluidic layer 300 has a reduced thickness in each of the valve regions 302.
  • the projections 330 extend from the first surface 308 of the fluidic layer 300.
  • the projections 330 include openings that define a plurality of chambers 332, as described in more detail with reference to FIGS. 25 and 26.
  • Implementing projections 330 that extend from the first surface 308 of the fluidic layer 300 means that the volume of the chambers 332 defined by the projection 330 is not limited by the thickness of the fluidic layer 300 between its first and second surfaces 308, 310.
  • the fluidic layer 300 further comprises the plurality of openings 350 that extend through the thickness of the fluidic layer 300.
  • the fluidic layer 300 further comprises the plurality of pneumatic ports 312 (for example, three pneumatic ports 312a, 312b and 312c as shown in FIG. 26). Each pneumatic port 312 comprises a protrusion 314 extending from the first surface 308.
  • Each port 312 further comprises an opening 316 extending through the protrusion 314 and at least part of the thickness of the fluidic layer. In the example shown in FIGS. 26 and 27, the opening 316 extends through the whole thickness of the fluidic layer 300.
  • the fluidic layer 300 therefore comprises two sets of openings: a first plurality of openings 350, that are disposed directly below the liquid storage capsules 120 and are aligned with the protrusions 242 on the actuatable portion 240; and a second plurality of openings 316, each of which extends through a corresponding protrusion 314 of a pneumatic port 312.
  • These sets of openings allow for communication between the network of channels 304 in the fluidic layer 300 and other fluidic components of the cartridge 100 (e.g. the capsules 120 and the pneumatic ports 312).
  • All components of the fluidic layer 300 described above are integral with the fluidic layer 300, meaning that they are all formed of the same elastomeric material as the fluidic layer 300. More specifically, the projection 330 and protrusions 314, are all integral with the fluidic layer 300 and formed of the same elastomeric material as the fluidic layer 300.
  • the first sealing layer 400 includes a plurality of apertures 454, each of which defines in part a corresponding measurement chamber 610 of the cartridge 100 and is accessed via two channels 304 in the fluidic layer 300, which provide an inlet and outlet to the measurement chamber 610.
  • FIG. 26 shows a top view of the fluidic layer 300, showing the first surface 308.
  • FIG. 26 shows the locations of the valve regions 302, ports 312, projections 330 (including chambers 332a to 332c, shown in FIG. 27) and openings 350. As explained above, openings 350 and openings 316 extend through the thickness of the fluidic layer 300.
  • Each of the valve regions 302 allows the flow of fluid through one of the conduits 600 of the cartridge 100 to be controlled.
  • Each valve is defined by one of the valve regions 302 (each of which is disposed above a corresponding channel 304) and the sealing layer 400 that seals the corresponding channel 304.
  • a force is applied to the valve region 302 to compress the corresponding channel 304 against the sealing layer 400.
  • Closing a valve prevents fluid flow through the corresponding conduit 600.
  • the force applied to the valve region 302 to close the valve is withdrawn. Opening a valve permits fluid flow through the corresponding conduit 600.
  • each of the pneumatic ports 312 can either: (i) receive a positive pressure via a corresponding pneumatic actuator; (ii) receive a negative pressure via the corresponding pneumatic actuator; (iii) be vented (i.e. opened to atmospheric pressure) via the corresponding pneumatic actuator; or (iv) be closed (i.e. unvented), meaning that the pneumatic port 312 is disconnected from the pneumatic actuator. In case (iv), there is no air flow through the pneumatic port 312.
  • a number of the channels 304 in the fluidic layer extend from a point in the fluidic layer that overlies one of the troughs 514 in the second part 500. This means that, for example, when a positive pneumatic pressure is applied to the first pneumatic port 312a, the pressurised air flows through the corresponding opening 316 in the first pneumatic port 312a, through a corresponding hole in the sealing layer 400, through the channel 518a of the first port support region 516a, through the trough 514a, and into one of the channels 304.
  • a negative pressure is applied in the same way, but with opposite air flow.
  • This arrangement reduces the risk of liquid being drawn into a pneumatic actuator (e.g. during application of a negative pressure to aspirate liquid). This is because any liquid that is drawn through the channel 304 falls to the bottom of the trough 514a under gravity. As shown in FIGS. 23 and 24, the channel 518a is on the flat upper surface of the port support region 516a, meaning that the channel 518a is disposed above the base of the trough 514a. Therefore, any pooled liquid in the trough 514a is not drawn through the channel 518a and into the pneumatic actuator via the first pneumatic port 312a.
  • a first projection 330a includes holes defining, in part, a first chamber 332a a second chamber 332b.
  • a second projection 330b includes a hole defining, in part, a third chamber 332c.
  • the holes in the first and second projections 330 define the inner walls of the chambers 332, and therefore define the height of the chambers 332.
  • the holes defined by the projections 330 extend through the whole thickness of the fluidic layer 300 in the region of the protrusions 330 (as shown, for example, in the underside view of the fluidic layer 300 as shown in FIG. 27).
  • each chamber 332 includes protrusions 338 extending from an inner wall 340 (see FIG. 31 ) of the chamber 332, as described in more detail below with reference to FIGS. 31 to 34.
  • a liquid handling device (such as the microfluidic cartridge 100) comprises a first liquid storage container (for example, a first one of the liquid storage capsules 120) and a second liquid storage container (for example, a second one of the liquid storage capsules 120), wherein each of the first and second liquid storage containers is configured to be opened by creating an inlet and an outlet in the liquid storage container; and a fluidic layer (e.g. the fluidic layer 300), comprising: a network of channels (e.g. channels 304); and a pneumatic port (e.g. pneumatic port 312b) configured to receive a positive pressure; wherein the network of channels comprises: a first liquid storage container inlet channel (e.g.
  • a first one of the liquid storage capsule inlet channels 360, 362, 364 described below configured to provide a fluidic connection between the pneumatic port and the inlet in the first liquid storage container when the first liquid storage container is opened
  • a second liquid storage container inlet channel e.g. a second one of the liquid storage capsule inlet channels 360, 362, 364 described below
  • Such an arrangement is not limited to a liquid handling device that includes liquid storage capsules 120 having the specific structure of those described herein (i.e. with the chambers 122, 124, 126 and restrictions 123, 125), and may be implemented with any liquid storage containers that are configured to be opened by creating an inlet and an outlet in the liquid storage container.
  • FIG. 26 shows the channels 304 in the first surface 308 of the fluidic layer 300.
  • the channels 304 in the first surface of the fluidic layer include a first liquid storage container inlet channel 360 (also referred to herein as a first liquid storage capsule inlet channel 360), a second liquid storage container inlet channel 362 (also referred to herein as a second liquid storage capsule inlet channel 362), and a third liquid storage container inlet channel 364 (also referred to herein as a third liquid storage capsule inlet channel 364).
  • the first liquid storage capsule inlet channel 360 provides a fluidic connection between the inlet chamber 122a (see FIG. 8) of the first liquid storage capsule 120a and the second pneumatic port 312b.
  • the second liquid storage capsule inlet channel 362 provides a fluidic connection between the inlet chamber 122b of the second liquid storage capsule 120b and the second pneumatic port 312b.
  • the third liquid storage capsule inlet channel 364 provides a fluidic connection between the inlet chamber 122c of the third liquid storage capsule 120c and the second pneumatic port 312b.
  • the second pneumatic port 312b is in fluidic communication with the second trough 514b via the connector channel 518b in the second pneumatic port support region 516b, meaning that the second pneumatic port 312b is in fluidic communication with the well 602.
  • Each of the liquid storage capsule inlet channels 360, 362, 364 is connected to the opening 324, meaning that each of the liquid storage capsule inlet channels 360, 362, 364 is in fluidic communication with the well 602. Therefore, each of the liquid storage capsule inlet channels 360, 362, 364 is in fluidic communication with the second pneumatic port 312b via the well 602.
  • Each liquid storage capsule inlet channel 360, 362, 364 includes a plurality of regions, in the form of one or more first channel regions 366a and one or more second channel regions 366b.
  • Each first channel region 366a is provided in the first surface 308 of the fluidic layer 300 and has a depth that is a fraction of the thickness of the fluidic layer 300.
  • Each second channel region 366b is provided in the first surface 308 of the fluidic layer 300 and has a depth that is greater than the depth of the first channel regions 366a and a width that is greater than the width of the first channel regions 366a.
  • the liquid storage container inlet channels 360, 362, 364 each include two first channel regions 366a and two second channel regions 366b.
  • the second channel regions 366b have a depth equal to the thickness of the fluidic layer 300 and are provided in the form of circular holes extending through the fluidic layer 300 (as seen from FIG. 27).
  • the second channel regions 366b are therefore sealed using the first sealing layer 400 and the second sealing layer 410.
  • some of the liquid from the liquid storage capsules 120 may flow through the respective liquid storage capsule inlet channel 360, 362, 364 in the direction of the second pneumatic port 312b.
  • Providing the first and second channel regions 366 of the liquid storage capsule inlet channels 360, 362, 364 and the well 602 prevents the liquid from flowing to the second pneumatic port 312b and therefore prevents the liquid from reaching the analyser that applies pneumatic pressure via the second pneumatic port 312b.
  • the depths of the second channel regions 366b and the well 602 mean that liquid pools in the second channel regions 366b and the well 602, while the absorbent material in the well 602 absorbs any liquid in the well 602.
  • the lower depth of the first channel regions 366a compared to the second channel regions 366b provides a barrier to liquid movement from the second channel regions 366b to the first channel regions 366a. Accordingly, the arrangement of liquid storage capsule inlet channels 360, 362, 364 and the well 602 reduces the risk of liquid reaching the analyser that applies pressure via the second pneumatic port 312b.
  • the fluidic network includes the first pneumatic port 312a (P1 ), the second pneumatic port 312b (P2) and the third pneumatic port 312c (P3).
  • the fluidic network also includes the first chamber 332a (M 1 ), the second chamber 332b (M2) and the third chamber 332c (M3).
  • One or more of the first chamber 332a (M1 ), the second chamber 332b (M2) and the third chamber 332c (M3) may house a dry reagent, for example a lyophilised reagent provided in the form of a reagent ball.
  • Having a third chamber 332c to that may be used for storing reagents allows the cartridge 100 to run more complex assay methods that require an additional reagent that is not to be mixed with the sample in the first reaction (for example methods 1500 and 1800 described below).
  • having chambers 332 configured to store dry reagents is advantageous because (i) dry reagents are generally more stable for long-term storage, and (ii) different dry reagents can be stored in different chambers and re-suspended with the same liquid buffer, thereby allowing different liquid reagents to be formed during operation of the cartridge 100.
  • One or more of the first chamber 332a (M1 ), the second chamber 332b (M2) and the third chamber 332c (M3) may be used as a mixing chamber for mixing of sample and liquid (e.g. reagent, diluent), or for mixing of dried reagent with a liquid used to resuspend the dried reagent.
  • sample and liquid e.g. reagent, diluent
  • the fluidic network includes the liquid reagent capsule inlet channels 360, 362, 364 described above, in addition to three measurement chambers 610 in the form of a first flow cell 610a (F1), a second flow cell 610b (F2), and a sample flow cell 610c (F3). Further, the fluidic network includes the first and second waste chambers 508a, 508b. The venting state of the first waste chamber 508a is controlled using the first pneumatic port 312a, as described above.
  • a sample inlet channel 367 provides a fluidic connection to the permanently vented sample inlet chamber 236 (S1 ). Flow through the sample inlet channel 367 is controlled using a sample inlet valve region 302a (V2). The sample inlet channel 367 provides a fluidic connection to a first junction 306a. Two other channels are connected to the first junction 306a, as described below.
  • a chamber inlet channel 368 provides a fluidic connection between the first junction 306a and the second chamber 332b (M2) (also referred to herein as a “mixing chamber”). Flow through the chamber inlet channel 368 is controlled using a chamber inlet valve 302b (V6).
  • the second chamber 332b (M2) is in permanent fluidic communication with the third pneumatic port 312c (P3), meaning that there is no valve between the second chamber 332b (M2) and the third pneumatic port 312c (P3).
  • a sample flow channel 370 provides a fluidic connection between the first junction 306a and a second junction 306b.
  • a sample flow cell inlet channel 372 provides a fluidic connection between the second junction 306b and the sample flow cell 610c (F3)
  • a sample flow cell outlet channel 374 provides a fluidic connection between the sample flow cell 610c (F3) and the first waste chamber 508a.
  • Flow through the sample flow cell inlet channel 372, the sample flow cell 610c (F3) and the sample flow cell outlet channel 374 is controlled using a sample flow cell valve 302c (V9).
  • the second chamber 332b (M2) and the first chamber 332a (M1 ) are fluidically connected using a mixing channel 376.
  • a chamber outlet channel 378 provides a fluidic connection between the first chamber 332a (M1 ) and a third junction 306c. Flow through the chamber outlet channel 378 is controlled using a chamber outlet valve 302d (V12).
  • the first chamber 332a (M1 ) is in permanent fluidic communication with the first pneumatic port 312a (P1 ), meaning that there is no valve between the first chamber 332a (M1 ) and the first pneumatic port 312a (P1 ).
  • a first flow cell inlet channel 380 provides a fluidic connection between the third junction 306c and the first flow cell 610a (F1 ). Accordingly, the first flow cell 610a (F1 ) is in fluidic communication with the first chamber 332a (M1 ) via the chamber outlet channel 378 and the first flow cell inlet channel 380. Having the first flow cell 610a (F1 ) connected to the first chamber 332a (M1 ) in this way (i.e.
  • the bypass channel 384 provides the option of selecting which liquids move through only the first flow cell 610a (F1 ), and which liquids move through both the first flow cell 610a (F1 ) and the second flow cell 610b (F2). Another advantage relates to the use of magnetic beads in assays carried out using the cartridge 100.
  • the configuration of the bypass channel 384 allows the first flow cell 610a (F1) to be used as an off sensor wash cell, and allows the beads to only be transferred to the measurement flow cell (e.g. the second flow cell 610b (F2)) once the beads have reacted with the detection solution.
  • a second flow cell outlet channel 386 fluidically connects the second flow cell 610b (F2) to the second waste chamber 508b via the second waste chamber port 358b (W2).
  • Flow through the second flow cell outlet channel 386 is controlled using a second flow cell outlet valve 302f (V10). Therefore, a flow circuit including the second flow cell 610b (F2) can be connected to a permanently vented waste chamber (i.e. the second waste chamber 508b) using valves (i.e. the second flow cell outlet valve 302f (V10)), and without requiring the use of a pneumatic port 312.
  • the second pneumatic port 312b (P2) is in permanent fluidic communication with the first liquid storage capsule 120a (B1 ), the second liquid storage capsule 120b (B2), and the third liquid storage capsule 120c (B3), meaning that there is no valve between the second pneumatic port 312b and each of the liquid storage capsules 120.
  • the second pneumatic port 312b is in permanent fluidic communication with the first liquid storage capsule 120a (B1 ), the second liquid storage capsule 120b (B2), and the third liquid storage capsule 120c (B3) via, respectively, the first liquid storage capsule inlet channel 360, the second liquid storage capsule inlet channel 362, and the third liquid storage capsule inlet channel 364.
  • a first liquid storage capsule outlet channel 388 (also referred to herein as a first liquid storage container outlet channel) provides an outlet from the first liquid storage capsule 120a (B1 ). Flow through the first liquid storage capsule outlet channel 388 is controlled using a first liquid storage capsule valve 302g (V4) (also referred to herein as a first liquid storage container valve).
  • the first liquid storage capsule 120a (B1 ) can be placed in fluidic communication with the first flow cell 610a (F1 ) via the first flow cell inlet channel 380 using the first liquid storage capsule valve 302g (V4).
  • the second liquid storage capsule 120b (B2) is in fluidic communication with a fifth junction 306e on the second flow cell outlet channel 386 via a second liquid storage capsule outlet channel 390 (also referred to herein as a second liquid storage container outlet channel).
  • Flow through the second liquid storage capsule outlet channel 390 is controlled using a second liquid storage capsule valve 302h (V5) (also referred to herein as a second liquid storage container valve).
  • V5 also referred to herein as a second liquid storage container valve
  • a third liquid storage capsule outlet channel 392 (also referred to herein as a third liquid storage container outlet channel) provides an outlet from the third liquid storage capsule 120c (B3). Flow through the third liquid storage capsule outlet channel 392 is controlled using a third liquid storage capsule valve 302i (V7) (also referred to herein as a third liquid storage container valve).
  • the third liquid storage capsule outlet channel 392 and the first liquid storage capsule outlet channel 388 are each in fluidic communication with a third chamber inlet channel 394, which provides a fluidic connection to the third chamber 332c (M3).
  • Flow through the third chamber inlet channel 394 is controlled using a third chamber inlet valve 302j ( V8), which therefore controls flow into the third chamber 332c (M3).
  • the third chamber 332c (M3) is in permanent fluidic communication with the third pneumatic port 312c (P3), meaning that there is no valve between the third pneumatic port 312c and the third chamber 332c (M3).
  • the third liquid storage capsule outlet channel 392 and the first liquid storage capsule outlet channel 388 are also each in fluidic communication with a priming channel 396.
  • the priming channel 396 provides a fluidic connection between the second junction 306b and a sixth junction 306f on an air/wash supply channel 398.
  • Flow through the priming channel 396 is controlled using a priming channel valve 302k (V1 ).
  • V1 a priming channel valve
  • the air/wash supply channel 398 provides a fluidic connection between the second pneumatic port 312b and the third junction 306c. Air flow through the air/wash supply channel 398 is controlled using an air supply valve 302I (V3), while a flow of liquid (e.g. wash liquid) through the air/wash supply channel 398 is controlled using the first liquid storage capsule valve 302g (V4).
  • V3 air supply valve
  • V4 first liquid storage capsule valve
  • Each of the channels 304 in the fluidic layer 300 described above is sealed using the first sealing layer 400 and/or the second sealing layer 410. Once sealed, conduits are formed.
  • the sample inlet channel 367 is sealed by the first sealing layer 400 to form a sample inlet conduit.
  • the references to “conduits” of the fluidic network refers to the channels 304 of the fluidic network that have been sealed using the first sealing layer 400 and/or the second sealing layer 410.
  • FIG. 30 is a side view of the fluidic layer 300, showing the projections 330 that extend from the first surface 308 of the fluidic layer 300.
  • the protrusions 314 of the pneumatic ports 312 can also be seen in the side view shown in FIG. 30.
  • FIG. 31 is a cross-section through the fluidic layer 300, which shows the cross-section through one of the chambers 332.
  • the chamber 332 includes a plurality of protrusions 338 extending from the inner wall 340 of the chamber 332.
  • the protrusions 338 prevent the reagent ball 344 from contacting the sealing layer (i.e. sealing tape 130) that seals the chamber 332.
  • the projection 330 defining the chambers 332 extends from the first surface 308 of the fluidic layer 300 and is therefore integral with the fluidic layer 300.
  • the protrusions 338 extend from the inner walls 340 of the chambers 332 are therefore integral with the projection 330. Consequently, the protrusions 338 are resiliently deformable, because the material of the fluidic layer 300 is elastomeric (e.g. a thermoplastic elastomer). This allows a reagent ball 344 to be inserted into the chamber 332 through the protrusions 338 when a force is applied to the reagent ball 344.
  • the reagent ball 344 can, for example, be inserted through the protrusions 338 prior to sealing the chamber 332 using the sealing tape 130.
  • FIG. 32 is a top view of a fluidic layer assembly comprising the fluidic layer 300 with the sealing layer 410 attached, while FIG. 33 is a cross-section along line Z-Z through the fluidic layer assembly shown in FIG. 32.
  • FIG. 34 is an enlarged view of region T in FIG. 33.
  • each chamber 332 includes an opening 342 at its upper end 343 (i.e. adjacent to the sealing tape 130 when the cartridge 100 is assembled).
  • the opening 342 provides an entry point into the hole defined by the projection 330, meaning that the opening 342 permits the reagent balls 344 to be inserted into the chamber 332.
  • the sealing tape 130 is configured to seal the opening 342 of the chamber 332.
  • Reagent handling can be automated, but tightly controlled humidity is still required, adding cost and complexity to the reagent handling process.
  • the use of the resiliently deformable protrusions 338 to allow the reagent ball 344 to be inserted into the chambers 332 and to hold the reagent ball 344 in place during application of the sealing tape 130 reduces the length of time required for handling the reagent ball 344. Consequently, these features also reduce the cost and complexity of the manufacturing process, along with reducing human exposure to the low humidity conditions.
  • each of the protrusions 338 extends from the inner wall 340 at the upper end 343 of the chamber 332. In other words, each of the protrusions 338 extends from the inner wall 340 adjacent to the opening 342. As shown in FIGS. 32 to 34, the opening 342 is, in fact, defined by the protrusions 338, because the protrusions 338 define the perimeter of the opening 342. Consequently, the sealing tape 130 contacts the protrusions 338 when attached to the projection 330 to seal the chamber 332.
  • Each of the protrusions 338 comprises a first protrusion portion 339a, which extends from the inner wall 340 of the chamber 332, and a second protrusion portion 339b that extends from a distal end of the first protrusion portion 339a.
  • the second protrusion portion 339b extends away from the upper end 343 of the chamber 332, so that the protrusion 338 has a “claw” shape.
  • the use of the second protrusion portion 339b minimises the amount of material in contact with the reagent ball 344.
  • reagent ball 344 can be resuspended without wetting the protrusions 338 (as around half to two-thirds of the reagent ball 344 needs to be wetted in order to resuspend the reagent).
  • each chamber 332 also includes at least one liquid flow orifice 346, which allows liquid to flow into and out of the chamber 332.
  • one liquid flow orifice 346 allows liquid to flow from the first chamber 332a into the chamber outlet channel 378 and from the chamber outlet channel 378 into the first chamber 332a, while another liquid flow orifice 346 allows liquid to flow from the first chamber 332a into the mixing channel 376 and from the mixing channel 376 into the first chamber 332a.
  • one liquid flow orifice 346 allows liquid to flow from the second chamber 332b into the chamber inlet channel 368 and from the chamber inlet channel 368 into the second chamber 332b, while another liquid flow orifice 346 allows liquid to flow from the second chamber 332b into the mixing channel 376 and from the mixing channel 376 into the second chamber 332b.
  • a liquid flow orifice 346 allows liquid to flow from the third chamber 332c into the third chamber inlet channel 394 and from the third chamber inlet channel 394 into the third chamber 332c.
  • FIGS. 33 and 34 show one liquid flow orifice 346 of each of the first chamber 332a and the second chamber 332b, in the form of the liquid flow orifice 346 that allows liquid to flow from the chamber 332a, 332b into the mixing channel 376 and from the mixing channel 376 into the chamber 332a, 332b.
  • the channels 304 that connect to the chambers 332 are in the same plane, all of the liquid flow orifices 346 are provided at the same level (with respect to the height of the chamber 332) as the liquid flow orifices 346 shown in FIGS. 33 and 34. As shown in FIGS.
  • each liquid flow orifice 346 is located below the protrusions 338, such that a distance between the upper end 343 and the liquid flow orifices 346 is greater than a distance between the upper end 343 and the distal end of the second protrusion portion 339b.
  • Each chamber 332 also includes an air orifice 348, which is also located in the inner wall 340.
  • the air orifice 348 provides a fluidic connection to an pneumatic connection conduit 349 that extends vertically between the air orifice 348 and the second surface 310 of the fluidic layer 300 (as shown in FIGS. 26 to 28) and provides the fluidic connection to the pneumatic port 312 to which the chamber 332 is connected (i.e. via a corresponding trough 514 in the second part 500).
  • a first maximum distance (measured normal to the first surface 308) between the air orifice 348 and the upper end 343 of the chamber 332 is less than or equal to a second maximum distance (measured normal to the first surface 308) between the protrusions 338 (specifically, the second protrusion portion 339b) and the upper end 343.
  • the protrusions 338 extend away from the upper end 343 so that the distal end of the second protrusion portions 339b are located below the level of the air orifice 348. Consequently, liquid does not flow into the air orifice 348 during resuspension of the reagent ball 344.
  • FIG. 35 is a flowchart of a method 1000 of controlling liquid flow in a liquid handling device (e.g. the microfluidic cartridge 100 described above).
  • a liquid handling device e.g. the microfluidic cartridge 100 described above.
  • an inlet and an outlet are created in a first liquid storage container (e.g. a liquid storage capsule 120) of the liquid handling device to create a fluidic connection between a pneumatic port (e.g. 312b) of the liquid handling device and the inlet in the first liquid storage container.
  • a first liquid storage container e.g. a liquid storage capsule 120
  • a pneumatic port e.g. 312b
  • an inlet and an outlet are created in a second liquid storage container (e.g. a liquid storage capsule 120) of the liquid handling device to create a fluidic connection between the pneumatic port 312b of the liquid handling device and the inlet in the second liquid storage container.
  • a second liquid storage container e.g. a liquid storage capsule 120
  • an inlet and an outlet are created in a third liquid storage container (e.g. a liquid storage capsule 120) of the liquid handling device to create a fluidic connection between the pneumatic port 312b of the liquid handling device and the inlet in the third liquid storage container.
  • a third liquid storage container e.g. a liquid storage capsule 120
  • liquid is dispensed from the outlet in the first liquid storage container by applying a positive pressure via the pneumatic port 312b.
  • Dispensing liquid from the outlet in the first liquid storage container may comprise opening a first liquid storage container valve configured to control the flow of liquid from the outlet in the first liquid storage container.
  • Dispensing liquid from the outlet in the first liquid storage container may comprise opening one or more valves of the liquid handling device to create a fluidic connection between the outlet in the first liquid storage container and a second pneumatic port (e.g. 312a) of the liquid handling device, and venting the second pneumatic port during application of the positive pressure via the (first) pneumatic port 312b.
  • a second pneumatic port e.g. 312a
  • liquid is dispensed from the outlet in the second liquid storage container by applying a positive pressure via the pneumatic port 312b.
  • Dispensing liquid from the outlet in the second liquid storage container may comprise opening a second liquid storage container valve configured to control the flow of liquid from the outlet in the second liquid storage container.
  • Dispensing liquid from the outlet in the second liquid storage container may comprise opening one or more valves of the liquid handling device to create a fluidic connection between the outlet in the second liquid storage container and the second pneumatic port (e.g. 312a) of the liquid handling device, and venting the second pneumatic port during application of the positive pressure via the (first) pneumatic port 312b.
  • liquid may be dispensed from the outlet in the third liquid storage container by applying a positive pressure via the pneumatic port 312b.
  • Dispensing liquid from the outlet in the third liquid storage container may comprise opening a third liquid storage container valve configured to control the flow of liquid from the outlet in the third liquid storage container.
  • Dispensing liquid from the outlet in the third liquid storage container may comprise opening one or more valves of the liquid handling device to create a fluidic connection between the outlet in the third liquid storage container and a third pneumatic port (e.g. 312c) of the liquid handling device, and venting the third pneumatic port during application of the positive pressure via the (first) pneumatic port 312b.
  • a third pneumatic port e.g. 312c
  • FIG. 36 is a flowchart of a method 1100 of metering liquid in a channel.
  • a first pressure is applied to move a first liquid from a first chamber through a first fluidic path including two junctions.
  • the first pressure may be applied to aspirate the first liquid from a chamber (e.g. a vented sample chamber) through the first fluidic path (i.e. using negative pressure).
  • the first pressure may be applied to dispense the first liquid from a chamber such as a liquid reagent capsule (i.e. using positive pressure).
  • a second pressure is applied to move a fluid through a second fluidic path including a portion of the first fluidic path between the two junctions, such that the fluid displaces a volume of the first liquid between the two junctions.
  • the fluid may be a second liquid, which may be dispensed from a second chamber (such as a liquid reagent capsule).
  • the fluid may be air, which may be supplied via an air supply conduit in fluidic communication with a pneumatic port.
  • the fluid may displace the volume of the first liquid by moving the volume of the first liquid to a chamber.
  • Using the second fluid to displace the volume of the first liquid means that a precise, metered volume of liquid can be moved to a chamber.
  • This precise volume is the volume of liquid between the two junctions (e.g. junctions 306a and 306b) of the fluidic network shown in FIG. 28.
  • Steps 1102 and 1104 may be repeated in order to meter a specific volume of the first liquid that is a multiple of the volume of the first fluidic path between the two junctions. For example, if the volume of the first fluidic path between the two junctions is 5 pL, then steps 1102 and 1104 may be carried out in order to move a 20 L volume of the first liquid to a chamber.
  • FIG. 37 is a flowchart of a method 1200 of priming a fluidic circuit.
  • a first pressure is applied to move liquid from a chamber into a first channel.
  • the first pressure is continued to be applied to move the liquid, until the liquid has filled the first channel beyond a junction on the first channel, wherein the junction connects the first channel to a second channel.
  • a second pressure is applied to move liquid from the chamber into the second channel via the first channel and the junction.
  • FIG. 38 is a flowchart of a method 1300 of diluting a sample.
  • a negative pressure is applied to aspirate a volume of a first liquid into a first flow cell.
  • a detection signal is measured in the first flow cell.
  • a negative pressure is applied to aspirate a volume (e.g. a metered volume) of the first liquid into a first chamber.
  • a positive pressure is applied to dispense a volume (e.g. a metered volume) of a second liquid into the first chamber.
  • a positive pressure is applied to dispense the first liquid and the second liquid from the first chamber to the second chamber.
  • a negative pressure is applied to aspirate the first liquid and the second liquid from the second chamber to the first chamber.
  • steps 1310 and 1312 are repeated one or more times.
  • a positive pressure is applied to move the mixture from the first chamber or the second chamber to a second flow cell.
  • a detection signal is measured in the second flow cell.
  • FIG. 39 is a flowchart of a method 1400 of resuspending dry reagents.
  • a first pressure is applied to transfer a metered volume of a first liquid into a first chamber to resuspend one or more first dry reagents, wherein resuspending the one or more first dry reagents in the first liquid forms a first reagent.
  • a second pressure is applied to transfer a metered volume of the first liquid into a second chamber to resuspend one or more second dry reagents, wherein resuspending the one or more second dry reagents in the first liquid forms a second reagent.
  • a third pressure is applied to move the first reagent through at least one flow cell.
  • a fourth pressure is applied to move the second reagent through the at least one flow cell.
  • a detection signal is measured in the at least one flow cell.
  • the methods 1000, 1100, 1200, 1300, 1400 described with reference to FIGS. 35 to 39 may be carried out using the cartridge 100 having the fluidic circuit described with reference to FIGS. 26 to 28. It will be appreciated that the steps of these methods may be carried out in a different order to that described above. That is, the specific order of the method steps described above is not intended to be limiting, and is instead optional.
  • FIGS. 40 to 43 describe examples of assays that may be carried out using the cartridge 100 having the fluidic circuit described with reference to FIGS. 26 to 28.
  • the assays described below may include one or more of the methods 1000, 1100, 1200, 1300, 1400 described above. Accordingly, the methods 1000, 1100, 1200, 1300, 1400 described above may further comprise one or more steps of the example assays described with reference to FIGS. 40 to 43.
  • FIG. 40 is a flowchart of a method 1500 of carrying out a first assay.
  • a negative pressure is applied to the first pneumatic port 312a (P1) to flow sample from the permanently vented sample inlet chamber 236 (S1 ) to the first waste chamber port 358a (W1 ) and fill the sample flow cell 610c (F3), with valves 302a (V2) and 302c (V9) open.
  • a detection signal is measured from the sample present in the sample flow cell 610c (F3).
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow diluent from and the outlet of the third liquid storage capsule 120c (B3B) to the first waste chamber port 358a (W1 ), with valves 302k (V1), 302i (V7) and 302c (V9) open and the first pneumatic port 312a (P1 ) vented.
  • the venting state of the first waste chamber 508a is controlled via the first pneumatic port 312a (P1 )
  • the first pneumatic port 312a (P1 ) needs to be vented in order to permit flow to the first waste chamber port 358a (W1 ).
  • a positive pressure is applied to the second pneumatic port 312b (P2) to transfer a metered volume of diluent from the outlet of the third liquid storage capsule 120c (B3B) to the second chamber 332b (M2), with valves 302k (V1), 302b (V6) and 302i (V7) open and the third pneumatic port 312c (P3) vented.
  • the second chamber 332b (M2) contains dry reagents in the form of two lyobeads: one with magnetic beads coated with a capture agent, and another lyobead with sample treatment reagents. The two lyobeads are hydrated during this step.
  • a positive pressure is applied to the second pneumatic port 312b (P2) to transfer a metered volume of diluent from the outlet of the third liquid storage capsule 120c (B3B) to the third chamber 332c (M3), with valves 302i (V7) and 302j (V8) open and the third pneumatic port 312c (P3) vented.
  • the third chamber 332c (M3) contains dry reagents in the form of one lyobead, having secondary antibodies and an enzyme label. This lyobead is hydrated during this step.
  • a negative pressure is applied to the third pneumatic port 312c (P3) to flow a metered volume of sample from the permanently vented sample inlet chamber 236 (S1 ) to the second chamber 332b (M2), with valves 302a (V2) and 302b (V6) open.
  • cycles of positive pressure and negative pressure are applied to the third pneumatic port 312c (P3), with the first pneumatic port 312a (P1) vented, to mix the sample with diluent and resuspend dry reagents stored in the first chamber 332a (M)1 and/or the second chamber 332b (M2) by moving the liquids back and forth between the first chamber 332a (M1 ) and the second chamber 332b (M2).
  • Step 1514 may also be applied by applying cycles of positive and negative pressure to the first pneumatic port 312a (P1 ), with the third pneumatic port 312c (P3) vented.
  • a positive pressure is applied to the third pneumatic port 312c (P3) to flow the mixture from the first chamber 332a (M1 ) or the second chamber 332b (M2) to the third waste chamber port 358c (W3) through the first flow cell 610a (F1 ), with valves 302e (V11 ) and 302d (V12) open and a magnet active on the first flow cell 610a (F1 ).
  • the magnet may be activated by an analyser device that receives the cartridge 100 and carries out the method 1500 of the first assay using the cartridge 100.
  • the magnet can be actuated by the analyser device to apply a localised magnetic field to the first flow cell 610a (F1 ).
  • the magnet may be a moveable permanent magnet or a fixed electromagnet.
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow wash solution from the outlet of the first liquid storage capsule 120a (B1 B) to the first waste chamber port 358a (W1 ), with valves 302k (V1 ), 302g (V4) and 302c (V9) open, and the first pneumatic port 312a (P1 ) vented.
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow wash solution from the outlet of the first liquid storage capsule 120a (B1 B) to the third waste chamber port 358c (W3) through the first flow cell 610a (F1 ), with valves 302g (V4) and 302e (V11 ) open and the magnet active on the first flow cell 610a (F1 ).
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow air through the first flow cell 610a (F1 ) to the third waste chamber port 358c (W3), with valves 302I (V3) and 302e (V11 ) open and the magnet active on the first flow cell 610a (F1).
  • a positive pressure is applied to the third pneumatic port 312c (P3) to flow detection solution from the third chamber 332c (M3) to the third waste chamber port 358c (W3) through the first flow cell 610a (F1), with valves 302j (V8) and 302e (V11 ) open and the magnet active on the first flow cell 610a (F1 ).
  • the detection solution is prepared in the third chamber 332c (M3) at step 1510 from the diluent solution and the detection lyobead.
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow wash solution from the outlet of the first liquid storage capsule 120a (B1 B) to the third waste chamber port 358c (W3) through the first flow cell 610a (F1), with valves 302g (V4) and 302e (V11 ) open and the magnet active on the first flow cell 610a (F1 ).
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow air through the first flow cell 610a (F1 ) to the third waste chamber port 358c (W3), with valves 302I (V3) and 302e (V11 ) open and the magnet active on the first flow cell 610a (F1 ).
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow wash solution from the outlet of the first liquid storage capsule 120a (B1 B) to the second waste chamber port 358b (W2) through the first flow cell 610a (F1 ) and the second flow cell 610b (F2), with valves 302g (V4) and 302f (V10) open and a magnet active on the second flow cell 61 Ob (F2).
  • This step transfers magnetic beads from the first flow cell 610a (F1 ) to the second flow cell 610b (F2).
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow air through the first flow cell 610a (F1) and the second flow cell 610b (F2) to the second waste chamber port 358b (W2), with valves 302I (V3) and 302f (V10) open and the magnet active on the second flow cell 610b (F2).
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow signal solution from the outlet of the second liquid storage capsule 120b (B2B) to the second waste chamber port 358b (W2), with valves 302h (V5) and 302f (V10) open.
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow signal solution from the outlet of the second liquid storage capsule 120b (B2B) to the first waste chamber port 358a (W1 ) through the first flow cell 610a (F1 ) and the second flow cell 610b (F2), with valves 302k (V1 ), 302h (V5) and 302c (V9) open, the first pneumatic port 312a (P1 ) vented, and the magnet active on the second flow cell 610b (F2).
  • detection signals are measured in flow cells 610a (F1 ) and/or 610b (F2).
  • FIG. 41 is a flowchart of a method 1600 of carrying out a second assay.
  • a negative pressure is applied to the first pneumatic port 312a (P1 ) to flow sample from the permanently vented sample inlet chamber 236 (S1 ) to the first waste chamber port 358a (W1 ) and fill the sample flow cell 610c (F3), with valves 302a (V2) and 302c (V9) open.
  • a detection signal is measured from the sample present in the sample flow cell 610c (F3).
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow diluent from the outlet of the third liquid storage capsule 120c (B3B) to the first waste chamber port 358a (W1 ), with valves 302k (V1), 302i (V7) and 302c (V9) open and the first pneumatic port 312a (P1) vented.
  • a positive pressure is applied to the second pneumatic port 312b (P2) to transfer a metered volume of diluent from the outlet of the third liquid storage capsule 120c (B3B) to the second chamber 332b (M2), with valves 302k(V1 ), 302b(V6) and 302i (V7) open and the third pneumatic port 312c (P3) vented.
  • the diluent will move the portion of the sample metered and retained in the U- shaped channel between valves 302k (V1), 302a (V2) and 302b (V6).
  • cycles of positive pressure and negative pressure are applied to the third pneumatic port 312c (P3), with the first pneumatic port 312a (P1 ) vented, to mix the sample with diluent and resuspend dry reagents stored in the first chamber 332a (M1 ) and/or the second chamber 332b (M2) by moving the liquids back and forth between the first chamber 332a (M1 ) and the second chamber 332b (M2).
  • Step 1610 may also be applied by applying cycles of positive and negative pressure to the first pneumatic port 312a (P1 ), with the third pneumatic port 312c (P3) vented.
  • a positive pressure is applied to the third pneumatic port 312c (P3) to flow the mixture from the first chamber 332a (M1 ) or the second chamber 332b (M2) to the third waste chamber port 358c (W3) through the first flow cell 610a (F1 ), with valves 302e (V11 ) and 302d (V12) open and a magnet active on the first flow cell 610a (F1 ).
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow signal solution from the outlet of the second liquid storage capsule 120b (B2B) to the second waste chamber port 358b (W2), with valves 302h (V5) and 302f (V10) open.
  • FIG. 42 is a flowchart of a method 1700 of carrying out a third assay.
  • a negative pressure is applied to the first pneumatic port 312a (P1 ) to flow sample from the permanently vented sample inlet chamber 236 (S1 ) to the first waste chamber port 358a (W1 ) and fill the sample flow cell 610c (F3), with valves 302a (V2) and 302c (V9) open.
  • a detection signal is measured from the sample present in flow cell the sample flow cell 610c (F3).
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow diluent from the outlet of the third liquid storage capsule 120c (B3B) to the first waste chamber port 358a (W1 ), with valves 302k (V1), 302i (V7) and 302c (V9) open and the first pneumatic port 312a (P1) vented.
  • cycles of positive pressure and negative pressure are applied to the third pneumatic port 312c (P3), with the first pneumatic port 312a (P1 ) vented, to mix the sample with diluent and resuspend dry reagents stored in the first chamber 332a (M1 ) and/or the second chamber 332b (M2) by moving the liquids back and forth between the first chamber 332a (M1 ) and the second chamber 332b (M2).
  • a positive pressure is applied to the third pneumatic port 312c (P3) to flow the mixture from the first chamber 332a (M1 ) or the second chamber 332b (M2) to the second waste chamber port 358b (W2) through the first flow cell 610a (F1 ) and the second flow cell 610b (F2), with valves 302f (V10) and 302e (V11 ) open.
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow wash solution from the first liquid storage capsule 120a (B1 B) to the first waste chamber port 358a (W1 ), with valves 302k (V1 ), 302g (V4) and 302c (V9) open, and the first pneumatic port 312a (P1 ) vented.
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow wash solution from the first liquid storage capsule 120a (B1 B) to the second waste chamber port 358b (W2) through the first flow cell 610a (F1 ) and the second flow cell 610b (F2), with valves 302g (V4) and 302f (V10) open.
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow air through the first flow cell 610a (F1 ) and the second flow cell 610b (F2) to the second waste chamber port 358b (W2), with valves 302I (V3) and 302f (V10) open.
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow signal solution from the outlet of the second liquid storage capsule 120b (B2B) to the second waste chamber port 358b (W2), with valves 302h (V5) and 302f (V10) open.
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow signal solution from the outlet of the second liquid storage capsule 120b (B2B) to the third chamber 332c (M3) through the first flow cell 610a (F1 ) and the second flow cell 610b (F2), with valves 302h (V5) and 302j (V8) open and the third pneumatic port 312c (P3) vented.
  • detection signals from the are measured in flow cells the first flow cell 610a (F1 ) and the second flow cell 610b (F2).
  • FIG. 43 is a flowchart of a method 1800 of carrying out a fourth assay.
  • a negative pressure is applied to the first pneumatic port 312a (P1 ) to flow sample from the permanently vented sample inlet chamber 236 (S 1 ) to the first waste chamber port 358a (W1 ) and fill the sample flow cell 610c (F3), with valves 302a (V2) and 302c (V9) open.
  • a detection signal is measured from the sample present in the sample flow cell 610c (F3).
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow diluent from the outlet of the third liquid storage capsule 120c (B3B) to the first waste chamber port 358a (W1 ), with valves 302k (V1 ), 302i (V7) and 302c (V9) open and the first pneumatic port 312a (P1 ) vented.
  • a positive pressure is applied to the second pneumatic port 312b (P2) to transfer a metered volume of diluent from the outlet of the third liquid storage capsule 120c (B3B) to the second chamber 332b (M2), with valves 302k (V1 ), 302b (V6) and 302i (V7) open and the third pneumatic port 312c (P3) vented.
  • a positive pressure is applied to the second pneumatic port 312b (P2) to transfer a metered volume of diluent from the outlet of the third liquid storage capsule 120c (B3B) to the third chamber 332c (M3), with valves 302i (V7) and 302j (V8) open and the third pneumatic port 312c (P3) vented.
  • a negative pressure is applied to the third pneumatic port 312c (P3) to flow a metered volume of sample from the permanently vented sample inlet chamber 236 (S1 ) to the second chamber 332b (M2), with valves 302a (V2) and 302b (V6) open.
  • cycles of positive pressure and negative pressure are applied to the third pneumatic port 312c (P3), with the first pneumatic port 312a (P1 ) vented, to mix the sample with diluent and resuspend dry reagents stored in the first chamber 332a (M1 ) and/or the second chamber 332b (M2) by moving the liquids back and forth between the first chamber 332a (M1 ) and the second chamber 332b (M2).
  • a positive pressure is applied to the third pneumatic port 312c (P3) to flow the mixture from the first chamber 332a (M1 ) or the second chamber 332b (M2) to the second waste chamber port 358b (W2) through the first flow cell 610a (F1 ) and the second flow cell 610b (F2), with valves 302f (V10) and 302e (V11 ) open.
  • a positive pressure is applied to the third pneumatic port 312c (P3) to flow detection solution from the third chamber 332c (M3) to the second waste chamber port 358b (W2) through the first flow cell 610a (F1) and the second flow cell 610b (F2), with valves 302j (V8) and 302f (V10) open.
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow wash solution from the outlet of the first liquid storage capsule 120a (B1B) to the second waste chamber port 358b (W2) through the first flow cell 610a (F1 ) and the second flow cell 610b (F2), with valves 302g (V4) and 302f (V10) open.
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow air through the first flow cell 610a (F1 ) and the second flow cell 610b (F2)to the second waste chamber port 358b (W2), with valves 302I (V3) and 302f (V10) open.
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow signal solution from the outlet of the second liquid storage capsule 120b (B2B) to the second waste chamber port 358b (W2), with valves 302h (V5) and 302f (V10) open.
  • a positive pressure is applied to the second pneumatic port 312b (P2) to flow signal solution from the outlet of the second liquid storage capsule 120b (B2B) to the first waste chamber port 358a (W1 ) through the first flow cell 610a (F1 ) and the second flow cell 610b (F2), with valves 302k ( V1 ), 302h ( V5) and 302c ( V9) open and the first pneumatic port 312a (P1 ) vented.
  • detection signals are measured in the first flow cell 610a (F1 ) and the second flow cell 610b (F2).
  • Methods 1500, 1600, 1700 and 1800 can each be implemented using the fluidic circuit of the cartridge 100 described above.
  • the cartridge 100 is capable of carrying out a number of different assay protocols.
  • the same assay method can be used for singleplex detection (one biomarker) or for multiplex detection (two or more biomarkers).
  • Methods 1500 and 1600 are designed to enable liquid phase reaction of the sample with capture agents (e.g. antibodies or antigens) coated on magnetic beads.
  • Methods 1700 and 1800 are designed to enable solid phase reaction of the sample with capture agents (e.g. antibodies or antigens) coated on a sensor surface.
  • the sensors and flow cells can be configured for different types of detection, such as electrochemical detection (as shown in FIG. 3) or optical detection (e.g. photometry or surface plasma resonance). It will be appreciated that the steps of methods 1500, 1600, 1700, 1800 may be carried out in a different order to that described above. That is, the specific order of the method steps described above is not intended to be limiting, and is instead optional.
  • Embodiments described herein also include an analyser device configured to receive the cartridge 100.
  • the analyser device may be configured to operate the cartridge 100 in order to carry out one or more of the methods described with reference to FIGS. 35 to 43.
  • the analyser device may therefore comprise a computer readable medium storing computer executable instructions that, when executed by a processor of the analyser device, cause the analyser device to carry out one or more of the methods described with reference to FIGS. 35 to 43.
  • the analyser device may comprise one or more of the following hardware components: one or more valve actuators configured to deform the valve regions 302 of the cartridge 100 in order to close valves of the cartridge 100; one or more capsule actuators configured to actuate the actuatable portion 240 of the first part 200 of the cartridge 100 in order to create an inlet and an outlet in each of one or more liquid storage capsules 120; one or more pneumatic actuators configured to supply positive pressure or negative pressure to each of the pneumatic ports 312 of the cartridge 100, to vent the pneumatic ports 312 of the cartridge 100, and/or to close the pneumatic ports 312 of the cartridge 100; one or more magnets (e.g.
  • a moveable permanent magnet or an electromagnet that can be actuated to apply a localised magnetic field to one or more of the flow cells 610 of the cartridge 100 (e.g. to hold magnetic beads within the one or more flow cells 610); and a detection module to measure detection signal in one or more of the flow cells 610 of the cartridge 100.
  • the specific hardware requirements of the analyser device will depend on which of the above-described methods the analyser device is being used to implement, and will be appreciated by the skilled person from the steps of the methods described above.
  • a computer program product or computer readable medium may comprise or store the computer executable instructions.
  • the computer program product or computer readable medium may comprise a hard disk drive, a flash memory, a read-only memory (ROM), a CD, a DVD, a cache, a random-access memory (RAM) and/or any other storage media in which information is stored for any duration (e.g., for extended time periods, permanently, brief instances, for temporarily buffering, and/or for caching of the information).
  • a computer program may comprise the computer executable instructions.
  • the computer readable medium may be a tangible or non-transitory computer readable medium.
  • the term “computer readable” encompasses “machine readable”.
  • channel refers to a groove provided in a surface, with an open crosssection (i.e. the cross-section is not sealed).
  • conduit refers to (i) a channel that has been sealed (e.g. by a sealing layer), thereby providing a closed cross-section; or (ii) a hole or tunnel extending at least partially through a body.
  • a liquid handling device comprising: a fluidic layer comprising: a plurality of channels; and an opening in a surface of the fluidic layer, wherein the opening extends through at least part of the thickness of the fluidic layer to one of the plurality of channels; a rigid layer comprising an actuatable portion; and a liquid storage capsule positioned between the fluidic layer and the actuatable portion, wherein the liquid storage capsule comprises: a body defining a volume in which a liquid is stored, the body comprising a first deformable portion, a main liquid storage portion, and a restriction connecting the first deformable portion to the main liquid storage portion; and a sealing layer configured to seal the volume; wherein the liquid storage capsule is positioned over the opening such that a portion of the sealing layer covers the opening; wherein the actuatable portion comprises a protrusion extending towards the liquid storage capsule, wherein the actuatable portion is actuatable from a first position, in which the protrusion does not deform the first deformable portion
  • a liquid handling device according to clause A1 , wherein the protrusion is unable to pass into the opening.
  • a liquid handling device according to clause A1 or clause A2, wherein the liquid storage capsule is positioned over the opening such that the first deformable portion and the restriction are at least partly positioned over the opening.
  • a liquid handling device according to any of clauses A1 to A3, wherein the opening has an obround shape.
  • a liquid handling device according to any of clauses A1 to A4, wherein the first deformable portion comprises a first region and a second region, wherein a first distance between the first region and the sealing layer is greater than a second distance between the second region and the sealing layer.
  • a liquid handling device according to clause A5, wherein the first region and the second region are concentric, such that the first region surrounds the second region.
  • a liquid handling device according to any of clauses A1 to A6, wherein a width of the opening is less than a width of the protrusion.
  • a liquid handling device according to any of clauses A1 to A7, wherein the protrusion comprises an end that engages the first deformable portion of the liquid storage capsule.
  • a liquid handling device according to clause A6, wherein the end of the protrusion is flat.
  • a liquid handling device according to clause A8 or clause A9, wherein the end of the protrusion has a cross-section with a major sector shape.
  • a liquid handling device according to any of clauses A8 to A10 wherein the protrusion comprises a groove defining a cross-section of the end of the protrusion.
  • a liquid handling device according to clause A11 , wherein the groove is aligned with the restriction of the liquid storage capsule.
  • A13. A liquid handling device according to clause A11 or clause A12 when dependent on clause A10, wherein the groove defines the major sector shape of the cross-section of the end ofthe protrusion.
  • a liquid handling device according to any of clauses A8 to A13, wherein the crosssection of the end of the protrusion includes one or more outwardly extending projecting ribs.
  • a liquid handling device when dependent on clause A10, wherein the one or more outwardly extending projecting ribs extend from a curved portion of the major sector shape.
  • a liquid handling device according to any of clauses A1 to A15, wherein: the protrusion is a first protrusion and the actuatable portion comprises a second protrusion extending towards the liquid storage capsule; the body of the liquid storage capsule comprises a second deformable portion; the opening is a first opening and the fluidic layer comprises a second opening that extends through at least part of the thickness of the fluidic layer to one of the plurality of channels; the portion of the sealing layer is a first portion of the sealing layer, and the liquid storage capsule is positioned over the second opening such that a second portion of the sealing layer covers the second opening; wherein, in the first position, the second protrusion does not deform the second deformable portion; wherein, in the second position, the second protrusion deforms the second deformable portion into contact with the second portion of the sealing layer to cause rupture of the second portion of the sealing layer.
  • a liquid handling device according to any of clauses A1 to A16, wherein: the liquid storage capsule is a first liquid storage capsule and the liquid handling device comprises a second liquid storage capsule, the second liquid storage capsule comprising: a body defining a volume in which a liquid is stored, the body comprising a first deformable portion and a second deformable portion; and a sealing layer configured to seal the volume; the actuatable portion comprises: a third protrusion extending towards the first deformable portion of the second liquid storage capsule; and a fourth protrusion extending towards the second deformable portion of the second liquid storage capsule; the fluidic layer comprises: a third opening that extends through at least part of the thickness of the fluidic layer to one of the plurality of channels; and a fourth opening that extends through at least part of the thickness of the fluidic layer to one of the plurality of channels; wherein the second liquid storage capsule is positioned over the third opening and the fourth opening such that a first portion of the sealing layer of the second liquid storage capsule covers the third opening
  • a liquid handling device comprising: a fluidic layer comprising: a plurality of channels; and an opening in a surface of the fluidic layer, wherein the opening extends through at least part of the thickness of the fluidic layer to one of the plurality of channels; a rigid layer comprising an actuatable portion; and a liquid storage capsule positioned between the fluidic layer and the actuatable portion, wherein the liquid storage capsule comprises: a body defining a volume in which a liquid is stored; and a sealing layer configured to seal the volume; wherein the liquid storage capsule is positioned over the opening such that a portion of the sealing layer covers the opening; wherein the actuatable portion comprises a protrusion extending towards the liquid storage capsule, wherein the actuatable portion is actuatable from a first position, in which the protrusion does not deform the body, to a second position, in which the protrusion deforms the body into contact with the portion of the sealing layer to cause rupture of the portion of the sealing layer; and wherein
  • a liquid handling device according to clause B1 or clause B2, wherein the body of the liquid storage capsule comprises a first deformable portion configured to be deformed by the protrusion when the actuatable portion is in the second position.
  • a liquid handling device according to clause B3, wherein the body further comprises a main liquid storage portion and a restriction connecting the first deformable portion to the main liquid storage portion, wherein the liquid storage capsule is positioned over the opening such that the first deformable portion and the restriction are at least partly positioned over the opening.
  • a liquid handling device according to clause B3 or clause B4, wherein the first deformable portion comprises a first region and a second region, wherein a first distance between the first region and the sealing layer is greater than a second distance between the second region and the sealing layer.
  • a liquid handling device according to any of clauses B1 to B6, wherein a width of the opening is less than a width of the protrusion.
  • a liquid handling device according to any of clauses B1 to B7, wherein the protrusion comprises an end that engages the body of the liquid storage capsule.
  • a liquid handling device according to clause B8 or clause B9, wherein the end of the protrusion has a cross-section with a major sector shape.
  • a liquid handling device according to any of clauses B8 to B10 wherein the protrusion comprises a groove defining a cross-section of the end of the protrusion.
  • a liquid handling device according to any of clauses B8 to B13, wherein the crosssection of the end of the protrusion includes one or more outwardly extending projecting ribs.
  • a liquid handling device according to clause B14 when dependent on clause B10, wherein the one or more outwardly extending projecting ribs extend from a curved portion of the major sector shape.
  • a liquid handling device according to any of clauses B1 to B15, wherein: the protrusion is a first protrusion and the actuatable portion comprises a second protrusion extending towards the liquid storage capsule; the opening is a first opening and the fluidic layer comprises a second opening that extends through at least part of the thickness of the fluidic layer to one of the plurality of channels; the portion of the sealing layer is a first portion of the sealing layer, and the liquid storage capsule is positioned over the second opening such that a second portion of the sealing layer covers the second opening; wherein, in the first position, the second protrusion does not deform the body of the liquid storage capsule; wherein, in the second position, the second protrusion deforms the body into contact with the second portion of the sealing layer to cause rupture of the second portion of the sealing layer.
  • a liquid handling device according to any of clauses B1 to B16, wherein: the liquid storage capsule is a first liquid storage capsule and the liquid handling device comprises a second liquid storage capsule, the second liquid storage capsule comprising: a body defining a volume in which a liquid is stored; and a sealing layer configured to seal the volume; the actuatable portion comprises: a third protrusion extending towards the second liquid storage capsule; and a fourth protrusion extending towards the second liquid storage capsule; the fluidic layer comprises: a third opening that extends through at least part of the thickness of the fluidic layer to one of the plurality of channels; and a fourth opening that extends through at least part of the thickness of the fluidic layer to one of the plurality of channels; wherein the second liquid storage capsule is positioned over the third opening and the fourth opening such that a first portion of the sealing layer of the second liquid storage capsule covers the third opening and a second portion of the sealing layer of the second liquid storage capsule covers the fourth opening; wherein, in the first position, the third protrusion does
  • a liquid handling device comprising: a fluidic layer comprising a chamber, wherein the chamber comprises: an opening at an upper end of the chamber; and a sealing layer configured to seal the opening of the chamber; wherein the chamber comprises one or more protrusions, wherein each of the one or more protrusions extends from an inner wall of the chamber; wherein when a reagent ball is housed in the chamber, the one or more protrusions prevent the reagent ball from contacting the sealing layer.
  • a liquid handling device according to clause C1 , wherein the opening is configured to permit the reagent ball to be inserted into the chamber.
  • a liquid handling device according to any of clauses C1 to C3, wherein the fluidic layer is formed of a thermoplastic elastomer.
  • a liquid handling device according to any of clauses C1 to C4, wherein each of the one or more protrusions extends from the inner wall of the chamber at the upper end of the chamber.
  • a liquid handling device according to clause C5, wherein the opening is defined in part by each of the one or more protrusions.
  • C7. A liquid handling device according to any of clauses C1 to C6, wherein the fluidic layer comprises a projection extending from an upper surface of the fluidic layer, wherein the projection defines, in part, the chamber.
  • a liquid handling device according to any of clauses C1 to C7, wherein the chamber further comprises: a fluid inlet located below the one or more protrusions; and an air outlet located in the inner wall; wherein a first maximum distance between the air outlet and the upper end base is less than or equal to a second maximum distance between the one or more protrusions and the upper end.
  • each of the one or more protrusions comprises: a first protrusion portion extending from the inner wall of the chamber; and a second protrusion portion extending from a distal end of the first protrusion portion, wherein the second protrusion portion extends away from the upper end of the chamber.
  • a liquid handling device comprising: a first liquid storage container and a second liquid storage container, wherein each of the first and second liquid storage containers is configured to be opened by creating an inlet and an outlet in the liquid storage container; and a fluidic layer, comprising: a network of channels; and a pneumatic port configured to receive a positive pressure; wherein the network of channels comprises: a first liquid storage container inlet channel configured to provide a fluidic connection between the pneumatic port and the inlet in the first liquid storage container when the first liquid storage container is opened; and a second liquid storage container inlet channel configured to provide a fluidic connection between the pneumatic port and the inlet in the second liquid storage container when the second liquid storage container is opened.
  • a liquid handling device further comprising: a first liquid storage container valve configured to control the flow of liquid from the outlet of the first liquid storage container; and a second liquid storage container valve configured to control the flow of liquid from the outlet of the second liquid storage container.
  • the network of channels further comprises: a first liquid storage container outlet channel configured to be in fluidic communication with the outlet in the first liquid storage container when the first liquid storage container is opened, wherein the first liquid storage container valve is on the first liquid storage container outlet channel.
  • a liquid handling device according to clause D2 or clause D3, wherein the network of channels further comprises: a second liquid storage container outlet channel configured to be in fluidic communication with the outlet in the second liquid storage container when the second liquid storage container is opened, wherein the second liquid storage container valve is on the second liquid storage container outlet channel.
  • liquid handling device according to any of clauses D1 to D4, wherein the liquid handling device further comprises a well, wherein the well is defined at least partially by an opening extending through at least part of the thickness of the fluidic layer, wherein the well is in fluidic communication with the pneumatic port, the first liquid storage container inlet channel and the second liquid storage container inlet channel.
  • a liquid handling device according to clause D5, wherein the opening, the first liquid storage container inlet channel and the second liquid storage container inlet channel are each provided in an upper surface of the fluidic layer, and wherein a depth of the opening is greater than a depth of the first and second liquid storage container inlet channels.
  • a liquid handling device according to clause D5 or clause D6, wherein: the liquid handling device further comprises a lower part, the lower part comprising a trough in an upper surface of the lower part; the fluidic layer is positioned on top of the lower part; and the well is defined at least partially by the opening in the fluidic layer and the trough in the lower part.
  • a liquid handling device according to clause D7, wherein the opening in the fluidic layer extends through the thickness of the fluidic layer.
  • a liquid handling device according to clause D7 or clause D8, wherein the pneumatic port extends through the thickness of the fluidic layer, wherein the pneumatic port is in fluidic communication with the trough via a connector channel in the lower part.
  • D10 A liquid handling device according to any of clauses D5 to D9, wherein the well comprises an absorbent material.
  • each of the first liquid storage container inlet channel and the second liquid storage container inlet channel comprises: one or more first channel regions; and a second channel region, wherein a first depth of the one or more first channel regions is less than a second depth of the second channel region.
  • a liquid handling device according to clause D11 , wherein the second depth is equal to the thickness of the fluidic layer.
  • a liquid handling device according to clause D11 or clause D12, wherein a first width of the one or more first channel regions is less than a second width of the second channel region.
  • a liquid handling device according to any of clauses D1 to D13 wherein the liquid handling device further comprises a third liquid storage container, wherein the third liquid storage container is configured to be opened by creating an inlet and an outlet in the liquid storage container, and wherein the network of channels further comprises a third liquid storage container inlet channel configured to provide a fluidic connection between the pneumatic port and the inlet in the third liquid storage container when the third liquid storage container is opened.
  • a liquid handling device according to any of clauses D1 to D14, wherein the pneumatic port is a first pneumatic port and wherein the liquid handling device further comprises a second pneumatic port configured to be placed in fluidic communication with the outlet in the first liquid storage container.
  • a liquid handling device according to clause D15, wherein the second pneumatic port is configured to be placed in fluidic communication with the outlet in the second liquid storage container.
  • a liquid handling device according to clause D15 or clause D16, wherein the liquid handling device further comprises a third pneumatic port configured to be placed in fluidic communication with the outlet in the second liquid storage container.
  • a method of controlling liquid flow in a liquid handling device comprising: creating an inlet and an outlet in a first liquid storage container of the liquid handling device to create a fluidic connection between a pneumatic port of the liquid handling device and the inlet in the first liquid storage container; creating an inlet and an outlet in a second liquid storage container of the liquid handling device to create a fluidic connection between the pneumatic port and the inlet in the second liquid storage container; dispensing liquid from the outlet in the first liquid storage container by applying a positive pressure via the pneumatic port; and dispense liquid from the outlet in the second liquid storage container by applying a positive pressure via the pneumatic port.
  • dispensing liquid from the outlet in the first liquid storage container comprises opening a first liquid storage container valve configured to control the flow of liquid from the outlet in the first liquid storage container.
  • dispensing liquid from the outlet in the second liquid storage container comprises opening a second liquid storage container valve configured to control the flow of liquid from the outlet in the second liquid storage container.
  • the pneumatic port is a first pneumatic port
  • the liquid handling device comprises a second pneumatic port
  • dispensing liquid from the outlet in the first liquid storage container comprises: opening one or more valves of the liquid handling device to create a fluidic connection between the outlet in the first liquid storage container and the second pneumatic port; and venting the second pneumatic port during application of the positive pressure via the first pneumatic port.
  • dispensing liquid from the outlet in the second liquid storage container comprises: opening one or more valves of the liquid handling device to create a fluidic connection between the outlet in the second liquid storage container and the second pneumatic port; and venting the second pneumatic port during application of the positive pressure via the first pneumatic port.
  • liquid handling device comprises a third pneumatic port
  • dispensing liquid from the outlet in the second liquid storage container comprises: opening one or more valves of the liquid handling device to create a fluidic connection between the outlet in the second liquid storage container and the third pneumatic port; and venting the third pneumatic port during application of the positive pressure via the first pneumatic port.
  • a liquid handling device comprising: a first chamber in fluidic communication with a second chamber; a first pneumatic port in fluidic communication with one of the first chamber and the second chamber; a second pneumatic port in fluidic communication with the other one of the first chamber and the second chamber; a chamber inlet conduit configured to permit liquid to flow into the first chamber; a chamber outlet conduit configured to permit liquid to flow out of the second chamber; and a third pneumatic port in fluidic communication with a first liquid reagent capsule, wherein when the first liquid reagent capsule is opened, the first liquid reagent capsule is in selective fluidic communication with the first chamber or the second chamber.
  • a liquid handling device according to clause F1 , wherein liquid flow through the chamber inlet conduit is controlled using a chamber inlet valve.
  • a liquid handling device according to clause F1 or clause F2, wherein liquid flow through the chamber outlet conduit is controlled using a chamber outlet valve.
  • a liquid handling device according to any of clauses F1 to F3, wherein liquid flow from the first liquid reagent capsule is controlled using a first liquid reagent capsule valve.
  • a liquid handling device according to any of clauses F1 to F4, wherein the first pneumatic port is in permanent fluidic communication with the first chamber.
  • a liquid handling device according to any of clauses F1 to F6, further comprising: a first flow cell in fluidic communication with the second chamber via the chamber outlet conduit; a second flow cell in fluidic communication with the first flow cell; and a bypass conduit configured to permit liquid to bypass the second flow cell after flowing through the first flow cell,
  • a liquid handling device according to clause F7, wherein liquid flow through the bypass conduit is controlled using a bypass conduit valve.
  • a liquid handling device according to clause F7 or clause F8, wherein the first flow cell is in fluidic communication with a waste chamber via a first flow cell outlet conduit.
  • a liquid handling device according to clause F9 when dependent on clause F8, wherein liquid flow into the waste chamber via the first flow cell outlet conduit is controlled using the bypass conduit valve.
  • a liquid handling device according to any of clauses F7 to F11 , wherein the second flow cell is in fluidic communication with the waste chamber via a second flow cell outlet conduit.
  • a liquid handling device according to clause F12, wherein liquid flow into the waste chamber via the second flow cell outlet conduit is controlled using a second flow cell outlet valve.
  • a liquid handling device according to any of clauses F1 to F13 , wherein the third pneumatic port is in fluidic communication with a second liquid reagent capsule.
  • a liquid handling device according to clause F14, wherein liquid flow from the second liquid reagent capsule is controlled using a second liquid reagent capsule valve.
  • a liquid handling device according to clause F14 or clause F15 when dependent on clause F7, wherein the when the second liquid reagent capsule is opened, the second liquid reagent capsule is in selective fluidic communication with the second flow cell.
  • a liquid handling device according to clause F18, wherein liquid flow from the third liquid reagent capsule is controlled using a third liquid reagent capsule valve.
  • a liquid handling device according to clause F18 or clause F19, wherein when the third liquid reagent capsule is opened, the third liquid reagent capsule is in selective fluidic communication with the first chamber.
  • a liquid handling device according to any of clauses F18 to F20, wherein when the third liquid reagent capsule is opened, the third liquid reagent capsule is in selective fluidic communication with the first flow cell.
  • a liquid handling device according to any of clauses F1 to F21 , further comprising a sample inlet chamber in fluidic communication with the chamber inlet conduit.
  • a liquid handling device according to clause F22, wherein liquid flow from the sample inlet chamber is controlled using a sample inlet valve.
  • a liquid handling device according to any of clauses F22 to F24, further comprising a sample flow cell in fluidic communication with the sample inlet chamber via a sample flow cell inlet conduit.
  • a liquid handling device according to clause F25, wherein liquid flow into the sample flow cell is controlled using a sample flow cell valve.
  • a liquid handling device according to clause F25 or clause F26, wherein the sample flow cell is in fluidic communication with a sample flow cell waste chamber via a sample flow cell outlet conduit.
  • a liquid handling device according to clause F27 or clause F28, wherein the sample flow cell waste chamber is in fluidic communication with the second pneumatic port.
  • F30. A liquid handling device according to any of clauses F1 to F29, further comprising a third chamber, wherein the third chamber is in fluidic communication with the first pneumatic port.
  • a liquid handling device according to clause F30 or clause F31 , wherein liquid flow into the third chamber is controlled using a third chamber valve.
  • a liquid handling device according to any of clauses F30 to F32, wherein the third chamber is in fluidic communication with the first liquid reagent capsule.
  • a liquid handling device according to any of clauses F30 to F33, wherein the third chamber houses a dry reagent.
  • a liquid handling device according to any of clauses F1 to F34, wherein the first liquid reagent capsule is in fluidic communication with the first chamber via a priming conduit.
  • a liquid handling device according to clause F35, wherein liquid flow through the priming conduit is controlled using a priming conduit valve.
  • a liquid handling device according to clause F35 or clause F36 when dependent on clause F25, wherein the priming conduit is in fluidic communication with the sample flow cell inlet conduit via the priming conduit valve.
  • a liquid handling device according to any of clauses F1 to F37, wherein the third pneumatic port is in fluidic communication with an air/wash supply conduit.
  • a liquid handling device according to clause F38 or clause F39, wherein the air/wash supply conduit is in fluidic communication with the chamber outlet conduit.
  • F41 A liquid handling device according to any of clauses F1 to F40, wherein one or more of the first chamber and the second chamber houses a dry reagent.
  • G1 A method of metering liquid in a channel of a liquid handling device, the method comprising: applying a first pressure to move a first liquid from a first chamber through a first fluidic path including two junctions; applying a second pressure to move a fluid through a second fluidic path including a portion of the first fluidic path between the two junctions, such that the fluid displaces a volume of the first liquid between the two junctions.
  • a method of priming a fluidic circuit of a liquid handling device comprising: applying a first pressure to move liquid from a chamber into a first channel; continuing to apply the first pressure to move the liquid until a liquid front of the liquid has moved beyond a junction on the first channel, wherein the junction connects the first channel to a second channel; and applying a second pressure to move liquid from the chamber into the second channel via the first channel and the junction.
  • applying the first pressure comprises applying a negative pressure to move the liquid.
  • applying the second pressure comprises applying a negative pressure to move the liquid.
  • applying the first pressure comprises applying a negative pressure to a first pneumatic port of the liquid handling device
  • applying the second pressure comprises applying a negative pressure to a second pneumatic port of the liquid handling device
  • applying the first pressure comprises applying a positive pressure to move the liquid.
  • applying the first pressure comprises applying a positive pressure to a first pneumatic port of the liquid handling device while venting a second pneumatic port of the liquid handling device.
  • applying the second pressure comprises applying a positive pressure to move the liquid.
  • applying the second pressure comprises applying a positive pressure to the first pneumatic port of the liquid handling device.
  • applying the second pressure comprises applying a positive pressure to the first pneumatic port of the liquid handling device while venting a third pneumatic port of the liquid handling device.
  • a method of diluting a sample using a liquid handling device comprising: applying a negative pressure to aspirate a volume of a first liquid into a first flow cell of the liquid handling device; applying a negative pressure to aspirate a volume of the first liquid into a first chamber ofthe liquid handling device; applying a positive pressure to dispense a volume of a second liquid into the first chamber; repeating, one or more times, the steps of: applying a positive pressure to dispense the first liquid and the second liquid from the first chamber to the second chamber; and applying a negative pressure to aspirate the first liquid and the second liquid from the second chamber to the first chamber; applying a positive pressure to move a mixture comprising the first liquid and the second liquid from the first chamber or the second chamber to the second flow cell.
  • a method according to clause 11 further comprising measuring a detection signal in the first flow cell.
  • a method of resuspending dry reagents using a liquid handling device comprising: applying a first pressure to transfer a metered volume of a first liquid into a first chamber to resuspend one or more first dry reagents, wherein resuspending the one or more first dry reagents forms a first reagent; applying a second pressure to transfer a metered volume of the first liquid into a second chamber to resuspend one or more second dry reagents, wherein resuspending the one or more second dry reagents forms a second reagent; applying a third pressure to move the first reagent through at least one flow cell; applying a fourth pressure to move the second reagent through the at least one flow cell; and measuring a detection signal in the at least one flow cell.
  • J2 A method according to clause J1 , wherein the volume of the first liquid transferred into the first chamber is a metered volume of the first liquid.

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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)
  • Automatic Analysis And Handling Materials Therefor (AREA)

Abstract

La présente divulgation concerne un dispositif de manipulation de liquide, comprenant : une couche fluidique comprenant : une pluralité de canaux ; et une ouverture dans une surface de la couche fluidique, l'ouverture s'étendant à travers au moins une partie de l'épaisseur de la couche fluidique jusqu'à l'un de la pluralité de canaux ; une couche rigide comprenant une partie actionnable ; et une capsule de stockage de liquide positionnée entre la couche fluidique et la partie actionnable, la capsule de stockage de liquide comprenant : un corps définissant un volume dans lequel un liquide est stocké, le corps comprenant une première partie déformable, une partie de stockage de liquide principale, et un étranglement reliant la première partie déformable à la partie de stockage de liquide principale ; et une couche d'étanchéité conçue pour fermer de manière étanche le volume ; la capsule de stockage de liquide étant positionnée sur l'ouverture de sorte qu'une partie de la couche d'étanchéité recouvre l'ouverture ; la partie actionnable comprenant une saillie s'étendant vers la capsule de stockage de liquide, la partie actionnable pouvant être actionnée depuis une première position, dans laquelle la saillie ne déforme pas la première partie déformable, jusqu'à une seconde position, dans laquelle la saillie déforme la première partie déformable en contact avec la partie de la couche d'étanchéité pour provoquer la rupture de la partie de la couche d'étanchéité, lorsque la partie actionnable se trouve dans la seconde position, la saillie ne déformant pas l'étranglement.
PCT/EP2024/067864 2023-06-28 2024-06-25 Dispositif de manipulation de liquide Pending WO2025003168A1 (fr)

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Application Number Priority Date Filing Date Title
GBGB2309793.4A GB202309793D0 (en) 2023-06-28 2023-06-28 Liquid handling device
GB2309793.4 2023-06-28

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140194305A1 (en) * 2012-10-24 2014-07-10 Jon Faiz Kayyem Integrated multiplex target analysis
US20140255275A1 (en) * 2013-03-07 2014-09-11 Quidel Corporation Dual chamber liquid packaging system
US20190337690A1 (en) * 2015-12-01 2019-11-07 Illumina, Inc. Liquid storage and delivery mechanisms and methods
WO2022207927A1 (fr) * 2021-04-01 2022-10-06 Osler Diagnostics Limited Appareil de manipulation de liquide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140194305A1 (en) * 2012-10-24 2014-07-10 Jon Faiz Kayyem Integrated multiplex target analysis
US20140255275A1 (en) * 2013-03-07 2014-09-11 Quidel Corporation Dual chamber liquid packaging system
US20190337690A1 (en) * 2015-12-01 2019-11-07 Illumina, Inc. Liquid storage and delivery mechanisms and methods
WO2022207927A1 (fr) * 2021-04-01 2022-10-06 Osler Diagnostics Limited Appareil de manipulation de liquide

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