WO2020191428A1 - Method and device for measuring the fibrinogen concentration in blood samples. - Google Patents
Method and device for measuring the fibrinogen concentration in blood samples. Download PDFInfo
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- WO2020191428A1 WO2020191428A1 PCT/AU2020/000024 AU2020000024W WO2020191428A1 WO 2020191428 A1 WO2020191428 A1 WO 2020191428A1 AU 2020000024 W AU2020000024 W AU 2020000024W WO 2020191428 A1 WO2020191428 A1 WO 2020191428A1
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5023—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures with a sample being transported to, and subsequently stored in an absorbent for analysis
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- 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
- B01L3/502753—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 bulk separation arrangements on lab-on-a-chip devices, e.g. for filtration or centrifugation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54366—Apparatus specially adapted for solid-phase testing
- G01N33/54386—Analytical elements
- G01N33/54387—Immunochromatographic test strips
- G01N33/54388—Immunochromatographic test strips based on lateral flow
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- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/56—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving blood clotting factors, e.g. involving thrombin, thromboplastin, fibrinogen
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
- G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
- G01N21/78—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator producing a change of colour
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
- G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
- G01N21/82—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator producing a precipitate or turbidity
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/86—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood coagulating time or factors, or their receptors
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
- B01L2200/16—Reagents, handling or storing thereof
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0809—Geometry, shape and general structure rectangular shaped
- B01L2300/0825—Test strips
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/12—Specific details about materials
- B01L2300/126—Paper
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- 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
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- 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
- B01L2400/0406—Moving fluids with specific forces or mechanical means specific forces capillary forces
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2337/00—N-linked chromogens for determinations of peptidases and proteinases
- C12Q2337/10—Anilides
- C12Q2337/12—Para-Nitroanilides p-NA
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/745—Assays involving non-enzymic blood coagulation factors
- G01N2333/75—Fibrin; Fibrinogen
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/914—Hydrolases (3)
- G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
- G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
- G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
- G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
- G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
- G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
- G01N2333/96433—Serine endopeptidases (3.4.21)
- G01N2333/96441—Serine endopeptidases (3.4.21) with definite EC number
- G01N2333/96463—Blood coagulation factors not provided for in a preceding group or according to more than one of the proceeding groups
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- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/914—Hydrolases (3)
- G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
- G01N2333/974—Thrombin
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/22—Haematology
- G01N2800/224—Haemostasis or coagulation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/22—Haematology
- G01N2800/226—Thrombotic disorders, i.e. thrombo-embolism irrespective of location/organ involved, e.g. renal vein thrombosis, venous thrombosis
Definitions
- the present invention relates to diagnostic methodologies and associated equipment and more specifical ly relates to a diagnostic method which enables measurement of fibrinogen concentration in blood samples. More particularly the present invention also relates to a visual colorimetric method of testing for fibrinogen concentration in a blood sample using a device having an indicator which enables determination of fibrinogen concentration in the sample.
- the invention further relates to a method of testing of blood samples using fibrinogen and thrombin solutions suppl ied to a device such as an indicator strip and observing a dyed fluid elution.
- the invention further relates to method for determination of fibrinogen concentration in a blood sample using a cellulose fiber indicator strip charged with fibrinogen and thrombin solutions and applying a dye droplet to the strip to observe a lengthwise extent of elution.
- Fibrinogen is a protein, (a coagulation factor) that is essential for blood clot formation. Fibrinogen is produced by the liver and released into circulation along with several other coagulation factor proteins. Normal ly, when a body tissue or blood vessel wall is injured, a process cal led hemostasis begins to arrest bleeding by forming a plug at the injury site. Smal l cell fragments called platelets adhere to and aggregate at the site and clotting factors are activated one after the other eventually forming a clot.
- Fibrinogen is one of those clotting factors. Its concentration can be measured to ascertain a patient’s capacity for blood coagulation in the event of a cut or impact injury. As clotting occurs, fibrinogen is converted into insoluble fibrin threads which crosslink together to form a fibrin net that stabi l izes at the injury site. The fibrin net adheres to the site of injury along with the platelets to form a stable blood clot. For a stable clot to form there must be enough normal ly functioning platelets and coagulation factors. If there are dysfunctional factors or platelets, or too little or too much of them, this can lead to bleeding episodes and/or to formation of an in appropriate blood clot- known as thrombosis. It is therefore important to determine clotting capacity in a patient and particularly fibrinogen concentration.
- a fibrinogen activity test which evaluates how wel l fibrinogen functions in helping to form a blood clot.
- a second test known as a fibrinogen antigen test measures the amount of fibrinogen in the blood. The tests are intended to ( but do not necessari ly ) reflect in vivo haemostasis.
- a laboratory test may not reflect the in vivo behaviour but its aim is to indicate ( if not simulate) fibrinogen concentration and it is also useful to evaluate specific components of haemostasis.
- the known fibrinogen activity test evaluates that part of the haemostatic process in which soluble fibrinogen is converted into fibrin threads. With the addition of thrombin to the test sample, the fibrinogen test focuses on the function of fibrinogen and measures the time that it takes for a fibrin clot to form fol lowing the addition of a standard amount of thrombin to blood plasma. The time that is required for a clot to form directly correlates with the amount of active fibrinogen that is present. This test evaluates the function of fibrinogen, its abil ity to be converted into fibrin. It is known that prolonged clot-formation times may be due to decreased concentrations of normal fibrinogen or due to dysfunctional fibrinogen.
- fibrinogen antigen test which uses a fibrinogen antibody to bind to fibrinogen in a blood sample. This test allows the quantity, but not activity, of fibrinogen to be measured. Concentrations of fibrinogen rise sharply with conditions causing acute tissue inflammation or damage. Tests for these acute phase reactants, including fibrinogen, may be performed using a blood sample to determine the extent of inflammation in the body.
- plastics diagnostic device which has no inherent capi l lary action to facilitate fluid flow. Accordingly, as plastics diagnostic devices have no capillary action to facil itate fluid flow, it has to be artificially induced by the inclusion of micropillars. Also the plastics diagnostic must be coated with SiOx and treated with polyelectrolytes to increase the hydrophilicity of the flow path zone.
- This disclosure does not teach or allude to an arrangement in which a pigmented solution or dye moves under capil lary a distance through clotted plasma after plasma is added to thrombin to react for a period of time and after water is added to the dye or pigment.
- the prior art does not teach a method in which water wicks a dye through clotted plasma.
- a testing device having one part coated with thrombin and another part coated with a dye. Another device for measuring fibrinogen concentration is disclosed in the following publication:
- This publication teaches a lateral flow assay to measure fibrinogen concentrations using a thermoplastic resin as the substrate.
- the test described incorporates a flow receiving sample and a flow path zone made of a thermoplastic resin.
- a flow path zone induces capillary action by the presence of micro pillar.
- This test pre-immobilises 250-1000 mU of thrombin in the flow path zone and adds 15 pL of plasma preheated at 37°C to the flow receiving sample.
- the plasma migrates through the flow path zone where it is clotted.
- the test stops when plasma movement is arrested. The distance the plasma moves up the flow path zone is correlated to the fibrinogen concentration where higher concentrations lead to lower migrations.
- the test measures from 0-11 mm for >4 g/L fibrinogen, 12-20 mm for 2-4 g/L fibrinogen and 21-27 mm for 1-2 g/L fibrinogen.
- the device doesn’t reach further than 27 mm length.
- the mechanism appears to be related to clotting time (as with Clauss Assay). Lower concentration fibrinogen solutions will take longer to form a clot that eventually halts plasma movement. This causes the plasma to travel further up the flow path zone before stopping.
- test method described which relies of clot formation time, employs micro-structured thermoplastic as a substrate and measures low (1-2 g/L), medium (2-4 g/L) and high (>4 g/L) fibrinogen to cover both haemorrhage and cardiovascular disease risk. Also the prior art method separates 1-2 g/L fibrinogen in mm increments.
- the present invention provides a diagnostic method which enables measurement of fibrinogen concentration in blood samples using a visual indicator. More particularly the present invention provides a visual colorimetric method of testing for fibrinogen concentration in a blood sample using an indicator which enables determination of fibrinogen concentration in the sample. The invention further provides a method of testing of blood samples using thrombin solutions suppl ied to an indicator strip and observing a dyed fluid elution. More particularly the invention provides a method for determination of fibrinogen concentration in a blood sample using a cel lulose fiber indicator strip charged with thrombin solutions and applying a dye to the strip to observe a lengthwise extent of wicking/elution.
- the present invention provides a handheld diagnostic indicator which may comprise a strip or plate which enables visual measurement of fibrinogen concentration in human blood samples using an increase in hydrophobicity induced by the conversion of fibrinogen to fibrin.
- a solution of fibrinogen and thrombin allowing thrombosis to occur, is added to a paper strip.
- Fol lowing that, an aqueous dye is deposited on the strip allowing wicking/elution to occur, thereby enabl ing a visual indication of fibrinogen concentration of the solution related to a distance the dyed fluid wicks/elutes up each strip.
- the visual test enables a determination of concentration of fibrinogen from the length of wicking.
- the dye is used to improve the visibility of the solution wicking.
- the plate or strip is comprised of paper (cel lulose fibre).
- the increase in hydrophobicity is dramatic and depends on the concentration of fibrinogen. If the elution is small the fibrinogen concentration is high and if the elution distance is large ( lower hydrophobicity) the concentration is small or very low.
- the indicator is a paper strip of a predetermined length and width. Wicking and capillary flow is induced by hydrophilic porous and fibrous media and films.
- the parameters which impact on the testing methodolgy and outcomes include: the type of paper or porous media (including wettabi l ity and pore size distribution), the strip width, the volume of blood sample added, the individual concentrations of thrombin and FXI I Ia used as well as the reaction and elution times. There are 3 other aspects that also have a major effect:
- a reference to elution can be taken to include a reference to phenomena including absorption, capillarity.
- the purpose of an elution is to cause the release of antibody molecules from the red blood cel l membrane. Once free in solution the eluted antibodies are tested against reagent red blood cel ls to determine if an immune antibody specificity is present. Elution is the process of removing antibodies from the surface of red blood cel ls.
- a reference to a plasma sample can be taken to include a reference to blood sample and a reference to blood sample can be taken to include a reference to a plasma sample.
- a reference in the specification to elution can be taken to include a reference to wicking and a reference to wicking can be taken to include a reference to elution.
- a reference to a kit can be taken to include a reference to a testing device and any associated accessories or simply to a testing device.
- a reference to clotting can be taken to include a reference to coagulation.
- the present invention comprises:
- a disposable diagnostic device which enables measurement of fibrinogen concentration in a blood sample
- the device comprising a wettable porous testing substrate and viewing indicators which allow determination of a test status; the substrate having a first end and second end and intermediate therebetween a flow receiving zone, a flow path zone and a reaction zone; the reaction zone pre charged with Thrombin and an indicating dye or Thrombin and a fibrinogen solution and a dye; wherein when the sample for testing is deposited in said flow receiving zone, or in said reactions zone, porosity in said substrate urges said fluid a distance along said substrate, the distance travel led along said substrate providing a measure of concentration of fibrinogen in said blood sample under test.
- the device includes a housing which includes the viewing windows that indicate to the user along the flow path zone, the fibrinogen concentration
- the present invention comprises: a disposable diagnostic strip which enables measurement of fibrinogen concentration in a blood plasma sample applied to said strip, the strip comprising: a wettable porous testing substrate, the substrate having a first end and second end and intermediate therebetween a flow receiving zone, a flow path zone and a reaction zone; the reaction zone pre charged with Thrombin and an indicating dye; wherein when a sample fluid to be tested is deposited in said receiving zone or reaction zone, the sample reacts with said Thrombin inducing clotting; the sample when deposited creating a zone of hyd rophobicity; whereby water added to the dye advances along a distance in the flow path zone; the distance travel led along said substrate providing a measure of concentration of fibrinogen in said blood sample under test.
- the present invention comprises:
- a disposable diagnostic indicator device which enables measurement of fibrinogen concentration in a blood plasma sample applied to said device, the indicator comprising: a wettable porous testing substrate, the porous testing substrate having a first end and second end and intermediate therebetween a flow receiving zone, a flow path zone and a reaction zone; the reaction zone of the substrate pre charged with Thrombin and an indicating dye; wherein, when said sample is deposited in said flow receiving zone or in said reaction zone, a zone of hydrophobicity is created; and wherein when water mixes with the dye, the dye advances along the flow path zone; also urging said sample a distance along said substrate, the distance travel led along said substrate of the indicating dye providing a measure of concentration of fibrinogen in said blood sample under test.
- the present invention comprises:
- the device comprising; a porous testing substrate, the substrate having a first end and second end and intermediate therebetween a flow receiving zone, a flow path zone and a reaction zone; the reaction zone comprised of biological factors, chemical factors and/or derivatives of the biological factors and/or chemical factors pre-applied to the substrate.
- the present invention comprises:
- a diagnostic device which enables measurement of fibrinogen concentration in a blood sample
- the device comprising; a wettable testing substrate including viewing indicators which allow determination of a status of a test; the substrate having a first end and second end and intermediate therebetween a flow receiving zone, a flow path zone and a reaction zone; the reaction zone pre charged with at least one reagent; wherein, when a blood sample to be tested is deposited near or in either said flow receiving zone or said reaction zone, reacts with said reagents inducing clotting of the sample; a dye added to said reaction zone, advances a distance along said substrate; the distance travelled along said substrate by the dye and through the sample providing a measure of concentration of fibrinogen in said blood sample under test.
- the porous substrate is manufactured from cel lulose fibre (paper).
- the reaction zone is pre charged with Thrombin and an indicating dye; wherein when a sample fluid is deposited in said flow receiving zone, porosity in said substrate urges said fluid under the action of capi l lary, a distance along said substrate.
- a dye mixed with water advances along the substrate in the flow path zone with the distance of travel related of the dye providing an indicator from which concentration of fibrinogen in said blood sample under test can be ascertained.
- the wettable porous substrate is modified with a physical factor and/or chemical factor or biological factor that wi l l or may increase or decrease the hydrophobicity of the substrate.
- the chemical factor modification of the substrate comprises coating the substrate.
- the blood plasma is according to one embodiment appl ied on the porous substrate outside the reaction zone. Alternatively the blood or plasma is applied to the reaction zone to form a zone of hydrophobicity after initiating clot formation.
- Measuring the hydrophobicity refers to measuring the zone of hydrophobicity’s hydrophobicity.
- the aforesaid biological factors, chemical factors and/or derivatives of the biological factors and/or chemical factors used are involved in the initiation, execution, ampl ification and/or acceleration of the clot formation.
- the biological factors, chemical factors and/or derivatives of the biological factors and/or chemical factors used are involved in the enhancement or diminishment of the clot’s hydrophobicity.
- the biological factors, chemical factors and/or derivatives of the biological factors and/or chemical factors used may be applied and/or pre-applied outside of the reaction zone.
- the aforesaid physical factors used will or may allow or prevent the initiation of the clot formation. Physical factors used may enhance or diminish the clot’s hydrophobicity. Alternatively any physical factors used that wi ll or may increase or decrease the execution, ampl ification and/or acceleration of the clot formation.
- the present invention comprises:
- a method of diagnosis of concentration of fibrinogen in a blood or plasma sample using at least one capillary in a centrifuge, said at least one capi l lary each including a reaction mixture of biological factors, chemical factors and/or derivatives of the biological factors and/or chemical factors appl ied and/or pre-applied inside of the at least one capi l lary, the method including the step of applying blood or plasma to said reaction mixture to form a clot and measuring an extent of clotting after initiating clotting of the sample. Measuring the extent of clotting refers to quantifying the mass, volume or height of the clot in the capi l lary.
- An indicating dye is mixed with water and advances along a flow path with the distance advanced determinant of concentration of fibrinogen in the bold sample.
- the present invention comprises: a testing method for determining the concentration of fibrinogen in a test sample using a porous substrate; the substrate having a first end and second end and intermediate therebetween a flow receiving zone, a flow path zone and a reaction zone; the method comprising the steps of:
- the method of quantifying the zone of hydrophobicity/hydrophobicity consists of measuring the distance travel led by at least one chromogenic marker through or away from the zone of hydrophobicity in a lateral flow set-up.
- the present invention comprises: a method of testing for the concentration of fibrinogen in a blood sample using a diagnostic device which enables measurement of fibrinogen concentration in a blood sample, the device comprising; a wettable testing substrate and a housing including viewing indicators which al low determination of a status of a test; the substrate having a first end and second end and intermediate therebetween a flow receiving zone, a flow path zone and a reaction zone; the reaction zone pre charged with reagents; the method comprising the steps of:
- the present invention comprises:
- a testing method for determining the concentration of fibrinogen in a test sample using a porous substrate comprising the steps of:
- the hydrophobicity is induced by the polymerization of the fibrinogen in the blood sample to fibrin upon enzymatic reaction with thrombin and/or FXI I Ia deposited onto the receiving surface.
- the method of quantifying the zone of hydrophobicity’s surface hydrophobicity consists of measuring the shape, height and/or contact angle of any deposited liquid droplets on top of the non- porous substrate’s surface.
- capillarity distributes the blood sample into the receiving zone treated with thrombin, and a wash solution is transported through the receiving zone to remove dye deposited in the receiving zone out of the porous material .
- the colour intensity after washing is used to measure and visualize the hydrophobicity of the zone. Therefore, colour intensity is correlative to the fibrinogen concentration in the blood sample.
- a diagnosis of fibrinogen concentration can be made using the following combined three mechanisms.
- the first mechanism is a change in dye adhesiveness induced by polymerization of the fibrinogen in the blood sample to fibrin upon enzymatic reaction with thrombin and/or FXI I Ia deposited onto the receiving zone.
- the second mechanism is the adhesion of the dye deposited in the receiving zone to the fibrin directly (or indirectly via the assistance of dye binders).
- the third mechanism is capi l larity used to: 1) distribute the blood sample into the receiving zone treated with thrombin, and 2) transport wash solution through the receiving surface to remove dye out of the porous material.
- said indicator or said strip comprises cellulose fibre or other suitable porous and wettable material.
- a blood sample is deposited in the reaction zone of the indicator device and is al lowed to react with a precharge of Thrombin.
- the indicator is preferably pre-charged with Thrombin and/or FXI I Ia or simi lar.
- the indicator is either pre charged with a dye/buffer solution to the reaction zone or to a different receiving zone. Alternatively, the dye is added during or after introduction of the blood/plasma sample.
- the indicative dye or solution may contain a buffer.
- the dye al lows a visual indication of distance that fluid added to the flow receiving zone travels dictated by the zone of hydrophobicity which is in turn dictated by the reaction between a plasma sample and Thrombin. This al lows a diagnostic result for Fibrinogen concentration based on the measured distance.
- said dye in said reaction zone acts as a visual indicator and is blue in colour.
- said Thrombin is Lyophi I Used.
- said reaction zone is in said flow path zone. Plasma advances along the substrate through capillary action.
- Figure 1 shows a schematic arrangement of a fibrinogen concentration diagnostic testing device including a porous substrate.
- Figure 2 shows the device of figure 1 in a first stage of testing
- Figure 3 shows the device of figure 1 at a second stage of testing.
- Figure 4 shows the testing device of figure 1 with an outer casing completi ng a testing kit and with visual indicators indicating an unused state.
- Figure 5 shows the casing of figure 4 indicating a first stage of testing with visual indicators indicating a reaction and a val id test.
- Figure 6 shows the device of figure 4 at a second stage of testing with visual indicators indicating a result.
- a reference to substrate can be taken to include a reference to: Active Base/medium of diagnostic which faci l itates assaying.
- a reference to Factor can be taken to include a reference to: a component of diagnostic that impacts on results, a reference to Biological factor can be taken to include a reference to: a Factor derived from biological source. Eg. Thrombin, Platelets, etc...
- a reference to Chemical Factor can be taken to include a reference to: a factor derived from non-biological source.
- Eg. Calcium Chloride, etc...A reference to physical factor can be taken to include a reference to: a Factor: not composed of chemical matter.
- a reference to apply/applied can be taken to include a reference to: the addition of a chemical to diagnostic as a part of test procedure.
- a reference to pre - apply can be taken to include a reference to: incorporation of a chemical into diagnostic as part of intrinsic design.
- a reference to clot can be taken to include a reference to: a Network composed of polymerized fibrin monomers and a reference to clotting or clot formation can be taken to include a reference to Conversion of fibrinogen into fibrin network.
- a reference to Amplification (of clot formation) can be taken to include a reference to: generation of a larger magnitude clot network in the time allowed for reacting.
- a reference to Chromogenic Marker also termed a dye, can be taken to include a reference to: a coloured chemical that is clearly visible to the naked eye.
- a reference to Lateral Flow can be taken to include a reference to: movement of liquid through a long, narrow channel via capillary forces.
- a reference to Wicking Liquid can also be taken to include a reference to: a liquid that moves through a substrate through the action of capil lary forces.
- a wicking fluid is also a fluid that saturates the flow receiving zone in order to travel through the flow path zone.
- a reference to a flow receiving zone can be taken to include a reference to: a zone in which wicking l iquid can be appl ied.
- a reference to a flow path zone can be taken to include a reference to: a Zone in which wicking liquid can move into from the flow receiving zone.
- a reference to a Washing Liquid can be taken to include a reference to: a liquid used to dislocate the chromogenic marker(s) out of the substrate.
- the plasma/blood solution too can be defined as washing l iquid in this case as it is able to dislocate the dye out of the paper (if the dye is pre-charged Into the reaction zone).
- a reference to a, Threshold Result can be taken to include a reference to: a simpl ified quantification in which the result provided from a measurement is only readable as above or below a certain value (i.e. the reading is positive or negative).
- a reference to a, surface (of substrate) can be taken to include a reference to: a solid interface of substrate’s surface that is only exposable to liquid or gas; includes any chemical modifications or coatings applied and/or pre-applied to this interface.
- a reference to Capillary can be taken to include a reference to: a thin tube which can hold blood or plasma.
- a reference to a centrifuge or centrifuge device can be taken to include a reference to: a device that applies centripetal or centrifugal forces ( to a sample).
- a paper indicator using thrombin and a dyed solution to ascertain concentration of fibrinogen in a blood sample using distance increments which can potential ly be measured in mm or cms.
- the indicator is intended for measuring between 0-2 g/L to diagnose hypofibrinogenemia (especially in the early stages of hemorrhage).
- the test employs plasma and measures based on clot hydrophobicity rather than clot formation time as in the known art.
- a paper substrate which has one section coated with thrombin and another section coated with blue dye.
- Plasma is added to the section with thrombin to react for a short period of time, then water is added to the section with blue dye.
- the distance that is measured is how far that the water wicks the blue dye through the clotted plasma. In reality it also moves the zone of hydrophobicity with it (whilst simultaneously moving through it). This is to be distinguished from the prior art which measures how far the plasma moves through the device whi lst clotting.
- the front of the zone of hydrophobicity can be used as a distance marker as it can be much clearer than that produced by the wicking fluid moving through it.
- FIG. 1 shows according to one embodiment, a schematic arrangement of a fibrinogen concentration diagnostic testing device 1 ( see figure 2) including a porous substrate 2.
- substrate 2 is provided in the form of a strip but it will be appreciated that other geometries are feasible as long as it includes a flow path zone.
- substrate 2 comprises a first end 3 and second end 4. In between ends 3 and 4 are a flow receiving zone 5 and a flow path zone 6 for analyzing test results.
- Substrate 2 includes in the flow path zone 6 a Thrombin Chromogenic substrate (for example S2238).
- Thrombin Chromogenic substrate for example S2238.
- Adjacent flow receiving zone 5 for receiving water and near end 3 is a wax boundary 7 which provides a flow limit for water introduced into the flow receiving zone 5 during testing.
- Substrate 2 further comprises a reaction zone 8 which preferably incorporates Lyophilised thrombin and a blue dye. Reaction zone 8 is pre charged with Thrombin and the dye.
- Figure 2 shows with corresponding numbering the substrate device 2 of figure 1 in a first stage of testing to determine fibrinogen concentration in a blood plasma sample.
- plasma is added to reaction zone 8 preferably using a pipette. Capillary forces in the substrate 2 wicks the plasma, blue dye and thrombin lateral ly in the direction of either of ends 3 and/or 4.
- Thrombin reacts with plasma fibrinogen and the thrombin chromogenic substrate. This creates a zone of hydrophobicity 9.
- Indication zone 20 undergoes a colour change as Thrombin cleaves the Chromogenic substrate.
- Figure 3 shows the device of figure 1 at a second stage of testing.
- water is added to flow receiving zone 5. This may be done using a pipette or alternatively placing the substrate 2 into a beaker of a wicking fluid such as but not l imited to water. Capi l lary forces in porous substrate 2 urges/wicks the wicking fluid along flow path zone 6.
- a distance L that the wicking fluid travels along flow path 6 is a function of a level of hydrophobicity in the zone of hydrophobicity 9. The distance that the water travels along the substrate is a visual indication of the fibrinogen concentration in the plasma sample.
- Figure 4 shows an unused testing device 1 comprising substrate 2 of figure 1 inside and housed in an outer/housing/casing 11 completing testing device 1 and with visual indicators indicating an unused state.
- Casing 11 is divided into application indicator windows and analysis windows.
- an indication window 13 which indicates plasma introduction
- window 12 which indicates location of water introduction.
- window 13 undergoes a colour change.
- a quality check window 14 is provided which is used to assess pre reaction of a plasma/blood sample and Thrombin. Window 14 posses the thrombin Chromogenic substrate. When thrombin is spread to it after the addition of the plasma or blood sample ( from window 13), it changes colour to indicate that the thrombin hasn’t degraded indicating that the test is valid.
- Zone 6 (which contains the uncleaved thrombin chromogenic substrate) l ies under Window 14.
- the inactive thrombin chromogenic marker can be placed in a separate area upstream from the reaction zone. This can be denoted by an extra box in figure 4 (not shown) without shading to indicate its lack of colour instead.
- the plasma/blood sample it becomes coloured as indicated in figure 5. If the thrombin is working, it will then cleave the thrombin chromogenic substrate, and cause window 14 to change colour to indicate a valid test.
- window 15 wil l provide an indication of a low fibrinogen or window 16 wi l l provide an indication of a very low fibrinogen. This is preferably effected by a colour indication appearing in either window 15 or 16.
- Figure 5 shows with corresponding numbering, the housing/casing 11 of figure 4 indicating a first stage of testing with visual indicator quality check window 14 indicating a reaction has occurred between the sample and Thrombin chromogenic substrate and that there is a val id test ( qual ity check).
- the indication of a val id test in window 14 is preferably achieved by a colour change- for example, but not limited to, white to green.
- a dye can also be incorporated into the reaction zone.
- Zone 6 (which contains the uncleaved thrombin chromogenic substrate) l ies under Window 14. When the blood or plasma sample is added to window 13, it allows the pre-charged thrombin from the reaction zone to spread to zone 6.
- FIG. 6 shows the indications at a second stage of testing. Referring to indicator windows, window 13 indicates that plasma was added and that from window 14 a valid test was performed.
- window 16 shows no indication ( remains white) but window 15 shows that the patient tested has a low concentration of Fibrinogen between l-2g/L. of device of figure 4 at a second stage of testing with visual indicators indicating a result. In this case Fibrinogen concentrate is needed.
- the present invention employs paper, cel lulose or any porous and wettable material as a medium for both the plasma and water to wick through.
- the porous structure of the cellulose induces a capil lary action but without reliance on action from micropi l lar extrusions.
- Paper is economic in comparison to plastics, glass or si l icon (AU$5 cents per test vs AU$50 cents per test).
- Paper is a flexible material that can be cut into many different shapes, configurations and structures and can be easi ly incorporated with hydrophobic barriers and hydrophi l ic channels. Therefore, its fabrication costs are very economic compared to the prior art.
- the present invention presents many advantages over the prior art.
- a plastics diagnostic device is used which has no inherent capillary action to faci l itate fluid flow. Accordingly, fluid flow must be artificial ly induced by the inclusion of micropi l lars.
- the prior art plastics diagnostic device needs to be coated with SiOx and treated with polyelectrolytes to increase the hydrophilicity of the flow path zone as in US20120107851A1. The extra manufacturing adds significantly to the costs of producing the device.
- a paper indicator is used which requires no pre treatment to induce capi l larity as the material itself has inherent capillarity requiring no pretreatment or modification to induce capillarity.
- One advantage of the present invention is that use of a paper indicator, has natural capi l lary flow without the need to add in parts or modify surfaces.
- Another advantage is that the disadvantages of variabi l ity related to thrombin kinetics is el iminated. Furthermore, the employment of a porous material such as paper, al lows fibrinogen concentration to be measured in other ways than a lateral flow assay. For example, the test can be converted into a flow-through type detection system that measures colour intensity after a certain number of washes. Another advantage of the present invention is that the sensitivity for the test is higher for concentration ranges of 1-2 g/L Fibrinogen. For example in the cited prior art US20120107851A1 a distance travel led for between 1 and 2 g/L plasma is only 0.6 cm before stopping.
- substrate 2 includes a variety of user options for wicking fluid, including a wetable fibrous material and includes but is not limited to, non wetable materials treated by plasma treatment, radiation, surfactant coating and/or chemical reaction to make it wettable.
- the substrate may be woven or non -woven. It may be pre or post treated with thrombin and/or FXI I Ia or derivatives of these enzymes. It may be treated with deposited desorbable dyes and/or desorbable dye binders and particles and nanoparticles.
- the substrate is charged with water, buffer solution, dye solution and/or washing solution- collectively wicking fluids.
- a method of quantifying the zone of hydrophobicity/hydrophobicity includes measuring the distance travel led by at least one chromogenic marker with he zone of hydrophobicity 9 in a lateral flow.
- the lateral flow occurs in porous substrate 2 in flow receiving zone 5 and flow path zone 6.
- flow path zone 6 has a length LI and a width Wl.
- Flow receiving zone 5 has a length L2 and a width W2.
- LI may be the same or different length from L2.
- Wl may be the same or a different length from W2.
- a lateral flow regime traverses the flow receiving zone 5 and flow path zone 6 and as described earl ier.
- the biological factors, chemical factors and/or derivatives of the biological factors and/or chemical factors pre charge substrate 2 in flow path zone 6.
- those factors may be applied during testing to at least part of the flow path zone 6 and/or the flow receiving zone 5.
- a blood or plasma sample is introduced into either at least part of the flow path zone 6 and/or the flow receiving zone 5.
- Chromogenic marker(s) can be applied at this time or pre-applied to the substrate 2.
- a wicking fluid is applied to the flow receiving zone 5 in order to induce the movement of the chromogenic marker(s) through the flow path zone 6
- the wicking fluid is according to one embodiment applied to the flow receiving zone in the form of a finite reservoir or an infinite volume reservoir.
- the distance travel led by the chromogenic marker(s) is measured with rul ing markers next to the flow path zone 6.
- the distance travel led by the chromogenic marker(s) is/are measured via by observing the flow path zone 6 through transparent windows 12, 13, 14, 15 and 16 in casing 11.
- Windows 12, 14, 15 and 16 al ign with the flow path zone 6 and enable the observations described earl ier with reference to figures 5 and 6.
- the indicating windows al ign with key d istances up the flow path zone 6 and wi l l show wherever the chromogenic marker(s) have reached and/or gone past the key distances or not.
- hydrophobicity of the zone of hydrophobicity 9 is determined by measurement of degree of retention of at least one chromogenic marker appl ied and/or pre-appl ied in ( or outside of) the reaction zone, along with al l the other biological factors, chemical factors and/or derivatives of the biological factors and/or chemical factors, after rinsing the porous substrate with a washing l iquid.
- Hydrophobicity refers to the hydrophobicity at the surface of the non-porous substrate.
- the substrate’s surface hydrophobicity is used to influence shape, height and/or contact angle of any deposited l iquid droplets.
- Hydrophobicity can be modified with a physical factor and/or chemical factor that will or may increase or decrease the hydrophobicity of the substrate.
- One method of modifying the hydrophobicity is to apply a chemical coating to the substrate.
- the clot formed acts as a hydrophobic barrier to prevent the washing l iquid from dislocating of the chromogenic marker(s) out of the substrate.
- the forming or formed clot can coat the surface of the non-porous substrate to modify its hydrophobicity.
- Physical factors may al low or prevent the initiation of the clot formation.
- Physical, Biological factors, chemical factors and/or derivatives of the biological factors and/or chemical factors used are involved in the initiation, execution, ampl ification and/or acceleration of the clot formation. These factors also affect the clot’s hydrophobicity.
- the retention of chromogenic marker(s) is measured by the absolute and/or relative colour intensity after washing the substrate with a given volume of washing l iquid.
- the chromogenic marker(s) is appl ied and/or pre-appl ied in the reaction zone, along with all the other biological factors, chemical factors and/or derivatives of the biological factors and/or chemical factors.
- a threshold result for height measurements which can be determined by placing a porous, absorbent substrate directly above the non-porous substrate and allowing any deposited liquid droplet to make contact with the porous, absorbent substrate.
- the method contemplates a process of measuring chromogenic staining which refers to the binding of at least one chromogenic substrate directly and/or indirectly to the formed or forming clot. Blood or plasma is applied to the reaction zone to form a zone of stained clot after initiating clot formation. Biological factors, chemical factors and/or derivatives of the biological factors and/or chemical factors can be used enhance the colour intensity of the chromogenic marker(s).
- the present invention one method of diagnosis of concentration of fibrinogen in a blood or plasma sample, involves using at least one capi l lary in a centrifuge, each including a reaction mixture of biological factors, chemical factors and/or derivatives of the biological factors and/or chemical factors appl ied and/or pre-applied inside of the at least one capillary. Blood or plasma is appl ied to the reaction mixture which forms a clot and the extent of clotting after initiating clotting is measured. Measuring the extent of clotting refers to quantifying the mass, volume or height of the clot in the capi l lary.
- a centrifugal force is appl ied to the capillaries such that it causes the clot to compress in the direction away from the axis of spin.
- the extent of clotting is determined by measuring the height of the centrifugally compressed clot in the capillary.
- the height of the compressed clot can be measured with rul ing markers on top of and/or next to the capi I lar(ies).
- the compressed clot is measured by containing the capi l lary in an external casing with transparent windows that al ign with key heights up the capi l lary and hence will show whether the clot has reached and/or gone past the key heights or not.
- a chromogenic dye or other suitable marker is used.
- Biological factors, chemical factors and/or derivatives of the biological factors and/or chemical factors are used enhance the colour intensity of the chromogenic dye(s) and are involved in the initiation, execution, ampl ification and/or acceleration of the clot formation.
- Physical factors used that will or may allow or prevent the initiation of the clot formation the biological factors, chemical factors and/or derivatives of the biological factors and/or chemical factors used are involved in the enhancement or diminishment of the clot’s hydrophobicity.
- the biological factors, chemical factors and/or derivatives of the biological factors and/or chemical factors used are involved in the enhancement or diminishment of the clot’s abil ity to bind directly and/or indirectly to at least one chromogenic marker.
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Abstract
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Priority Applications (7)
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CA3135087A CA3135087A1 (en) | 2019-03-27 | 2020-03-27 | Method and device for measuring the fibrinogen concentration in blood samples |
US17/598,080 US20220187292A1 (en) | 2019-03-27 | 2020-03-27 | Method and device for measuring the fibrinogen concentration in blood samples |
CN202080039153.0A CN115087870A (en) | 2019-03-27 | 2020-03-27 | Method and device for measuring fibrinogen concentration in blood samples |
EP20779715.0A EP3948302A4 (en) | 2019-03-27 | 2020-03-27 | Method and device for measuring the fibrinogen concentration in blood samples |
AU2020245898A AU2020245898A1 (en) | 2019-03-27 | 2020-03-27 | Method and device for measuring the fibrinogen concentration in blood samples. |
SG11202110642VA SG11202110642VA (en) | 2019-03-27 | 2020-03-27 | Method and device for measuring the fibrinogen concentration in blood samples. |
JP2021557413A JP2022528364A (en) | 2019-03-27 | 2020-03-27 | Methods and Devices for Measuring Fibrinogen Concentrations in Blood Samples |
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AU2019901020A AU2019901020A0 (en) | 2019-03-27 | Method and apparatus for measuring the fibrinogen concentration in blood samples. | |
AU2019901020 | 2019-03-27 |
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US (1) | US20220187292A1 (en) |
EP (1) | EP3948302A4 (en) |
JP (1) | JP2022528364A (en) |
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AU (1) | AU2020245898A1 (en) |
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Cited By (2)
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CN113552122A (en) * | 2021-04-13 | 2021-10-26 | 山东省分析测试中心 | Detection method of biological molecules and inhibitor molecules |
CN113740326A (en) * | 2021-09-06 | 2021-12-03 | 中国人民解放军军事科学院军事医学研究院 | Device and method for rapidly detecting concentration of fibrinogen in whole blood |
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WO2015134497A1 (en) * | 2014-03-03 | 2015-09-11 | University Of Cincinnati | Devices and methods for analyzing a blood coagulation property |
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2020
- 2020-03-27 CA CA3135087A patent/CA3135087A1/en active Pending
- 2020-03-27 CN CN202080039153.0A patent/CN115087870A/en active Pending
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- 2020-03-27 AU AU2020245898A patent/AU2020245898A1/en not_active Abandoned
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WO2010122158A1 (en) * | 2009-04-23 | 2010-10-28 | Dublin City University | A lateral flow assay device for coagulation monitoring and method thereof |
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Cited By (4)
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CN113552122A (en) * | 2021-04-13 | 2021-10-26 | 山东省分析测试中心 | Detection method of biological molecules and inhibitor molecules |
CN113552122B (en) * | 2021-04-13 | 2024-02-20 | 山东省分析测试中心 | Detection method of biological molecules and inhibitor molecules |
CN113740326A (en) * | 2021-09-06 | 2021-12-03 | 中国人民解放军军事科学院军事医学研究院 | Device and method for rapidly detecting concentration of fibrinogen in whole blood |
CN113740326B (en) * | 2021-09-06 | 2022-04-29 | 中国人民解放军军事科学院军事医学研究院 | Device and method for rapidly detecting concentration of fibrinogen in whole blood |
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EP3948302A1 (en) | 2022-02-09 |
US20220187292A1 (en) | 2022-06-16 |
AU2020245898A1 (en) | 2021-11-11 |
JP2022528364A (en) | 2022-06-10 |
CA3135087A1 (en) | 2020-10-01 |
EP3948302A4 (en) | 2023-01-04 |
SG11202110642VA (en) | 2021-10-28 |
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