WO2006047831A1 - Detection device and method - Google Patents

Detection device and method Download PDF

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Publication number
WO2006047831A1
WO2006047831A1 PCT/AU2005/001694 AU2005001694W WO2006047831A1 WO 2006047831 A1 WO2006047831 A1 WO 2006047831A1 AU 2005001694 W AU2005001694 W AU 2005001694W WO 2006047831 A1 WO2006047831 A1 WO 2006047831A1
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WO
WIPO (PCT)
Prior art keywords
passageway
fluid
analyte
fluid flow
sample
Prior art date
Application number
PCT/AU2005/001694
Other languages
French (fr)
Inventor
Philip Gerard Toye
Original Assignee
Agen Biomedical Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Agen Biomedical Limited filed Critical Agen Biomedical Limited
Publication of WO2006047831A1 publication Critical patent/WO2006047831A1/en

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Classifications

    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/536Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers 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
    • B01L3/502746Containers 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
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0809Geometry, shape and general structure rectangular shaped
    • B01L2300/0816Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0809Geometry, shape and general structure rectangular shaped
    • B01L2300/0825Test strips
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0861Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0864Configuration of multiple channels and/or chambers in a single devices comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00Moving or stopping fluids
    • B01L2400/04Moving fluids with specific forces or mechanical means
    • B01L2400/0403Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0406Moving fluids with specific forces or mechanical means specific forces capillary forces
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00Moving or stopping fluids
    • B01L2400/08Regulating or influencing the flow resistance
    • B01L2400/084Passive control of flow resistance

Definitions

  • This invention relates generally to a device and method for determining the presence of an analyte in a test sample. More particularly, the present invention relates to a device and method for use in an agglutination assay process or test. It is particularly well suited, but not exclusively so, to processes and tests for agglutination reactions (e.g., haemagglutination reactions).
  • the antigen-antibody reaction is the basis for all immunological test methods. Certain proteins known as antibodies are produced by mammals in response to the presence of an antigen which is often another protein or can be a carbohydrate or other component. This normal body response to foreign substances has led to the development of a number of techniques which are used to diagnose various diseases, disorders and physiological conditions.
  • the component of the antigen-antibody reaction to be detected is defined as an analyte while the other corresponding component is considered the ligand.
  • the analyte may be an antigen or an antibody.
  • This member can be a bibulous material (paper), a membrane or a reagent film.
  • the dry and stable reagent may then be contained within a reactive zone of the device.
  • analysis fluid makes contact with the dry reagent, the reagents are at least partially resolubilised to react with an analyte of interest.
  • the present applicant provides several commercial assays which rely on specific reagents which, when added to a patient's sample, result in agglutination of the patient's red blood cells if the sample is positive. This is usually due to interaction between antibody-based reagents in the test kit, the analyte of interest in a patient's plasma and patient red blood cells. This haemagglutination is readily observed as clumping of the red blood cells.
  • the existing assays are supplied in kit form, which includes three small plastic vials containing the buffer, test reagent and positive control together with pipette stirrers and plastic plates.
  • the vials must be stored at 4° C.
  • the existing assays are reasonably reliable and have widespread acceptance, they involve the necessity of considerable handling of material with subsequent risk of contamination and/or escape of dangerous organisms. Further, the assays involve a number of steps including the need to add specific volumes of fluids, thereby increasing the chance of variability in test technique. Individual proficiency can therefore become an issue in the reliability of the results.
  • the present invention provides methods and devices for determining the presence or quantity of an analyte in a fluid sample. These methods and devices are generally based on (1) the formation of an agglutination complex in the presence of the analyte and (2) the use of a fluid passageway that includes a first part and a second part. The first part of the passageway permits the flow of the agglutination complex downstream to the second part and the second part impedes the downstream flow of the agglutination complex. Detection of the agglutination complex in or adjacent to the second part indicates the presence of the analyte in the fluid sample.
  • the present invention provides assay devices, which include at least one passageway that comprises a wall on which one or more assay reagents (e.g., an agglutinating agent or agglutinable component) are releasably disposed thereon.
  • assay reagents e.g., an agglutinating agent or agglutinable component
  • the articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
  • an element means one element or more than one element.
  • the present invention provides methods for determining the presence of an analyte in a fluid sample. These methods generally comprise:
  • cross section refers to a surface or shape of a passageway that is exposed, or a section of the passageway made, by a plane cutting the passageway transversely, especially at right angles, to an axis, including the longest axis, of the passageway.
  • the fluid flow cross section of the first part of the passageway may have a shape, surface or cross sectional area that permits the flow of an agglutination complex downstream to the second part and the fluid flow cross section of the second part has a shape, surface or cross sectional area that impedes the flow therethrough of some or all of the agglutination complex.
  • the cross section of the passageway may have any suitable shape that has the fluid flow characteristics referenced herein, including circular, ovoid, elliptical, square, rectangular, irregular, U-shaped, V-shaped or with internal projections.
  • the passageway may contain one or more bends, curves bifurcations and the like, which regulate flow of fluid or the agglutination complex.
  • the passageway may have a surface characteristic that regulates the flow of fluid and/or the agglutination complex to a downstream location of the passageway.
  • the surface characteristic is provided at least in part by a wall of the passageway that comprises at least one flow-regulating component that is capable of interacting (e.g., binding, reacting etc) with a component of the agglutination complex including, for example, the ligand, the analyte and the agglutinable component.
  • the surface of the passageway includes an antibody or antibody fragment that binds to the analyte. In illustrative examples of this type, the antibody or antibody fragment binds to a different epitope on the analyte than the one to which the ligand binds.
  • the passageway further comprises a third part that receives components of the contacted sample that are permitted to flow downstream of the second part, wherein the third part is in fluid flow communication with the first part and the second part.
  • the third part may include an immobilised capturing element that captures such components (e.g., free ligand and/or agglutinable component).
  • the agglutination complex is associated with a first detectable signal and the agglutinable component is associated with a second detectable signal and the method further comprises comparing the first detectable signal in or adjacent to the second part and the second detectable signal in the second or third parts to provide a quantitative or semi-quantitative assay of the analyte in the fluid sample.
  • the ligand and optionally other assay components are releasably disposed in the first part of the passageway and the method comprises contacting the fluid sample with the ligand and optionally other assay components in that part.
  • the first part of the passageway has a fluid flow cross section that permits mixing of the analyte, if present in the fluid sample, with the ligand and the agglutinable component.
  • the first part of the passageway is of appropriate shape or dimensions or has fluid flow surface characteristics, to permit agglutination to occur in a positive sample (i.e., a sample that contains the analyte) before the fluid sample arrives at the second part of the passageway.
  • ligand associates with an agglutinable component is meant: (i) direct attachment of the agglutinable component to the ligand or a subsequent reaction product of the ligand; and (ii) indirect attachment of the agglutinable component to the ligand or a subsequent reaction product of the ligand, e.g., attachment of the agglutinable component to another assay reagent that subsequently binds to the ligand.
  • the second part does not permit some or all of the agglutination complex to flow therethrough. In some embodiments, the second part does not permit at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the agglutination complex to flow therethrough.
  • the analyte is selected from an antigen, a hapten, an antibody, a protein, a peptide, an amino acid, a nucleic acid, a hormone, a steroid, a vitamin, a carbohydrate, a lipid, a blood clotting factor, a pathogenic organism, a natural or synthetic chemical substance, a contaminant, a drug including those administered for therapeutic purposes as well as those administered for illicit purposes, and metabolites of or antibodies to any of the above substances.
  • the analyte and the ligand will each be member of a binding pair, illustrative examples of which include antigens and antibodies, lectins and carbohydrates, complementary peptides, protein, carbohydrate and nucleic acid molecules, enzyme inhibitors and enzymes, Protein A and IgG, Fc receptors and immunoglobulins, as well as effector and receptor molecules.
  • the agglutinable component is typically a particle which is suitably but not exclusively selected from polymeric particles (e.g., latex particles), ceramic particles (e.g., silica particles), metal particles, liposomes, carbon particles, bacteria and erythrocytes.
  • the particle may comprise one or more dyes or fluorescent, phosphorescent or other light-emitting material, either singly or in combination.
  • the agglutinable component may be conjugated with the ligand or it may be a separate component. In the latter case, the ligand suitably comprises a moiety (e.g., an antibody or antibody fragment) that is interactive with the agglutinable component.
  • the ligand comprises an agglutinating agent that agglutinates the agglutinable component.
  • agglutinating agents include bifunctional antibody conjugates in which one antibody or antibody fragment binds, for example, to red blood cells and the other antibody or antibody fragment binds, for example, to D-dimer.
  • Representative assays that use such bifunctional antibody conjugates include the SimpliRED® assay (Agen Biomedical Limited, Brisbane, Australia).
  • These devices generally comprise: at least one inlet port; and, for each analyte, at least one passageway that is in fluid flow communication with the at least one inlet port and that changes in fluid flow cross section or surface characteristics downstream of the at least one inlet port, wherein a fluid sample deposited in an individual inlet port travels along a flow path between a proximal end and a distal end of a respective passageway.
  • the fluid flow cross section or surface characteristic of an individual passageway at a location between its proximal and distal ends changes sufficiently to impede flow along the pathway of the agglutination complex.
  • the fluid flow cross section of an individual passageway is defined at least in part by the cross sectional area of the passageway itself.
  • the cross sectional area of the passageway decreases in size from the first part to the second part. Representative dimensions for this decrease are from about 500 - 3000 ⁇ m to about 2 - 10 ⁇ m in width or diameter. In specific embodiments, the sizes may range between about 800 ⁇ m - 1400 ⁇ m decreasing to about 2 ⁇ m - 20 ⁇ m in width or diameter. Other ranges may be suitable.
  • the fluid flow cross section of an individual passageway is defined at least in part by the pore size of a filter.
  • the second part of the passageway is defined by a pore of the filter.
  • the fluid flow cross section of an individual passageway is defined at least in part by a pair of spaced pillars disposed within a conduit.
  • the second part of the passageway is defined by a plurality of spaced pillars disposed within the conduit, and individual pairs of pillars are suitably spaced to allow passage between the pillars of components of the contacted sample other than some or all of the agglutination complex.
  • the pillars are columnar but may be of any suitable cross sectional shape.
  • individual passageways are dimensioned to provide a positive zone area and a negative zone area. Where multiple stepdown decreases in fluid flow cross sectional area are provided, a semi-quantitative result may be obtained.
  • an individual passageway has a fluid flow cross sectional area that permits the flow of fluid therethrough by capillary action.
  • the passageway is suitably formed of a capillary conduit or channel.
  • an individual passageway has a fluid flow cross sectional area that does not permit the flow of fluid therethrough by capillary action.
  • the method suitably further comprises forcing the contacted sample along the passageway (e.g., using centrifugal force air pressure, vacuum, electroosmosis, heating and the like).
  • an individual passageway comprises at least two spaced segments, wherein an individual downstream segment inhibits the passage of components of the contacted sample whose passage was permitted by an adjacent upstream segment.
  • the fluid flow cross sectional area of an individual passageway gradually decreases along at least a portion of the pathway, which gradually inhibits the passage of smaller components of the contacted sample.
  • an individual passageway has a single stepped decrease in fluid flow cross sectional area.
  • an individual passageway may have two or more stepped decreases in fluid flow cross sectional areas.
  • an individual passageway has a gradual or constant decrease in fluid flow cross sectional area.
  • the device comprises, for an individual analyte, multiple parallel passageways that form subconduits of a larger conduit.
  • the device comprises a plurality of such conduits, wherein the number of conduits corresponds to the number of analytes testable by the device.
  • an individual subconduit may have a single stepped decrease in fluid flow cross sectional area, which is preferably aligned or in register with a similar decrease in fluid flow cross sectional areas in other subconduits.
  • the subconduits may have two or more stepped decreases in fluid flow cross sectional area, again, preferably, with each aligned or in register with corresponding stepped decreases in other parallel subconduits.
  • individual subconduits are in fluid flow communication with a plurality of downstream subconduits that have smaller fluid flow cross sectional areas than the upstream subconduit.
  • the individual passageways are in fluid flow communication with a reservoir that receives the fluid sample and/or other fluids.
  • the other fluids may comprise one or more buffer solutions or wash solutions, or fluids containing testing reagents.
  • the reservoir comprises a capturing element that captures or immobilises components (any free ligand and/or agglutinable component) that flow downstream of the decrease in fluid flow cross section or surface characteristic of the passageway(s).
  • the reservoir may contain an absorbent material to facilitate the flow of fluid sample and/or other fluids.
  • the passageway(s) is (are) in fluid communication with a at least one vent for venting fluid (e.g., air) to atmosphere.
  • fluid e.g., air
  • the device comprises a body or housing that is preferably elongate and formed with a planar or slide-like configuration.
  • the body or housing may be formed from two sections. The sections may be halves which are joined face-to-face.
  • the body or housing may comprise a fluid sample inlet compartment that communicates with the inlet port.
  • the inlet compartment may be a well or a chamber.
  • the body or housing comprises a window that permits viewing of the change in fluid flow cross section or surface characteristic of the passage(s) and viewing, for example, of any immobilised agglutination complex.
  • the device further comprises a ligand for detecting one or more analytes.
  • the ligand may be releasably disposed on a wall of the inlet port or preferably on a wall of an individual passageway adjacent to its proximal end. Where a plurality of passageways are supplied, a range of different ligands may be applied to conduct simultaneous testing of the fluid sample for different analytes.
  • kits for detecting at least one analyte These kits generally comprise a device as broadly described above and reagents required for detecting the or each analyte.
  • the kits may optionally include appropriate reagents for detection of labels, positive and negative controls, washing solutions, dilution buffers, calibration standards and the like.
  • the kits comprise distinct containers for each individual reagent.
  • the kits are supplied with instructions, which instruct the user how to use the device and method as broadly described above.
  • the present invention provides assay devices for determining the presence or quantity of an analyte.
  • These devices generally comprise at least one passageway that comprises a wall having one or more assay reagents releasably disposed thereon.
  • the or each assay reagent is in dry form on the wall surface.
  • the passageway permits capillary flow of a fluid sample from a location upstream of the assay reagent(s).
  • the passageway is dimensioned or has a surface to permit contact and mixing of the assay reagent(s) with the fluid sample and downstream flow of the contacted fluid sample.
  • the assay reagent(s) comprise(s) an agglutinable component or agglutination agent as broadly described above.
  • Figure 1 is a top plan view of a first embodiment of the test device of the present invention
  • Figure 3 is a top plan view of the device of Figure 1 showing a negative result
  • Figure 4 is a top plan view of the device of Figure 1 showing a positive result. DESCRIPTION OF PREFERRED EMBODIMENTS
  • Passage of the sample may be enhanced by addition of other fluids such as a buffer or wash solutions.
  • the presence of fluid in the proximal portion 16 will, at least partially, resolubilise the reagent, thereby leading to mixing with the testing sample and institution of the diagnostic reaction if the target substance is present.
  • the capillary conduit can be completely contained within the substance of the body so that there is no external leakage of the material. Alternatively, the conduit may comprise an open channel through which the fluid sample and reactants may pass.
  • An intermediate section 20 is provided and comprises a series of parallel capillary channels 22.
  • a distal zone 24 comprises a series of parallel narrow channels in the form of narrow capillary channels.
  • the transfer from broad capillary channels to narrow capillary channels occurs at interface 26, thereby providing a well-demarcated transition between the broad and narrow channels.
  • the capillary conduit 18 is in fluid communication with a reservoir 28 adapted to receive any transferred fluid, either sample or other material, and provide an outlet for the capillary transfer of materials.
  • the reservoir may be vented to the outside to avoid increased pressure resisting capillary transfer. Additionally or alternatively, the reservoir may have an absorbent material located in it to receive and retain any fluid.
  • Figure 2 shows a variation of testing device 110 with a port 112 which feeds into a manifold 130 which subsequently feeds into parallel capillary conduits 131, 132, 133 all with a similar structure to that described in relation to Figure 1.
  • each of the conduits may have a different reagent located in the proximal zone 116 to provide a multiple testing capacity.
  • One of the capillary channels may comprise a positive test reagent and one may comprise a negative test reagent for checking of testing device integrity.
  • Figure 3 shows an example of a negative test result in an arrangement similar to that of Figure 1.
  • the test sample 40 is shown contained in the reservoir 28. It has therefore flowed through the entire length of the testing conduit without being obstructed.
  • the capillary conduit may incorporate two or more stepdown shoulders to provide a gradation of results and therefore give a more informative visual result.
  • This provides a semi-quantitative result which may be calibrated or classified according to a range such as strong, intermediate, weak and negative.
  • a variety of manufacturing processes all well known to those skilled in the art may be applied to provide the present test device.
  • a first test device section and a second test device section are fused together during production to form the test body.
  • the reagent may be placed on one of the sections and dried or, alternatively, placed on both prior to joining.
  • Beneficial methods of application of the reagent may include screen or inkjet printing, spraying by use of an airbrush technique or conventional dispensing of quantities using a positive displacement microvolume dispenser.
  • the reagents may be dried by stationary or forced air which may be heated or at room temperature.
  • the reagent may be dried in the presence of stabilisers and agents which facilitate resolubilisation.
  • the capillary conduit and the capillary channels may be achieved by etching and also by a punch-out and laminating technique, by embossing, heat stamping or by flow injection or compression moulding. Injection or compression moulding may be preferred because of their accuracy and precision. This accuracy may be important to provide appropriate flow dynamics through the capillary conduits and capillary channels.
  • the first test device section and the second test device section may be constructed or composed of the same or different material and may be fused, for example, by adhesive tape, adhesive bonding, ultrasonic welding or even by a mechanical snap-in technique.
  • a clear plastic, glass or other such material for the body and to define the capillary conduits and capillary channels.
  • the body may be formed from polycarbonate, polymethylmethacrylate or polystyrene.
  • Advantages of the present invention include an enclosed reaction area to reduce the possibility of contamination from infected blood samples, removal of any necessity to rock a reaction combination, fewer procedural steps, long-term stability of the reagents at room temperature and a more objective indication of agglutination and, in particular, haemagglutination.
  • blood is applied to the sample port and flows into and through a region of parallel capillary channels, the first part of which is coated with the dried reagent.
  • the reagent is solubilised and mixes with the blood, causing haemagglutination in a positive sample.
  • the channels in this region are wide enough to allow the passage of agglutinated blood cells.
  • the mixture eventually reaches a region of narrow capillary channels to allow the passage of individual red blood cells but not agglutinated cells.
  • a negative sample all of the blood sample reaches and accumulates in the reservoir.
  • a positive sample all or some of the sample may be retarded at the junction of the wide and narrow capillary tube.
  • the device may be used to type human blood or blood from other species, wherein the reagent is an antibody or other agglutinating reagent directed against red blood cell typing antigens. It is further within the scope of this invention that the reagent is an active component of a particulate agglutination assay where the particles are, for example, coloured latex particles or fixed red blood cells conjugated to an antibody or antigen reactive with the analyte of interest.

Abstract

The present invention discloses methods and devices for determining the presence or quantity of an analyte in a fluid sample. These methods and devices are based on (1) the formation of an agglutination complex in the presence of the analyte and (2) the use of a fluid passageway that includes a first part and a second part. The first part of the passageway permits the flow of the agglutination complex downstream to the second part and the second part impedes the downstream flow of the agglutination complex. Detection of the agglutination complex in or adjacent to the second part indicates the presence of the analyte in the fluid sample.

Description

TITLE OF THE INVENTION
"DETECTION DEVICE AND METHOD"
FIELD OF THE INVENTION
[0001] This invention relates generally to a device and method for determining the presence of an analyte in a test sample. More particularly, the present invention relates to a device and method for use in an agglutination assay process or test. It is particularly well suited, but not exclusively so, to processes and tests for agglutination reactions (e.g., haemagglutination reactions).
BACKGROUND OF THE INVENTION [0002] The antigen-antibody reaction is the basis for all immunological test methods. Certain proteins known as antibodies are produced by mammals in response to the presence of an antigen which is often another protein or can be a carbohydrate or other component. This normal body response to foreign substances has led to the development of a number of techniques which are used to diagnose various diseases, disorders and physiological conditions. In a general sense, the component of the antigen-antibody reaction to be detected is defined as an analyte while the other corresponding component is considered the ligand. The analyte may be an antigen or an antibody.
[0003] Commonly, in vitro tests for the presence of a suspected antigen or antibody in a biological sample are carried out by adding the immunologically corresponding ligand to the biological sample. If the suspected analyte under investigation is present, the resulting antigen-antibody reaction can be demonstrated by, for example, precipitation of the antigen- antibody complex. This reaction complex is generally difficult to observe. For this reason, either antibodies or antigens are often bound to insoluble particles, for example, polymer latex particles, so that when the antigen-antibody complex is formed, it is readily detectable from the resulting agglutination of the particles or a detectable tracer associated with the particles. Agglutination is then characterised by the clumping of particles from a suspension.
[0004] Many devices are available for testing of blood samples at the patient point of care (POC). Testing at the POC offers advantages of fast turnaround time, timely intervention, miniaturised cost-effective equipment and improved patient outcome. Some "dry chemistry" technologies have been introduced and these have reagents contained within the test strip or device in dry but not liquid form. Since the reagents are more stable when stored in dry form, products employing dry reagent technology usually have a longer shelf life than those using liquid reagents. [0005] In most devices, the reagents are applied to a test strip by some impregnation or coating method whereby a liquid reagent is impregnated or coated onto an integrated reagent- carrying member. This member can be a bibulous material (paper), a membrane or a reagent film. After evaporation of the reagent solvent, the dry and stable reagent may then be contained within a reactive zone of the device. As analysis fluid makes contact with the dry reagent, the reagents are at least partially resolubilised to react with an analyte of interest.
[0006] The present applicant provides several commercial assays which rely on specific reagents which, when added to a patient's sample, result in agglutination of the patient's red blood cells if the sample is positive. This is usually due to interaction between antibody-based reagents in the test kit, the analyte of interest in a patient's plasma and patient red blood cells. This haemagglutination is readily observed as clumping of the red blood cells.
[0007] These existing assays typically involve the following steps:
[0008] (i) adding a drop (e.g., 20 μL) of the patient's blood sample to the wells of a simple two-well clear plastic plate; [0009] (ii) adding a drop of reagent to the test blood sample and a drop of buffer to the negative control sample;
[0010] (iii) agitating the plate typically by manually rocking for two minutes or until a positive result is observed;
[0011] (iv) if after two minutes there is no haemagglutination, adding a positive control reagent to the test sample which causes haemagglutination irrespective of the disease status of the patient.
[0012] The existing assays are supplied in kit form, which includes three small plastic vials containing the buffer, test reagent and positive control together with pipette stirrers and plastic plates. The vials must be stored at 4° C. [0013] While the existing assays are reasonably reliable and have widespread acceptance, they involve the necessity of considerable handling of material with subsequent risk of contamination and/or escape of dangerous organisms. Further, the assays involve a number of steps including the need to add specific volumes of fluids, thereby increasing the chance of variability in test technique. Individual proficiency can therefore become an issue in the reliability of the results.
[0014] It would be advantageous, therefore, to provide a simple to use, reliable and accurate test device which minimises or eliminates at least one of the above problems. SUMMARY OF THE INVENTION
[0015] The present invention provides methods and devices for determining the presence or quantity of an analyte in a fluid sample. These methods and devices are generally based on (1) the formation of an agglutination complex in the presence of the analyte and (2) the use of a fluid passageway that includes a first part and a second part. The first part of the passageway permits the flow of the agglutination complex downstream to the second part and the second part impedes the downstream flow of the agglutination complex. Detection of the agglutination complex in or adjacent to the second part indicates the presence of the analyte in the fluid sample. [0016] In related aspects, the present invention provides assay devices, which include at least one passageway that comprises a wall on which one or more assay reagents (e.g., an agglutinating agent or agglutinable component) are releasably disposed thereon.
DETAILED DESCRIPTION OF THE INVENTION
[0017] As used herein, the articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.
[0018] Throughout this specification, unless the context requires otherwise, the words "comprise," "comprises" and "comprising" will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements.
[0019] Thus, in one aspect, the present invention provides methods for determining the presence of an analyte in a fluid sample. These methods generally comprise:
[0020] - contacting the fluid sample with a ligand, which is interactive directly or indirectly with the analyte and which associates with an agglutinable component that forms an agglutination complex in the presence of the analyte;
[0021] - allowing the contacted sample to flow along a fluid passageway that comprises a first part having a fluid flow cross section or surface characteristic that permits the flow of the agglutination complex downstream to a second part having a fluid flow cross section or surface characteristic that impedes the flow therethrough of some or all of the agglutination complex, wherein the first part of the passageway is in fluid flow communication with the second part of the passageway; and
[0022] — determining the presence of the analyte by detecting the presence of the agglutination complex in or adjacent to the second part. [0023] As used herein, the term "cross section" refers to a surface or shape of a passageway that is exposed, or a section of the passageway made, by a plane cutting the passageway transversely, especially at right angles, to an axis, including the longest axis, of the passageway. Thus, the fluid flow cross section of the first part of the passageway may have a shape, surface or cross sectional area that permits the flow of an agglutination complex downstream to the second part and the fluid flow cross section of the second part has a shape, surface or cross sectional area that impedes the flow therethrough of some or all of the agglutination complex. The cross section of the passageway may have any suitable shape that has the fluid flow characteristics referenced herein, including circular, ovoid, elliptical, square, rectangular, irregular, U-shaped, V-shaped or with internal projections.
[0024] The passageway may contain one or more bends, curves bifurcations and the like, which regulate flow of fluid or the agglutination complex.
[0025] In accordance with the present invention, the passageway may have a surface characteristic that regulates the flow of fluid and/or the agglutination complex to a downstream location of the passageway. In illustrative examples of this type, the surface characteristic is provided at least in part by a wall of the passageway that comprises at least one flow-regulating component that is capable of interacting (e.g., binding, reacting etc) with a component of the agglutination complex including, for example, the ligand, the analyte and the agglutinable component. In some embodiments, the surface of the passageway includes an antibody or antibody fragment that binds to the analyte. In illustrative examples of this type, the antibody or antibody fragment binds to a different epitope on the analyte than the one to which the ligand binds.
[0026] In some embodiments, the passageway further comprises a third part that receives components of the contacted sample that are permitted to flow downstream of the second part, wherein the third part is in fluid flow communication with the first part and the second part. The third part may include an immobilised capturing element that captures such components (e.g., free ligand and/or agglutinable component).
[0027] In some embodiments, the agglutination complex is associated with a first detectable signal and the agglutinable component is associated with a second detectable signal and the method further comprises comparing the first detectable signal in or adjacent to the second part and the second detectable signal in the second or third parts to provide a quantitative or semi-quantitative assay of the analyte in the fluid sample.
[0028] In some embodiments, the ligand and optionally other assay components are releasably disposed in the first part of the passageway and the method comprises contacting the fluid sample with the ligand and optionally other assay components in that part. Suitably, the first part of the passageway has a fluid flow cross section that permits mixing of the analyte, if present in the fluid sample, with the ligand and the agglutinable component. Suitably, the first part of the passageway is of appropriate shape or dimensions or has fluid flow surface characteristics, to permit agglutination to occur in a positive sample (i.e., a sample that contains the analyte) before the fluid sample arrives at the second part of the passageway. In illustrative examples, the fluid sample is allowed to flow along a plurality of passageways for determining the presence of a plurality of different analytes, wherein the first part of an individual passageway comprises a ligand that is directly or indirectly interactive with a different analyte than the analyte with which a ligand in the first part of another passageway interacts.
[0029] By "ligand associates with an agglutinable component" is meant: (i) direct attachment of the agglutinable component to the ligand or a subsequent reaction product of the ligand; and (ii) indirect attachment of the agglutinable component to the ligand or a subsequent reaction product of the ligand, e.g., attachment of the agglutinable component to another assay reagent that subsequently binds to the ligand.
[0030] In accordance with the present invention, the second part does not permit some or all of the agglutination complex to flow therethrough. In some embodiments, the second part does not permit at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the agglutination complex to flow therethrough.
[0031] Suitably, the analyte is selected from an antigen, a hapten, an antibody, a protein, a peptide, an amino acid, a nucleic acid, a hormone, a steroid, a vitamin, a carbohydrate, a lipid, a blood clotting factor, a pathogenic organism, a natural or synthetic chemical substance, a contaminant, a drug including those administered for therapeutic purposes as well as those administered for illicit purposes, and metabolites of or antibodies to any of the above substances. Typically, the analyte and the ligand will each be member of a binding pair, illustrative examples of which include antigens and antibodies, lectins and carbohydrates, complementary peptides, protein, carbohydrate and nucleic acid molecules, enzyme inhibitors and enzymes, Protein A and IgG, Fc receptors and immunoglobulins, as well as effector and receptor molecules.
[0032] Generally, the fluid sample comprises a biological sample, including biological fluids and tissue or biopsy samples, and fluid samples containing microorganisms, which may be extracted, untreated, treated, diluted or concentrated from a plant or animal or environmental sample. Illustrative examples of biological fluids include whole blood, serum, plasma, saliva, urine, sweat, ascitic fluid, peritoneal fluid, synovial fluid, amniotic fluid, cerebrospinal fluid, milk, faeces, faecal extracts, lesion exudates, vesicular fluid, aspirated material, bronchial or gastric lavage fluid, swab material, plant tissue and the like. [0033] The agglutinable component is typically a particle which is suitably but not exclusively selected from polymeric particles (e.g., latex particles), ceramic particles (e.g., silica particles), metal particles, liposomes, carbon particles, bacteria and erythrocytes. The particle may comprise one or more dyes or fluorescent, phosphorescent or other light-emitting material, either singly or in combination. The agglutinable component may be conjugated with the ligand or it may be a separate component. In the latter case, the ligand suitably comprises a moiety (e.g., an antibody or antibody fragment) that is interactive with the agglutinable component.
[0034] In some embodiments, the ligand comprises an agglutinating agent that agglutinates the agglutinable component. Illustrative examples of agglutinating agents include bifunctional antibody conjugates in which one antibody or antibody fragment binds, for example, to red blood cells and the other antibody or antibody fragment binds, for example, to D-dimer. Representative assays that use such bifunctional antibody conjugates include the SimpliRED® assay (Agen Biomedical Limited, Brisbane, Australia).
[0035] In another aspect, the invention provides devices for determining the presence or quantity in a fluid sample of at least one analyte, for example, using a ligand which • is interactive with a respective analyte and which is associated with an agglutinable component that forms an agglutination complex in the presence of the analyte. These devices generally comprise: at least one inlet port; and, for each analyte, at least one passageway that is in fluid flow communication with the at least one inlet port and that changes in fluid flow cross section or surface characteristics downstream of the at least one inlet port, wherein a fluid sample deposited in an individual inlet port travels along a flow path between a proximal end and a distal end of a respective passageway. In some embodiments, the fluid flow cross section or surface characteristic of an individual passageway at a location between its proximal and distal ends changes sufficiently to impede flow along the pathway of the agglutination complex. Suitably, in these embodiments, the passageway at the location has a fluid flow cross section that is suitably dimensioned or shaped, or has a surface characteristic, to permit the flow downstream of the location of non-agglutinated matter including, for example, any agglutinable component that has not agglutinated. In specific embodiments of this type, the passageway at the location has a fluid flow cross section that is suitably dimensioned or shaped, or has a surface characteristic, to permit the flow downstream of the location of non-agglutinated red blood cells. In a preferred embodiment, the size, shape or surface characteristic may allow the passage of a single red blood cell at a time.
[0036] In some embodiments, the fluid flow cross section of an individual passageway is defined at least in part by the cross sectional area of the passageway itself. In illustrative examples of this type, the cross sectional area of the passageway decreases in size from the first part to the second part. Representative dimensions for this decrease are from about 500 - 3000 μm to about 2 - 10 μm in width or diameter. In specific embodiments, the sizes may range between about 800 μm - 1400 μm decreasing to about 2 μm - 20 μm in width or diameter. Other ranges may be suitable.
[0037] The term "about" is used herein to refer to dimensions or sizes (e.g., widths, cross sectional areas, radiuses etc) that vary by as much as 30%, preferably by as much as 20%, and more preferably by as much as 10% to a specified dimension or size.
[0038] In other embodiments, the fluid flow cross section of an individual passageway is defined at least in part by the pore size of a filter. In illustrative examples of this type, the second part of the passageway is defined by a pore of the filter. [0039] In still other embodiments, the fluid flow cross section of an individual passageway is defined at least in part by a pair of spaced pillars disposed within a conduit. In illustrative examples of this type, the second part of the passageway is defined by a plurality of spaced pillars disposed within the conduit, and individual pairs of pillars are suitably spaced to allow passage between the pillars of components of the contacted sample other than some or all of the agglutination complex. Suitably, the pillars are columnar but may be of any suitable cross sectional shape.
[0040] In some embodiments, individual passageways are dimensioned to provide a positive zone area and a negative zone area. Where multiple stepdown decreases in fluid flow cross sectional area are provided, a semi-quantitative result may be obtained. [0041] In some embodiments, an individual passageway has a fluid flow cross sectional area that permits the flow of fluid therethrough by capillary action. In these embodiments, the passageway is suitably formed of a capillary conduit or channel. In other embodiments, an individual passageway has a fluid flow cross sectional area that does not permit the flow of fluid therethrough by capillary action. In these embodiments, the method suitably further comprises forcing the contacted sample along the passageway (e.g., using centrifugal force air pressure, vacuum, electroosmosis, heating and the like).
[0042] In some embodiments, an individual passageway comprises at least two spaced segments, wherein an individual downstream segment inhibits the passage of components of the contacted sample whose passage was permitted by an adjacent upstream segment. In other embodiments, the fluid flow cross sectional area of an individual passageway gradually decreases along at least a portion of the pathway, which gradually inhibits the passage of smaller components of the contacted sample.
[0043] In some embodiments, an individual passageway has a single stepped decrease in fluid flow cross sectional area. Alternatively, an individual passageway may have two or more stepped decreases in fluid flow cross sectional areas. In other embodiments, an individual passageway has a gradual or constant decrease in fluid flow cross sectional area.
[0044] Suitably, the device comprises, for an individual analyte, multiple parallel passageways that form subconduits of a larger conduit. In some embodiments, the device comprises a plurality of such conduits, wherein the number of conduits corresponds to the number of analytes testable by the device. In illustrative examples, an individual subconduit may have a single stepped decrease in fluid flow cross sectional area, which is preferably aligned or in register with a similar decrease in fluid flow cross sectional areas in other subconduits. The subconduits may have two or more stepped decreases in fluid flow cross sectional area, again, preferably, with each aligned or in register with corresponding stepped decreases in other parallel subconduits. In other illustrative examples, individual subconduits are in fluid flow communication with a plurality of downstream subconduits that have smaller fluid flow cross sectional areas than the upstream subconduit.
[0045] In some embodiments, the individual passageways are in fluid flow communication with a reservoir that receives the fluid sample and/or other fluids. The other fluids may comprise one or more buffer solutions or wash solutions, or fluids containing testing reagents. In some embodiments, the reservoir comprises a capturing element that captures or immobilises components (any free ligand and/or agglutinable component) that flow downstream of the decrease in fluid flow cross section or surface characteristic of the passageway(s). In some embodiments, the reservoir may contain an absorbent material to facilitate the flow of fluid sample and/or other fluids.
[0046] In some embodiments, the passageway(s) is (are) in fluid communication with a at least one vent for venting fluid (e.g., air) to atmosphere.
[0047] In some embodiments, the device comprises a body or housing that is preferably elongate and formed with a planar or slide-like configuration. The body or housing may be formed from two sections. The sections may be halves which are joined face-to-face. The body or housing may comprise a fluid sample inlet compartment that communicates with the inlet port. The inlet compartment may be a well or a chamber. In some embodiments, the body or housing comprises a window that permits viewing of the change in fluid flow cross section or surface characteristic of the passage(s) and viewing, for example, of any immobilised agglutination complex. Alternatively, or in addition, in embodiments in which the passageway(s) fluidly communicate(s) with a reservoir, this window, or another window that is provided by the device, permits viewing of the reservoir of one or more components that flow downstream of the decrease in fluid flow cross sectional area of the passageway(s). [0048] In some embodiments, the device further comprises a ligand for detecting one or more analytes. The ligand may be releasably disposed on a wall of the inlet port or preferably on a wall of an individual passageway adjacent to its proximal end. Where a plurality of passageways are supplied, a range of different ligands may be applied to conduct simultaneous testing of the fluid sample for different analytes. At least one of the passageways may be formed as a negative control and one may be formed as a positive control. [0049] In yet another aspect, the invention provides kits for detecting at least one analyte. These kits generally comprise a device as broadly described above and reagents required for detecting the or each analyte. The kits may optionally include appropriate reagents for detection of labels, positive and negative controls, washing solutions, dilution buffers, calibration standards and the like. In some embodiments, the kits comprise distinct containers for each individual reagent. Generally, the kits are supplied with instructions, which instruct the user how to use the device and method as broadly described above.
[0050] In still another aspect, the present invention provides assay devices for determining the presence or quantity of an analyte. These devices generally comprise at least one passageway that comprises a wall having one or more assay reagents releasably disposed thereon. Suitably, the or each assay reagent is in dry form on the wall surface. In some embodiments, the passageway permits capillary flow of a fluid sample from a location upstream of the assay reagent(s). Typically, the passageway is dimensioned or has a surface to permit contact and mixing of the assay reagent(s) with the fluid sample and downstream flow of the contacted fluid sample. In some embodiments, the assay reagent(s) comprise(s) an agglutinable component or agglutination agent as broadly described above.
BRIEF DESCRIPTION OF THE DRAWINGS
[0051] In order to provide a better understanding of the present invention, preferred embodiments will be described in detail, by way of example only, with reference to the accompanying drawings in which: [0052] Figure 1 is a top plan view of a first embodiment of the test device of the present invention;
[0053] Figure 2 is a top plan view of a second embodiment of the test device of the present invention;
[0054] Figure 3 is a top plan view of the device of Figure 1 showing a negative result; and
[0055] Figure 4 is a top plan view of the device of Figure 1 showing a positive result. DESCRIPTION OF PREFERRED EMBODIMENTS
[0056] Referring to Figure 1, there is seen a test device 10 comprising a body 11 with a slide-like configuration. The body 11 contains a sample port 12 for receiving a fluid sample. A capillary conduit 18 is formed with the body. In a preferred embodiment, the device has a proximal section 16 which has a dried reagent reservoir, preferably dried to the inner surface of the capillary conduit. The dried reagent may be any suitable active material that may form an agglutination complex with particulate matter in the fluid sample from a positive subject. Alternatively, the reagent is mixed with the test sample prior to application to the device. The proximal section may comprise a single bore or multiple parallel bore. [0057] In use, a fluid sample is added to the sample port. Capillary action draws the fluid along the conduit 18. Alternatively, the fluid sample may be drawn through the conduit by external pressure from, for example, a manually operated pressure bulb, or a miniature motor.
[0058] Passage of the sample may be enhanced by addition of other fluids such as a buffer or wash solutions. The presence of fluid in the proximal portion 16 will, at least partially, resolubilise the reagent, thereby leading to mixing with the testing sample and institution of the diagnostic reaction if the target substance is present. The capillary conduit can be completely contained within the substance of the body so that there is no external leakage of the material. Alternatively, the conduit may comprise an open channel through which the fluid sample and reactants may pass. [0059] An intermediate section 20 is provided and comprises a series of parallel capillary channels 22. The parallel channels are preferably dimensioned in the order of 1000 Dm to 1500 Dm in diameter and, more preferably, in the range of about 1100 Dm to 1200 Dm. The wider capillary channels are of appropriate length and width to permit mixing of the reagent with a test sample and allow time for the reaction to develop during transfer across the intermediate zone 20.
[0060] A distal zone 24 comprises a series of parallel narrow channels in the form of narrow capillary channels. The transfer from broad capillary channels to narrow capillary channels occurs at interface 26, thereby providing a well-demarcated transition between the broad and narrow channels. The capillary conduit 18 is in fluid communication with a reservoir 28 adapted to receive any transferred fluid, either sample or other material, and provide an outlet for the capillary transfer of materials. The reservoir may be vented to the outside to avoid increased pressure resisting capillary transfer. Additionally or alternatively, the reservoir may have an absorbent material located in it to receive and retain any fluid.
[0061] Figure 2 shows a variation of testing device 110 with a port 112 which feeds into a manifold 130 which subsequently feeds into parallel capillary conduits 131, 132, 133 all with a similar structure to that described in relation to Figure 1. However, each of the conduits may have a different reagent located in the proximal zone 116 to provide a multiple testing capacity. One of the capillary channels may comprise a positive test reagent and one may comprise a negative test reagent for checking of testing device integrity. [0062] Figure 3 shows an example of a negative test result in an arrangement similar to that of Figure 1. The test sample 40 is shown contained in the reservoir 28. It has therefore flowed through the entire length of the testing conduit without being obstructed. It is reasonable to infer that no cells have therefore agglutinated and the test result is negative. A positive test result is shown in Figure 4 where agglutinated sample 41 is dammed against the demarcation point 26 due to an inability of the bulk of the sample to pass into the smaller conduit channels as a result of agglutination.
[0063] It is envisaged that the capillary conduit may incorporate two or more stepdown shoulders to provide a gradation of results and therefore give a more informative visual result. This provides a semi-quantitative result which may be calibrated or classified according to a range such as strong, intermediate, weak and negative.
[0064] A variety of manufacturing processes all well known to those skilled in the art may be applied to provide the present test device. In one form, a first test device section and a second test device section are fused together during production to form the test body. The reagent may be placed on one of the sections and dried or, alternatively, placed on both prior to joining. Beneficial methods of application of the reagent may include screen or inkjet printing, spraying by use of an airbrush technique or conventional dispensing of quantities using a positive displacement microvolume dispenser. The reagents may be dried by stationary or forced air which may be heated or at room temperature. The reagent may be dried in the presence of stabilisers and agents which facilitate resolubilisation. [0065] Definition of the capillary conduit and the capillary channels may be achieved by etching and also by a punch-out and laminating technique, by embossing, heat stamping or by flow injection or compression moulding. Injection or compression moulding may be preferred because of their accuracy and precision. This accuracy may be important to provide appropriate flow dynamics through the capillary conduits and capillary channels. [0066] The first test device section and the second test device section may be constructed or composed of the same or different material and may be fused, for example, by adhesive tape, adhesive bonding, ultrasonic welding or even by a mechanical snap-in technique.
[0067] In general, it is preferred to use a clear plastic, glass or other such material for the body and to define the capillary conduits and capillary channels. The body may be formed from polycarbonate, polymethylmethacrylate or polystyrene. [0068] Advantages of the present invention include an enclosed reaction area to reduce the possibility of contamination from infected blood samples, removal of any necessity to rock a reaction combination, fewer procedural steps, long-term stability of the reagents at room temperature and a more objective indication of agglutination and, in particular, haemagglutination.
[0069] In operation of one embodiment, blood is applied to the sample port and flows into and through a region of parallel capillary channels, the first part of which is coated with the dried reagent. The reagent is solubilised and mixes with the blood, causing haemagglutination in a positive sample. However, the channels in this region are wide enough to allow the passage of agglutinated blood cells. The mixture eventually reaches a region of narrow capillary channels to allow the passage of individual red blood cells but not agglutinated cells. In a negative sample, all of the blood sample reaches and accumulates in the reservoir. In a positive sample, all or some of the sample may be retarded at the junction of the wide and narrow capillary tube. [0070] The present invention may be applied to a wide range of assays including detection of human d-dimer, antibodies to HTVl and 2, Hepatitis B sAg and canine heartworm. It may also be satisfactorily applied to Dengue Fever, Malaria, Sudden Acute Respiratory Syndrome ("SARS"), Syphilis, Foot-and-mouth disease and West Nile viruses. The device may also be used in the detection of tumours such as prostrate cancer and various leukaemias. There are many infectious and other diseases that could be beneficially investigated using the testing device of the present invention. It is also within the scope of this invention that the device may be used to type human blood or blood from other species, wherein the reagent is an antibody or other agglutinating reagent directed against red blood cell typing antigens. It is further within the scope of this invention that the reagent is an active component of a particulate agglutination assay where the particles are, for example, coloured latex particles or fixed red blood cells conjugated to an antibody or antigen reactive with the analyte of interest.
[0071] The disclosure of every patent, patent application, and publication cited herein is hereby incorporated herein by reference in its entirety.
[0072] The citation of any reference herein should not be construed as an admission that such reference is available as "Prior Art" to the instant application.
[0073] Throughout the specification the aim has been to describe the preferred embodiments of the invention without limiting the invention to any one embodiment or specific collection of features. Those of skill in the art will therefore appreciate that, in light of the instant disclosure, various modifications and changes can be made in the particular embodiments exemplified without departing from the scope of the present invention. All such modifications and changes are intended to be included within the scope of the appended claims.

Claims

WHAT IS CLAIMED IS:
1. A method for determining the presence or quantity of an analyte in a fluid sample, the method comprising
- contacting the fluid sample with a ligand, which is interactive directly or indirectly with the analyte and which associates with an agglutinable component that forms an agglutination complex in the presence of the analyte;
- allowing the contacted sample to flow along a fluid passageway that comprises a first part having a fluid flow cross section or surface characteristic that permits the flow of the agglutination complex downstream to a second part having a fluid flow cross section or surface characteristic that impedes the flow therethrough of some or all of the agglutination complex, wherein the first part of the passageway is in fluid flow communication with the second part of the passageway; and
- determining the presence of the analyte by detecting the presence of the agglutination complex in or adjacent to the second part.
2. A method according to claim 1, wherein the cross section of the first part or second part has a circular, ovoid, elliptical, square, rectangular, irregular, U or V shape or has internal projections.
3. A method according to claim 1, wherein the first part or the second part comprises one or more bends, curves or bifurcations, which regulate flow of fluid or the agglutination complex.
4. A method according to claim 1, wherein the surface characteristic regulates the flow of fluid or the agglutination complex to a downstream location of the passageway.
5. A method according to claim 4, wherein the surface characteristic is provided at least in part by a wall of the passageway that comprises at least one flow-regulating component that is capable of interacting with a component of the agglutination complex.
6. A method according to claim 5, wherein the flow-regulating component interacts with any one or more of the ligand, the analyte and the agglutinable component.
7. A method according to claim 5, wherein the flow-regulating component comprises an antibody or antibody fragment that binds directly or indirectly to the analyte.
8. A method according to claim 5, wherein the flow-regulating component comprises an antibody or antibody fragment that binds directly or indirectly to a different epitope on the analyte than the one to which the ligand binds.
9. A method according to claim 1, wherein the passageway further comprises a third part that receives components of the contacted sample that are permitted to flow downstream of the second part, wherein the third part is in fluid flow communication with the first part and the second part.
10. A method according to claim 9, wherein the third part includes an immobilised capturing element that captures components of the contacted sample.
11. A method according to claim 1, wherein the agglutination complex is associated with a first detectable signal and the agglutinable component is associated with a second detectable signal and the method further comprises comparing the first detectable signal in or adjacent to the first part and the second detectable signal in the second or third parts to provide a quantitative or semi-quantitative assay of the analyte in the fluid sample.
12. A method according to claim 1, wherein the ligand and optionally other assay components are releasably disposed in the first part of the passageway and the method comprises contacting the fluid sample with the ligand and optionally other assay components in the first part.
13. A method according to claim 12, wherein the first part of the passageway has a fluid flow cross section that permits mixing of the analyte, if present in the fluid sample, with the ligand and the agglutinable component.
14. A method according to claim 1, wherein the first part of the passageway is of appropriate shape or dimensions or has fluid flow surface characteristics, to allow agglutination to occur in a positive sample before the sample fluid arrives at the second part of the passageway.
15. A method according to claim 1, wherein the fluid sample is allowed to flow along a plurality of passageways for determining the presence of a plurality of different analytes, wherein the first part of an individual passageway comprises a ligand that is interactive with a different analyte than the analyte with which a ligand in the first part of another passageway interacts.
16. A method according to claim 1, wherein the analyte is selected from an antigen, a hapten, an antibody, a protein, a peptide, an amino acid, a nucleic acid, a hormone, a steroid, a vitamin, a carbohydrate, a lipid, a blood clotting factor, a pathogenic organism, a natural or synthetic chemical substance, a contaminant, a drug including those administered for therapeutic purposes as well as those administered for illicit purposes, and metabolites of or antibodies to any of the above substances.
17. A method according to claim 1, wherein the fluid sample comprises a biological sample, including biological fluids and tissue or biopsy samples, and fluid samples containing microorganisms, which may be extracted, untreated, treated, diluted or concentrated from a plant or animal or environmental sample.
18. A method according to claim 1, wherein the agglutinable component is a particle selected from polymeric particles, ceramic particles, metal particles, liposomes, carbon particles, bacteria and erythrocytes.
19. A method according to claim 18, wherein the particles comprise one or more dyes or fluorescent, phosphorescent or other light-emitting material, either singly or in combination.
20. A method according to claim 1, wherein the agglutinable component is conjugated with the ligand.
21. A method according to claim 1, wherein the agglutinable component and the ligand are separate components
22. A method according to claim 21, wherein the ligand comprises a moiety that is interactive with the agglutinable component.
23. A method according to claim 1, wherein the ligand comprises an agglutinating agent.
24. A method according to claim 1, wherein the ligand comprises a haemagglutination agent.
25. A method according to claim 24, wherein the haemagglutination agent comprises a bifunctional antibody conjugate in which one antibody or antibody fragment binds to red blood cells and the other antibody or antibody fragment binds to D-dimer.
26. A device for determining the presence or quantity in a fluid sample of at least one analyte using a ligand which is interactive with a respective analyte and which is associated with an agglutinable component that forms an agglutination complex in the presence of the analyte, the device comprising: - at least one inlet port; and,
- for each analyte, at least one passageway that is in fluid flow communication with the at least one inlet port and that changes in fluid flow cross section or surface characteristics downstream of the at least one inlet port, wherein a fluid sample deposited in an individual inlet port travels along a flow path between a proximal end and a distal end of a respective passageway.
27. A device according to claim 26, wherein the fluid flow cross section or surface characteristic of an individual passageway at a location between its proximal and distal ends changes sufficiently to impede flow along the pathway of the agglutination complex.
28. A device according to claim 27, wherein the passageway at the location has a fluid flow cross section that is dimensioned or shaped, or has a surface characteristic, to permit the flow downstream of the location of non-agglutinated matter.
29. A device according to claim 27, wherein the passageway at the location has a fluid flow cross section that is dimensioned or shaped, or has a surface characteristic, to permit the flow downstream of the location of non-agglutinated red blood cells.
30. A device according to claim 26, wherein the fluid flow cross section of an individual passageway is defined at least in part by the cross sectional area of the passageway itself.
31. A device according to claim 30, wherein the cross sectional area of the passageway decreases in size from the first part to the second part.
32. A device according to claim 30, wherein the cross sectional area of the passageway decreases from about 500 - 3000 μm to about 2 - 10 μm in width or diameter.
33. A device according to claim 26, wherein the fluid flow cross section of an individual passageway is defined at least in part by the pore size of a filter.
34. A device according to claim 33, wherein the second part of the passageway is defined by a pore of the filter.
35. A device according to claim 26, wherein the fluid flow cross section of an individual passageway is defined at least in part by a pair of spaced pillars disposed within a conduit.
36. A device according to claim 35, wherein the second part of the passageway is defined by a plurality of spaced pillars disposed within the conduit, and individual pairs of pillars are spaced to allow passage between the pillars of components of the contacted sample other than some or all of the agglutination complex.
37. A device according to claim 26, wherein individual passageways are dimensioned to provide a positive zone area and a negative zone area.
38. A device according to claim 26, wherein an individual passageway has a fluid flow cross sectional area that permits the flow of fluid therethrough by capillary action.
39. A device according to claim 38, wherein the passageway is formed of a capillary conduit or channel.
40. A device according to claim 26, wherein an individual passageway has a fluid flow cross sectional area that does not permit the flow of fluid therethrough by capillary action.
41. A device according to claim 40, wherein the method suitably further comprises forcing the contacted sample along the passageway.
42. A device according to claim 26, wherein an individual passageway comprises at least two spaced segments, wherein an individual downstream segment inhibits the passage of components of the contacted sample whose passage was permitted by an adjacent upstream segment.
43. A device according to claim 26, wherein the fluid flow cross sectional area of an individual passageway gradually decreases along at least a portion of the pathway, which gradually inhibits the passage of smaller components of the contacted sample.
44. A device according to claim 26, wherein an individual passageway has a single stepped decrease in fluid flow cross sectional area.
45. A device according to claim 26, wherein an individual passageway has two or more stepped decreases in fluid flow cross sectional areas.
46. A device according to claim 26, wherein an individual passageway has a gradual or constant decrease in fluid flow cross sectional area.
47. A device according to claim 26, further comprising for an individual analyte, multiple parallel passageways that form subconduits of a larger conduit.
48. A device according to claim 47, wherein the device comprises a plurality of such larger conduits, wherein the number of conduits corresponds to the number of analytes testable by the device.
49. A device according to claim 47, wherein an individual subconduit has a single stepped decrease in fluid flow cross sectional area, which is aligned or in register with a similar decrease in fluid flow cross sectional areas in other subconduits.
50. A device according to claim 47, wherein the subconduits have two or more stepped decreases in fluid flow cross sectional area, with each aligned or in register with corresponding stepped decreases in other parallel subconduits.
51. A device according to claim 47, wherein individual subconduits are in fluid flow communication with a plurality of downstream subconduits that have smaller fluid flow cross sectional areas than the upstream subconduit.
52. A device according to claim 26, wherein the individual passageways are in fluid flow communication with a reservoir that receives the fluid sample or other fluids.
53. A device according to claim 52, wherein the other fluids comprise one or more buffer solutions or wash solutions, or fluids containing testing reagents.
54. A device according to claim 52, wherein the reservoir comprises a capturing element that captures or immobilises components that flow downstream of the change in fluid flow cross section or surface characteristic of the passageway(s).
55. A device according to claim 52, wherein the reservoir contains an absorbent material to facilitate the flow of fluid sample or other fluids.
56. A device according to claim 26, wherein the passageway(s) is (are) in fluid communication with a at least one vent for venting fluid to atmosphere.
57. A device according to claim 26, wherein the device comprises a body or housing that is elongate and formed with a planar or slide-like configuration.
58. A device according to claim 57, wherein the body or housing is formed from two sections.
59. A device according to claim 57, wherein the sections represent halves which are joined face-to-face.
60. A device according to claim 57, wherein the body or housing comprises a fluid sample inlet compartment that communicates with the inlet port.
61. A device according to claim 60, wherein the inlet compartment is a well or a chamber.
62. A device according to claim 57, wherein the body or housing comprises a window that permits viewing of the change in fluid flow cross section or surface characteristic of the passage(s) and viewing of any immobilised agglutination complex.
63. A device according to claim 26, further comprising a ligand for detecting one or more analytes.
64. A device according to claim 63, wherein the ligand is releasably disposed on a wall of the inlet port.
65. A device according to claim 63, wherein the ligand is releasably disposed on a wall of an individual passageway adjacent to its proximal end.
66. A device according to claim 63, wherein when a plurality of passageways are provided, a range of different ligands is applied to conduct simultaneous testing of the fluid sample for different analytes.
67. A device according to claim 63, wherein at least one of the passageways is formed as a negative control and one is formed as a positive control.
68. A kit for detecting or quantifying at least one analyte, the kit comprising a device according to claim 26 and reagents required for detecting the or each analyte.
69. A kit according to claim 68, further comprising one or more of reagents for detection of labels, positive and negative controls, washing solutions, calibration standards and dilution buffers.
70. A kit according to claim 68, wherein the kit comprises distinct containers for each individual reagent.
71. A kit according to claim 68, wherein the kit is supplied with instructions, which instruct the user how to use the device.
72. An assay device for determining the presence or quantity of an analyte, the assay device comprising at least one passageway that comprises a wall having one or more assay reagents releasably disposed thereon.
73. A device according to claim 72, wherein the or each assay reagent is in dry form on the wall surface.
74. A device according to claim 72, wherein the passageway permits capillary flow of a fluid sample from a location upstream of the assay reagent(s).
75. A device according to claim 72, wherein the passageway is dimensioned or has a surface to permit contact and mixing of the assay reagent(s) with the fluid sample and downstream flow of the contacted fluid sample.
76. A device according to claim 72, wherein the assay reagent(s) comprise(s) an agglutinable component.
77. A device according to claim 72, wherein the assay reagent(s) comprise(s) an agglutinating agent.
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