Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
  • B01F35/71—Feed mechanisms
  • B01F35/717—Feed mechanisms characterised by the means for feeding the components to the mixer
  • B01F35/7172—Feed mechanisms characterised by the means for feeding the components to the mixer using capillary forces
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
  • G01N35/00029—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor provided with flat sample substrates, e.g. slides
  • G01N35/00069—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor provided with flat sample substrates, e.g. slides whereby the sample substrate is of the bio-disk type, i.e. having the format of an optical disk
• • B—PERFORMING OPERATIONS; TRANSPORTING
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  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
  • B01F25/40—Static mixers
  • B01F25/42—Static mixers in which the mixing is affected by moving the components jointly in changing directions, e.g. in tubes provided with baffles or obstructions
  • B01F25/43—Mixing tubes, e.g. wherein the material is moved in a radial or partly reversed direction
  • B01F25/433—Mixing tubes wherein the shape of the tube influences the mixing, e.g. mixing tubes with varying cross-section or provided with inwardly extending profiles
• • B—PERFORMING OPERATIONS; TRANSPORTING
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  • B01F25/40—Static mixers
  • B01F25/42—Static mixers in which the mixing is affected by moving the components jointly in changing directions, e.g. in tubes provided with baffles or obstructions
  • B01F25/43—Mixing tubes, e.g. wherein the material is moved in a radial or partly reversed direction
  • B01F25/433—Mixing tubes wherein the shape of the tube influences the mixing, e.g. mixing tubes with varying cross-section or provided with inwardly extending profiles
  • B01F25/4331—Mixers with bended, curved, coiled, wounded mixing tubes or comprising elements for bending the flow
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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  • B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
  • B01F25/40—Static mixers
  • B01F25/42—Static mixers in which the mixing is affected by moving the components jointly in changing directions, e.g. in tubes provided with baffles or obstructions
  • B01F25/43—Mixing tubes, e.g. wherein the material is moved in a radial or partly reversed direction
  • B01F25/433—Mixing tubes wherein the shape of the tube influences the mixing, e.g. mixing tubes with varying cross-section or provided with inwardly extending profiles
  • B01F25/4338—Mixers with a succession of converging-diverging cross-sections, i.e. undulating cross-section
• • B—PERFORMING OPERATIONS; TRANSPORTING
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  • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
  • B01F33/30—Micromixers
• • B—PERFORMING OPERATIONS; TRANSPORTING
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  • B01F35/712—Feed mechanisms for feeding fluids
• • B—PERFORMING OPERATIONS; TRANSPORTING
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  • B01F35/717—Feed mechanisms characterised by the means for feeding the components to the mixer
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• • B—PERFORMING OPERATIONS; TRANSPORTING
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  • B01F35/717—Feed mechanisms characterised by the means for feeding the components to the mixer
  • B01F35/7173—Feed mechanisms characterised by the means for feeding the components to the mixer using gravity, e.g. from a hopper
• • B—PERFORMING OPERATIONS; TRANSPORTING
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  • B01L3/5025—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures for parallel transport of multiple samples
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  • 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
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  • 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
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  • 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
• • G—PHYSICS
  • G01—MEASURING; TESTING
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  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
  • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
  • G01N33/54366—Apparatus specially adapted for solid-phase testing
• • H—ELECTRICITY
  • H01—ELECTRIC ELEMENTS
  • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
  • H01J49/00—Particle spectrometers or separator tubes
  • H01J49/02—Details
  • H01J49/04—Arrangements for introducing or extracting samples to be analysed, e.g. vacuum locks; Arrangements for external adjustment of electron- or ion-optical components
• • B—PERFORMING OPERATIONS; TRANSPORTING
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  • B01F35/71—Feed mechanisms
• • B—PERFORMING OPERATIONS; TRANSPORTING
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  • 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
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  • B01L2200/14—Process control and prevention of errors
  • B01L2200/142—Preventing evaporation
• • B—PERFORMING OPERATIONS; TRANSPORTING
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  • B01L2300/06—Auxiliary integrated devices, integrated components
  • B01L2300/069—Absorbents; Gels to retain a fluid
• • B—PERFORMING OPERATIONS; TRANSPORTING
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• • B—PERFORMING OPERATIONS; TRANSPORTING
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• • B—PERFORMING OPERATIONS; TRANSPORTING
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• • B—PERFORMING OPERATIONS; TRANSPORTING
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  • B01L2300/0864—Configuration of multiple channels and/or chambers in a single devices comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
• • B—PERFORMING OPERATIONS; TRANSPORTING
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• • B—PERFORMING OPERATIONS; TRANSPORTING
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• • B—PERFORMING OPERATIONS; TRANSPORTING
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• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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  • B01L2400/04—Moving fluids with specific forces or mechanical means
  • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
  • B01L2400/0406—Moving fluids with specific forces or mechanical means specific forces capillary forces
• • B—PERFORMING OPERATIONS; TRANSPORTING
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  • B01L2400/0409—Moving fluids with specific forces or mechanical means specific forces centrifugal forces
• • B—PERFORMING OPERATIONS; TRANSPORTING
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  • B01L2400/0415—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
  • B01L2400/0418—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic electro-osmotic flow [EOF]
• • B—PERFORMING OPERATIONS; TRANSPORTING
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• • B—PERFORMING OPERATIONS; TRANSPORTING
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Definitions

• the microchannel structure of the present invention is intended for transport and processing of one or more liquid aliquots.
• the aliquots may have the same or different compositions.
• the invention also concerns various methods in which the microfluidic device is used.
• Figure 1 illustrates the definitions of "edge” and “circumferential zone”.
• Figure 2 illustrates a functional unit that enables split flow (unit 1).
• Figures 3a-c illustrate a functional unit that enables mixing (unit 2).
• Figures 4a-c illustrate a functional unit that enables partition of a larger liquid aliquot to smaller aliquots and distribution of these into different microchannel structures (unit 3).
• Figure 5 illustrates a plurality of microchannel structures that has been arranged in subgroups in the form of three annular rings/zones on a planar substrate and functional units that are preferred for this kind of arrangement (unit 4).
• Figures 6a-c illustrate a functional unit that enables transport back and forth of a liquid aliquot within a microchannel structure (unit 5).
• Figures 7a-b illustrate a functional unit that enables controlled evaporation (unit 6).
• Figure 11 illustrates a functional unit that facilitates liquid penetration from an inlet port
• Figure 12 illustrates a functional unit that comprises a volume-defining structure that can be integrated in a microchannel structure (unit 11).
• microchambers/ microcavities intended for application of sample and/or washing liquids intended for application of sample and/or washing liquids.
• Typical volumes in these latter cases are within intervals such as 1-10 ⁇ l, 1-100 ⁇ l, 1- 1000 ⁇ l (mikro-litre range) or even broader intervals.
• the present invention is primarily intended for geometric arrangements in which the microchannel structure is present in a substrate having an axis of symmetry (spinning axis).
• the term "radial distance" means the shortest distance between an object and the axis of symmetry.
• a microchannel structure has an inlet port which is upstream a structural unit.
• the radial distance for an inlet port and a structural unit may be the same, or the inlet port may be at a shorter or longer radial distance compared to the structural unit.
• the microchannel structure may or may not be oriented in a plane perpendicular to the axis of symmetry.
• Axes of symmetry are n-numbered (C n ) where n is an integer between 2 and oo, preferably 6, 7, 8 and larger, for instance ⁇ .
• the substrate as such has a cylindrical, spherical or conical symmetry (C ⁇ ).
• a preferred substrate is in the form of a disk.
• Each microchannel structure of the invention contains the functional units necessary to carry out a predetermined protocol within the structure. Parts that are common for several microchannel structures, such as common distribution channels, common waste channels, common inlet ports, common outlet ports etc, are considered to be part of each microchannel structure to which they are connected.
• microconduit means a part of a microchannel structure.
• edge of a microchannel/microconduit will refer to the intersection of two inner walls of a microchannel. This kind of edges is typically more or less length-going in the flow-direction. See figure 1 which shows a microchannel having a rectangular cross-section (101), four inner walls (102) with four wall intersections or edges (103). The a ⁇ ow (105) gives the flow direction.
• a circumferential zone of a microchannel is also illustrated in figure 1. It is a surface zone (104) in the inner wall of a microchannel and extends in a sleeve-like manner fully around the flow direction (105). The length of this kind of zone is at least from 0.1 to 10, 100, 1000 or more times the breadth or depth of the microchannel/microconduit at the upstream end of the zone.
• a “segment” (106) of a circumferential zone is a part that stretches across the zone in the flow direction (flow-directed segment). A segment may extend into one, two, three or four of the inner walls of the microchannel.
• surface characteristics refers to the surface of an inner wall of a microchannel.
• geometric surface characteristics for instance presence of projections/protrusions from and depressions in the inner wall
• chemical surface characteristics for instance presence of projections/protrusions from and depressions in the inner wall
• Wettability of a surface depends on surface characteristics and on properties of the liquid aliquot in contact with the surface. Wettability is often measured as the liquid contact angle: By the term “wettable” is mostly contemplated that the liquid contact angle is ⁇ 90°, such as ⁇ 70° or ⁇ 40°. By the term “non-wettable” is mostly contemplated that the liquid contact angle is > 90°.
• the term non-wettable may sometimes refer to liquid contact angles that are less than 90°, e.g. > 40° such as > 70°, however, it then mostly refer to a bordering area that has a lower liquid contact angle.
• the liquid contact angle in the normal case refers to equilibrium contact angles although it sometimes may refer to receding and/or advancing contact angles depending on the purpose of a measurement.
• non-closing valves refers to valves in which a liquid is stopped at the valve even if the microconduit at the valve position is opened. This kind of valves may also be called passive valves.
• closing valves refers to valves in which a valve part is used to physically close a microconduit.
• geometric valves means that the valving function is obtained by a specific curvature possibly combined with a branching of a microconduit/microchannel.
• surface break refers to a change in chemical surface characteristics. The change may be local and present in a circumferential zone or in a segment of such a zone. In the context of the present invention the term typically means a decrease in wettability of an inner surface in a microchannel/microconduit when moving in the downstream direction.
• Microfluidic structures have been considered promising for assays, chemical synthesis etc which are to be performed with a high degree of parallelity.
• a generally expressed desire has been to run the complete sequence of steps of test protocols, including sample treatment within microfluidic devices. This has lead to a desire to dense-pack microchannel structures on planar substrates (chips) and to integrate valve functions, separation functions, means for moving liquids etc within microfluidic devices.
• these kinds of functionalities can easily be integrated into various kinds of liquid transportation systems, but in the microscopic world it has become expensive, unreliable etc to miniaturize the macroscopic designs.
• There has thus been a desire to redesign the functionalities The situation becomes still worse when moving from ⁇ l- to nl-aliquots or from microchannel dimensions of above 100 ⁇ m down to those less than 100 ⁇ m.
• the present invention provides novel fluidic functionalities that can be used when transporting and processing nl- volumes of liquids in microchannel systems of the kind defined under the heading "Technical Field".
• a particular intention is to create functionalities that do not require movable mechanical parts, e.g. to accomplish valving, pumping, mixing etc, and can be integrated into the microchannels and/or the substrates.
• the various novel functionalities are based on local surface characteristics of the inner walls of the microchannels and/or on properties of the liquids, such as surface tension and wetting ability.
• a second objective is to provide a microfluid functionality that is simple and permits quick, safe and reliable mixing of two liquid aliquots that are miscible with each other.
• a third objective is to provide a microfluid functionality for distributing liquid aliquots in parallel to separate substructures of a plurality of microchannel structures.
• a fourth objective is to provide microfluid functionalities that facilitate
• a fifth objective is to provide a microfluid functionality in which a liquid aliquot can be transported back and forth between two microcavities.
• a sixth objective is to provide a microfluid functionality that enables quick and controlled evaporation of a liquid from a microchannel structure.
• a seventh objective is to provide a microfluid functionality that is anti-wicking.
• An eighth objective is to provide a microfluid functionality that can be used for creating a prezone of a first liquid in front of a second main liquid (bulk aliquot). This functionality may be useful when dispensing a liquid aliquot under the protection of another liquid and/or when improving liquid penetration into a microchamber/microcavities.
• a ninth objective is to provide an alternative inner valve for microfluidic systems.
• a tenth objective is to provide a microfluid functionality facilitating rapid introduction of a liquid aliquot into a microchannel structure.
• An eleventh objective is to provide a microfluid functionality which enables reproducibly metering of a liquid aliquot within a microchannel structure before the aliquot is transported further downstream.
• a twelfth objective is to provide a liquid functionality facilitating separation of particulate material from a liquid aliquot within a microchannel structure.
• the invention is among others based on the recognition that the appropriate surface tension of a liquid is important for controlling a liquid flow in a microsystem. This in particular applies when dealing with liquid aliquots in the nano-litre range and/or if the control is exerted without mechanical valves and pumps, i.e. by driving the transport of liquid aliquots through a functional unit of the invention by capillary force and/or inertia force etc. Typical examples of inertia force are gravitational force and centrifugal force. Summary of the first main aspect of the invention.
• the invention is a method for transporting one, two or more liquid aliquots through a microchannel structure of the microfluidic device, which is generally defined under the heading "Technical Field”.
• the method comprises the steps of
• This first aspect is characterized in that one, two, three or more of the liquid aliquots that are to be introduced through an inlet port of the microchannel structures have a surface tension which is > 5 mN/m, such as > 10 mN/m or > 20 mN/m.
• the microfluidic device provided in step (i) comprises in the preferred variants a structural unit that may be of the kind discussed below for the various subaspects of the microfluidic device of the invention, for instance structural units 1-12 including units that may combine the functionalities and/or structures of two or more of the units 1-12.
• step (ii) at least one of the liquid aliquots has a volume in the nano-litre range.
• step (iii) two or more of the aliquots may be introduced via the same or different inlet ports.
• the driving force utilized for transport of the aliquots typically is capillary force and/or inertia force without excluding other kinds of forces as discussed elsewhere in this specification.
• the term "treated form" contemplates that the aliquots have passed the structure and been subjected to one or more predetermined treatments. This means that the chemical composition may have changed and/or that aliquots may have been mixed during passage of the microchannel structure. Typical treatments include bioaffmity reactions, chemical reactions, depletion of one or more predetermined components of a starting aliquot, buffer exchange, concentrating, mixing of aliquots etc.
• At least one of the aliquots is typically aqueous and/or may contain one or more surface- active agents that increase or decrease the surface-tension of a liquid, such as water.
• Typical agents that reduce surface tension are detergents that may be cationic, anionic, amphoteric or non-ionisable.
• Surface-active agents also include organic solvents, preferably miscible with water. Examples are methanol, ethanol, isopropanol, formamide, acetonitrile etc. Charged or chargeable polymers, biomolecules such as proteins, certain sugars etc may also act as surface-active agents.
• the volumes of the liquid aliquots which are to be transported according to the invention are typically in the nanoliter range, i.e. ⁇ 1000 nl, such as ⁇ 500 nl or ⁇ 100 nl or ⁇ 50 nl. These small volumes primarily refer to sample and/or reagent volumes and do not exclude that other volumes may be used in combination with a volume in the nanoliter range.
• the volume and composition of the different aliquots transported through a microchannel structure of the invention may be identical or different.
• the invention in a second main aspect, relates to the microfluidic device as generally defined in the first paragraph under the heading "Technical Field".
• the main characteristic of this aspect of the invention is that at least one of the structural units that are positioned downstream an inlet port is selected amongst units 1-12 as described below. Units that combine the functionality and/or structure of two or more of the units 1- 12 may be included. In preferred variants of this aspect at least one of the aliquots referred to in the description of a structural unit should have a surface tension, which is > 5 mN/m, such as 10 mN/m or > 20 mN/m.
• microchannel structure may also comprise alternatives to units 1-12 and their combinations as long as at least one unit 1-12 is present. Alternative units are in many cases known in the field. See the background publications discussed below.
• the microchannel structures may also comprise hitherto unknown units.
• a microchannel structure may comprise a number of functional units, such as one or more units selected amongst inlet ports, outlet ports, units for distributing samples, liquids and/or reagents to individual microchannel structures, microconduits for liquid transport, units for defining liquid volumes, valving units, units venting to ambient atmosphere, units for mixing liquids, units for performing chemical reactions or bioreactions, units for separating soluble constituents or particulate materials from a liquid phase, waste liquid units including waste cavities and overflow channels, detection units, units for collecting a liquid aliquot processed in the structure and to be transferred to another device e.g. for analysis, branching units for merging or dividing a liquid flow, etc.
• functional units such as one or more units selected amongst inlet ports, outlet ports, units for distributing samples, liquids and/or reagents to individual microchannel structures, microconduits for liquid transport, units for defining liquid volumes, valving units, units venting to ambient atmosphere, units for mixing liquids, units for performing chemical reactions or bio
• microchannel structure there may be several inlet ports and/or several outlet ports that are located at the same or different levels and connected to the main flow path via microchannel parts at a different or at the same downstream position.
• microchannel parts may also contain functional units as discussed above.
• the microfluidic device of the present invention typically comprises one, two, three, four or more sets of microchannel structures. Typically there are in total > 50, such as > 100 or > 200, microchannel structures per microfluidic device.
• the microchannel structures of a set are essentially identical and may or may not extend in a common plane of a substrate. There may be channels providing liquid communication between individual microchannel structures of a set and/or to one or more other sets that may be present in the same substrate.
• the microchannels are typically covered, i.e. surrounded by walls or other means for directing the flow and to lower evaporation. Openings such as in inlet ports, outlet ports, vents etc are typically present where appropriate.
• the cross-section of a microchannel may have rounded forms all around, i.e.
• a microchannel structure may be arranged with an inlet port at an inner position and a downstream structural unit at an outer position in a substrate having an axis of symmetry.
• the microchannel structures may define an annular zone/ring.
• the breadth of the zone is equal to the difference in radial distance for the outermost and innermost part of the microchannel structures.
• the microchannel structures may be distributed evenly over the zone or only in one or more of its sectors.
• the center of the zone/ring may or may not coincide with the axis of symmetry. Different annular zones may be partly over-lapping.
• Circular discs as substrates containing radially oriented microchannel structures have been described in a number of patent applications. See for instance A number of publications referring to the use of centrifugal force for moving liquids within microfluidic systems have appeared during the last years. See for instance WO 9721090 (Gamera Bioscience), WO 9807019 (Gamera Bioscience) WO 9853311 (Gamera Bioscience), WO 9955827 (Gyros AB), WO 9958245 (Gyros AB), WO 0025921 (Gyros AB), WO 0040750 (Gyros AB), WO 0056808 (Gyros AB), WO 0062042 (Gyros AB), WO 0102737 (Gyros AB), WO 0146465 (Gyros AB), WO 0147637, (Gyros AB), WO 0154810 (Gyros AB), WO 0147638 (Gyros AB), See also presentations made
• the microfluidic device is typically in the form of a disc.
• the devices can be manufactured from inorganic or organic material.
• Typical inorganic materials are silicon, quartz, glass etc.
• Typical organic materials are plastics including elastomers, such as rubber silicone polymers (for instance poly dimethyl silicone) etc.
• open microstructures are formed in the surface of a planar substrate by various techniques such as etching, laser ablation, lithography, replication etc. Each substrate material typically has its preferred techniques.
• the microstructures are designed such that when the surfaces of two planar substratres are apposed the desired enclosed microchannel structure is formed between the two substrates.
• the surfaces of the open microchannel structures are typically hydrophilised, for instance as described in WO 0056808 (Gyros AB) and covered by a lid, for instance by thermo laminating as described in WO 0154810 (Gyros AB). If necessary the inner surfaces is subsequently coated with a non-ionic hydrophilic polymer as described in WO 0056808 (Gyros AB).
• the preferred variants are the same as given in these publications. Where appropriate hydrophobic surface breaks are introduced as outlined in WO 9958245 (Gyros AB). See also WO 0185602 (Amic AB & Gyros AB)
• the discs are preferably of the same dimension as a conventional CD, but may also be smaller, for instance down to 10% of conventional CDs, or larger, for instance up more than 200% or more than 400 % of a conventional CD. These percentage values refer to the radius.
• liquid contact angles of inner surfaces of the microchannel structure may vary between different functional units. Except for local hydrophobic surface breaks the liquid contact angel for at least two or three inner walls of a microconduit at a particular location should be wettable for the liquid to be transported, with preference for liquid contact angels that are ⁇ 60°, such as ⁇ 50° or ⁇ . 40° or ⁇ 30° or ⁇ 20°. In the case one or more walls have higher liquid contact angles, for instance by being non-wettable, this can be compensated by a lowered liquid contact angle on the remaining walls. This may be particular important if non-wettable lids are used to cover open microchannel structures.
• the values above apply to the liquid to be transported, to the functional units given above (except for local hydrophobic surface breaks) and at the temperature of use. Surfaces having water contact angles within the limits given above may often be used for other aqueous liquids.
• Valves that comprise intersecting channels and means that determine through which channel a liquid flow shall be created A typical example is electrokinetic flow in two or more intersecting channels and switching the electrodes in order to regulate through which channels the flow shall be guided.
• Type 1 valves typically require physically closing a microconduit and are therefore "closing".
• Type 2 valves function without closing a microchannel and are therefore "non-closing". They are illustrated in US 5,716,825 Hewlett Packard) and US 5,705,813 (Hewlett Packard).
• type 3 valves non-passage or passage of a liquid may be based on:
• Type 3 a valves are illustrated by valves in which a physical closure is removed or created by applying energy to the material in the wall of the microconduit at the valve position.
• WO 0102737 Gyros AB
• WO 9721090 Gamera
• WO 97210190 also suggests valves that are based meltable wax plugs.
• WO 9955827 (Amersham Pharmacia Biotech AB, Tooke) which describes a microstructure: conduit 1 - chamber 1 - conduit 2 - chamber 2 - conduit 3 in which a valve function is suggested before each conduit/chamber if the cross- sectional areas of the conduits are decreasing (channel 1 > channel 2 > channel 3) and/or the internal surface hydrophobicities are increasing (channel 1 ⁇ channel 2 ⁇ channel 3),
• WO 0146465 (Gyros AB) which describes a centrifugal based system and suggests an inner valve for directing a single liquid aliquot into a predetermined branch by changing the spinning speed
• US SN 09/812,123, US SN 09/811,741 and co ⁇ esponding PCT-applications (Gyros AB) (including SE priorities) give a similar system as in WO 0146465 for directing two aqueous liquid aliquots containing different amounts of an organic solvent into different branches.
• the present application bases its priority on these US and SE filings. See also WO 0147638 (Gyros AB), and WO 0040750 (Amersham Pharmacia Biotech AB).
• WO 0185602 (Amic AB & Gyros AB) suggests that inner valves based on hydrophobic surface breaks can easily be created in a rectangular microchannel having projections and/or depressions between length-going edges by applying a liydrophobizing liquid agent between the projections and/or in the depressions.
• WO 9615576 (David Sarnoff Res. Inst.)
• EP 305210 (Biotrack) describe capillary valves that are based on an abrupt increase of the cross-sectional area of a microchannel, typically combined with a dam in the bottom part of the channel.
• WO 9807019 (Gamera) describes a capillary valve that is based on a change of at least one lateral dimension of a microchannel.
• Type 3 c valves have been suggested in form of linked U/Y-shaped microconduits for centrifugal based systems (e.g. WO 0146465 Gyros AB, and WO 0040750 Amersham Pharmacia Biotech AB).
• WO 0146645 (Gyros AB) gives a structure that is said to facilitate mixing in centrifugal based systems (page 10, lines 15-16).
• US 4279862 (Bretaudiere et al) suggests a centrifugal based system with a mixing channel which has separate means for creating turbulence. This patent gives no information about dimensions and the particular problems encountered when downscaling into the nano-litre range.
• Unit for defining a plurality of liquid aliquots in a microfluidic device.
• US 6,117,396 gives a non-centrifugal gravity based microfluidic device in which a common reagent channel is used both as an overflow channel and as a reagent fill channel. A plurality of parallel volume metering capillaries is connected at different positions to the reagent fill channel from below.
• Microfluidic devices with a microchannel structures that comprises a part that bents towards a lower level (downward bent) and/or a part that bents towards a higher level (upward bent) have been described previously. Downward and upward bents has been linked to each other in series. Bent structures for centrifugal based system have been used for metering liquids, process chambers etc.
• the microchannel part in a bent may or may not have an enlarged cross-sectional area.
• Downward bents have had an opening in its lower part that via a connecting microconduit has rendered it possible to transport a retained liquid aliquot from the bent further into another part of the microchannel structure, for instance to another downward bent.
• the connecting microconduit typically has been equipped with a valve function of the kinds discussed elsewhere in this specification, preferably an inner valve.
• One of the shanks of a downward bent typically has communicated directly or indirectly with an inlet port or with a separate vent.
• Upward bents typically have had a vent in its top part (top vent).
• one of the shanks of an upward bent have been connected to one of the shank of a downward bent.
• U-shaped and Y-shaped structures are meant any downward bent structures rrrespective of the angles between the shanks at the lowest part or at a branching point (only Y-shaped forms).
• Bents have been smooth (curved) or sharp (angled).
• wicking The creeping of liquid in edges from one microcavity is called wicking.
• Surface modifications physical as well as chemical
• anti-wicking means Anti-wicking means in the form of hydrophobic surface break between two length-going edges have been described previously (WO 9958245, Amersham Pharmacia Biotech AB).
• Imbibing has also been utilized to promote liquid penetration into microchannel structures by including edge/corner structures associated with inlet ports. See US 4,233,029 (Eastman Kodak) and US 4,254,083 (Eastman Kodak).
• the definition of the volume of a liquid aliquot to be distributed to a microchannel structure can take place outside the structure and/or within the structure.
• the alternative to be used depends on different factors: (a) kind of dispenser, (b) accuracy needed, (c) kind and amount liquid to be dispensed, (d) process protocol to be run within the structure etc.
• Means for driving a liquid flow through microchannel structures are provided.
• the liquid flow may be driven in microfluidic structures by distinct means that either is present on the substrate or is external to the substrate.
• the former variants typically means liquid flow created by electroendosmosis, by micropumps that are present on the substrate, expanding gas etc.
• the latter variants typically mean external pressure- generating means that create a liquid flow that is in fluid communication with the microchannel structure.
• Another alternative is to use forces such as capillary forces and inertia force including gravitational force and centrifugal force. In this latter case no means for moving the liquids is required in the microchannel structures or in the substrates ca ⁇ ying the microchannel structures.
• Variants in which the microchannel structures are oriented from an inward position to an outward position in relation to an axis of symmetry of a substrate as described above are typically combined with a spinner that is capable of spinning the substrate around the axis of symmetry.
• This kind of spinners should be able to create the necessary centrifugal force for driving the liquids through at least a part of a microchannel structure.
• the centrifugal force may be utilized in combination with a second liquid aliquot to create a sufficient local hydrostatic pressure within a structure to drive a first liquid aliquot through an outward (downward) and/or an inward (upward) bent of a microchannel structure. See for instance WO 0146465 (Gyros AB).
• spinning speeds are within the interval 50-25000 rpm, such as 50-15000 rpm.
• the spinning speed within a given protocol may vary and depends on the part structure that is to be passed by a liquid, for instance. A rapid passage for instance will require a higher speed and a slow or controllable passage a lower speed.
• the microfluidic device contains a plurality of microchannel structures that are to be run in parallel, it may be beneficial to start the passage of a particular structural unit with a short pulse of increased spinning followed by a slower spinning.
• Plurality in this context refers to the number of microchannel structures given above.
• Inlet ports typically have hydrophobised areas to direct applied liquid into the ports. See for instance figures 6 and 13. Local surface breaks that are hydrophobic for aqueouse liquids are represented by straight or bent rectangles. They are primarily present for controlling liquid flow, e.g. in valves (inner valves), in anti-wicking means, in vents and for directing liquid inwards the structures in inlet ports.
• circles represent openings to ambient atmospheres (inlet port, outlet ports, vents etc).
• the first subaspect of the invention is a microfluidic device comprising a microchannel structure in which there is a structural unit accomplishing split flow as discussed for the first objective.
• Unit 1 is illustrated in figure 2.
• Unit 1 enables selectively directing a first liquid aliquot (aliquot 1) into one branch (202) and a subsequent liquid aliquot (aliquot 2) into another branch (203) of a common microconduit (201).
• the expression "selectively directing” in this context comprises that more than 50%, such as more than 75% or essentially 100 % of at least one aliquot goes into the same branch.
• the composition of the aliquots may be identical or different. At least one of the aliquots should have a surface tension, which is > 5 mN/m, such as > 10 mN/m or > 20 mN/m.
• the unit comprises
• the inner valve function comprises that either one or both of the branches have an inner valve including also the kind of valve defined for unit 9.
• the inner valve function at least partially is related to a difference between inner wall surface characteristics of the two branches. This difference may be local, i.e. be present in a circumferential zone in one or both of the two branches, or extend althroughout the branches.
• Typical differences in surface characteristics include that one of the branches is more constricted or wider or otherwise more physically deformed than the other.
• Examples of other physical deformations are protrusions/projections and/or depressions/grooves that may be present in at least one of the branches.
• Physical deformations are typically present as ridges or valleys in one or more sidewalls and stretch between two edges. If the deformation starts from an edge this will mean that the deformation will be present in the two side- walls that define the edge. If the deformation goes from one edge to another in the same sidewall this will also mean that the deformation is present in three sidewalls.
• Physical deformation in forms of ridges and valleys and the like are typically essentially perpendicular to the flow direction by which is meant 90° ⁇ 45°:
• the difference in surface characteristics may also include a chemical difference in the inner surface of the two branches.
• the inner surface of one of the branches may, for instance, expose more hydrophilic groups compared to the other (qualitatively and/or quantitatively).
• the wettability relative a liquid may differ between the branches. In a typical case this means that
• unit 1 comprises a downward bent, which in its lower part has an opening for downstream transport of liquid as illustrated in figure 2.
• One of the upwardly directed shanks of the bent corresponds to the common (incoming) microconduit (201) and the other shank to a branch (202).
• the opening in the lower part of the downward bent corresponds to the branching point (204) and is linked to a microconduit that corresponds to the other branch (203).
• An inner valve (205a) for instance in the form of a local surface break (non-wettable) and or in the form of a change of geometric surface characteristics, may be associated with branch (203), for instance close to the branching point (204).
• Branch (202) typically is part of an upward bent, the top level of which is at a higher level than the lowest level of the downward bent and also at a lower level than the inlet end (206) of the incoming microconduit (201).
• Branch (202) may also contain an inner valve (205b).
• the upper part of the upward bent typically contains an opening to ambient air (top vent/inlet vent, 207) and/or broadens into a cavity permitting venting (not shown) of the top part of the bent.
• the top vent may be in the form of a venting conduit which preferably has an inner valve (207), for instance in form of a circumferential surface break (non-wettable). Under certain circumstances it may suffice if the top vent only has anti-wicking means of the type discussed elsewhere in this specification.
• the volumes of aliquots 1 and 2 are selected such that aliquot 2 is able to replace aliquot 1 in the downward bent by pushing it over the top part of the upward bent.
• a microchannel structure which comprises unit 1, is arranged as discussed elsewhere in this specification for spinnable substrates; With respect to unit 1 and the variant shown in figure 2, this typically means that the extreme of the downward bent is at a larger radial distance than the extreme of the upward bent, if present.
• unit 1 for directing two liquid aliquots selectively into two different branches
• (202,203) of an incoming microconduit (201) comprises the steps of:
• a microchannel structure comprising unit 1 as defined above and a first liquid aliquot (aliquot 1) and a second liquid aliquot (aliquot 2);
• aliquot 1 and aliquot 2 in sequence into the unit via incoming microconduit (201), wherein aliquot 1 will pass out through branch (203);
• a driving force to pass aliquot 2 selectively through branch (202), by the assistance of the inner valve function of the unit.
• At least one of the aliquots should have a surface tension, which is > 5 mN/m, such as > 10 mN/m or > 20 mN/m, tentatively aliquot 1.
• the driving force preferably is gravitational or centrifugal.
• Figure 2 illustrates the most prefe ⁇ ed mode of unit 1 at the filing date.
• the second subaspect of the invention is a microfluidic device comprising a microchannel structure in which there is a structural unit accomplishing mixing of liquid aliquots (unit
• This subaspect is based on our recognition that quick mixing of liquid aliquots that are miscible can take place by first collecting the aliquots in a microcavity, preferably under the formation of a phase system, and then permitting the aliquots to pass through a microchannel of sufficient length to permit homogeneous mixing.
• FIGS. 3a-c Preferred variants of our mixing units are illustrated in figures 3a-c.
• the variants shown are arranged as discussed above on a spinnable substrate (compare the arc-like arrangement).
• Figures 3a-b comprises four microchannel structures connected to each other by a common distribution channel.
• unit 2 comprises an inlet arrangement (301) and a mixing microconduit
• This precollecting microcavity may have various designs with one feature being that it should enable formation of a liquid interface between the two aliquots to be mixed.
• the flow direction should be essentially perpendicular at the interface, i.e. 90° ⁇ 45°.
• figures 3a-b show:
• the distribution channel is filled with liquid and a downward driving force is applied, liquid will be forced out through the microconduits connecting the distribution channel (304) with the microcavities (303). At the same time air will enter through the vents (308).
• Non-wettable are represented by straight or arc-formed rectangles (e.g. 321a,b,c etc and 322, respectively).
• the inlet arrangement is connected to the upper or lower part of the microcavity (303).
• a valve associated with the mixing conduit (302), preferably close to its joint to microcavity (303).
• This valve function is preferably an inner valve of the same kind as discussed elsewhere in this specification, for instance in the form of a surface break (non-wettable) (321b).
• the valve may also be mechanical.
• the mixing microconduit (302) is of sufficient length in relation to the flow rate and the constituents of the aliquots, complete mixing will have occurred at the end of the mixing microconduit (302).
• Sufficient length typically means that the phase system should have a smaller volume than the volume of the mixing microcoduit (302).
• microcavity (329) of figure 3c may be part of two aligned common distribution channels of the same kind as outlined in figures 3a-b.
• a microchannel structure comprising unit 2 is oriented on a substrate having an axis of symmetry (spinnable) as discussed elsewhere in this specification.
• the flow direction through the outlet opening of microcavity (303) is typically oriented essentially outward in relation to the axis of symmetry (spinning axis).
• submicrocavities (326,327) are present in the inlet arrangement (301), the aliquots to be mixed may be individually predispensed to these submicrocavities before the driving force for transport into microcavity (303) is applied.
• At least one of the aliquots should have a surface tension, which is > 5 mN/m, such as > 10 mN/m or > 20 mN/m.
• Common waste channel In figures 3a-b the common waste channel (310) have supporting means for minimize the risk for collapse due to the breadth of the channel.
• the surface break (327) improves the emptying of the overflow channel (317) and facilitate its refilling.
• the third subaspect of the invention is a microfluidic device comprising a microchannel structure in which there is a structural unit (unit 3) accomplishing metering one, two or more liquid aliquots (plurality of aliquots). This subaspect is based on our recognition that:
• the relative loss of liquid by evaporation may be significant when dispensing small liquid aliquots, in particular nl-volumes, to individual microchannel structures in a microfluidic device, and
• Unit 3 presents a solution to these problems and makes it possible to reproducibly meter a number of smaller aliquots within the same microfluidic device and transport of these aliquots in parallel into separate microchannel structures of the microfluidic device or into separate parts of the same microchannel structure.
• the aliquots may be identical or different with respect to size, composition etc.
• Unit 3 is represented in figures 4a-c which show variants that are a ⁇ anged in a substrate having an axis of symmetry as discussed above.
• the distribution unit as such is encircled and labeled (400).
• the unit comprises
• each of the upper parts (402, 403, 405a-e) has means for venting (top vent, inlet vents) (406a-g) to ambient atmosphere;
• each of the lower parts (404a-f) has an emptying opening which in a downstream direction via a connecting microconduit (407a- f) communicates with a substructure of a microchannel structure and/or with a co ⁇ esponding substructure of another microchannel structure;
• each of the connecting microconduits (407a-f) has a valve (408a-f);
• an inlet port (409) is connected to the continuous microconduit (401) directly or indirectly at one of the upper parts (402, 403, 405 a-e), preferably via one of the end parts (402 or 403);
• an outlet port (410) is connected to the continuous microconduit (401) directly or indirectly at another upper part (402, 403, 405a-f), preferably via one of the end parts (402 or 403) (which is not connected to the inlet port).
• the continuous microconduit (401) is preferably shaped as a downward bent. This kind of bents includes that the microconduit in the bent is enlarged to a microchamber or microcavity. Similarly an upper part is preferably in the form of an upward bent of the channel. This part may also include an enlargement similar to the downward bent.
• the cross-sectional area of the continuous microconduit (401) is typically of constant size and/or shape along the length of the continuous microconduit.
• the inlet ports (409) and the outlet ports (410) are typically at a lower level than the extremes of the upward bents and may even be at a lower level than the extremes of the lower parts (404) and/or than a desired part of the individual microchannel structures that are downstream the lower parts (404) (for instance at a lower level than a waste outlet port).
• the liquid aliquot is preferably transported from an inlet port (409) to an outlet port (410) of the continuous microconduit (401) by capillarity meaning that the liquid contact angle in this part of the microchannel structure has to be well below 90°, i.e. preferably ⁇ 40°, such as ⁇ 30° or ⁇ 20°.
• the continuous microconduit (401) has meander-form.
• n is preferably > 2, such as 3, 4, 5, 7, 8, 9, 10, 11, 12 or more.
• All the joints between a connecting microconduit (407a-f) and a lower part (404a-f) are preferably located at the same level and/or at the lowest part of a downward bent.
• the valves (408a-f) in the connecting microconduit (407a-f)) preferably are inner valves that may be closing or non-closing.
• All the top vents (406a-g) are preferably located at the same level on the upward bents (402, 403, 405a-e). Each top vent (406a-g) comprises an opening in an upper part (402, 403, 405a-f) of the continuous microconduit (401) and possibly also a microconduit.
• the top vent may have an inner valve and/or may be equipped with anti-wicking means in case the top vent has a length-going edge that might promote imbibing and evaporation of liquid.
• anti-wicking means see e.g. unit 7, below.
• the top vents may be connected via a common venting channel (411) and an inlet (425) to ambient atmosphere.
• Unit 3 is primarily intended for distributing (n-1) liquid aliquots to (n-1) microchannel structures or (n-1) part structures of a microchannel structure.
• the volume between two close top vents (406a-g) will define the volume of the aliquot to be dispensed through the connecting microconduit (407a-f) between these top vents (segment).
• the connecting microconduit (407a-f) can differ in a controlled manner.
• Figure 4b illustrates a non-meander form of unit 3 (straight form) in which the lower parts (404a-h) are in form of microcavities that are connected to each other via upper parts (405a-g). At the end of the continuous microconduit (401) there are also upper parts (402,403) via which an inlet and an outlet port may be connected (409 and 410, respectively). Means for venting (406a-i) the continuous microconduit (401) are associated with upper parts of the continuous microconduit, for instance in the conduit parts (405-a-g) and or in the end parts (402-403).
• each microcavity (404a-h) has an outlet opening to which a connecting microconduit (407a-h) with a valve function (408a-h) is associated.
• the anti-wicking means maybe of the same kind as discussed elsewhere inthis specification.
• Figure 4c represents a variant of unit 3, which will enable distribution of aliquots of different compositions to individual microchannel substructures.
• the distribution unit as such is encircled (400). Upstream the distribution unit (400) there is a microchannel substructure (411), which will enable filling segments between close top vents (406a-d) of the continuous microchannel (401) with liquid aliquots of different compositions, if so desired.
• substructure (411) comprises a volume-defining unit (412), which is capable of metering a liquid volume that is equal to the volume of the segment between two close top vents (406a-d) in the continuous microchannel (401). If the volumes of the segments are different, it may be necessary to include different volume defining units in the substructure.
• substructure (411) upstream the distribution unit (400) may comprise further functionalities in addition to the metering functionality.
• substructure (411) may comprise a first downward bent (413) which has one of its shanks (414) connected to the end part (402) of the continuous microchannel (401) and the other shank (415) connected to the lower part of a second downward bent (416) that in turn is connected to a volume-defining unit (412) at the upper part of one of its shanks (417).
• the other shank (418) of the second downward bent (416) is venting to ambient atmosphere via an inlet (427).
• the volume-defining unit (412) shown is of the same kind as unit 11 including an overflow system and has an inlet port (419) of the same kind as unit 10.
• the volume of the metering microcavity (420) of the volume-defining unit (412) is the same as in a segment between two close top vents (406a-d).
• the substructure (411) of figure 4c also comprises (a) a large waste chamber
• Step 3 Aliquot 3 is metered in the volume-defining unit (412) and transported into the downward bent (413). This will push aliquot 1 to the next segment and place aliquot 2 in the first segment. When the desired number of segments has been filled a downwardly directed driving force is applied to pass the aliquots through their respective connecting microconduit/valve (407a-d 408a-d).
• the first downward bent is designed as a volume-defining unit, for instance by placing an overflow system at the same level as the top vents (406a-d) of the continuous microconduit (401) in shank (415).
• unit 3 may be used for collecting separate fractions between each pair of neighboring the top vents in the continuous microconduit (401 from liquids that have passed through the reaction zone.
• the size of a fraction will be defined by the volume between two close top vents in the continuous microconduit.
• Such fractions can then be further processed, for instance analysed, by taking them further down into the microchannel structure via the connecting microconduits (407a-d).
• reaction zone suitably is positioned between the first and second downward bents (416 and 413, respectively), for instance combined with the valve (423)
• the reaction zone may for instance comprise an immobilized reactant, for instance (a) a catalysts such as an enzyme, (b) a ligand capable of binding to component of a liquid which is to pass through the zone, (c) an affinity complex between a ligand and a binder etc.
• a catalysts such as an enzyme
• a ligand capable of binding to component of a liquid which is to pass through the zone
• affinity complex between a ligand and a binder etc etc. Based on the presence of particular components in the fractions that are collected one can analyse for features related to the zone as such or to the liquids applied, e.g. features of compounds present in the zone and/or a fraction.
• Unit 3 is preferably present on a spinnable substrate of the kind discussed elsewhere in this specification.
• the continuous microconduit (401) is thereby oriented in an annular- like fashion around the spinning axis and occupies at least a sector of the annular zone defined by the continuous microconduit.
• the sector typically covers at least 0.5-10° and at most 360°.
• the lower parts (404) of the unit are directed outwards from the spinning axis and the upper parts (402, 403, 405) inwards towards the spinning axis.
• the driving force is selected according to the same principles as outlined for unit 1.
• the aliquot applied should have a surface tension, which is > 5 mN/m, such as > 10 mN/m or > 20 mN/m.
• UNIT 4 ANNULAR ARRANGEMENTS OF MICROCHANNEL STRUCTURES
• the present inventors have recognized microchannel substructures and arrangements that are beneficial for increasing the total number of microchannel structures on a given planar substrate.
• the substrate in this unit is spinnable as discussed elsewhere in this specification.
• the objects of this subaspect are among others:
• FIG. 5 illustrates this subaspect of the invention.
• the individual microchannel structures (501a,b,c etc, encircled) are defined under the heading "Technical Field"
• the characteristic feature is that: (a) the microfluidic device comprises a plurality of individual microchannel structures (501a,b,c etc, encircled) which are
• Each microchannel structure typically has an inlet port that is at a shorter radial distance from the axis of symmetry than the substructures that are capable of retaining liquid while spinning the disc.
• the corresponding substructures of the microchannel structures of the same annular zone/ring or sector are present at the same radial distance while the corresponding substructures, if any, of other rings/zones are present at different radial distances.
• the plurality of microchannel structures according to this subaspect can be divided into two or more subgroups (subgroups a, b, c etc) such that the
• corresponding substructures means substructures that have essentially the same function and the same relative position in the flow path of the microchannel structures which are compared.
• the substructure preferably is capable of retaining liquid while spinning the disc, for instance with a downward bent as desribed for substructures (506a,b,c, 518, encircled).
• the center of the annular zones/rings typically coincides with the intersection between the spinning axis/axis of symmetry of the substrate.
• the annular zones of different subgroups may be partly overlapping or completely separate.
• the individual microchannel structures of one annular zone/ring may be equal or different.
• the individual members of an annular ring can be evenly spread over the zone or only occupy one or more sectors of the zone. See figure 5 in which the sector (507) is devoid of microchannel structures.
• This opening may also communicate directly or indirectly with an outlet port for waste.
• This microconduit (511) may have a valve function (512) as described above, typically of type 1 or type 3 a or b as defined above. Inner valves that are non-closing are preferred.
• the downward bent may be devoid of a microconduit in its lower part for downstream transportation (518).
• the substructure may also be in the form of a chamber having an inlet directed upwards and an outlet downwards and associated with a mechanical valve in its outlet.
• This feature minimizes the risk that waste from an open waste outlet port shall contaminate inlet ports.
• inlet ports and outlet ports may be on different sides of the microfluidic disc.
• microchannel structures of the same annular zone are divided into minor groups, and that microchannel structures of each minor group are connected to each other via a common inlet microcoduit or a common waste microconduit.
• This common microconduits extends essentially parallel to to the periphery of the disc and has fewer inlet ports and/or outlet ports, respectively than the number of microchannel structures in th group.
• the anti-wicking means comprises a change in both geometric and chemical surface characteristics. In connection with the anti-wicking means there is also a vent to ambient atmosphere (not shown).
• the fifth subaspect of the invention is a microfluidic device comprising a microchannel structure in which there is a structural unit accomplishing back and forth transport unit (unit 5).
• Unit 5 enables controlled transport of a liquid aliquot between two microcavities by wicking.
• An Y-shaped variant of unit 5 is illustrated in Figures 6a-c. In reference to figure 6a the unit comprises:
• a microconduit (606) permitting venting to ambient atmosphere in a dead end, if present, of the unit;
• both the inlet and the outlet opening (604 and 605) in the same microcavity preferably with a vent to ambient atmosphere in the other microcavity, or
• one of the openings (604 or 605) in capillary microconduit (603) and the other opening in one of the microcavities (601 or 602) preferably with a vent to ambient atmosphere in the other microcavity, for instance with the inlet opening (604) in capillary microconduit (603) and the outlet opening (605) in microcavity (601) and the vent in microcavity (602).
• Figure 6a illustrates variant (3).
• capillary microconduit is meant that the microconduit in relation to microcavty (601) and the liquid aliquot has dimensions and surface characteristics such that the liquid aliquot will be transported from microcavity (601) to microcavity (602) by capillary action (wicking). This capillary action is enhanced by the presence of one or more edges starting in microcavity (601) or capillary microconduit (603) and going in direction towards microcavity (602).
• the capillary action can be enhanced, a) if a bed of particles is placed in the capillary microconduit (603), for instance in front of a constriction (608) that is capable of retaining the particles, and b) if microcavity (602) by itself is able to exert capillary suction, for instance by being segmented into capillary vessels as illustrated in figures 6a-c.
• the venting microconduit (606) may be replaced with a transport microconduit in the case liquid is to be transported out of the unit via microcavity (602). It is the important to equip such a transport microcavity with venting means.
• the transport microconduit may be in the form of an upward bent with a top vent (inlet vent) at the upper part of the bent.
• the inlet opening (604) typically communicates with the inlet port via an inlet conduit (609) in which there may be anti-wicking means and/or a valve (610) preventing wicking out of the unit.
• valve function (607) associated with the outlet opening of the unit shall prevent undesired exit of liquid from the unit.
• This valve may be closing or non-closing.
• inertia force such as centrifugal force
• microcavity 602
• microcavity 601
• Capillary microconduit (603) may have an infmitesmal length (including being absent).
• microcavity (602) is typically placed at a higher level than microcavity (601).
• microcavity (602) should be at a shorter radial distance than microcavity (601).
• the two microcavities can be placed in the same order or the reversed order.
• the use of the unit comprises the steps of: i) providing the liquid aliquot and a microchannel structure comprising unit 5, ii) introducing the aliquot into one of the microcavities (601 or 602) depending on where the inlet opening (604) is, iii) permitting the liquid aliquot to be transported into the other microcavity and back to the microcavity into which it was initially introduced, iv) possibly repeating step (iii), v) applying a driving force that transport the aliquot from the unit via the outlet opening (605)
• the transport into the unit (step (ii)) is by applying a driving force and/or by capillary action.
• the driving force may be selected as generally discussed for the driving force in this specification.
• the protocol will mean that the contact time and also reaction time can be increased by back and forth transport of a liquid aliquot.
• the reactant is an affinity ligand for a solute
• the use of unit 5 in many cases will improve the adsorption of the solute.
• This kind of reactant may be immobilized to particles that in turn are retained in front of a protrusion of an inner wall, for instance at (608).
• Figures 6b-c further illustrate the invention by showing unit 5 integrated into a complete microchannel structure and giving typical sizes ( ⁇ m) of various parts and their position relative to each other.
• UNIT 6 (STRUCTURE PROMOTING CONTROLLED EVAPORATION)
• Controlled evaporation can be used for concentrating a liquid aliquot that has been processed in a microchannel structure. Concentrating includes evaporation to dryness and/or crystallization of one or more constituents of a aliquot that has been processed in a microchannel structure etc.
• the sixth subaspect of the invention is a microfluidic device comprising a microchannel structure in which there is a structural unit accomplishing controlled evaporation (unit 6).
• FIG. 7a is a view of the unit from above and figure 7b is a cross-sectional view along the line A-A.
• the unit comprises
• an outlet port (701) may be in the form of a well (703) with an opening (702), a bottom (708) and side walls (707), and
• the opening (702) may have various shape, such has rectangular, rounded etc. It may be elongated, circular, compact such as in a regular polygon with the same size of all sides etc.
• the well (703) may have a deeper central part (705) and a shallow peripheral part (706).- Either one or both of these parts may slope inwards towards the center of the well.
• the microconduit (704) may enter the well in a side-wall (707) and/or in the bottom (708). In the latter case, entrance may be in the deeper central part (705) and/or in the shallow peripheral part (706).
• the peripheral part (706) of the bottom (708) may also be non-wettable except for the open depression (709), if present.
• the design with a deeper central part and a shallow peripheral part and/or wettable/non- wettable parts will promote concentrating the aliquot to a smaller area and possibly increase the sensitivity of a detection principle utilizing the concentrated form of the aliquot.
• the bottom (708) of the well and possible also parts su ⁇ ounding the well and/or the opening may comprise a conducting material in case the concentrated material is to be ionized after having been concentrated.
• a conducting material in case the concentrated material is to be ionized after having been concentrated.
• the conducting material may be at the surface or covered by some dielectric material (non-conducting material).
• Typical conducting materials comprise metals and/or conducting polymer materials. Typical non-conducting materials are made of plastics, ceramics etc. See also the co ⁇ esponding International Patent Applications filed in parallel with this application.
• Figure 7c illustrates a variant of unit 6 that at the filing date was prefe ⁇ ed for the application described in the preceding paragraph.
• the incoming microconduit (704) passes into the bottom (708) of the well (703) in uncovered form, which means it will look like a groove/depression (709) of constant depth that may widen in a drop-like manner (as shown) in the bottom (708).
• a non-wettable surface break (711) (hydrophobic) is positioned around the opening (702). In the variant shown this surface break extends as illustrated down into the bottom of the well and also covers parts of the sidewalls. Other parts of the well are wettable (hydrophilic). Further details are given in the applications refe ⁇ ed to in the preceding paragraph.
• the well may contain an affinity ligand that is capable of binding to a compound of interest in a liquid sample applied at the inlet port or in the processed sample.
• an affinity ligand is suitably immobilized to the bottom (708) by chemical means or by physical or bioaffinity adsorption.
• Affinity ligands comprise members of pairs such as antigens/haptens and antibodies and antibody active fragments, lectins and compounds containing carbohydrate structures, enzymes and their substrates/coenzymes/ inhibitors, charged compounds and compounds having the opposite charge (ion exchangers) etc.
• a microchannel structure which contains unit 6, is oriented as discussed elsewhere in this specification on a spinnable substrate, typically with an inlet port positioned at a shorter radial distance than unit 6.
• the transport direction into the well (703) may be perpendicular to a side-wall (707) or at an angle ⁇ 90°.
• Evaporation is controlled among others by the rate at which a liquid aliquot merges into the inlet port. Evaporation will also depend on chemico-physical parameters of the liquid in the aliquot, for instance vapor pressure, surface tension etc, and the size and shape of the well.
• Transport may be caused by an applied driving force, for instance by spinning if the unit is present on a spinnable substrate. A too high spinning speed will increase the risk for drop/aerosol formation and counteract controlled evaporation.
• At least one of the aliquots applied should have a surface tension, which is ⁇ 5 mN/m, such as > 10 mN/m or > 20 mN/m UNIT 7 (ANTI-WICKING MEANS BASED ON A CHANGE IN GEOMETRIC SURFACE
• Anti-wicking means that are based on local changes in chemical surface characteristics in the walls between two close inner edges of a microchannel have been described previously (WO 9958245, Amersham Pharmacia Biotech AB, Larsson,
• Anti-wicking means should in most cases counteract wicking in one direction but permit bulk liquid transport in the opposite direction through a microconduit.
• the seventh subaspect of the invention is a microfluidic device comprising a microchannel structure in which there is a structural unit comprising anti-wicking means (unit 7).
• Unit 7 is illustrated in Figure 8a and comprises:
• the microchannel conduit (801) may be positioned either upstream or downstream microcavity (802).
• the microconduit of figure 9 is rectangular and seen from above which means that only two edges (803a-b) are seen in the figure.
• the change in geometrical surface characteristics is a deformation in the form of an indentation, which may be ear-like. In the figure the identation is going in the side-wall from each viewable edge to the edge below.
• the inside of each ear-like indentation has a non-wettable (hydrophobised) surface, which co ⁇ esponds to a change in chemical surface characteristics.
• Figure 8a shows unit 7 applied to a volume-defining unit as defined for unit 11 with an overflow channel (806), a volume-metering microcavity (807), an inlet port (808), and a valve function (809) at the outlet opening of the volume-defining unit.
• Figures 8b-c gives alternative suggestions for changes in geometric surface characteristics of a rectangular microconduit (801) connected to a microcavity (802).
• the a ⁇ angement is seen from above in the same manner as for figure 8a.
• the change in geometric surface characteristics may be selected from indentations (810), protrusions (811) and an increase in the angle between the two inner wall parts defining a length-going inner edge.
• other physical deformations of the edges may be used.
• An indentation or a protrusion may be extending from an edge into one or both of the inner wall parts defining the edge. In most cases the deformation will also stretch across the wall between two length-going edges.
• An increase in the angle between two intersecting walls means in its extreme that the inner edge can be rounded within the zone ca ⁇ ying the antiwicking means but not rounded between the zone and the microcavity.
• the microconduit (801) may locally be cylindrical.
• the change in surface characteristics in anti-wicking means typically leads to decreased wettability by the liquid aliquot when going from microcavity (802) to the anti-wicking zone.
• This subaspect of the invention also comprises inner valve functions (passive valves) in which a non-wettable surface break is combined with a change in chemical and geometric surface characteristics at essentially the same position along the length of all edges of a microconduit.
• inner valve functions passive valves
• a non-wettable surface break is combined with a change in chemical and geometric surface characteristics at essentially the same position along the length of all edges of a microconduit.
• the change in chemical surface characteristics non- wettability
• the antiwicking means in the valve should be located at the same position along the microconduit (801).
• the microconduit (801) with anti-wicking means (804, 805) may be placed between the microcavity and a vent to ambient atmosphere, including an inlet port (808).
• the anti-wicking means will lower undesired losses of liquid due to evaporation through the inlet port and/or the vent.
• the flow direction may also be selected such that the microconduit is used for transporting liquid into the microchannel structure. In this case the anti-wicking means will hinder undesired leakage into the structure. If the microconduit is branched it becomes important to equip both branches with anti-wicking means as discussed above.
• one branch may be used to introduce liquid into the microcavity from an inlet port (808) and the other branch used as an overflow (806) channel and/or inlet channel for other liquids in both cases with a venting function (inlet and/or outlet venting function).
• Anti-wicking means will be beneficial for both branches.
• This kind of inventive anti-wicking means is adapted to prevent wicking for liquid aliquots that have a surface tension, which is > 5 mN/m, such as > 10 mN/m or > 20 mN/m.
• UNIT 8 UNIT FOR CREATING A LIQUID FRONT OF DIFFERENT COMPOSITION COMPARED TO THE BULK LIQUID FLOW.
• the present inventors have recognized that there may be advantages with introducing a liquid aliquot into a microcavity, if the front of the liquid has a different composition compared to the bulk.
• This kind of liquid transport can avoid problems associated with incomplete filling of a microcavity and also be used to protect a bulk liquid from oxidation reactions and evaporation losses during the dispensasation of ⁇ l- and in particular nl-volumes to microfluidic devices.
• Unit 8 and its uses enables liquid transport in which the front zone (liquid 1) is of a different composition compared to the bulk (liquid 2).
• the unit is illustrated in figures 9a-b.
• the unit comprises a microconduit (901) for transport of a bulk liquid (liquid 2).
• a microconduit (901) for transport of a bulk liquid (liquid 2).
• inlet end (902) which communicates with an inlet port (not shown) of the microchannel structure comprising this unit, and one outlet end (903), which communicates with downstream parts of the same microchannel structure or directly with an inlet opening that can function as an outlet and/or inlet vent to ambient atmosphere.
• an opening (904) into a microcavity (905) which comprises the liquid (liquid 1) that will form the front zone.
• Liquid 1 (906) fills up the cavity (905) so that its meniscus (907) is in the opening (904).
• liquid 1 with proper surface tension in relation to the surface tension of liquid 2
• the flow geometry of the front will be improved when the liquid transport enters microchannel parts that have i ⁇ egularities, for instance corners that may create "dead ends" in microcavities and microchambers. Filling of this kind of microcavities may thus be more efficient.
• a front zone of this kind will also protect liquid 2 from oxidation reactions caused by contact with ambient air and/or evaporation losses via the outlet end (903), e.g. via downstream connections to ambient atmosphere of the microconduit (901).
• liquid 1 is less volatile than liquid 2.
• FIG. 9b A design that is adapted to a spinnable substrate is illustrated in figure 9b.
• the main flow direction is indicated with an a ⁇ ow.
• This variant may comprise two downward bents (908,909) that are directed outwards from the spinning axis, and an upward bent (910) that is directed inwards towards the spinning axis (axis of symmetry).
• the first downward bent (908) has one shank comprising the inlet end (902) and the other shank the outlet end (903).
• the lower part of the first downward bent (908) comprises an opening (904) to a microcavity (905).
• This microcavity (905) comprises the second downward bent (909) and downstream possibly also the upward bent (910) followed by a waste chamber (911).
• the connection between the first and the second downward bent (908,909) is via one of the shanks of the second downward bent (909) and the opening (904) in the first downward bent (908).
• the top part of the microcavity (905) is at essentially the same level as the opening (904) in the first downward bent (908).
• the waste chamber (911) will then function as an overflow channel.
• the appropriate valving in the microcavity (905) may be needed to reduce the risk that the driving force will transport liquid 2 out through the microcavity (905).
• an inner valve typically in the form of non-wettable surface breaks, may be placed in microcavity (905) in association with the opening (904).
• the non- wettability in this valve is selected such that liquid 1 is more prone to penetrate the valve than liquid 2.
• the variant also comprises a valve in the outlet microconduit (914) close to the intersection between the second downward bent (909) and the outlet microconduit (914).
• This valve prevents liquid 1 to pass through. It is preferably an inner valve typically based on non-wettable surface breaks that liquid 2 passes easier than liquid 1.
• the liquid front of liquid 2 that leaves the unit will be of the same composition as the bulk. The front of different composition will only be present in microconduit (901).
• the variant thus is primarily intended for protecting a dispensed liquid aliquot from evaporation and/or oxidation reaction during dispensation procedures that require some time, e.g. comprising dispensation to several inlet ports in series.
• the lower channel wall (915) at the extreme of the upward bent (910) is preferably located at essentially the same level as the opening (904) in the microconduit (901) (not shown).
• the driving force for transport of liquid 2 through microconduit (901) may be selected among those discussed elsewhere in this specification for the other units, with preference for centrifugal force in combination with microchannel structure comprising unit 6 being present on a spinnable substrate.
• this unit defines a method for creating a liquid front zone of different composition compared to a bulk liquid that is transported in a microconduit.
• This method is characterized by comprising the steps of: (i) providing a microchannel structure comprising unit 9 with liquid 1 (906) placed in the microcavity (905) and exposing its meniscus (907) in the opening (904), (ii) introducing an aliquot of liquid 2 through the inlet end (902), (iiii) applying a driving force so that the front of liquid 2 passes the opening (904) between the inlet end (902) and the outlet end (903) of the microconduit (901).
• UNIT 9 NON-CLOSING INNER VALVE
• This kind of valves is primarily intended to control transport of liquid aliquots that have a surface tension, which is lower than normal.
• At least one, preferably all of the liquid aliquots used should have a surface tension that is > 5 mN/m, such as > 10 mN/m or > 20 mN/m.
• the ninth subaspect of the invention is a microfluidic device comprising a microchannel structure in which there is a structural unit with a non-closing inner valve (unit 9).
• Unit 9 is illustrated in figure 10 and comprises a microconduit (1001) with a defined flow direction (1002, a ⁇ ow).
• the unit may be connected directly or indirectly via a part of the microconduit (1001) to a microcavity/microchamber (1003).
• the microconduit (1001) comprises a circumferential zone (1004) in which there is a non-closing inner valve function defined by (i) a change in geometric surface characteristics (1005) in at least one sidewall (1006) within the zone, and (ii) at least one sidewall (1007) that does not have having the change in geometric surface characteristics being non-wettable, preferably a sidewall opposing a side wall having a change in geometric surface characteristics.
• non-wettable refer to chemical surface characteristics of the sidewall.
• sidewalls containing the change in geometric surface characteristics are wettable at least in the circumferential zone hi case the microconduit at the valve is rounded, a sidewall and the opposing sidewall simple refer to opposing parts of the circumferential zone. Such a part typically occupies 45°- 150° of the circumferential zone comprising the valve function.
• the change in geometric surface characteristics is typically a physical deformation (1005) that preferably extends across essentially the whole sidewall. If it connects to bordering/intersecting sidewalls a part of the bordering sidewalls will also contain a physical deformation.
• the useful physical deformations are preferably in form of protrusions (projections) that extend as one or more ridges across the sidewall.
• microconduit of unit 9 may be linked to a chamber-like structure (1003), by which is meant that the cross-sectional area at one end of the microconduit (1001) increases, for instance more than twice.
• the length of the circumferential zone in which the change in geometric surface characteristics occurs is typically at least 10%, such as at least 50% or at least 100%, of the depth and/or of the width of the microconduit immediately upstream and/or immediately downstream the zone.
• this subaspect of the invention defines a method for controlling transport of a liquid aliquot through a non-closing inner valve function.
• the method comprises the steps of: (i) providing a microchannel structure comprising unit 9 as defined in the present specification and a liquid aliquot, preferably having a surface tension which is > 5 mN/m, such as > 10 mN/m or > 20 mN/m; (ii) introducing the liquid aliquot into the microchannel structure by assistance of a driving force of a magnitude that will not allow the aliquot to pass through the non-closing inner valve of unit 9; and (iii) increasing the driving force to a magnitude that is sufficient for transporting the liquid through the non-closing inner valve of the microconduit.
• step (ii) the front of the aliquot may be allowed to proceed into the microconduit up to the circumferential zone.
• the driving force may be as described above.
• the driving force is inertia force including gravitational forces and centrifugal forces.
• centrifugal force the microchannel structure is typically oriented as discussed above for spinnable substrates.
• this kind of substrates is spun at a rate sufficient for overcoming the non-closing inner valve of unit 9.
• the kind of driving force may differ between steps (ii) and (iii). For instance capillary force or inertia force of the kind discussed elsewhere in this specification may be used in step (ii) while step (iii) may solely rely upon centrifugal force, or an externally applied pressure.
• the tenth subaspect of the invention is a microfluidic device comprising a microchannel structure in which there is an inlet unit promoting liquid entrance into a microchannel structure.
• the unit is illustrated in figures 1 la-b.
• the unit comprises:
• the inner wall of the microcavity (1101) comprises one or more grooves and/or projections (ridges/valleys) (1104) directed towards the connection between the inlet conduit (1103) and the microcavity (1101).
• the microcavity (1101) is tapered when approaching the inlet microconduit (1103).
• the main purpose of the grooves and/or the projections is to increase the capillary suction in the inlet port. This will speed up liquid penetration and lower the time for undesired evaporation and loss of liquid during the dispensing operation.
• Figure 1 lb illustrates a variant comprising a non-wetting surface break (1105) in association with the rim of the inlet opening (1101), primarily at a side which is closest to spinning axis if the inlet port is located on a spinning substrate.
• This figure also illustrates a variant of unit 10 that comprises anti-wicking means downstream the inlet opening (1101).
• antiwicking means in general, these antiwicking means may comprise changes in geometric surface characteristics (1106) and/or in chemical surface characteristics (1107).
• the projections may have a height that at maximum is equal to the depth of the microcavity (1101) but may be significantly lower as long as a sufficient capillary action is maintained in the inlet port.
• the liquid to be introduced typically has a surface tension as discussed above.
• the width of the inlet opening is typically smaller than the width of microcavity (1101) as illustrated in figures lla-b.
• the inlet opening (1102) may have one or more edges directed inwards the port, preferably with an n-numbered axis of symmetry perpendicular to the opening, n is preferably an integer ⁇ 7, such as 3, 4, 5 or 6. See for instance US 4,233,029 (Eastman Kodak) and US 4,254,083 (Eastman Kodak).
• the unit is typically combined with a dispenser that is capable of dispensing a liquid aliquot of ⁇ 10 ⁇ l, such as ⁇ 1 ⁇ l, or ⁇ 500 nl or ⁇ 100 nl or ⁇ 50 nl to the inlet port.
• the dispenser can be one of the dispensers generally described elsewhere in this specification.
• Penetration after dispensing is typically taking place by utilizing capillary forces, interaction forces between a dispensed liquid and the inner surfaces in the inlet unit and other driving forces as discussed elsewhere in this specification.
• suitable forces other than capillary force
• inertia force including centrifugal force.
• MicroChannel structures comprising this kind of inlet port are in a prefe ⁇ ed variant of this subaspect placed on a spinnable substrate and used as discussed elsewhere in this specification.
• This kind of inlet unit is particularly well adapted to receive liquid aliquots that are inn form of particle suspensions.
• the present inventors have recognized these problems and designed a volume-metering unit (unit 11) to meter primarily nl- volumes of liquids.
• the unit can be integrated into microchannel structures of microfluidic devices.
• the eleventh subaspect of the invention thus is a microfluidic device comprising a microchannel structure in which there is volume-defining unit enabling accurate metering of small volumes within a microfluidic device.
• Unit 11 is illustrated in figure 12. The figure also illustrates the unit may comprise units 7 and 10.
• Unit 11 comprises
• the overflow opening is at a higher level than the outlet opening (1203) and the volume between these two openings defines the volume to be metered in the volume-defining microcavity (1201).
• This volume is typically ⁇ 1000 nl such as ⁇ 500 nl, ⁇ 100 nl or ⁇ 50 nl but may also be larger such as ⁇ 10 ⁇ l or ⁇ 100 ⁇ l or ⁇ 1000 ⁇ l.
• the liquid typically has a surface tension as discussed above.
• the overflow microconduit (1204) is typically communicating with ambient atmosphere at one or more positions, for instance at large waste chamber or waste conduit (1212), which is at a lower level than the connection between the overflow microconduit (1204) and the volume-defining microcavity (1201).
• the outlet microconduit (1203) is used to transport a metered liquid aliquot further into the microchannel structure.
• the cross-sectional area (a ) in the volume-defining microcavity (1201) at the overflow opening is in prefe ⁇ ed variants smaller than the largest cross-sectional area (a ) between the overflow opening and the outlet opening.
• the ratio aj/a 2 typically is ⁇ 1/3, such as ⁇ 1/10. This means a constriction of the microcavity (1201) at the joint between the overflow microconduit (1203) and the microcavity (1201), i.e. at the joint between inlet microconduit (1202) and volume-defining microcavity (1201).
• the inlet microconduit (1202) upstream the overflow opening typically widens, for instance to an inlet port (1205), such as unit 10.
• volume-defining unit and a true inlet port there may other structural/functional units, for instance a unit for sample treatment such as for the removal of particulate materials.
• a unit for sample treatment such as for the removal of particulate materials.
• Unit 11 may have a valve function (1206,1207,1208) associated with at least one of
• the valve may be a mechanical valve but is preferably an inner valve of the closing or non-closing type.
• At least one of the inlet microconduit (1202), outlet microconduit (1203) and the overflow microconduit (1204) contains anti-wicking means of the kinds defined elsewhere in this th specification.
• This variant of the 11 subaspect particularly applies if a microconduit has geometries promoting imbibing and wicking, for instance length-going edges.
• anti-wicking means (1209) are present in inlet microconduit (1202)
• a microchannel structure comprising unit 11 may in its prefe ⁇ ed variants be placed on a spinnable substrate as discussed elsewhere in this specification and equipped with valve functions (1203,1208), preferable inner valves that maybe of the non-closing type. If the intention is to drive the liquid out of the over-flow channel (1204) before the metered aliquot is released via the outlet microconduit (1203), it becomes important to have a sufficiently large difference in radial distance between the overflow opening in the volume-defining microcavity (1201) and the ending of the overflow microconduit (1204) (rj) in a waste chamber relative the difference in radial distance between the overflow opening and the valve (1206) in the outlet microcoduit (1203) (r ).
• n shall be essentially larger than r 2 . This particularly applies if the valve function (1206) in the outlet microconduit (1203) is an inner non-closing valve.
• the valve function (1206) in the outlet microconduit (1203) is an inner non-closing valve.
• a variant that also is adapted to spinnable substrates comprises a downward bent with the volume-defining microcavity being a part of the lower part of the bent.
• the overflow microconduit typically is connected to one of the shanks of the downward bent and forms together with the lower part of this shank an upward bent.
• the upper part of the same shank vents to ambient atmosphere (inlet vent).
• An inlet port for sample (co ⁇ esponds to 1205) may then be connected to the other shank of the same downward bent.
• the vent to ambient atmosphere may also have a sample inlet function.
• the outlet conduit with a valve is connected to the lower part of the downward bent (co ⁇ esponds to 1203 and 1206, respectively).
• the overflow microconduit (co ⁇ esponds to 1204) ends in a waste channel or waste chamber with a valve function (co ⁇ esponds to 1208).
• outlet opening connected to the outlet microconduit (1203) on microcavity (1201) somewhat higher than the lowest part of the volume- defining microcavity.
• it will be possibly to sediment particulate materials and only collect a supernatant of defined volume through the outlet microconduit (1203). Sedimenting can be assisted by the use of centrifugal force (spinning).
• unit 11 defines a method for introducing metered liquid aliquots into microchannel structures.
• the method comprises the steps of:
• the driving force is selected as discussed above for the other units with preference for inertia force including gravitational force and centrifugal force when the substrate is spinnable.
• unit 12 may also be used as a volume- defining unit, with the advantage that both the front zone and the tailing zone may be removed in the volume-metering process. This may often be advantageous because the front zone often is depleted of components that adsorb to surfaces.
• the microchannel structure of the present invention may contain a functional unit (particle separator) that enables separation of particulate material and further processing within the structure of either the liquid free of the particulate material or of the particulate material as such.
• a functional unit particle separator
• Particulate material is often present in samples and may interfere with or disturb downstream fluidics.
• This functional unit is therefore often positioned early in the microchannel structure, for instance linked directly to an inlet port.
• the separation unit may also be positioned after a processing unit and used to separate added particulate materials that has been or will be modified during the processing of a sample in the unit.
• the twelth subaspect of the invention is a microfluidic device comprising a microchannel structure in which there is a structural unit enabling separation of particulate material (unit 12).
• Unit 12 is illustrated in figure 13. It comprises a microcavity (1301) in which there are: (i) a lower part ( 1302) for particulate material, (ii) an upper part (1303) for liquid free of particulate material, (iii) an inlet opening (1304) at the top of the upper part (1303) of the microcavity (1301), and (iv) an outlet opening (1305) between the lower part (1302) and the upper part (1303).
• the inlet opening (1304) is intended for introduction of a liquid aliquot containing particulate material. This opening communicates in its upstream direction with an inlet port (1311) of the microchannel structure. Communication is via an inlet microconduit (1306).
• the outlet opening (1305) is intended for withdrawal of and further transport of liquid, which is free of particulate material, into other parts of a microchannel structure via an outlet microconduit (1308) attached to this outlet opening.
• the lowest part of the lower part (1302) may be equipped with a second outlet opening and a second outlet microconduit (not shown), which is intended for withdrawal of particulate materials assembled in the lower part (1302).
• the microcavity (1301) may be constricted (1309) at the outlet opening (1305) and/or the lower part (1302) may have a constant or diminishing cross-sectional area from the first outlet opening (1305) and downwards.
• a valve function (1310) is preferably associated with outlet microconduit (1308), preferably close to the outlet opening (1305).
• valve function (not shown) connected to the second outlet opening/outlet microconduit for withdrawal of particulate materials.
• the overflow microconduit (1307) if present, is associated with a valve function (1313), for instance in the lower part of the over-flow microconduit (1307) or in the waste chamber (1317a) next to the end of the overflow microconduit.
• the valve functions used in unit 12 may be selected amongst the various kinds of valves discussed elsewhere in this specification, with preference for inner valves, for instance of the non-closing type. The preferences are essentially the same.
• valve function in the overflow microconduit (1307), in the outlet microconduit (1308) and in the possible second outlet microconduit are designed such that liquid can pass through in the order given.
• the first (1305) and the second (not shown) outlet openings may be connected to separate funtional units of a microchannel structure.
• liquid free of particulate material or the particulate material as such, respectively, can be further processed separately, e.g. assayed with respect to at least one component.
• a microchannel structure which comprises unit 12 is adapted to be placed on a spinnable substrate of the kind discussed elsewhere in this specification.
• the inlet opening (1304) is then placed at a shorter radial distance (higher level) than the first outlet opening (1305), which in turn is placed at shorter radial distance (higher level) than the second outlet opening (if present).
• the particulate material When subjected to spinning the particulate material will sediment and assemble in the lower part (1302) of the microcavity (1301).
• valve function (1313) at the outlet (1314) of the overflow microconduit (1307) is larger than the radial distance of the valve function (1310) in the first outlet, microconduit (1305) or of the inlet opening (1304), the liquid in the overflow microconduit (1307) will leave at a lower spinning speed than the liquid in the first outlet microconduit (1308). This applies if the valve functions are inner valves of the non- closing type.
• this subaspect of the invention defines a method for processing a liquid aliquot/sample containing particulate material in a microchannel structure that is present on a spinnable substrate as discussed elsewhere in this specification. Processing typically means that at least one component in the aliquot/sample is assayed.
• the method comprises the steps of:
• a microchannel structure comprising unit 12 and a functional unit in which either a component in the liquid as such (for instance a solute or the like) or in the particulate material can be processed,
• the driving force in step (iv) may be inertia force such as gravitational force or centrifugal force or any of the other forces discussed elsewhere in this specification for transport of a liquid aliquot.
• Figure 13a also shows that there maybe anti-wicking means (1312) associated with the microconduit (1306) downstream the inlet port (1311).
• microchannel structures and functional units 1-13) have been manufactured and tested as outlined in the patent applications in the name of Amersham Pharmacia Biotech AB and/or Gyros refe ⁇ ed to above.

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