WO2003072227A1 - Systemes fluidiques comprenant des champs magnetiques ou electriques et leurs procedes d'utilisation - Google Patents

Systemes fluidiques comprenant des champs magnetiques ou electriques et leurs procedes d'utilisation Download PDF

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Publication number
WO2003072227A1
WO2003072227A1 PCT/US2003/004647 US0304647W WO03072227A1 WO 2003072227 A1 WO2003072227 A1 WO 2003072227A1 US 0304647 W US0304647 W US 0304647W WO 03072227 A1 WO03072227 A1 WO 03072227A1
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Prior art keywords
fluid
channel
fluidics system
species
electric
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PCT/US2003/004647
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English (en)
Inventor
Gary Zabow
Mara G. Prentiss
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President And Fellows Of Harvard College
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Priority to AU2003219775A priority Critical patent/AU2003219775A1/en
Publication of WO2003072227A1 publication Critical patent/WO2003072227A1/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D57/00—Separation, other than separation of solids, not fully covered by a single other group or subclass, e.g. B03C
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502746—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means for controlling flow resistance, e.g. flow controllers, baffles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502761—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 specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/16—Surface properties and coatings
    • B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0415—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/043—Moving fluids with specific forces or mechanical means specific forces magnetic forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/08—Regulating or influencing the flow resistance
    • B01L2400/084—Passive control of flow resistance
    • B01L2400/088—Passive control of flow resistance by specific surface properties

Definitions

  • This invention relates to fluidics systems and, in particular, to fiuidics systems that are used in combination with a magnetic or an electric field.
  • the ability to manipulate different species is important in many applications, for example, in the fields of biotechnology, analysis, purification, detection, and synthesis, amongst others.
  • the manipulations may involve accumulating, separating, transporting, positioning, and/or storing the species.
  • fluidic systems that are formed from a substrate.
  • the substrate may have a network of channels formed therein in which fluid is contained.
  • the species can be caused to flow through the fluid to different locations on the substrate as desired for a particular application.
  • a number of species may be located proximate to the channel walls as they flow through the fluid. This can be the result of normal flow distribution across width of the channel, diffusion within the fluid, and gravitational settling. Such species may adhere to channel walls as a result of nonspecific binding. This adherence can prevent the species from reaching their desired location and, thus, can affect the performance of the fluidics system. Furthermore, the buildup of species adhered to the channels walls can restrict flow through the channels. The restriction of flow can especially be problematic at small channel widths. Even in cases in which species do not adhere to the channel walls, species proximate the channel walls may lag behind other species because the wall functioning as a boundary condition for flow.
  • This invention relates to fluidic systems, as well as methods of manufacturing and using the same.
  • a fluidics system in one aspect, includes a substrate having a surface defining a channel.
  • the surface includes a first region having a first affinity for a fluid and a second region having a second affinity different from the first affinity.
  • the system further includes an a source of an electric or magnetic field. The source is capable of applying the electric or magnetic field to the substrate.
  • a fluidics system in another aspect, includes a substrate having a surface that defines a channel.
  • the surface that defines the channel includes a first region having a first affinity and a second region having a second affinity different from the first affinity.
  • the surface is able to produce a pinned meniscus in a fluid within the channel.
  • a fluidics system in another aspect, includes a substrate having a surface that defines a channel.
  • the fluidics system is designed to produce a static potential minimum located within the channel in an electric or magnetic field when the channel contains a fluid and is exposed to a respective electric or magnetic field.
  • a fluidics system in another aspect, includes a substrate having a surface including a portion that defines a fluid channel and a non-channel portion.
  • the non-channel portion being coated with an agent able to substantially alter an electric or magnetic field applied to the substrate.
  • the portion that defines the channel being substantially free of the agent.
  • a method in another aspect, includes adding a fluid to a channel.
  • the fluid carrying a plurality of species.
  • the method further includes applying an electric or a magnetic field to the species to move the species away from the surface that defines the channel.
  • a method in another aspect, includes passing a fluid laminarly through a channel The fluid carries a species that defines a longitudinal flow distribution width within the fluid in the channel. The method further includes substantially controlling the longitudinal flow distribution width of the species in the fluid.
  • a method in another aspect, includes applying an electric or magnetic force to a fluid containing a species to produce a concentrated portion of the fluid carrying a majority of the species and a dilute portion of the fluid carrying a minority of the species. The method further includes removing some of the dilute portion of the fluid.
  • Figs. 1 and IB respectively illustrates embodiment of fluidics systems of the invention
  • Figs. 2A-2C respectively illustrate different cross-sections of channels formed in substrates used in fluidics systems
  • Fig. 3 illustrates a substrate that includes a plurality of intersecting channels
  • Figs.4A-4F illustrate the localization of a species within a fluid using methods of the present invention
  • Figs. 5A-5D respectively illustrate various meniscus types formed using methods of the present invention
  • Figs. 6A-6C respectively illustrate a method that employs a mask in connection with an embodiment of the present invention
  • Figs. 7A-7C respectively illustrate masks used in different embodiments of the invention.
  • Figs. 8A and 8B respectively illustrate masks used in other embodiments of the invention.
  • Figs. 9A-9E illustrate a method of manufacturing an embodiment of the invention
  • Figs. 10A-10C illustrate the flow of a species in an embodiment of the invention
  • Fig. 11 is a photocopy of a photomicrograph of a fluid profile created in one embodiment of the invention.
  • FIGs. 12, sections A and B, show methods of the invention used to accumulate (A) or separate (B) a species;
  • Fig. 13 is a graph illustrating an embodiment of the invention used to accumulate or separate a species
  • Figs. 14A and 14B show a system used to accumulate or trap species
  • Fig. 15, sections a-d, is an illustration of an embodiment of the invention, as compared to a mathematical model. Detailed Description
  • This invention relates to fluidic systems, as well as methods of manufacturing and using the same.
  • the invention involves manipulating species within a fluid, for example causing species within a fluid to preferentially reside in or migrate to a particular section of the fluid by application of a magnetic and/or electric field to the fluid.
  • systems of the invention include a substrate having a surface that defines one or more channels.
  • the channels contain a fluid (e.g., water) into which different species (e.g., biological or chemical materials) are introduced.
  • the species are generally caused to flow through the channels to a desired location within the system.
  • the species can be attracted away from the channel walls using magnetic or electric fields while they flow through the channels. This attraction can enhance the flow of species through the system and can limit problems associated with the species adhering to channel walls such as increased drag or clogging channels.
  • the systems can be used to perform various functions, for example, the separation or accumulation of different species.
  • the systems are particularly well-suited for use in microfluidic applications which include channels with relatively small widths, and detection/purification of minute quantities of species in large volumes of fluids.
  • a static electric or magnetic field potential minimum can be produced at an interface between two fluids using various embodiments of this invention, to which an electrically or magnetically susceptible species is attracted.
  • the potential minimum can be located inside the channel, rather than along a wall or surface of the channel.
  • the invention is able to move the species away from the walls of the channel, for example, as shown in Fig. 11.
  • the species may be, for example, concentrated within a particular region of the fluid.
  • the species may then be collected, for example, for detection purposes or for purification of the species or the fluid.
  • Drawing the species away from the walls may also reduce nonspecific binding of the species within the channel, which may, for example, reduce adsorption of the species within the fluidics system, or result in improved flow properties of the fluid, for example, due to lower surface drag.
  • the field potential minimum can be created in any channel where the surface tension is dominant over the gravitational force, for example, a channel of less than about a few centimeters in width for air and water.
  • the potential minimum can be created by producing a curved interface between at least two incompatible fluids at an interface, and applying a substantially homogeneous field at least to the area of the interface, where the potential minimum is created at the peak (or minimum, depending on the perspective) of the curved interface.
  • the invention involves application of an electric field that is substantially homogeneous in a plane tangent to the peak (or minimum) of the curved meniscus, with the field in the third axis (the axis perpendicular to the plane being irrelevant.
  • a substantially homogeneous magnetic field is applied in the plane tangent to the peak (or minimum) of the curved meniscus and increases monotonically in the third axes perpendicular to the peak (or minimum) of the curved meniscus'.
  • the curved interface can be produced, for example, using a pinned meniscus, where differences in affinities between regions of channel walls cause a pinned meniscus to form within a channel.
  • a potential minimum can also be created by producing a field that attracts species to a specific region of a fluid/fluid interface, regardless of any shape of the interface, thus, a minimum in energy can be created in connection with a fluid/fluid interface that is not necessarily curved, or is not curved to the extent that a substantially homogeneous field (as described above) creates a minimum energy position for any species within either fluid. For example, an applied homogeneous field can be partially masked to create a potential minimum within the interface.
  • static in referring to electric or magnetic fields, refers to electric or magnetic fields that are not periodically variable with respect to time, at least on the timescale of concentration, separation, etc. of species in accordance with the invention.
  • a static electric or magnetic field potential minimum may be created when there is a difference in curvature between the static field and the fluid. This difference in curvature between may be created by a variety of methods.
  • a uniform electric or magnetic field may be applied to a system where the surface of the fluid is substantially curved.
  • a non-uniform or "curved" electric or magnetic field may be applied such that the applied field creates a local potential minimum region within the surface of the fluid.
  • fluidics system 10 uses an electric field to manipulate a species carried by a fluid according to one embodiment of the invention.
  • fluidics system 10 includes substrate 11 having channels 12 formed thereon and/or therein. It is to be understood that wherever channels are described in connection with any embodiment of the invention, channels can take the form of any channels as broadly defined below.
  • the substrate 11 is placed between plates of a capacitor 13 which generates the electric field, in the embodiment illustrated.
  • Fig. IB illustrates an embodiment similar to Fig. 1A except that a magnetic field is used to manipulate a species carried by a fluid.
  • magnet 14 is used to apply the magnetic field to substrate 11.
  • Fig. 3 further illustrates substrate 11 according to one embodiment of the present invention.
  • substrate 11 illustrates a plurality of intersecting channels 12, which may contain fluid 41 carrying species 42.
  • the channels are designed to carry species 42 to different locations as desired for a particular application.
  • Other fluids or species may also be present within channels 12 as well.
  • the substrate may include only a single channel, and in other embodiments any number of channels, any of which may intersect other channels (allowing fluid flow between channels) or be separated from other channels (isolating fluid flow within that channel).
  • a “fluidics” system is any system that contains at least one channel for fluid flow.
  • the system may use flowing gases or liquids to perform various functions or manipulations, in some cases without the use of moving or other mechanical parts.
  • microfluidics generally refers to fluidics systems that have a characteristic dimension that is on the border of micrometers, i.e., ⁇ 1 cm. For example, any one of the length, width, or height of a channel of the microfluidics system is less than 1 cm (or other dimensions, described below).
  • a static field potential minimum can be created by producing a curved interface between two fluids (e.g., water and air) and applying a substantially homogeneous electric or magnetic field.
  • a curved interface is formed between two fluids 51, 52. Either fluid may carry species 41.
  • the curved interface also referred to herein as the "meniscus,” may be produced by any technique.
  • the meniscus may have any shape, for example, flat, concave up (e.g., Fig. 5A), or concave down (e.g., Fig. 5B) (of course, "up” and “down” depends upon perspective; it is to be understood that, e.g.
  • a curved interface in a two-fluid system, can have a maximum, or minimum, from the perspective of either fluid).
  • the shape of the meniscus is related to the difference in affinity between the two fluids and the wall of the channel containing the fluids, as well as the relative volumes of the two fluids within the channel.
  • affinity refers to the hydrophobic/hydrophilic properties of the fluid, i.e., a measure of attraction of the fluid to water or other charged solutions (a polar or a "hydrophilic" fluid), or to organic or uncharged solutions (a non-polar or a "hydrophobic" fluid).
  • One technique for determining the affinity of a fluid is to measure the partitioning of the fluid between an organic solvent and an aqueous solvent, for example, between n-octanol and water.
  • Other techniques such as contact angle measurements on various surfaces can be useful, and are known to those skilled in the art.
  • Figs. 4A-4F Examples of embodiments having curved meniscuses are illustrated in Figs. 4A-4F.
  • the meniscus may have any curvature, for example, concave up (e.g., Fig. 4A) or concave down (e. g., Fig. 4D).
  • fluid 41 within channel 40 contains species 42 homogeneously dispersed therein.
  • Species 42 may be any electrically or magnetically susceptible species.
  • Fig. 4B a uniform electric or magnetic field 43 is applied. Field 43, in this embodiment, causes the species to be attracted towards static potential minimum 44 created in the peak of the meniscus.
  • species 42 have been concentrated near static potential minimum 44, creating a non-homogeneous fluid, where a portion of the fluid has been enriched with species 42.
  • the curved meniscus may be a pinned meniscus, as illustrated in Figs. 5C and 5D.
  • a "pinned meniscus” is a meniscus that has generally fixed endpoints, such that a change in volume of fluid 52 alters the curvature of meniscus, for example, from a negative curvature to a positive curvature, rather than moves the endpoints of the meniscus.
  • a pinned meniscus formed in channel 40 can range between a concave up profile, as shown in Fig. 5C, and a concave down profile, as shown in Fig. 5D, for example, by altering the volume of fluid within channel 40.
  • the endpoints of the meniscus do not change between the concave up and concave down profiles.
  • the volume of fluid 52 within channel 40 may be altered by any suitable means, for example, by changing the volume of fluid directly, or by changing the flow rate of fluid within channel 40, or the pressure drop across channel 40.
  • fluid 51 is a gas that can leave channel 40 upon a change in the volume of fluid 51.
  • channel 40 may be a covered channel (e. g., as is shown in Figs. 2C and 2D), or fluid 51 may be a gas or a liquid. In covered channel embodiments, the volume of gas can be compressed to increase the volume of liquid therein.
  • any pinned meniscus may be used in accordance with this invention.
  • the pinned meniscus may be caused by the physical geometry of the channel, or, in certain embodiments, by the construction of channels having a first region having one affinity, and a second region having an affinity different from the first region, as shown in Fig. 5C.
  • a pinned meniscus may be formed at the uppermost portion of an open channel, for example, a channel as is shown in Fig. 2A.
  • the pinned meniscus forms when the endpoints of the meniscus reach the rim of the channel.
  • the pinned meniscus may also be created using a change in affinity along the channel wall to "pin" the meniscus at a certain location, for example at a junction between two regions having different affinities.
  • the lower region may be a hydrophilic region, while the upper region may be a hydrophobic region. Note that these terms are used in a relative sense; the lower region may be more hydrophobic or hydrophilic compared to the upper region, but both regions may have a high affinity for water and be considered to be hydrophilic surfaces.
  • a pinned meniscus formed at a junction is as follows.
  • a hydrophilic fluid in the channel if a hydrophilic fluid in the channel, the meniscus of the hydrophilic fluid normally assumes a concave up shape when in contact with the lower hydrophilic region, as is shown in Fig. 5C.
  • the edge of the meniscus eventually reaches the junction between the hydrophilic surface and the hydrophobic surface.
  • the meniscus is unable to rise past the junction, as the hydrophilic fluid is repelled by the hydrophobic surface.
  • the meniscus is said to be "pinned" at the junction.
  • the edge of the meniscus cannot rise beyond the junction, the addition of more fluid causes the meniscus to flatten and eventually form a concave down profile, as is shown in Fig. 5D.
  • the junction between the two regions having different affinities may be created in any suitable fashion.
  • two substrates having different affinities may be placed, or adhered, together to form a single substrate.
  • Channels may be formed in one or both of the substrates, for example, as shown in Figs. 2B and 2C.
  • a channel may be formed in a single substrate, but a portion of the channel may be coated with an agent that has a different affinity than the substrate.
  • Any agent able to coat the channel and alter the affinity of the channel may be used, for example, a silicon coating, a fluorocarbon polymer such as polytetrafluoroethylene, a surfactant, an ionic layer, or the like.
  • a static field potential minimum can be created by producing an inhomogeneous or "curved" electric or magnetic field.
  • This field may have a region of maximum field strength.
  • the inhomogeneous electric or magnetic field may be created by any suitable technique, for example, by the application of a non-uniform field source, or by the application of a homogenous source that is altered or "masked" to create the curved field.
  • a curved field will be created near holes or other defects within the mask as shown in the electric or magnetic contours of Figs. 6B and 6C.
  • the curvature of the field around the hole may be affected by the thickness or material of the mask, or by the size of the hole. Magnetically or electrically susceptible species in a fluid near the hole will be drawn towards the static field potential minimum, as is indicated by arrows 61 in Fig. 6 A.
  • the mask may be designed to conform with the arrangement of the channels.
  • mask 60 may be positioned at the top of the channels in an open arrangement, as shown in Fig. 7 A.
  • the mask may be an integral part of the substrate.
  • mask 60 may be positioned at the top of the channels or positioned to intersect with at least a portion of channels 40 within the substrate, as illustrated in Figs. 7B and 7C, respectively.
  • a field produced using a mask having this configuration will substantially conform to the shapes and positions of the channels.
  • the resulting field produced by the mask will conform to these channels.
  • the mask may be created out of any suitable material able to substantially block or alter an applied electric or magnetic field.
  • the applied field is an electric field
  • any material that alters the electric field can be used, such as copper or silver.
  • the applied field is a magnetic field
  • any material that alters the magnetic field can be used, for example, a ferromagnetic substance such as iron or nickel. Combinations or alloys of these materials can be used as well, for example, to achieve a certain field intensity.
  • the mask may have any dimension and be formed by any technique, for example, by sputtering the mask on the substrate, or by "painting" a thin coating of the material on the substrate to form the mask.
  • a substrate 11 having channels formed therein is fashioned out of a mold 90.
  • the mold is then removed in Fig. 9B.
  • the channels are filled with a discardable material 91, for example, a plastic.
  • a layer of a field-altering material 92 is then placed on top, for example, by sputtering, spraying, or painting, depending on the nature of the material. This is illustrated in Fig. 9D.
  • the discardable material is then removed, for example, physically or by burning or decomposing the material, as shown in Fig. 9E.
  • Field-altering material 92 that was attached to discardable material 91 is removed during this process, leaving behind a mask 93 having holes 94 that substantially conforms to the shape of the channels formed within substrate 11. Additional processing steps may occur afterwards, for instance, covering the substrate with other layers of material (e. g., to produce closed channels as is shown in Figs. 7B and 7C).
  • a mask may be used to create an inhomogeneous electric or magnetic field, but the substrate may not have channels formed therein.
  • mask 60 is placed near substrate 11, and the presence of the masked field on species 42 within fluid 41 defines specific channels of fluid located on top of substrate 11.
  • mask 60 may be placed near fluid 41 positioned on a substrate, which may be, for example, a thin film.
  • the masked field causes regions of localized field maxima to be formed near holes 94 within mask 60.
  • Species 42 that are electrically or magnetically susceptible are then attracted to the maxima.
  • fluidics channels 12 may be used to transport a fluid carrying a species through fluidics system 10.
  • Channels 12 may include any region within the system through which fluid flows or may be contained within, such as a reaction chamber or "cell.”
  • channel refers to any region within system 10 through which a fluid can flow, including, but not limited to, channels and other passageways, reaction chambers or cells, or the like, for example, as illustrated in Fig. 3.
  • Channels may be sealed at one end, be open at both ends, or may have a plurality of inlets and outlets. Multiple inlets and outlets within channels 12 may be able to handle one fluid or several fluids simultaneously.
  • Channels 12 may further be connected to other components within fluidics system 10 having other functions.
  • Channels 12 may also have different shapes or configurations, which include tapered channels or channels with enlarged regions.
  • channels 12 may include a closed end that defines, for example, an enlarged region that may have a width greater than that of the length of the channel. Such enlarged regions may be used, for example, storing or temporary holding of various species.
  • the term "substrate” refers to any article usable in fluidics applications in and/or on which a channel may be formed.
  • the substrate may be a substantially planar component (e.g., a chip), a tube, a network of tubes, and the like.
  • the substrate is a chip.
  • Suitable substrate materials include semiconductor (e. g., silicon) materials, glass materials, or polymeric materials (e. g, polydimethylsiloxane).
  • Substrate 11 may have a number of layers formed thereupon including oxide layers, metallic layers (which may be able to alter electric or magnetic fields applied to the substrate), and the like. The dimensions of substrate 11 may be determined, in part, by the application.
  • the surface area of substrate is less than about 10 cm 2 ; in others less than about 1 cm 2 ; and in others less than about 1 mm 2 .
  • the maximum dimension (e. g., length or width) of substrate 14 may be less than about 10 cm, 5 cm, in other cases less than 5 mm; and, in other cases, less than 1 mm.
  • substrate 11 is free of patterned wires or other conductive pathways. Such substrates may be easier to produce and may avoid problems of heat generation as compared to substrates that include such wires.
  • Fluidic channels 12 may have a variety of different dimensions, as required for a particular application of system 10. Certain systems and methods of the invention may be particularly useful when used in connection with channels that have relatively small cross- sectional dimensions (i.e., channel width). For example, in some cases, channel widths are less than about 5 cm, in some cases less than about 1 mm. In other cases, shorter channel widths are desired, such as widths of less than about 500 ⁇ m, in some cases less than about 100 ⁇ m, in some cases less than about 50 ⁇ m, and in some cases less than about 10 ⁇ m. "Width", in this context, means the smallest cross-sectional dimension of the channel at least one location along its length, in some cases along its entire length.
  • Shorter channel widths may be desired, for example, when a pattern requires a large number of channels. Generally, channel lengths are less than about 5-10 cm, but need not be. Shorter channel lengths may be utilized in some cases, such as channels with lengths of less than about 5 mm, or less than about 0.5 mm.
  • system 10 may include a number of channels 12 which have different lengths or widths. Channels 12 may be open and exposed to the atmosphere (see, for example, Fig. 2A), or the channels may be covered, for example, with a flat upper layer of material (e. g., as shown in Fig. 2B).
  • the channels may have any cross-sectional shape, for example, a square, a rectangle, a circle, a triangle, a trapezoid, a polygon, or the like, and different channels in a substrate may not all have the same cross-sectional shape (e. g., as is shown in Fig. 2C).
  • the channels may be free of features extending from the channel surface into the channel (for example, magnetic posts), which can facilitate construction and use.
  • the fluids in channel 12 may be any two fluids able to form a meniscus, preferably two immiscible fluids.
  • the fluids may include a liquid-gas system, such as air and water, or a liquid-liquid system, such as water and carbon tetrachloride. Any two-phase system may be used, preferably where the two fluids have different affinities.
  • Suitable fluids include water, non-aqueous fluids, or biological fluids, as well as mixtures and solutions thereof. Additives may be added to the fluid to promote dispersion or for other reasons.
  • fluids are pumped through fluidics channels 12. For example, in some embodiments, capillary action is used to draw fluid through fluidics channels 12.
  • the fluid is drawn through fluidics channels 12 using gravitational flow or siphoning techniques.
  • pressure-induced methods to cause fluid flow are used in some embodiments of the invention.
  • a syringe pump or a peristaltic pump may be used to drive fluid through fluidics channels 12.
  • fluid flow is electrically induced.
  • fluids containing charged particles or species move preferentially in a direction under the influence of an applied electric field.
  • fluid flow may be generated using electroosmotic techniques.
  • fluid flow is not required in all embodiments of the present invention.
  • the fluid remains relatively stagnant within the fluidics system.
  • the species may be caused to flow through the fluid.
  • the maximum width of channel 12 may be about several times the width at which gravitational forces on the fluid begins to dominate over the surface tension. At channel widths below this length, the surface tension dominates over gravity, allowing a curved meniscus to be maintained throughout the width of the channel.
  • the maximum width of the channel in some of these embodiments may be estimated by using the following relation:
  • ⁇ is the surface tension
  • ⁇ p is the density difference between the two fluids within the channel
  • g is the gravitational acceleration constant
  • x is the capillary length scale.
  • x is approximately 3-4 mm, so that the width of the channel can be any width which is less than or equal to several times this value, for example, a channel of about 100 ⁇ m or 1 ⁇ m in width.
  • the maximum width may have other values, which can be determined using the above equation.
  • x may be on the order of centimeters or tens of centimeters; conversely, if the density difference between the two fluids is large, x may have small values, for example, on the order of micrometers or nanometers.
  • the surface tension may be very large relative to the gravitational forces, such that gravity may be ignored at these scales, and the channels and the fluids contained therein may have any orientation.
  • Species 42 can be any species susceptible to an electric field or a magnetic field.
  • a species that is "susceptible" to an applied field such as an electric or magnetic field, is a species that experiences a substantial force able to alter the movement of the species, when the species is placed in an electric or a magnetic field.
  • the species is a chemical or biological material or molecule. Typical examples include chemical reagents, cellular material, nucleic acids, proteins, polypeptides, lipids, carbohydrates, and polymers including synthetic polymers. Any charged molecule, including charged biological molecules such as proteins or DNA, may be susceptible to external electric fields.
  • species susceptible to magnetic fields include paramagnetically, superparamagnetically, or ferromagnetically species, such as copper, silver, iron, nickel or neodymium.
  • species susceptible to magnetic fields include paramagnetically, superparamagnetically, or ferromagnetically species, such as copper, silver, iron, nickel or neodymium.
  • more than one type of species may be manipulated at the same time using system 10, or the susceptible species may further be attached to a nonsusceptible species, for example, as a molecular "tag.”
  • particles can be used as species 42, or species 42 may be attached to particles.
  • the particles may have a variety of shapes and sizes depending on the application.
  • a substantially spherical particle i.e., a bead
  • the particle size is less than about 10 ⁇ m; in others, the particle size is less than about 1 ⁇ m; in others less than about 100 nm. In some embodiments the particle size is between about 1 ⁇ m and about 10 ⁇ m. Smaller particle sizes may be desired, for example, in systems that have small channel widths.
  • any electrical or magnetic field may be used in accordance with this invention.
  • the electrical field can be created by placing the channels between two plates of a parallel-plate capacitor, as is shown in Fig. 1A, or by placing the channels near a charged object.
  • Magnetic fields can be created, for example, by placing the channels near an external permanent magnet is shown in Fig. IB, or an electromagnet, which may allow the field to be activated, deactivated, or altered as desired.
  • the application of an external field such as a magnetic or an electric field, thus does not require energy input to the channels or the substrate.
  • heating caused by the production of the electric or magnetic field would not occur within or near the channels.
  • the lack of heating may be advantageous in certain applications such as when the species may be temperature sensitive.
  • other effects for example, side chemical reactions, also would not affect the channels.
  • the electric or magnetic field may be maintained with minimal or negligible power requirements.
  • an external permanent magnet creates a magnetic field without requiring an additional energy source.
  • the electric field within the capacitor may be maintained without substantial power requirements, although minimal power may be needed to maintain the charge across the parallel-plate capacitor to control for leakage of charge.
  • a substantially homogenous or uniform electric field may be created by any suitable technique.
  • a substantially homogeneous electric field may be created in a parallel-plate capacitor (although some edge effects may be present). Other arrangements able to create a substantially uniform electric field may also be used with the present invention.
  • a substantially homogeneous or uniform magnetic field may be produced using any suitable technique.
  • a substantially homogeneous magnetic field may be created next to a permanent magnet or an electromagnetic coil.
  • System 10 may be used in any system where manipulation of a species may be desired. Such manipulations may include, but are not limited to, directing, transporting, storing, positioning, confining, separating, mixing, sorting, immobilization, trapping, segregating, filtration, assaying, purifying, concentrating, accumulating or detection. Other manipulations may include reducing fluid drag, controlling the flow distribution of the species, or trapping or releasing the species.
  • an embodiment of the invention may be used to control or maintain the flow distribution of a species 42 within fluid 41.
  • the channels may be filled with fluids moving in laminar flow with a parabolic profile, as illustrated in Fig. 10A. Under these conditions, fluids near the edges of the channel move slower and the fluids in the center of the channel move more quickly. The flow distribution of species 42 in this fluid thus increases due to the distribution in fluid velocities across the channel. For example, in Fig. 10B, a pulse of a species that initially starts out with a narrow distribution becomes broader and more diluted over time, as the particles are separated due to the effects of laminar flow within the channel.
  • Fig. IOC if an electric or a magnetic field is applied to attract species 42 to the center of the channel, for example, as shown in Fig. IOC, as the flow velocity near the center of the channel is approximately constant, the fluid does not separate quickly during flow.
  • the distribution of species along the longitudinal or transverse directions may be controlled, for example, so that an increase in width of greater than a certain value does not occur, e. g., a spreading of the species to twice the starting width.
  • the flow distribution width is maintained at a substantially constant width, even for longer distances of flow.
  • “longer distances” generally refers to distances that are greater than the characteristic size of the channel, i. e., a distance that is greater than the width or height of the channel.
  • an embodiment of the invention may be used as an accumulator.
  • An accumulator is a device that is able to concentrate a species in a fluid without physically trapping or immobilizing the species.
  • An example of an accumulator having a closed-loop path is shown in Figs. 14A and 14B.
  • Fig. 14B is a cross-sectional illustration taken along line B-B of Fig. 14A..
  • a fluid 41 carrying species 42 enters accumulator 141 through inlet 140.
  • the accumulator is constructed such that the application of an electric or magnetic field (not shown) produces a static potential minimum 44 at the meniscus of the fluid within the accumulator.
  • Species 42 is attracted to potential minimum 44, separating fluid 41 into a region 142 concentrated with species 42 and a diluted region 143.
  • a portion of diluted fluid 143 may be withdrawn, leaving the concentrated fluid 142 carrying species 42 within the accumulator.
  • concentration of species 42 within fluid 41 may be increased as desired.
  • Other configurations able to accumulate a species are also contemplated, for example, having multiple fluids or species contained therein.
  • the invention may be used to alternately trap or release a species within a fluid.
  • species 42 within fluid 41 are attracted to a static potential minimum 44 created by an applied field (not shown), located at the peak of the meniscus of fluid 41.
  • the curvature may be reversed, such that the particles are now drawn to the sides of the channel, where the static potential minimum now occurs. This process may also be reversed.
  • species 41 may initially be nonspecifically bound to the edges of the channel, then transported away from the walls upon a change in fluid volume, for example, for concentration or detection purposes.
  • This example illustrates theoretical calculations corresponding to an embodiment of the invention.
  • a uniformly applied magnetic field, together with a curved fluid interface was shown to be able to control movement of a species within a fluid within a channel.
  • a curved fluid interface was achieved by assuming an interface curvature between two immiscible fluids, as defined by the Young-Laplace equation:
  • ⁇ P ⁇ (l/R, +l/R 2 )
  • ⁇ P, ⁇ , and R are respectively the pressure difference across the fluid surface, the surface tension, and the surface radii of curvature for fluid 1 and fluid 2, respectively.
  • the interface was assumed to be pinned at a channel wall boundary, for example between a hydrophobic surface and a hydrophilic surface, as shown in Figs. 5C and 5D.
  • the pressure difference within the channel set the liquid-wall contact angle ⁇ .
  • the surface curvature of the interface could be readily controlled through, for example, controlling the fluid flow velocity, the pressure within the channel, the channel width, or the like.
  • a microfluidic channel width on the order of approximately 10-100 ⁇ m would require a pressure difference of approximately 1- 10% of atmospheric pressure, allowing the liquid-wall contact angle to be controlled as desired.
  • ⁇ > 90° the interface bulges upward in the center, creating a local electromagnetic potential minimum where the magnetic species would be attracted to, such as illustrated in Fig. 12A.
  • Fig. 12B the interface would be lower along the center than at the edge, and particles would be attracted towards the channel walls, where the electromagnetic potential minimum would be located.
  • ⁇ p is the density difference of the two fluids within the channel
  • g is the gravitational acceleration constant
  • the primes indicate derivatives with respect to the horizontal coordinate x.
  • Figs. 15A and 15B illustrate results based on these calculations.
  • Fig. 15A corresponds to a situation in which ⁇ > 90° (i. e., where the interface is bulges upward in the center);
  • Fig. 15B corresponds to a situation in which ⁇ ⁇ 90° (i. e., where the interface bends down in the center).
  • a 50 mm-diameter uniformly magnetized disk magnet or, equivalently, a current-curing coil
  • Figs. 15A and 15B The field of such a magnet interacting with the curved interface was numerically calculated over the interface, as defined by a solution of the surface tension equation given above.
  • the magnitude of the magnetic field is shown in Figs. 15A and 15B as a density plot overlaid on the fluid interface surface. In these figures, darker regions indicate magnetic fields of higher field strength, to which magnetic particles or other species would be attracted.
  • Fig. 15 A the region of maximum field strength corresponds to a annular region located between the surface of the channel.
  • Fig. 15B the regions of maximum field strength are created immediately next to the surface of the channel.
  • this example illustrates theoretical calculations corresponding to an embodiment of the invention.
  • a ring channel was fabricated out of polydimethylsiloxane (PDMS).
  • PDMS polydimethylsiloxane
  • a recirculating flow of water was set up in the ring channel with flow velocities ranging from 1 mm/s to several cm/s.
  • Superparamagnetic 4.5 ⁇ m diameter beads were dispersed within the recirculating flow. These bead sizes readily allowed optical detection of their location within the fluid. By restricting the position of the beads to the fluid interface within the ring, imaging was possible with minimal requirements on the optical depth of the field, as shown in Figs. 15C and 15D.
  • Fig. 13A is a figure showing the number of magnetic beads detected within the ring as a function of time.
  • the observed bead counts showed no measurable decay, with no loss due to outward diffusion, adhesion to the side walls, or gravitational settling.
  • the beads were confined about the channel center, within a defined width, allowing accurate control over longitudinal spreading due to Poiseuille flow as is shown in Fig. 15C.
  • the application of higher magnetic fields gave tighter confinement of the beads within the channel, which focused the particles more tightly and created a particle accumulator able to concentrate the particles within the channel.

Abstract

La présente invention a trait à des systèmes fluidiques, ainsi qu'à leurs procédés de fabrication et d'utilisation. Les systèmes comportent un substrat présentant une face définissant un ou des canaux. Les canaux contiennent un fluide (par exemple, de l'eau) dans lesquels les différentes espèces (par exemple, des matières biologiques ou chimiques) sont introduites. De manière générale on fait circuler les espèces à travers les canaux vers un emplacement souhaité au sein du système. Les espèces sont attirés en éloignement des parois des canaux au moyen de champs magnétiques ou électriques lors de leur écoulement dans les canaux. Cette attraction peut améliorer la circulation des espèces à travers le système et peut limiter les problèmes liés à l'adhésion des espèces aux parois tels qu'une résistance de frottement accrue ou l'encrassement des canaux. Les système peuvent être utilisés pour effectuer diverse fonctions, par exemple, la séparation ou l'accumulation de différentes espèces. Les systèmes sont particulièrement adaptés pour une utilisation dans des applications micro-fluidiques qui comportent des canaux relativement étroits.
PCT/US2003/004647 2002-02-15 2003-02-18 Systemes fluidiques comprenant des champs magnetiques ou electriques et leurs procedes d'utilisation WO2003072227A1 (fr)

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GB2446309A (en) * 2006-03-29 2008-08-06 Inverness Medical Switzerland Assay device and method
WO2009022994A1 (fr) * 2007-08-13 2009-02-19 Agency For Science, Technology And Research Système de séparation microfluidique
EP2081686A1 (fr) * 2006-09-29 2009-07-29 GE Healthcare Bio-Sciences AB Procédé et dispositif pour réactions à petite échelle
WO2010007431A2 (fr) * 2008-07-15 2010-01-21 L3 Technology Limited Carte d'essai de dosage
US8440150B2 (en) 2008-12-16 2013-05-14 Koninklijke Philips Electronics N.V. Hydrophobic valve
WO2014038943A1 (fr) * 2012-09-10 2014-03-13 Universiteit Leiden Perfectionnements apportés à des barrières de rétention de pression capillaire
US10058863B2 (en) 2011-08-12 2018-08-28 Molecular Vision Limited Device for performing an assay
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EP0376611A2 (fr) * 1988-12-30 1990-07-04 The Board Of Trustees Of The Leland Stanford Junior University Système électrophorétique
US5376252A (en) * 1990-05-10 1994-12-27 Pharmacia Biosensor Ab Microfluidic structure and process for its manufacture
WO2000050172A1 (fr) * 1999-02-23 2000-08-31 Caliper Technologies Corp. Manipulation de microparticules dans des systemes microfluidiques
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Publication number Priority date Publication date Assignee Title
EP1547688A1 (fr) * 2003-12-23 2005-06-29 STMicroelectronics S.r.l. Système microfluidique et procédé permettant la concentration de particules en suspension dans un liquide
GB2446309B (en) * 2006-03-29 2011-06-08 Inverness Medical Switzerland Assay device and method
GB2446309A (en) * 2006-03-29 2008-08-06 Inverness Medical Switzerland Assay device and method
AU2007231030B2 (en) * 2006-03-29 2011-09-29 Abbott Rapid Diagnostics International Unlimited Company Assay device and method
US8758682B2 (en) 2006-09-29 2014-06-24 Ge Healthcare Bio-Sciences Ab Method and device for small scale reactions
EP2081686A4 (fr) * 2006-09-29 2010-05-05 Ge Healthcare Bio Sciences Ab Procédé et dispositif pour réactions à petite échelle
EP2081686A1 (fr) * 2006-09-29 2009-07-29 GE Healthcare Bio-Sciences AB Procédé et dispositif pour réactions à petite échelle
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WO2009022994A1 (fr) * 2007-08-13 2009-02-19 Agency For Science, Technology And Research Système de séparation microfluidique
US10092903B2 (en) 2007-12-20 2018-10-09 Koninklijke Philips N.V. Multi-compartment device with magnetic particles
WO2010007431A3 (fr) * 2008-07-15 2010-03-11 L3 Technology Limited Carte d'essai de dosage
WO2010007431A2 (fr) * 2008-07-15 2010-01-21 L3 Technology Limited Carte d'essai de dosage
US9804091B2 (en) 2008-07-15 2017-10-31 L3 Technology Limited Assay test card
US8440150B2 (en) 2008-12-16 2013-05-14 Koninklijke Philips Electronics N.V. Hydrophobic valve
US10058863B2 (en) 2011-08-12 2018-08-28 Molecular Vision Limited Device for performing an assay
WO2014038943A1 (fr) * 2012-09-10 2014-03-13 Universiteit Leiden Perfectionnements apportés à des barrières de rétention de pression capillaire
CN113304787A (zh) * 2012-09-10 2021-08-27 莱顿大学 关于毛细管压力屏障的改进
US11344877B2 (en) 2012-09-10 2022-05-31 Universiteit Leiden Capillary pressure barriers

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