WO2018181540A1 - 膜担体及びそれを用いた液体試料検査キット - Google Patents
膜担体及びそれを用いた液体試料検査キット Download PDFInfo
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- WO2018181540A1 WO2018181540A1 PCT/JP2018/012901 JP2018012901W WO2018181540A1 WO 2018181540 A1 WO2018181540 A1 WO 2018181540A1 JP 2018012901 W JP2018012901 W JP 2018012901W WO 2018181540 A1 WO2018181540 A1 WO 2018181540A1
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- liquid sample
- membrane carrier
- substance
- detection zone
- fine structure
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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
- G01N33/558—Immunoassay; Biospecific binding assay; Materials therefor using diffusion or migration of antigen or antibody
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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
- 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
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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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- 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
- G01N33/544—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being organic
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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
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/585—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with a particulate label, e.g. coloured latex
Definitions
- the present invention relates to a membrane carrier and a liquid sample inspection kit using the membrane carrier.
- POCT Point of Care Test
- immediate on-site clinical examination reagents have been attracting attention, which measure antigen morbidity, pregnancy, blood glucose levels, etc. by using antigen-antibody reactions and the like.
- the POCT reagent is, for example, a test performed beside the subject or a test reagent performed by the subject himself / herself, and is characterized in that the result can be discriminated in a short time, the method of use is simple and inexpensive. Because of these characteristics, it is often used for medical examinations and regular medical examinations at a mild stage, and it is an important diagnostic tool in home medical care that is expected to increase in the future.
- determination is performed by introducing a liquid sample such as blood into a test kit and detecting a specific substance to be detected contained therein.
- An immunochromatography method is often used as a method for detecting a specific substance to be detected from a liquid sample.
- the substance to be detected and the labeling substance are combined, and these are further immobilized in the test kit.
- This is a technique that specifically binds to a substance (hereinafter referred to as a detection substance) and detects a change in color or mass resulting therefrom.
- the detection substance may be rephrased as a reagent.
- Nitrocellulose membrane is often used as a membrane carrier for moving a liquid sample (Patent Document 1).
- the nitrocellulose membrane has many fine holes with a diameter of about several ⁇ m, and the liquid sample moves through the holes by capillary force.
- the nitrocellulose membrane is derived from a natural product and the pore diameter and the way in which the pores are connected are not uniform, there is a difference in the flow rate of the liquid sample in each membrane. If there is a difference in flow rate, the time taken to detect the substance to be detected also changes, and as a result, the substance to be detected may be erroneously determined as non-detected before binding occurs.
- Patent Document 2 a liquid sample inspection kit in which a fine channel is artificially produced has been devised (Patent Document 2).
- Patent Document 2 can reduce the possibility that a substance to be detected is erroneously determined as non-detection before binding occurs because a membrane carrier having a uniform structure can be produced by using a synthetic material. .
- Patent Documents 3 to 9 When using a synthetic material, it is necessary to increase the affinity between the detection substance and the material in order to improve the detection sensitivity, and it is considered effective to perform various surface treatments on the material in advance (Patent Documents 3 to 9). 4).
- Patent Document 5 is a membrane carrier for a test kit that detects a substance to be detected in a liquid sample, and includes at least one flow channel capable of transporting the liquid sample, and for transporting the liquid sample to the bottom surface of the flow channel.
- a membrane carrier for a liquid sample test kit is disclosed, which is provided with a fine structure that causes the capillary action of
- JP 2014-0662820 A Japanese Patent No. 5799395 JP 2013-113633 A US Patent Application Publication No. 2011/0284110 International Publication No. 2016/098740
- Patent Documents 3 to 4 the influence of the surface treatment on the material and the appropriate treatment conditions for achieving higher sensitivity could not be presented, and as a result, the performance of the system could not be fully exhibited.
- Patent Documents 3 to 5 the average surface roughness in the fine structure of the film carrier and the ratio of the number of oxygen atoms on the surface of the detection zone (number of oxygen atoms / (number of carbon atoms + number of nitrogen atoms + number of oxygen atoms)) Not listed.
- the present invention provides a membrane carrier capable of highly sensitive determination.
- a membrane carrier comprising a flow path and a detection zone, having a fine structure on the bottom surface of the flow path, and having an average surface roughness of 0.005 to 10.0 ⁇ m in the fine structure.
- a flow path and a detection zone are provided, a fine structure is provided on the bottom surface of the flow path, and at least one of carbon atoms and nitrogen atoms and oxygen atoms are present on the surface of the detection zone.
- a ratio of the number of oxygen atoms to the total number of atoms of each atom (number of oxygen atoms / (number of carbon atoms + number of nitrogen atoms + number of oxygen atoms)) is 0.01 to 0.50.
- the present invention can provide a membrane carrier capable of highly sensitive determination.
- (A) is an example of embodiment by this invention, is an overhead view (top view) of a fine structure
- (b) is a perspective view of the convex part which comprises the fine structure shown to (a).
- (A) is an example of embodiment by this invention, is an overhead view (top view) of a fine structure
- (b) is a perspective view of the convex part which comprises the fine structure shown to (a).
- (A) is an example of embodiment by this invention, is an overhead view (top view) of a fine structure
- (b) is a perspective view of the convex part which comprises the fine structure shown to (a).
- (A) is an example of embodiment by this invention, is an overhead view (top view) of a fine structure
- (b) is a perspective view of the convex part which comprises the fine structure shown to (a). It is an example of embodiment by this invention, and is a typical top view of a microstructure. It is an example of embodiment by this invention and is the schematic of surface treatment.
- the membrane carrier is a membrane carrier for a liquid sample inspection kit that detects a substance to be detected in the liquid sample.
- the substance to be examined is not limited at all, and may be any substance capable of antigen-antibody reaction with an antibody such as various pathogens and various clinical markers.
- Specific examples of the substance to be detected include virus antigens such as influenza virus, norovirus, adenovirus, RS virus, HAV, HBs, and HIV, MRSA, group A streptococcus, group B streptococci, Legionella spp.
- Toxins, mycoplasma, Chlamydia trachomatis, hormones such as human chorionic gonadotropin, C-reactive protein, myoglobin, cardiac troponin, various tumor markers, pesticides, environmental hormones, etc. is not.
- the usefulness is particularly great when the substance to be detected is an item requiring urgent detection and treatment measures such as influenza virus, norovirus, C-reactive protein, myoglobin and cardiac troponin.
- the substance to be detected may be an antigen capable of inducing an immune reaction alone, or a hapten capable of binding an antibody by an antigen-antibody reaction although it cannot induce an immune reaction alone.
- the substance to be detected is usually suspended or dissolved in the liquid sample.
- the liquid sample may be, for example, a sample in which the substance to be detected is suspended or dissolved in a buffer solution.
- the liquid sample inspection kit (hereinafter also simply referred to as “inspection kit”) detects a substance to be detected in the liquid sample.
- FIG. 1 is a schematic top view of an inspection kit.
- the test kit 18 includes a membrane carrier 3 and a casing 18 a that houses the membrane carrier 3.
- the film carrier 3 has, on its surface, a dropping zone 3x where a liquid sample is dropped and a detection zone 3y for detecting a substance to be detected in the liquid sample.
- the dripping zone 3x is exposed at the first opening 18b of the housing 18a.
- the detection zone 3y is exposed at the second opening 18c of the housing 18a.
- FIG. 2 is a schematic top view of the membrane carrier 3.
- the membrane carrier 3 includes at least one flow path 2 for transporting a liquid sample.
- a fine structure is provided on the bottom surface of the flow path 2 (not shown, details will be described later).
- the fine structure is located at least between the dropping zone 3x and the detection zone 3y.
- a fine structure may be provided over the entire surface of the membrane carrier 3.
- the entire surface of the membrane carrier 3 may be the liquid sample flow path 2.
- the microstructure causes capillary action. Due to the capillary action of the microstructure, the liquid sample is transported from the dropping zone 3x to the detection zone 3y (along the transport direction d) via the microstructure. When the substance to be detected in the liquid sample is detected in the detection zone 3y, the color of the detection zone 3y changes.
- the overall shape of the membrane carrier 3 is not particularly limited, but may be, for example, a polygon such as a quadrangle, a circle, or an ellipse.
- the longitudinal width (length in the short direction) L1 of the membrane carrier 3 may be, for example, 2 mm to 100 mm
- the lateral width (length in the longitudinal direction) L2 of the membrane carrier 3 is For example, it may be 2 mm to 100 mm.
- the thickness of the membrane carrier excluding the height of the fine structure may be, for example, 0.1 mm to 10 mm.
- FIGS. 3 to 6 each show an example of the fine structure provided on the bottom surface of the flow path and the convex portions constituting the fine structure in the present embodiment.
- (a) is an overhead view (top view) of the fine structure
- (b) is a perspective view of convex portions constituting the fine structure shown in (a).
- the fine structure 7 is the total of the convex portions 8. That is, the membrane carrier 3 includes a flat portion 9 corresponding to the bottom surface of the liquid sample channel 2 and a plurality of convex portions 8 protruding from the flat portion 9.
- the space between the plurality of convex portions 8 functions as a flow path 2 for transporting the liquid sample along the surface of the membrane carrier 3.
- the gap in the fine structure 7 functions as the flow path 2 for transporting the liquid sample along the surface of the membrane carrier 3 by capillary action.
- the plurality of convex portions 8 may be arranged on the surface of the membrane carrier 3 regularly or translationally symmetrically.
- the shape of the plurality of convex portions 8 constituting the fine structure 7 can be freely selected.
- Examples of the shape of the convex portion 8 include a cone, a polygonal pyramid, a truncated cone, a polygonal frustum, a cylinder, a polygonal column, a hemisphere, and a semi-ellipsoid.
- Examples of the bottom surface of the fine structure include a circle or a polygon (for example, a square, a rhombus, a rectangle, a triangle, or a hexagon).
- the shape of the convex portion 8a may be a cone.
- FIG. 3 the shape of the convex portion 8a
- the shape of the convex portion 8b may be a quadrangular pyramid.
- the shape of the convex portion 8c may be a hexagonal pyramid.
- the shape of the convex portion 8d may be a quadrangular prism (a line and space structure in which the convex portion 8d has a line shape).
- a cone structure such as a cone or a polygonal pyramid is suitable as the shape of the convex portion 8. Among cone structures, cones are preferred.
- the shape of the convex portion 8 constituting the fine structure 7 does not need to be a geometrically accurate shape, and may be a shape with rounded corners or a shape with fine irregularities on the surface. Good.
- the diameter 4 of the bottom surface 10 of the convex portion 8 constituting the fine structure 7 is preferably 5 ⁇ m or more and 1000 ⁇ m or less, and more preferably 10 ⁇ m or more and 500 ⁇ m or less.
- the diameter 4 of the bottom surface 10 of the convex portion 8 is 5 ⁇ m or more, the precision of microfabrication can be kept low, and the cost for forming the microstructure 7 tends to be low.
- the diameter 4 of the bottom surface 10 of the convex portion 8 is 1000 ⁇ m or less, the number of the convex portions 8 in one test kit increases, and the liquid sample is easily developed.
- the diameter 4 of the bottom surface 10 of the convex portion 8 is defined as the representative length of the bottom surface 10 of the convex portion 8.
- the representative length of the bottom surface 10 is the diameter when the shape of the bottom surface 10 is a circle, the length of the shortest side when it is a triangle or a quadrangle, the length of the longest diagonal line when it is a pentagon or more polygon, In the case of a shape, the maximum length at the bottom surface 10 is used.
- the diameter 4a of the bottom surface 10a of the convex portion 8a is the diameter of the bottom surface (circle) of the cone.
- the diameter 4b of the bottom surface 10b of the convex portion 8b is the length of the side of the bottom surface (regular square) 10b.
- the diameter 4c of the bottom surface 10c of the convex portion 8c is the length of the diagonal line passing through the center of the bottom surface (regular hexagonal shape) 10c (the length of the longest diagonal line). That is).
- the diameter 4d of the bottom surface 10d of the convex portion 8d is the length of the shortest side of the bottom surface (rectangular) 10d (in FIG. 6, the transport direction d of the liquid sample). In the direction orthogonal to
- the height 6 of the convex portion 8 constituting the fine structure 7 is preferably 5 ⁇ m to 1000 ⁇ m, more preferably 10 ⁇ m to 500 ⁇ m.
- the height 6 of the convex portion 8 is 5 ⁇ m or more, the volume of the flow path 2 is increased, and the liquid sample can be developed in a shorter time.
- the height 6 of the convex portion 8 is 1000 ⁇ m or less, the time and cost for producing the fine structure 7 can be reduced, and the fine structure 7 can be produced more easily.
- the height 6 of the convex portion 8 is defined as the maximum length of the convex portion 8 in the direction orthogonal to the flat portion 9. As shown in FIG. 3, when the shape of the convex portion 8 a is a cone, the height 6 a of the convex portion 8 a is the maximum length (conical height) of the convex portion 8 a in the direction orthogonal to the flat portion 9. . As shown in FIG. 4, when the shape of the convex portion 8b is a quadrangular pyramid, the height 6b of the convex portion 8b is the maximum length of the convex portion 8b in the direction orthogonal to the flat portion 9 (height of the quadrangular pyramid). It is. As shown in FIG.
- the height 6c of the convex portion 8c is the maximum length of the convex portion 8c in the direction orthogonal to the flat portion 9 (the height of the hexagonal pyramid). It is.
- the height 6d of the convex portion 8d is the maximum length of the convex portion 8d in the direction orthogonal to the flat portion 9 (height of the quadrangular prism). It is.
- the closest distance 5 between the convex portions 8 constituting the fine structure 7 is preferably 0 to 500 ⁇ m. Preferably they are 500 micrometers or less, More preferably, they are 2 micrometers or more and 100 micrometers or less.
- the closest distance 5 between the convex portions 8 cannot be smaller than 0 ⁇ m, and when the distance is 500 ⁇ m or less, the contact area between the liquid sample and the flow path 2 increases, thereby increasing the capillary force, thereby increasing the liquid sample. It becomes easier to move.
- “the closest distance between the convex portions 8” is the closest distance between a pair of adjacent convex portions 8.
- the aspect ratio of the convex portion 8 constituting the fine structure 7 is preferably 0.1 to 10, and more preferably 0.1 to 2.0.
- the aspect ratio here is a value (Lh / Lv) obtained by dividing the height 6 (Lh) of the convex portion 8 by the representative length (diameter 4) (Lv) of the bottom surface 10 of the convex portion 8.
- the aspect ratio is 0.1 or more, the contact area between the liquid sample and the flow path 2 is increased, which increases the capillary force, so that it is easier to move the liquid sample.
- the aspect ratio is 10 or less, it becomes easier to produce a fine structure.
- the microstructure 7 and the membrane carrier 3 of the liquid sample inspection kit 18 of the present embodiment may be made of a thermoplastic plastic.
- the film carrier 3 having the fine structure 7 can be produced by processing a film-like substrate made of thermoplastic plastic.
- thermoplastic plastics include polyester resins, polyolefin resins, polystyrene resins, polycarbonate resins, fluorine resins, and acrylic resins.
- PET polyethylene terephthalate
- COP cycloolefin polymer
- PP polypropylene
- PS polystyrene
- PC polycarbonate
- PVDF polyvinylidene fluoride
- PMMA polymethyl methacrylate
- PE polyethylene
- the upper part of the cone is thinner than the bottom surface, so the volume cut out when making the mold is smaller than the column body on the bottom surface.
- the mold can be manufactured at a low cost. In this case, it becomes possible to detect the detection target substance in the liquid sample at a lower cost.
- the membrane carrier 3 includes the fine structure 7 provided on one surface of the membrane carrier 3, the flow path 2 for transporting the liquid sample formed by the fine structure 7, and the substance to be detected in the liquid sample. And a detection zone (detection unit) 3y for detecting.
- the membrane carrier 3 may be the membrane carrier 3 for the liquid sample inspection kit 18 that detects a substance to be detected in the liquid sample.
- the surface average roughness (Ra) in the microstructure 7 of the membrane carrier 3 is 0.005 to 10.0 ⁇ m.
- the surface average roughness of the fine structure 7 of the membrane carrier 3 is preferably 0.1 ⁇ m or more, more preferably 0.2 ⁇ m or more, still more preferably 0.5 ⁇ m or more, and even more preferably 1 ⁇ m or more.
- the surface average roughness of the membrane carrier 3 may be 10 ⁇ m or less, 5 ⁇ m or less, 1 ⁇ m or less, or 0.1 ⁇ m or less.
- the surface average roughness (Ra) in the microstructure 7 of the film carrier 3 means the surface average roughness of the convex portion 8 and uses the definition defined in JIS B0601: 2013.
- the surface average roughness in the microstructure 7 of the film carrier 3 can also be referred to as the surface average roughness of the convex portions 8 in the microstructure 7 of the film carrier 3.
- the surface average roughness (Ra) of the flat portion 9 may be 0.005 to 10.0 ⁇ m.
- the surface average roughness of the flat portion 9 may be a value exemplified as the average roughness of the film carrier.
- the surface average roughness (Ra) of the flat portion 9 is preferably 10 ⁇ m or less, more preferably 5 ⁇ m or less, still more preferably 3 ⁇ m or less, and even more preferably 2 ⁇ m or less.
- FIG. 7 is a diagram for explaining a method of measuring the surface average roughness of the convex portion 8 in the fine structure 7.
- the concavo-convex profile is measured along the surface of the convex portion 8 (along the straight line 20 when viewed from the upper surface) with the vertex central portion (for example, the convex portion center 19) as the central point.
- the straight line 20 is an arbitrary single straight line having a length of 20d with the central point of the vertex (for example, the convex part center 19) as a central point.
- the length 20 d is the same length as the diameter of the bottom surface of the convex portion 8.
- the straight line 20 is a straight line on the same plane (for example, when both ends and the center are on the same plane), that is, when the convex portion 8 has a shape of a truncated cone, a polygonal frustum, a cylinder, a polygonal column, etc.
- the surface average roughness (Ra) defined in JIS B0601 is calculated.
- the straight line 20 is not a straight line on the same plane, that is, when the convex portion 8 has a shape such as a cone, a polygonal pyramid, a hemisphere, or a semi-ellipsoid
- the inclination is corrected from the uneven profile, and the plane is defined by JIS B0601
- the surface average roughness (Ra) is calculated.
- the average surface roughness of the fine structure 7 of the film carrier 3 is the above numerical value when the film carrier 3 having the fine structure 7 is produced by thermal imprinting, for example, by etching, photolithography, mechanical cutting, laser processing or the like. Can be adjusted within the range.
- the surface average roughness of the fine structure 7 of the film carrier 3 is preferably adjusted by etching, photolithography, mechanical cutting, polishing, laser processing, or the like on the surface of the mold (mold). Examples of the polishing process include cutting by dicing, sandblasting, and the like.
- the surface average roughness can be adjusted by controlling the output of the laser.
- the manufacturing method of the inspection kit 18 includes a process (thermal imprint process) of manufacturing the film carrier 3 having the microstructure 7 by thermal imprint.
- a process thermal imprint process
- the surface of a mold (mold) in which a plurality of recesses are formed is applied to, for example, a film-like base material made of thermoplastic plastic, and the base material is heated, thereby forming the shape of the recesses.
- a film carrier 3 having a microstructure 7 (a plurality of convex portions 8) and a flat portion 9 corresponding to is formed.
- At least one of a carbon atom and a nitrogen atom and an oxygen atom are present on the surface of the detection zone.
- the ratio of the number of oxygen atoms to the total number of atoms of each atom is 0.01 to 0.50.
- the ratio of the number of oxygen atoms on the surface of the detection zone is 0.01 or more, and 0.05 or more Preferably, 0.10 or more is more preferable, and 0.20 or more is still more preferable.
- the ratio of the number of oxygen atoms on the surface of the detection zone is 0.50 or less, and 0.40 or less. Preferably, it is 0.38 or less, more preferably 0.36 or less, still more preferably 0.30 or less, and even more preferably 0.10 or less.
- the higher the oxygen atom number ratio on the surface of the detection zone the easier the detection substance adheres to the surface. Since the detection substance adheres to the surface, the detection substance that is flowed when the liquid sample is developed is reduced, and a highly sensitive test can be performed.
- the ratio of the number of oxygen atoms on the surface of the detection zone is 0.50 or less, the occurrence of false detection due to the reaction between the labeling substance and the detection substance when the solution not containing the detection substance is developed is further suppressed.
- the ratio of oxygen atoms on the surface of the detection zone is calculated by X-ray electron spectroscopy (XPS). The calculation of the oxygen atom number ratio by XPS will be described below.
- Correction of the binding energy of the spectrum obtained by the measurement is performed by CC bond in the C1s spectrum.
- the background (BG) is subtracted for each peak of the C1s spectrum, N1s spectrum, and O1s spectrum of the spectrum subjected to the binding energy correction.
- the peak area (signal intensity) of each atom calculated by subtracting BG from each peak is divided by the correction coefficient (relative sensitivity coefficient, transmission function, and kinetic energy correction) so that the total area after correction becomes 100. Calculated.
- the obtained values are defined as the number of carbon atoms, the number of nitrogen atoms and the number of oxygen atoms, respectively, and the oxygen atom number ratio (number of oxygen atoms / (number of carbon atoms + number of nitrogen atoms + number of oxygen atoms)) is calculated.
- the number ratio of oxygen atoms on the surface of the detection zone can be adjusted within the above range by surface-treating the surface of the detection zone.
- the method of surface treatment is not limited at all, and various methods such as various plasma treatments, corona treatment, UV irradiation, UV / ozone treatment, surface modification with 3-aminopropylethoxysilane, and Glutaraldehyde can be used.
- the surface treatment is preferably performed only in the detection zone.
- the detection substance is not fixed in the non-detection zone (region other than the detection zone) in the flow path, and the detection substance can be fixed only in the detection zone with high efficiency. As a result, the detection signal is easily recognized in the detection zone (S / N ratio is increased).
- FIG. 8 is a diagram for explaining a method of selectively surface-treating the surface of the detection zone.
- a shielding material 14 having a void portion is arranged on the membrane carrier 3 to expose the detection zone (surface treatment portion).
- a portion of the film carrier 3 covered with the shielding material 14 becomes an untreated portion (non-detection zone) 15.
- a metal plate is preferable.
- a resin having a surface oxygen atom number ratio (number of oxygen atoms / (number of carbon atoms + number of nitrogen atoms + number of oxygen atoms)) of less than 0.01 as the material of the film carrier, It is more preferable to use 0.005 or less resin.
- the resin having a surface oxygen atom number ratio of less than 0.01 is a resin that does not contain an oxygen atom in the main structural formula, and contains carbon atoms such as polyolefin resin, polystyrene resin, fluorine resin, etc. And a resin containing no oxygen atom.
- the resin having a surface oxygen atom number ratio of less than 0.01 may be a resin containing no carbon atom and no nitrogen atom, such as a polyimide resin.
- the ratio of the number of oxygen atoms in the detection zone (number of oxygen atoms / (number of carbon atoms + number of nitrogen atoms + number of oxygen atoms)) is calculated as follows: It becomes substantially equal to the value of (number of carbon atoms + number of oxygen atoms).
- the oxygen atom number ratio on the surface is 0.005 or less
- a membrane carrier is produced, a test kit is produced using the produced membrane carrier, and the labeling substance adheres to the non-detection zone when the liquid sample is developed. Is more suppressed. If the labeling substance adheres in the non-detection zone, even if a signal having the same intensity is generated in the detection zone, it becomes difficult to recognize (the S / N ratio becomes low).
- the detection zone 3y of the membrane carrier 3 shows a color change when a substance to be detected is detected.
- the color change may be a color change that can be confirmed by an optical method.
- the optical method there are mainly two methods: a visual determination and a method of measuring fluorescence intensity.
- a visual determination a method of measuring fluorescence intensity.
- the color difference between two color stimuli (described in JIS Z8781-4: 2013) when the color before detection and after detection is measured in the color system of CIE1976L * a * b * color space. It is preferable that a color change occurs such that ⁇ E) is 0.5 or more. When this color difference is 0.5 or more, it becomes easy to visually confirm the color difference.
- the detection substance is immobilized on at least a part of the flow path 2. That is, a detection substance that detects a substance to be detected is fixed in the detection zone 3y. The color change in the detection zone 3y occurs when the detection target substance is held in the detection zone 3y by the detection substance (reacts with the detection substance).
- the method of manufacturing the liquid sample inspection kit 18 includes a step of fixing a detection substance that causes a color change by holding the detection target substance in the detection zone 3y in the detection zone 3y.
- a surface treatment may be performed in advance on the portion of the membrane carrier 3 where the detection zone 3y is provided.
- the surface treatment method the method exemplified above can be used.
- examples of the detection substance include antibodies.
- the antibody is an antibody that reacts with a substance to be detected by antigen-antibody reaction, and may be a polyclonal antibody or a monoclonal antibody.
- the color change in the detection zone 3y may be caused by a label having an antibody or an antigen-binding fragment thereof that specifically reacts with the substance to be detected in the liquid sample.
- the color change is caused, for example, when the label is colored by being held in the detection zone 3y (reacted (bound) with the detection substance) by the detection substance.
- the labeled body may be, for example, one obtained by binding the antibody or antigen-binding fragment thereof to particles such as colloid particles or latex particles.
- An antigen-binding fragment refers to a fragment that can specifically bind to a substance to be detected, for example, an antigen-binding fragment of an antibody.
- the label can be bound to the substance to be detected via an antibody or an antigen-binding fragment thereof.
- the particles may be magnetic or fluorescent. Examples of the colloid particles include gold colloid particles and metal colloid particles such as platinum colloid particles.
- the particles are preferably latex particles in terms of particle size control, dispersion stability, and ease of bonding.
- the material for the latex particles is not particularly limited, but polystyrene is preferred.
- the particles are preferably colored particles or fluorescent particles, and more preferably colored particles, from the viewpoint of visibility.
- the colored particles may be any particles that can detect the color with the naked eye.
- the fluorescent particles may contain a fluorescent substance.
- the particles may be colored latex particles or fluorescent latex particles. When the particles are colored latex particles, the color change described above is suitably determined visually. Further, when the particles are fluorescent latex particles, the above-described color change is suitably determined by measuring the fluorescence intensity.
- the labeling body as described above is provided on at least a part of the test kit 18 so that it can react with the substance to be detected in the dropped liquid sample.
- the labeling body may be provided, for example, on a member in the test kit 18 or may be provided on at least a part of the flow path 2 of the membrane carrier 3 (upstream from the detection zone 3y).
- the labeled body that has reacted (bound) with the substance to be detected is held in the detection zone 3y by the detection substance (by the detection substance reacting (binding) with the substance to be detected). Thereby, a color change (coloration by a marker) in the detection zone 3y occurs.
- the liquid sample inspection method according to one aspect of the present embodiment is an inspection method using the inspection kit 18.
- a liquid sample and a label that specifically binds to a substance to be detected in the liquid sample are mixed to prepare a mixed liquid sample (mixed liquid sample),
- the step of binding the substance to be detected and the labeling body, the step of dropping the mixed liquid sample into the dropping zone 3x provided on the membrane carrier 3, and the microstructure 7 allow the mixed liquid sample to be detected from the dropping zone 3x to the detection zone 3y.
- a step of detecting a color change (coloration of the marker) in the detection zone 3y is detecting a color change (coloration of the marker) in the detection zone 3y.
- the step of dropping a liquid sample onto the dropping zone 3x of the surface of the film carrier 3 and the fine structure 7 (plural protrusions 8) formed on the surface of the film carrier 3 are provided.
- the substance to be detected is combined with a reagent that is fixed to the detection zone 3y to detect a color change in the detection zone 3y (the presence or absence of a color change is optically determined). And a process.
- the method of mixing the liquid sample and the label is not particularly limited in the step of binding the target substance and the label to each other.
- a method of adding a liquid sample to a container containing a labeled body may be used, or a liquid containing a labeled body and a liquid sample may be mixed, for example.
- a filter may be sandwiched between the dropping port of a container in which a liquid sample is placed, and a labeling body may be immobilized in the filter.
- Example 1-1 ⁇ Preparation of membrane carrier> A polystyrene sheet (Denka Co., Ltd. Denka Styrene Sheet, film thickness 300 ⁇ m) is subjected to thermal imprinting and is sometimes referred to as the diameter of the bottom surface of the microstructure (convex portion) (hereinafter referred to as “convex diameter” or “diameter”). 3) Conical convex part 8 of 10 ⁇ m and fine structure (convex part) height (hereinafter also referred to as “height”) 10 ⁇ m is a triangle as shown in FIG. Membrane carriers having an average surface roughness of 0.102 ⁇ m arranged in an array format were produced.
- the surface average roughness was set to a predetermined value by subjecting the surface of the mold (mold) to sandblasting.
- the surface average roughness in Tables 1 and 2 indicates the value of the surface average roughness (surface average roughness of the protrusions) in the microstructure.
- the surface average roughness was measured using a three-dimensional roughness analysis electron microscope (ERAION 600, manufactured by Elionix Co., Ltd.) (see FIG. 7).
- Three conical convex portions 8 were arbitrarily selected. With respect to the three convex portions 8, the concave / convex profile of the straight line 20 having a length 20 d of 10 ⁇ m with the central point of the convex portion 8 (the central point 19 of the convex portion) as the central point was measured.
- the unevenness profiles of the three straight lines 20 were subjected to inclination correction, and the surface average roughness (Ra) defined by JIS B0601 was calculated as a plane.
- ⁇ Detection substance set> The anti-influenza A influenza NP antibody suspension and the anti-influenza B influenza NP antibody suspension were applied at a line width of 1 mm on the UV-treated portion as described above (application amount: 3 ⁇ L) and dried well under warm air. . In this way, the anti-influenza A NP antibody and the anti-influenza B NP antibody were fixed in the detection zone 3y.
- a purified anti-influenza A virus NP antibody (an antibody different from the above) and a purified anti-influenza B virus NP antibody (an antibody different from the above) were used.
- Anti-influenza A virus NP antibody is labeled with red latex particles (CM / BL Ceradyne) having a particle size of 0.394 ⁇ m by covalent bond, and the concentration of latex particles is 0 in Tris buffer containing sugar, surfactant and protein.
- An anti-A-type labeled body was prepared by suspending it to 0.025 w / v% and performing ultrasonic treatment to sufficiently disperse and float it.
- an anti-B-type labeled body in which blue latex particles (manufactured by CM / BL Ceradine) were labeled on the anti-type B influenza virus NP antibody was prepared.
- the anti-A type label and the anti-B type label were mixed to prepare a mixed solution.
- An amount of a mixed solution of 50 ⁇ L per square centimeter was applied to glass fiber having a size of 3 cm ⁇ 1 cm (33GLASS NO.10539766, manufactured by Schleicher & Schuell), and dried well under warm air to prepare a marker pad.
- a labeling substance pad was placed on the end of the membrane carrier (corresponding to the surface-treated membrane carrier 3) produced as described above, which is closer to the detection zone 13y.
- the width (end width) of the membrane carrier on which the labeling substance pad overlaps was 2 mm.
- the membrane carrier on which the labeling substance pad overlaps was cut into a strip having a width of 5 mm with a cutter to prepare a liquid sample test kit composed of the integrated membrane carrier and the labeling substance pad.
- liquid sample 100 ⁇ L of a liquid sample (liquid sample) was dropped onto the end of the liquid sample inspection kit produced as described above.
- the end of the liquid sample inspection kit to which the liquid sample was dropped was the end closer to the detection zone.
- the liquid sample was prepared by diluting the influenza A virus A / Beijing / 32/92 (H3N2) 2 ⁇ 10 4 times using the specimen suspension attached to DENKA SEIKEN Quick Navi-Flu as a diluting solution.
- two types of influenza virus B / Shangdong / 7/97 diluted 2 ⁇ 10 3 times were used.
- Determination of detection is a portion where the coloring line (anti-influenza A influenza NP antibody and anti-influenza B influenza NP antibody is fixed) in the detection zone (influenza A virus detection part and influenza B virus detection part) after 15 minutes of dropping of the liquid sample ) was observed visually.
- the manner in which the liquid sample after dropping was moved on the test kit was confirmed by the average flow rate, and the presence or absence of movement of the liquid sample was confirmed.
- the average flow rate was calculated from the time from when the liquid sample was dropped onto the end of the liquid sample inspection kit and the liquid sample flowing out to the membrane carrier until reaching the colored line in the detection zone.
- Example 1-2 Liquid sample inspection under the same conditions as in Example 1-1, except that the microstructure in Example 1-1 was changed to a conical convex portion having a diameter of 100 ⁇ m and a height of 100 ⁇ m, and an average surface roughness of 0.094 ⁇ m. A kit was made.
- Example 1-3 A liquid sample inspection kit under the same conditions as in Example 1-1, except that the microstructure in Example 1-1 was changed to a conical convex portion having a diameter of 500 ⁇ m and a height of 500 ⁇ m, and an average surface roughness of 0.109 ⁇ m. Was made.
- Example 1-4 Liquid sample inspection under the same conditions as in Example 1-1, except that the microstructure in Example 1-1 was changed to a conical convex portion having a diameter of 1000 ⁇ m and a height of 100 ⁇ m, and an average surface roughness of 0.121 ⁇ m. A kit was made.
- Example 1-5 Liquid sample inspection under the same conditions as in Example 1-1, except that the microstructure in Example 1-1 was changed to a conical convex portion having a diameter of 100 ⁇ m and a height of 10 ⁇ m, and an average surface roughness of 0.094 ⁇ m. A kit was made.
- Example 1-6 Liquid sample inspection under the same conditions as in Example 1-1, except that the microstructure in Example 1-1 was changed to a conical convex portion having a diameter of 100 ⁇ m and a height of 200 ⁇ m, and an average surface roughness of 0.120 ⁇ m. A kit was made.
- Example 1-7 Liquid sample inspection under the same conditions as in Example 1-1, except that the microstructure in Example 1-1 was changed to a conical convex portion having a diameter of 100 ⁇ m and a height of 100 ⁇ m, and an average surface roughness of 0.048 ⁇ m. A kit was made.
- Example 1-8 Liquid sample inspection under the same conditions as in Example 1-1, except that the microstructure in Example 1-1 was changed to a conical convex portion having a diameter of 100 ⁇ m and a height of 100 ⁇ m, and an average surface roughness of 0.015 ⁇ m. A kit was made.
- Example 1-9 Liquid sample inspection under the same conditions as in Example 1-1, except that the microstructure in Example 1-1 was changed to a conical convex portion having a diameter of 100 ⁇ m and a height of 100 ⁇ m, and an average surface roughness of 0.27 ⁇ m. A kit was made.
- Example 1-10 A liquid sample inspection kit under the same conditions as in Example 1-1, except that the microstructure in Example 1-1 was changed to a conical convex portion having a diameter of 100 ⁇ m and a height of 100 ⁇ m, and an average surface roughness of 6.8 ⁇ m. Was made.
- Example 1-11 Example 1 except that the fine structure in Example 1-1 was changed to a conical convex portion having a diameter of 100 ⁇ m and a height of 100 ⁇ m, the closest distance between the fine structures was 100 ⁇ m, and the surface average roughness was 0.095 ⁇ m.
- a liquid sample inspection kit was prepared under the same conditions as for -1.
- Example 1-12 Example 1 except that the fine structure in Example 1-1 is a conical convex portion having a diameter of 100 ⁇ m and a height of 100 ⁇ m, the closest distance between the fine structures is 500 ⁇ m, and the surface average roughness is 0.058 ⁇ m.
- a liquid sample inspection kit was prepared under the same conditions as for -1.
- Example 1-1 Liquid sample inspection under the same conditions as in Example 1-1, except that the microstructure in Example 1-1 was changed to a conical convex portion having a diameter of 100 ⁇ m and a height of 100 ⁇ m, and an average surface roughness of 0.002 ⁇ m. A kit was made.
- Example 1-2 A liquid sample inspection kit was prepared under the same conditions as in Example 1-1, except that the microstructure in Example 1-1 was changed to a conical convex portion having a diameter of 100 ⁇ m and a height of 100 ⁇ m, and an average surface roughness of 17 ⁇ m. Produced.
- Table 1 shows the evaluation results of the liquid sample test membrane carriers and liquid sample test kits obtained in Examples 1-1 to 1-12 and Comparative Examples 1-1 to 1-2.
- the liquid sample inspection kit sets the height of the fine structure in the flow path, the diameter of the fine structure, the closest distance between the fine structures, and the aspect ratio to values in an appropriate range. Have been shown to produce capillary flow. It was shown that by setting the surface average roughness in the fine structure to a value in an appropriate range, the amount of antibody supported in the detection zone can be increased and the detection substance can be detected with high sensitivity.
- Examples 1-13 to 1-24 The particles used were changed from colored latex particles to fluorescent latex particles (micromer-F fluorescent latex particles, polystyrene core front), and the presence or absence of a colored line was read 10 minutes after the start of the test using an immunochromatographic reader (C11787, Hamamatsu Photonics). The magnification at which it was not possible (the limit magnification at which fluorescence could be determined), that is, the magnification at which the S / N ratio was 10 or less was determined. The diameter of the fine structure, the closest distance of the fine structure, the height of the fine structure, and the aspect ratio were set to values shown in Table 2. The other contents were the same as in Examples 1-1 to 1-12.
- Table 2 shows the evaluation results of the liquid sample inspection kit membrane carrier and liquid sample inspection kit obtained in Examples 1-13 to 1-24.
- the amount of the detection substance that can be carried can be increased, and the detection sensitivity can be improved.
- the surface average roughness of the material is controlled to enhance the detection zone signal and to perform highly sensitive determination.
- a possible liquid sample testing kit is provided.
- Example 2-1 ⁇ Preparation of membrane carrier> A polystyrene sheet (Denka Co., Ltd. Denka Styrene Sheet, film thickness 300 ⁇ m) is subjected to thermal imprinting, and the diameter of the bottom surface of the microstructure (hereinafter sometimes referred to as the diameter of the microstructure or the diameter) is 10 ⁇ m, the height of the microstructure.
- UV irradiation is performed, and the oxygen atom number ratio (oxygen atom number / (carbon atom Number + nitrogen atom number + oxygen atom number))).
- the oxygen atom number ratio was adjusted by changing the UV light intensity, intensity, wavelength, irradiation time, and UV irradiation energy.
- the metal plate was provided with a gap in the 0.7 to 1.0 cm portion to expose the membrane carrier.
- a masking method a method of arranging a metal plate on the film carrier was used. In this way, a surface-treated membrane carrier 3 was obtained.
- the portion of 0.7 to 1.0 cm corresponds to the detection zone 3y, and the metal plate corresponds to the shielding object 14.
- the peak area (signal intensity) calculated by subtracting BG from the peak obtained in the above measurement range is divided by the correction coefficient (relative sensitivity coefficient, transmission function, kinetic energy correction), and the area after correction is calculated.
- the total was calculated to be 100.
- Each value obtained was defined as the number of carbon atoms, the number of nitrogen atoms, and the number of oxygen atoms, and the oxygen atom number ratio (number of oxygen atoms / (number of carbon atoms + number of nitrogen atoms + number of oxygen atoms)) was calculated.
- a suspension of anti-influenza A influenza NP antibody and a suspension of anti-influenza B influenza NP antibody are applied to the surface-treated portion of the membrane carrier (corresponding to detection zone 3y) with a line width of 1 mm (application amount: 3 ⁇ L). ) And dried well under warm air. In this way, the anti-influenza A NP antibody and the anti-influenza B NP antibody were fixed in the detection zone 3y.
- a purified anti-influenza A virus NP antibody (an antibody different from the above) and a purified anti-influenza B virus NP antibody (an antibody different from the above) were used.
- Anti-influenza A virus NP antibody is labeled with red latex particles (CM / BL Ceradyne) having a particle size of 0.394 ⁇ m by covalent bond, and the concentration of latex particles is 0 in Tris buffer containing sugar, surfactant and protein.
- An anti-A-type labeled body was prepared by suspending it to 0.025 w / v% and performing ultrasonic treatment to sufficiently disperse and float it.
- an anti-B-type labeled body in which blue latex particles (manufactured by CM / BL Ceradine) were labeled on the anti-type B influenza virus NP antibody was prepared.
- the anti-A type label and the anti-B type label were mixed to prepare a mixed solution.
- An amount of a mixed solution of 50 ⁇ L per square centimeter was applied to glass fiber having a size of 3 cm ⁇ 1 cm (33GLASS NO.10539766, manufactured by Schleicher & Schuell), and dried well under warm air to prepare a marker pad.
- a labeling substance pad was overlaid on the end of the membrane carrier (corresponding to the surface-treated membrane carrier 3) prepared as described above, which is closer to the detection zone 3y.
- the width (end width) of the membrane carrier on which the labeling substance pad overlaps was 2 mm.
- the membrane carrier on which the labeling substance pad overlaps was cut into a strip having a width of 5 mm with a cutter to prepare a liquid sample inspection kit comprising the integrated membrane carrier and the labeling substance pad.
- liquid sample 100 ⁇ L of a liquid sample (liquid sample) was dropped onto the end of the liquid sample inspection kit produced as described above.
- the end of the liquid sample inspection kit to which the liquid sample was dropped was the end closer to the detection zone.
- Two types of liquid samples were prepared as follows.
- detection substances influenza A virus A / Beijing / 32/92 (H3N2) and influenza B virus B / Shangdong / 7/97 were used.
- As a diluting solution a specimen suspension attached to Quick Navi-Flu manufactured by Denka Seken Co., Ltd. was used.
- Liquid sample A was obtained by diluting influenza A virus A / Beijing / 32/92 (H3N2) 2 ⁇ 10 4 times with the sample suspension.
- a liquid sample B was obtained by diluting influenza B virus B / Shangdong / 7/97 2 ⁇ 10 3 times with the sample suspension.
- Liquid sample A and liquid sample B were dropped individually.
- Determination of detection is a portion where the coloring line (anti-influenza A influenza NP antibody and anti-influenza B influenza NP antibody is fixed) in the detection zone (influenza A virus detection part and influenza B virus detection part) after 15 minutes of dropping of the liquid sample ) was observed visually.
- the liquid sample after dropping was visually observed as moving on the test kit, and the presence or absence of movement of the liquid sample was confirmed.
- Example 2-2 A liquid sample inspection kit was produced under the same conditions as in Example 2-1, except that the fine structure of Example 2-1 was changed to a conical convex portion having a diameter of 100 ⁇ m and a height of 100 ⁇ m.
- Example 2-3 A liquid sample inspection kit was produced under the same conditions as in Example 2-1, except that the fine structure of Example 2-1 was changed to a conical convex portion having a diameter of 500 ⁇ m and a height of 500 ⁇ m.
- Example 2-4 A liquid sample inspection kit was produced under the same conditions as in Example 2-1, except that the fine structure of Example 2-1 was changed to a conical convex portion having a diameter of 1000 ⁇ m and a height of 100 ⁇ m.
- Example 2-5 A liquid sample inspection kit was prepared under the same conditions as in Example 2-1, except that the fine structure of Example 2-1 was changed to a conical convex portion having a diameter of 100 ⁇ m and a height of 10 ⁇ m.
- Example 2-6 A liquid sample inspection kit was prepared under the same conditions as in Example 2-1, except that the fine structure of Example 2-1 was changed to a conical convex portion having a diameter of 100 ⁇ m and a height of 200 ⁇ m.
- Example 2-7 A liquid was formed under the same conditions as in Example 2-1, except that the fine structure of Example 2-1 was a conical convex portion having a diameter of 100 ⁇ m and a height of 100 ⁇ m, and the oxygen atom number ratio was 0.12.
- a sample inspection kit was prepared.
- Example 2-8 A liquid was formed under the same conditions as in Example 2-1, except that the fine structure of Example 2-1 was a conical convex portion having a diameter of 100 ⁇ m and a height of 100 ⁇ m, and the oxygen atom number ratio was 0.05.
- a sample inspection kit was prepared.
- Example 2-9 The liquid was formed under the same conditions as in Example 2-1, except that the fine structure of Example 2-1 was a conical convex portion having a diameter of 100 ⁇ m and a height of 100 ⁇ m, and the oxygen atom number ratio was 0.01. A sample inspection kit was prepared.
- Example 2-10 Except for the fine structure of Example 2-1 having a cone-shaped convex part with a diameter of 100 ⁇ m and a height of 100 ⁇ m, and the closest distance between the fine structures being 100 ⁇ m, the same conditions as in Example 2-1 were used. A liquid sample inspection kit was prepared.
- Example 2-11 The conditions of Example 2-1 were the same as those of Example 2-1, except that the microstructure of Example 2-1 was a conical convex portion having a diameter of 100 ⁇ m and a height of 100 ⁇ m, and the closest distance between the microstructures was 500 ⁇ m.
- a liquid sample inspection kit was prepared.
- Example 2-12 A liquid was formed under the same conditions as in Example 2-1, except that the fine structure of Example 2-1 was a conical convex portion having a diameter of 100 ⁇ m and a height of 100 ⁇ m, and the oxygen atom number ratio was 0.50.
- a sample inspection kit was prepared.
- Example 2-1 except that the fine structure of Example 2-1 is a conical convex portion having a diameter of 100 ⁇ m and a height of 100 ⁇ m, and the oxygen atom number ratio is 0.005 without UV irradiation.
- a liquid sample inspection kit was prepared under the same conditions.
- Table 3 shows the evaluation results of the liquid sample test kit membrane carriers and liquid sample test kits obtained in Examples 2-1 to 2-12 and Comparative Example 2-1.
- Example 2-2 A liquid was formed under the same conditions as in Example 2-1, except that the fine structure of Example 2-1 was a conical convex portion having a diameter of 100 ⁇ m and a height of 100 ⁇ m, and the oxygen atom number ratio was 0.50.
- a sample inspection kit was prepared.
- Table 4 shows the evaluation results of the liquid sample inspection membrane carrier obtained in Comparative Example 2-2. A liquid sample containing no virus was used as the liquid sample. Examples 2-2 and 2-12 were also carried out in the same manner.
- the liquid sample inspection kit according to the present embodiment generates a capillary flow.
- the detection substance can be detected with high sensitivity by setting the oxygen atom number ratio to a value in an appropriate range, and the possibility of erroneous detection is small (for example, Example 2-2 and See Examples 2-7 to 2-9 and Example 2-12).
- the detection substance can be detected with high sensitivity by setting the height of the fine structure in the flow path to a value in an appropriate range (for example, Example 2-2 and Example 2- 4).
- the oxygen atom number ratio was small, a highly sensitive determination could not be made (Comparative Example 2-1).
- the oxygen atom number ratio was large, it was erroneously detected (Comparative Example 2-2).
- Examples 2-13 to 2-24 The particles used were changed from colored latex particles to fluorescent latex particles (micromer-F fluorescent latex particles, polystyrene core front), and the presence or absence of a colored line was read 10 minutes after the start of the test using an immunochromatographic reader (C11787, Hamamatsu Photonics).
- the magnification at which it was not possible (the limit magnification at which fluorescence could be determined), that is, the magnification at which the S / N ratio was 10 or less was determined.
- the diameter of the fine structure, the closest distance of the fine structure, the height of the fine structure, and the aspect ratio were set to values shown in Table 5.
- the other contents were the same as in Examples 2-1 to 2-12.
- Table 5 shows the evaluation results of the membrane carrier for liquid sample inspection kit and the liquid sample inspection kit obtained in Examples 2-13 to 2-24.
- the number of oxygen atoms in the detection zone is controlled to enhance the detection zone signal and enable highly sensitive determination.
- a liquid sample inspection kit is provided.
- test carrier membrane carrier Since the test carrier membrane carrier is mass-produced in a short time, the amount of surface treatment on the material tends to be relatively high, and the oxygen atom number ratio on the surface tends to be high.
- This embodiment has an effect that, for example, by specifying the oxygen atom number ratio, the labeling substance reacts with the detection substance when the solution not containing the detection substance is developed, and the possibility of erroneous detection is small. .
- the amount of antibody fixed in the detection zone can be increased, and the detection substance can be detected with high sensitivity.
- the liquid sample test kit of this embodiment is useful for a disposable POCT reagent because it can perform a highly sensitive test in a short time.
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Abstract
Description
(1)流路と、検知ゾーンと、を備え、流路の底面に微細構造が設けられ、微細構造における表面平均粗さが、0.005~10.0μmである、膜担体。
(2)流路と、検知ゾーンと、を備え、流路の底面に微細構造が設けられ、検知ゾーンの表面には、炭素原子及び窒素原子の少なくとも一方の原子と酸素原子とが存在しており、各原子の原子数の合計に対する酸素原子数比(酸素原子数/(炭素原子数+窒素原子数+酸素原子数))が0.01~0.50である、膜担体。
(3)微細構造の高さが、5~1000μmである、(1)又は(2)に記載の膜担体。
(4)微細構造の底面の径が5~1000μmである、(1)~(3)のいずれかに記載の膜担体。
(5)微細構造同士の最近接距離が、流路内で0~500μmである、(1)~(4)のいずれかに記載の膜担体。
(6)微細構造のアスペクト比が、0.1~10である、(1)~(5)のいずれかに記載の膜担体。
(7)膜担体が、液体試料中の被検出物質を検出する検査キット用膜担体である、(1)~(6)のいずれかに記載の膜担体。
(8)検知ゾーンが、被検出物質を検出した際に色変化を示す、(7)に記載の膜担体。
(9)被検出物質を検出した際に色変化を生じせしめる検出物質が、検知ゾーンに固定されている、(7)又は(8)に記載の膜担体。
(10)
(1)~(9)のいずれかに記載の膜担体を有する液体試料検査キット。
<膜担体の準備>
ポリスチレンシート(デンカ株式会社製デンカスチレンシート、膜厚300μm)に熱インプリントを施し、微細構造(凸部)の底面の径(以下、「凸部の径」又は、「径」ということもある)10μm、微細構造(凸部)の高さ(以下、「高さ」ということもある)10μmの円錐型の凸部8が、微細構造同士の最近接距離を5μmとして図3のような三角配列形式で並んだ表面平均粗さ0.102μmの膜担体を作製した。表面平均粗さは、金型(モールド)の表面にサンドブラスト処理を施すことにより、所定の値にした。表1及び2の表面平均粗さは、微細構造における表面平均粗さ(凸部の表面平均粗さ)の値を示した。表面平均粗さの測定には三次元粗さ解析電子顕微鏡(株式会社エリオニクス製ERA-600)を用いた(図7参照)。円錐型の凸部8を任意に3個選んだ。3個の凸部8について、凸部8の頂点中心部(凸部の中心点19)を中心点とした、長さ20dが10μmである直線20の凹凸プロファイルをそれぞれ測定した。3本の直線20の凹凸プロファイルに傾き補正を施し、平面としてJIS B0601で規定された表面平均粗さ(Ra)をそれぞれ算出した。得られた3つのデータを平均した値を評価値とした。
上記のように作製した膜担体の微細構造の端から0.7~1.0cmの部分にのみエネルギー照射できるように金属板でマスクした後、UVを照射した。金属板は、0.7~1.0cmの部分に空隙を設け、膜担体を露出させた。マスクする方法としては、膜担体に金属板を配置する方法を用いた。このようにして、表面処理した膜担体3を得た。図8において、0.7~1.0cmの部分は検知ゾーン3y(表面処理部)、金属板は遮へい物14に相当する。
上記のようにUV処理を施した部分に、抗A型インフルエンザNP抗体浮遊液、並びに抗B型インフルエンザNP抗体浮遊液を線幅1mmで塗布し(塗布量3μL)、温風下で良く乾燥させた。このようにして、抗A型インフルエンザNP抗体、並びに抗B型インフルエンザNP抗体を検知ゾーン3yに固定した。
精製抗A型インフルエンザウイルスNP抗体(上記と別の抗体)及び精製抗B型インフルエンザウイルスNP抗体(上記と別の抗体)を使用した。抗A型インフルエンザウイルスNP抗体に粒子径0.394μmの赤色ラテックス粒子(CM/BL セラダイン製)を共有結合で標識し、糖、界面活性剤及びタンパク質を含むトリス緩衝液にラテックス粒子の濃度が0.025w/v%になるように懸濁し、超音波処理を行って充分に分散浮遊させた抗A型標識体を調製した。同様に抗B型インフルエンザウイルスNP抗体に青色ラテックス粒子(CM/BL セラダイン製)を標識した抗B型標識体を調製した。
実施例1-1における微細構造を、径が100μm、高さが100μmの円錐型の凸部、表面平均粗さ0.094μmとした以外は、実施例1-1と同様の条件で液体サンプル検査キットを作製した。
実施例1-1における微細構造を、径が500μm、高さが500μmの円錐型の凸部、表面平均粗さ0.109μmとした以外は実施例1-1と同様の条件で液体サンプル検査キットを作製した。
実施例1-1における微細構造を、径が1000μm、高さが100μmの円錐型の凸部、表面平均粗さ0.121μmとした以外は、実施例1-1と同様の条件で液体サンプル検査キットを作製した。
実施例1-1における微細構造を、径が100μm、高さが10μmの円錐型の凸部、表面平均粗さ0.094μmとした以外は、実施例1-1と同様の条件で液体サンプル検査キットを作製した。
実施例1-1における微細構造を、径が100μm、高さが200μmの円錐型の凸部、表面平均粗さ0.120μmとした以外は、実施例1-1と同様の条件で液体サンプル検査キットを作製した。
実施例1-1における微細構造を、径が100μm、高さが100μmの円錐型の凸部、表面平均粗さ0.048μmとした以外は、実施例1-1と同様の条件で液体サンプル検査キットを作製した。
実施例1-1における微細構造を、径が100μm、高さが100μmの円錐型の凸部、表面平均粗さ0.015μmとした以外は、実施例1-1と同様の条件で液体サンプル検査キットを作製した。
実施例1-1における微細構造を、径が100μm、高さが100μmの円錐型の凸部、表面平均粗さ0.27μmとした以外は、実施例1-1と同様の条件で液体サンプル検査キットを作製した。
実施例1-1における微細構造を、径が100μm、高さが100μmの円錐型の凸部、表面平均粗さ6.8μmとした以外は実施例1-1と同様の条件で液体サンプル検査キットを作製した。
実施例1-1における微細構造を、径が100μm、高さが100μmの円錐型の凸部、微細構造同士の最近接距離を100μm、表面平均粗さ0.095μmとした以外は、実施例1-1と同様の条件で液体サンプル検査キットを作製した。
実施例1-1における微細構造を、径が100μm、高さが100μmの円錐型の凸部とし、微細構造同士の最近接距離を500μm、表面平均粗さ0.058μmとした以外は実施例1-1と同様の条件で液体サンプル検査キットを作製した。
実施例1-1における微細構造を、径が100μm、高さが100μmの円錐型の凸部、表面平均粗さ0.002μmとした以外は、実施例1-1と同様の条件で液体サンプル検査キットを作製した。
実施例1-1における微細構造を、径が100μm、高さが100μmの円錐型の凸部、表面平均粗さ17μmとした以外は、実施例1-1と同様の条件で液体サンプル検査キットを作製した。
用いる粒子を着色ラテックス粒子から蛍光ラテックス粒子(micromer-F 蛍光ラテックス粒子 材料ポリスチレン コアフロント社製)に変更し、試験開始10分後に着色ラインの有無をイムノクロマトリーダ(C11787 浜松ホトニクス株式会社製)で読み取りできなくなる倍率(蛍光判定可能な限界倍率)、即ち、S/N比が10以下を示す倍率を求めた。微細構造の径、微細構造の最近接距離、微細構造の高さ、アスペクト比は、表2に示す値にした。これ以外の内容は実施例1-1~1-12と同様に行った。
<膜担体の準備>
ポリスチレンシート(デンカ株式会社製デンカスチレンシート、膜厚300μm)に熱インプリントを施し、微細構造の底面の径(以下、微細構造の径や、径ということもある)10μm、微細構造の高さ(以下、高さということもある)10μmの円錐型の凸部8が、微細構造同士の最近接距離を5μmとして図3のような三角配列形式で並んだ膜担体3を作製した。作製した膜担体の微細構造の端から0.7~1.0cmの部分にのみエネルギー照射できるように金属板でマスクした後、UVを照射し、酸素原子数比(酸素原子数/(炭素原子数+窒素原子数+酸素原子数))0.35の膜担体を作製した。UV処理時に、UVの光量、強度、波長、照射時間、UV照射エネルギーを変更することにより、酸素原子数比を調整した。
各原子の半定量値をXPSにより求めた。測定装置はThermo SCIENTIFIC社製、K-ALPHAを用いた。測定条件について、X線源としてモノクロメータ付きAl-Kα線、帯電中和は低速電子と低速Ar+イオンの同軸照射型のデュアルビーム、検出角度は90°、出力:36W、測定領域は約400μm×200μm、パスエネルギーは50eV、データは0.1eV/step、50msecの条件下で取り込み、積算回数5回、測定範囲は以下にて行った。炭素C1sスペクトル:279~298eV、酸素O1sスペクトル:525~545eV、窒素N1sスペクトル:392~410eV。得られたスペクトルの結合エネルギー補正をC1sスペクトルにおけるC-C結合(284.8eV)で行った。結合エネルギー補正を行った上記記載のスペクトルについて、以下の範囲にてShirley法を用いてバックグラウンド(BG)を引いて、下記のように修正した。炭素C1sスペクトル:281~292eV、酸素O1sスペクトル:526~536eV、窒素N1sスペクトル:395~403eV。上記測定範囲にて得られたピークよりBGを差し引いて算出された各原子のピーク面積(信号強度)を補正係数(相対感度係数、透過関数、運動エネルギー補正)で割り算し、補正後の面積の合計が100になるように計算した。得られた各値をそれぞれ炭素原子数、窒素原子数、酸素原子数とし、酸素原子数比(酸素原子数/(炭素原子数+窒素原子数+酸素原子数))を算出した。
膜担体の表面処理を施した部分(検知ゾーン3yに相当)に、抗A型インフルエンザNP抗体の浮遊液、並びに、抗B型インフルエンザNP抗体の浮遊液を線幅1mmで塗布し(塗布量3μL)、温風下で良く乾燥させた。このようにして、抗A型インフルエンザNP抗体、並びに抗B型インフルエンザNP抗体を検知ゾーン3yに固定した。
精製抗A型インフルエンザウイルスNP抗体(上記と別の抗体)及び精製抗B型インフルエンザウイルスNP抗体(上記と別の抗体)を使用した。抗A型インフルエンザウイルスNP抗体に粒子径0.394μmの赤色ラテックス粒子(CM/BL セラダイン製)を共有結合で標識し、糖、界面活性剤及びタンパク質を含むトリス緩衝液にラテックス粒子の濃度が0.025w/v%になるように懸濁し、超音波処理を行って充分に分散浮遊させた抗A型標識体を調製した。同様に抗B型インフルエンザウイルスNP抗体に青色ラテックス粒子(CM/BL セラダイン製)を標識した抗B型標識体を調製した。
実施例2-1の微細構造を、径が100μm、高さが100μmの円錐型の凸部とした以外は、実施例2-1と同様の条件で液体サンプル検査キットを作製した。
実施例2-1の微細構造を、径が500μm、高さが500μmの円錐型の凸部とした以外は、実施例2-1と同様の条件で液体サンプル検査キットを作製した。
実施例2-1の微細構造を、径が1000μm、高さが100μmの円錐型の凸部とした以外は、実施例2-1と同様の条件で液体サンプル検査キットを作製した。
実施例2-1の微細構造を、径が100μm、高さが10μmの円錐型の凸部とした以外は、実施例2-1と同様の条件で液体試料検査キットを作製した。
実施例2-1の微細構造を、径が100μm、高さが200μmの円錐型の凸部とした以外は、実施例2-1と同様の条件で液体試料検査キットを作製した。
実施例2-1の微細構造を、径が100μm、高さが100μmの円錐型の凸部とし、酸素原子数比を0.12とした以外は、実施例2-1と同様の条件で液体試料検査キットを作製した。
実施例2-1の微細構造を、径が100μm、高さが100μmの円錐型の凸部とし、酸素原子数比を0.05とした以外は、実施例2-1と同様の条件で液体試料検査キットを作製した。
実施例2-1の微細構造を、径が100μm、高さが100μmの円錐型の凸部とし、酸素原子数比を0.01とした以外は、実施例2-1と同様の条件で液体試料検査キットを作製した。
実施例2-1の微細構造を、径が100μm、高さが100μmの円錐型の凸部とし、微細構造同士の最近接距離を100μmとした以外は、実施例2-1と同様の条件で液体試料検査キットを作製した。
実施例2-1の微細構造を、径が100μm、高さが100μmの円錐型の凸部とし、微細構造同士の最近接距離を500μmとした以外は、実施例2-1と同様の条件で液体試料検査キットを作製した。
実施例2-1の微細構造を、径が100μm、高さが100μmの円錐型の凸部とし、酸素原子数比を0.50とした以外は、実施例2-1と同様の条件で液体試料検査キットを作製した。
実施例2-1の微細構造を、径が100μm、高さが100μmの円錐型の凸部とし、UV照射を行なわず酸素原子数比を0.005とした以外は、実施例2-1と同様の条件で液体試料検査キットを作製した。
実施例2-1の微細構造を、径が100μm、高さが100μmの円錐型の凸部とし、酸素原子数比を0.50とした以外は、実施例2-1と同様の条件で液体試料検査キットを作製した。
用いる粒子を着色ラテックス粒子から蛍光ラテックス粒子(micromer-F 蛍光ラテックス粒子 材料ポリスチレン コアフロント社製)に変更し、試験開始10分後に着色ラインの有無をイムノクロマトリーダ(C11787 浜松ホトニクス株式会社製)で読み取りできなくなる倍率(蛍光判定可能な限界倍率)、即ち、S/N比が10以下を示す倍率を求めた。微細構造の径、微細構造の最近接距離、微細構造の高さ、アスペクト比は、表5に示す値にした。これ以外の内容は実施例2-1~2-12と同様に行った。
3 微細構造が設けられた膜担体
3x 滴下ゾーン
3y 検知ゾーン(検出部)
4,4a,4b,4c,4d 凸部の底面における代表長さ(凸部の底面の径)
5 最近接微細構造間距離
6,6a,6b,6c,6d 凸部の高さ
7,7a,7b,7c,7d 微細構造
8,8a,8b,8c,8d 凸部
9 平坦部
10,10a,10b,10c,10d 凸部の底面
遮へい部 14
18 液体試料用の検査キット
18a 筐体
18b 第一開口部
18c 第二開口部
19 凸部の中心
20 凸部の中心を通る直線
20d 凸部の中心を通る直線の長さ
d 液体試料の流れる方向(輸送方向)
Claims (10)
- 流路と、検知ゾーンと、を備え、
前記流路の底面に微細構造が設けられ、
前記微細構造における表面平均粗さが、0.005~10.0μmである、膜担体。 - 流路と、検知ゾーンと、を備え、
前記流路の底面に微細構造が設けられ、
前記検知ゾーンの表面には、炭素原子及び窒素原子の少なくとも一方の原子と酸素原子とが存在しており、前記各原子の原子数の合計に対する前記酸素原子数比(前記酸素原子数/(前記炭素原子数+前記窒素原子数+前記酸素原子数))が0.01~0.50である、膜担体。 - 前記微細構造の高さが、5~1000μmである、請求項1又は2に記載の膜担体。
- 前記微細構造の底面の径が5~1000μmである、請求項1~3のいずれか一項に記載の膜担体。
- 前記微細構造同士の最近接距離が、前記流路内で0~500μmである、請求項1~4のいずれか一項に記載の膜担体。
- 前記微細構造のアスペクト比が、0.1~10である、請求項1~5のいずれか一項に記載の膜担体。
- 前記膜担体が、液体試料中の被検出物質を検出する検査キット用膜担体である、請求項1~6のいずれか一項に記載の膜担体。
- 前記検知ゾーンが、前記被検出物質を検出した際に色変化を示す、請求項7に記載の膜担体。
- 前記被検出物質を検出した際に色変化を生じせしめる検出物質が、前記検知ゾーンに固定されている、請求項7又は8に記載の膜担体。
- 請求項1~9のいずれか一項に記載の膜担体を有する液体試料検査キット。
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KR20220137138A (ko) | 2022-10-11 |
EP3892998A1 (en) | 2021-10-13 |
EP3605096B1 (en) | 2022-05-18 |
EP3892998B1 (en) | 2022-05-18 |
CN115453112A (zh) | 2022-12-09 |
US11385227B2 (en) | 2022-07-12 |
CN110312934A (zh) | 2019-10-08 |
EP3605096A1 (en) | 2020-02-05 |
JPWO2018181540A1 (ja) | 2020-02-06 |
ES2923402T3 (es) | 2022-09-27 |
ES2923867T3 (es) | 2022-10-03 |
CN110312934B (zh) | 2023-02-17 |
JP7069125B2 (ja) | 2022-05-17 |
US20200132679A1 (en) | 2020-04-30 |
KR20190127667A (ko) | 2019-11-13 |
EP3605096A4 (en) | 2020-05-20 |
KR102547418B1 (ko) | 2023-06-23 |
KR102505285B1 (ko) | 2023-03-02 |
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