WO2023048214A1 - Sampling sheet, inspection sheet, and sample collection method - Google Patents

Sampling sheet, inspection sheet, and sample collection method Download PDF

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Publication number
WO2023048214A1
WO2023048214A1 PCT/JP2022/035338 JP2022035338W WO2023048214A1 WO 2023048214 A1 WO2023048214 A1 WO 2023048214A1 JP 2022035338 W JP2022035338 W JP 2022035338W WO 2023048214 A1 WO2023048214 A1 WO 2023048214A1
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Prior art keywords
sample
driving liquid
channel
sampling
capillary pump
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PCT/JP2022/035338
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French (fr)
Japanese (ja)
Inventor
浩二 太田
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三洋化成工業株式会社
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Publication of WO2023048214A1 publication Critical patent/WO2023048214A1/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/02—Devices for withdrawing samples
    • G01N1/10—Devices for withdrawing samples in the liquid or fluent state
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/02—Devices for withdrawing samples
    • G01N1/10—Devices for withdrawing samples in the liquid or fluent state
    • G01N1/12—Dippers; Dredgers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/08—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a stream of discrete samples flowing along a tube system, e.g. flow injection analysis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N37/00—Details not covered by any other group of this subclass

Definitions

  • the present invention relates to a sampling sheet, an inspection sheet, and a sample collection method.
  • biomarkers when biomarkers are measured by the above methods, it takes time from sample collection to analysis, and it is difficult to quickly confirm the state of the living body.
  • the apparatus for analyzing biomarkers since the apparatus for analyzing biomarkers is large, it is difficult to install it in an emergency site, an operating room, or the like, where space is limited.
  • this device since this device requires piping for the cleaning liquid and the waste liquid, it is installed fixedly at a predetermined location, making it extremely difficult to move or carry it to a patient at home or to the bedside.
  • Patent Literature 1 discloses a small-sized, portable, and easy-to-handle test sheet that enables rapid processing from sample collection to sample collection. That is, in Patent Document 1, a sheet-like paper substrate having swelling property due to water absorption, a first liquid-resistant film provided on the surface of the paper substrate, and the first liquid-resistant film a second liquid-resistant film that seals from the upper surface a concave-shaped flow path formed on the surface of the paper substrate provided, and a liquid sample is introduced to one end of the flow path.
  • An opening is provided, an air opening is provided at the other end, a sampling channel having a predetermined volume is provided between them, and the first liquid-resistant film and the second liquid-resistant film are provided with At least one of a first capillary force and a first pump pressure driven by expansion of the paper base material due to water absorption through the provided opening causes the liquid sample introduced into the opening to flow through the sampling channel.
  • a first flow path provided with a liquid feeding section for sending to the At least one of a second capillary force and a second pump pressure driven by expansion of the paper substrate due to water absorption through openings provided in the liquid-resistant film and the second liquid-resistant film, and a second flow path provided with a liquid feeding section that feeds the sample sent to the sampling flow path downstream, and is used for mixing the sent sample and a liquid reagent.
  • a test sheet is disclosed in which a cell and a detection cell for detecting characteristics of the sample mixed with the reagent in the mixing cell are formed.
  • Patent Document 1 has the problem that although one-time analysis can be performed quickly, continuous analysis cannot be performed.
  • the present invention is an invention made in view of the above problems, and an object of the present invention is to provide a test sheet that is small, portable, and capable of continuously analyzing samples.
  • An object of the present invention is to provide a sampling sheet, an inspection sheet containing these sheets, and a method for collecting a sample.
  • the present invention includes a sample suction layer, a microneedle formation surface on which sample collection microneedles are formed, and a microneedle layer having an adhesive surface facing the microneedle formation surface and in contact with the sample suction layer.
  • the sample suction layer comprises a first film having a concave channel, and a second film laminated on the first film so as to cover the channel
  • the channel includes a sample channel and a capillary pump connected to the sample channel, and the sample channel is formed with a sample inlet and a driving liquid inlet having a sealing function
  • the driving liquid introduction portion is opened to introduce an amount of the driving liquid that reaches the connection portion between the sample flow channel and the capillary pump, and then the When the driving liquid introduction part is closed, the driving liquid moves to the capillary pump due to capillary action, so that the sample flow path becomes in a negative pressure state, and the sample is sucked into the sample flow path in the negative pressure state.
  • the present invention relates to a sample collection method in which the sample channel is moved to a negative pressure state, and the sample is sucked into the negative pressure sample channel and reaches the capillary pump.
  • a sample suction layer for use in a test sheet that is small, portable, and capable of continuously analyzing samples.
  • FIG. 1 is a cross-sectional view schematically showing an example of a cross section perpendicular to the plane direction of the sampling sheet of the present invention.
  • FIG. 2A is a plan view schematically showing an example of the sample suction layer in the sampling sheet of the present invention.
  • FIG. 2B is a cross-sectional view taken along line AA of FIG. 2A.
  • FIG. 3 is a cross-sectional view schematically showing an example of the sample suction layer preparation step in the sample collection method of the present invention.
  • FIG. 4 is a cross-sectional view schematically showing an example of the sample inflow step in the sample collection method of the present invention.
  • FIG. 5 is a plan view schematically showing an example of the driving liquid introducing step in the sampling method of the present invention.
  • FIG. 6A is a plan view schematically showing an example of a sample collection step in the sample collection method of the present invention.
  • FIG. 6B is a plan view schematically showing an example of the sampling process in the sampling method of the present invention.
  • FIG. 6C is a plan view schematically showing an example of the sampling process in the sampling method of the present invention.
  • FIG. 6D is a plan view schematically showing an example of the sampling process in the sampling method of the present invention.
  • FIG. 7A is a plan view schematically showing an example of a capillary pump in which the sample suction layer of the sampling sheet of the present invention is formed with an atmosphere opening portion.
  • FIG. 7A is a plan view schematically showing an example of a capillary pump in which the sample suction layer of the sampling sheet of the present invention is formed with an atmosphere opening portion.
  • FIG. 7B is a plan view schematically showing an example of a capillary pump in which a liquid absorbing portion is formed in the sample suction layer of the sampling sheet of the present invention.
  • FIG. 8 is a plan view schematically showing an example of the sampling sheet of the present invention having sensor connections.
  • FIG. 9 is a cross-sectional view schematically showing an example of a cross section perpendicular to the planar direction of the inspection sheet of the present invention.
  • FIG. 10 is a schematic diagram schematically showing the transpiration test.
  • the sampling sheet of the present invention includes a sample suction layer, a microneedle formation surface on which sample collection microneedles are formed, and a microneedle having an adhesive surface facing the microneedle formation surface and in contact with the sample suction layer.
  • the sample suction layer includes a first film having a concave channel and a second film laminated on the first film so as to cover the channel.
  • the flow path includes a sample flow path and a capillary pump connected to the sample flow path, and the sample flow path is formed with a sample inflow portion and a driving liquid introduction portion having a sealing function.
  • the driving liquid introduction portion is opened to introduce an amount of the driving liquid that reaches the connection portion between the sample flow channel and the capillary pump, and then When the driving liquid introduction part is closed, the driving liquid moves to the capillary pump due to capillary action, so that the sample flow path becomes in a negative pressure state, and the sample is sucked into the sample flow path in the negative pressure state.
  • the capillary pump can be reached, and the sample-collecting microneedle communicates with the sample inflow portion of the sample suction layer.
  • sampling sheet of the present invention may have any other structure as long as the effect of the invention is exhibited.
  • FIG. 1 is a cross-sectional view schematically showing an example of a cross section perpendicular to the plane direction of the sampling sheet of the present invention.
  • the sampling sheet 2 shown in FIG. 1 faces the sample suction layer 1, the microneedle formation surface 71 on which the sample collection microneedles 80 are formed, and the microneedle formation surface 71, and contacts the sample suction layer 1. and a microneedle layer 70 having an adhesive surface 72 .
  • microneedle layer 70 will be described.
  • the material of the microneedle layer 70 is not particularly limited, for example, metals such as aluminum and stainless alloys, various inorganic materials such as silicon, carbon, ceramics, various mineral materials including calcium-based minerals, and organic polymer compounds. Preferably.
  • the thickness of the microneedle layer is preferably 200 to 3000 ⁇ m, more preferably 500 to 1000 ⁇ m.
  • the sample-collecting microneedle 80 is hollow so that the sample can pass through it.
  • the sample-collecting microneedle 80 communicates with the sample inflow portion 31 of the sample suction layer 1, which will be described later.
  • the material of the sample-collecting microneedle 80 is not particularly limited, but for example, various inorganic materials such as metals such as aluminum and stainless alloys, silicon, carbon, ceramics, various mineral materials including calcium-based minerals, and organic high-strength materials. It is preferably a molecular compound or the like.
  • polystyrene resin examples include polyethylene terephthalate, polyethylene, polypropylene, acrylic resin, epoxy resin, and polystyrene, as well as bioabsorbable polymers.
  • PET polyethylene terephthalate
  • polyethylene polyethylene
  • polypropylene polypropylene
  • acrylic resin epoxy resin
  • polystyrene polystyrene
  • bioabsorbable polymers can be used.
  • ester compounds such as polylactic acid, polyglycolic acid, poly- ⁇ -caprolactone, poly- ⁇ -dioxane, and polymalic acid
  • acid anhydrides such as polyanhydrides
  • orthoester compounds such as polyorthoesters
  • carbonates such as polycarbonates.
  • phosphazene compounds such as polydiaminophosphazene
  • peptide compounds such as synthetic polypeptides
  • phosphate ester compounds such as polyphosphoester urethane
  • carbon-carbon compounds such as polycyanoacrylate, poly- ⁇ -hydroxybutyric acid, polymalic acid, etc.
  • cellulose compounds ethyl cellulose, carboxymethyl
  • the outer diameter of the sample-collecting microneedle 80 is preferably 100-1000 ⁇ m, more preferably 300-700 ⁇ m.
  • the inner diameter of the sample-collecting microneedle 80 is preferably 10 to 100 ⁇ m, more preferably 30 to 70 ⁇ m.
  • the length of the sample-collecting microneedle 80 (distance indicated by symbol L in FIG. 1) is preferably 200 to 2000 ⁇ m, more preferably 500 to 1000 ⁇ m.
  • Only one sample-collecting microneedle 80 may be formed, or a plurality of sample-collecting microneedles 80 may be formed.
  • sample-collecting microneedles 80 are integrally formed with the microneedle layer 70 in FIG. 1, they may be formed as separate members. In this case, the materials of the microneedle layer and the sampling microneedles may be the same or different.
  • the microneedle forming surface 71 may be coated with a hypoallergenic skin adhesive (adhesive composition described in JP-A-2008-247820, etc.) or the like.
  • the microneedle layer can be manufactured by a known method (such as a method using a mold).
  • FIG. 2A is a plan view schematically showing an example of the sample suction layer in the sampling sheet of the present invention.
  • FIG. 2B is a cross-sectional view taken along line AA of FIG. 2A.
  • the sample suction layer 1 shown in FIGS. 2A and 2B comprises a first film 11 having a concave channel 20 and a second film 12 laminated on the first film 11 so as to cover the channel 20. Prepare.
  • the channel 20 includes a sample channel 30 and a capillary pump 40 connected to the sample channel 30.
  • the sample channel 30 includes a sample inlet 31 and a driving liquid inlet 32 having a sealing function. is formed.
  • the drive liquid introduction portion 32 in a state in which the sample can flow into the sample inflow portion 31, the drive liquid introduction portion 32 is opened, and the sample suction layer 1 has an amount that reaches the connection portion 21 between the sample flow path 30 and the capillary pump 40.
  • the driving liquid is introduced and then the driving liquid introduction part 32 is closed, the driving liquid moves to the capillary pump 40 due to capillary action, and the sample channel 30 is put in a negative pressure state. It has the function of being able to reach the capillary pump 40 by being sucked into the channel 30 .
  • the sample collection method of the present invention can be performed using the sampling sheet of the present invention having such functions.
  • the sample collection method of the present invention includes (0) a sample suction layer preparation step, (1) a sample inflow step, (2) a driving liquid introduction step, and (3) a sample collection step. Each step will be described below with reference to the drawings.
  • FIG. 3 is a cross-sectional view schematically showing an example of the sample-absorption layer preparation step in the sample-collecting method of the present invention.
  • a sampling sheet 2 having a sample suction layer 1 is prepared.
  • FIG. 4 is a sectional view schematically showing an example of the sample inflow step in the sample collection method of the present invention.
  • the state in which the sample can flow into the sample inlet of the sample suction layer means the state in which the sample can flow into the sample inlet 31 when the sample is sucked from the sample channel 30. It is not to actively flow the sample into the sample inlet 31 using a pump or the like.
  • the sample 50 can be flowed into the sample flow-in part 31 by the microneedle-derived capillary force, the pressure from the sample 50 side (pressure of body fluid, etc.), or the like. can be done.
  • FIG. 5 is a plan view schematically showing an example of the driving liquid introducing step in the sampling method of the present invention.
  • the driving liquid 60 may reach the connecting portion 21 by capillary force. Further, the drive liquid 60 may reach the connection portion 21 by contracting the volume of the flow path up to the connection portion 21 by deformation due to an external force.
  • the driving liquid 60 has a water-absorbing member (such as a member containing a water-absorbing resin described in Japanese Patent No. 5685007, etc.) at the driving liquid introduction portion, and the water-absorbing member expands as it absorbs the driving liquid.
  • the liquid may reach the connecting portion 21 by contracting the volume of the flow path leading to the connecting portion 21 .
  • FIGS. 6A to 6D are plan views schematically showing an example of the sampling process in the sampling method of the present invention.
  • the driving liquid 60 reaching the connecting portion 21 between the sample flow path 30 and the capillary pump 40 is sucked by the capillary action of the capillary pump 40 .
  • the driving liquid introduction part 32 is closed, as shown in FIG. 6B, the driving liquid 60 moves to the capillary pump 40 by capillary action, and the sample channel 30 becomes negative pressure.
  • FIG. 6C the sample 50 is sucked into the sample channel 30 in the negative pressure state.
  • the sample 50 reaches the capillary pump 40, the sample 50 is sucked into the capillary pump 40 as shown in FIG. 6D.
  • the arrows in FIGS. 6B to 6D indicate the direction of suction.
  • the sampling method of the present invention it is preferable to continuously collect the sample 50 in the sampling step, more preferably to perform the sampling step continuously for 1 to 30 days, and to collect the sample continuously for 14 to 30 days. It is more preferable to carry out the steps.
  • the sample 50 When the sample 50 is sucked into the capillary pump 40 , the sample 50 continuously flows from the sample inlet 31 due to the capillary force of the capillary pump. Therefore, a new sample 50 always flows to one point of the sample channel 30 . Therefore, by analyzing the sample 50 at that one point, the condition of the source of the sample can be monitored over time.
  • First film and second film Materials for the first film and the second film are not particularly limited, but preferably a liquid-resistant film, more preferably a resin film, a paper base film, or the like.
  • the resin film is preferably made of polyolefin, polyurethane, or the like.
  • the paper base film is preferably made of cellulose or the like.
  • the surface of the paper-based film is preferably coated with a waterproof sheet, a hydrophobizing agent, an antiblocking agent, or the like.
  • the first film and the second film may be made of the same material or may be made of different materials.
  • the thickness of the first film is preferably 100-1000 ⁇ m.
  • the thickness of the second film is preferably 1-50 ⁇ m.
  • the flow path is formed in the first film, and the second film is laminated on the first film. If the first film and the second film are laminated so that air does not enter the sample channel from the outside when the sample channel of the channel is in a negative pressure state, the lamination method is not particularly limited. Instead, for example, they may be connected with an adhesive, or they may be connected by thermocompression bonding.
  • a capillary pump has a function of moving a driving liquid and a sample into the capillary pump by capillary action.
  • the shape of the capillary pump in the sampling sheet of the present invention is not particularly limited as long as the driving liquid and the sample can be continuously sucked from the sample channel.
  • the capillary pump 40 may be formed by assembling a plurality of capillaries, as shown in FIG.
  • the capillary force may be exerted by gradually decreasing the cross-sectional area of the capillaries from the inlet of the capillary pump toward the back. Also, the capillary force may be exhibited by changing the material of the inner surface of the capillary so that the wettability of the surface increases as it goes deeper.
  • the inner diameter of the capillary is preferably 20 to 500 ⁇ m, more preferably 40 to 200 ⁇ m.
  • the length of the capillary tube is preferably 4 to 100 mm, more preferably 10 to 50 mm.
  • the number of capillaries is preferably 2-30, more preferably 5-10.
  • the capillary pump has an end connected to the sample channel and an end not connected to the sample channel, and the end not connected to the sample channel of the capillary pump has , an atmosphere opening portion and/or a liquid absorption portion are preferably formed.
  • FIG. 7A is a plan view schematically showing an example of a capillary pump in which the sample suction layer of the sampling sheet of the present invention is formed with an atmosphere opening portion.
  • FIG. 7B is a plan view schematically showing an example of a capillary pump in which a liquid absorbing portion is formed in the sample suction layer of the sampling sheet of the present invention.
  • the capillary pump 40 shown in FIG. 7A has an end portion 41 connected to the sample flow channel 30 and an end portion 42 not connected to the sample flow channel 30. is formed with an air release portion 43 .
  • the atmosphere opening portion 43 means that the capillary pump 40 communicates with the outside air without closing the ends of the capillaries constituting the capillary pump 40 .
  • the driving liquid 60 and the sample 50 that have moved inside the capillary pump 40 reach the atmosphere opening portion 43 .
  • Volatile components in the driving liquid 60 and the sample 50 evaporate from the atmosphere opening portion 43 . Therefore, the capillary pump 40 can constantly exert capillary force.
  • the driving liquid 60 and the sample 50 that have moved in the capillary pump 40 flow out from the end portion 42 that is not connected to the sample channel 30 at a liquid volume of 0.01 to 1 ⁇ L/min per unit time.
  • the volatile components of the driving liquid 60 and the sample 50 that have flowed out as described above evaporate from the atmosphere opening portion 43, but the amount of evaporation per unit time is equal to or greater than the amount of liquid that flows out per unit time. preferable.
  • the amount of liquid flowing out per unit time can be adjusted to a preferable range by adjusting the inner diameter of the sample-collecting microneedle 80 (for example, the amount of liquid flowing out per unit time is 1 ⁇ L/ If it exceeds min, there is a tendency that the amount of liquid flowing out per unit time can be reduced by reducing the inner diameter of the sample-collecting microneedle 80).
  • the capillary pump 40 shown in FIG. 7B has an end portion 41 connected to the sample channel 30 and an end portion 42 not connected to the sample channel 30. , a liquid absorbing portion 44 is formed.
  • the capillary pump 40 has the liquid absorbing section 44 , the driving liquid 60 and the sample 50 that have moved inside the capillary pump 40 reach the liquid absorbing section 44 . Liquid components of the driving liquid 60 and the sample 50 are absorbed by the liquid absorbing section 44 . Therefore, the capillary pump 40 can constantly exert capillary force.
  • the configuration of the liquid absorbing portion is not particularly limited as long as it can absorb liquid, but it is preferable that a water absorbing polymer, quick-drying fiber, or hydrophilic particles are dispersed.
  • the water-absorbing polymer is preferably composed of crosslinked polyacrylic acid sodium salt (water-absorbing resin described in Japanese Patent No. 5685007, etc.).
  • the quick-drying fibers are preferably made of quick-drying fibers such as polyester, cotton, rayon, and cupra. Examples of hydrophilic particles include colloidal silica and diatomaceous earth compounds (bentonite, etc.).
  • the quick-drying fiber from the viewpoint of long-term continuous use, the following test was carried out, and the "time until the residual water content became 10% by weight or less" is preferably a fiber of 145 min or less, and 100 min or less. is more preferred, and fibers with 90 min or less are particularly preferred.
  • ⁇ Evaluation test of quick-drying fiber> The quick-drying fiber is cut into a size of 100 mm ⁇ 100 mm to obtain a quick-drying fiber test piece. Next, the quick-drying fiber test piece is brought into contact with a 100 mm ⁇ 100 mm filter paper (circular quantitative filter paper No.
  • hydrophilic particles from the viewpoint of long-term continuous use, the following test was carried out, and "the time until the residual water content became 10% by weight or less" is preferably particles of 145 minutes or less, and 100 minutes or less. is more preferred, and particles with 90 min or less are particularly preferred.
  • Hydrophilic particles are dispersed in water to prepare a 30% by weight aqueous dispersion of hydrophilic particles.
  • a 100 mm ⁇ 100 mm filter paper (circular quantitative filter paper No. 5C) is impregnated with 1 mL of a 30% by weight aqueous dispersion of hydrophilic particles, and dried with a circulating air dryer under the conditions of 130 ° C. for 30 minutes.
  • sample flow path The sample channel is not particularly limited as long as the drive liquid and the sample can pass through it, but the width is preferably 20 to 500 ⁇ m, more preferably 4 to 200 ⁇ m.
  • Only one sample inlet portion may be formed in the sample channel, or a plurality of sample inlet portions may be formed.
  • the method of using the microneedles is mentioned as a means for inflowing the sample into the sample inflow part.
  • the driving liquid introduction part has a sealing function.
  • the driving liquid introduction part has a shape that allows the driving liquid to be introduced into the sample channel.
  • the "sealing function" means a function that can seal the driving liquid introduction part to such an extent that air does not flow in from the driving liquid introduction part when the sample channel is in a negative pressure state.
  • the driving liquid introduction section may have a pumping function for causing the driving liquid to reach the connecting section between the sample channel and the capillary pump.
  • the driving liquid introduction section is formed between the sample inflow section and the connection section. It should be noted that only one drive liquid introduction portion may be formed, or a plurality of drive liquid introduction portions may be formed.
  • Examples of the sealing function of the driving liquid introduction section include a function of sealing the driving liquid introduction section with a manual valve or an electric valve. Further, it may have a function of being deformed by an external force to seal the driving liquid introducing portion. Furthermore, the function may be such that the driving liquid introduction section has a water absorbing member, and the water absorbing member absorbs the driving liquid and expands to seal the driving liquid introduction section.
  • aspects such as the shape of the capillary pump and the sample flow channel are selected so that the sample suction layer of the sampling sheet of the present invention can exhibit its function. It is preferable to set appropriately according to the type.
  • FIG. 8 is a plan view schematically showing an example of the sampling sheet of the present invention having sensor connections.
  • the sample suction layer 1 shown in FIG. 8 has a sensor connection portion 33 formed in the sample channel 30 .
  • the sensor connecting portion 33 is not particularly limited in position as long as it is formed in the sample channel 30 . may be By connecting a sensor to the sensor connection portion 33, the sample 50 flowing through the sample channel 30 can be analyzed by the sensor.
  • the sample suction layer in the sampling sheet of the present invention can continuously suck the sample, it is possible to continuously monitor the state of the source of the sample.
  • the driving liquid used when collecting a sample using the sample suction layer in the sampling sheet of the present invention is water, physiological saline, or the like. Among these, physiological saline is more preferable.
  • the source of the sample collected using the sample suction layer in the sampling sheet of the present invention is preferably a living body such as a human.
  • the sample to be collected is preferably body fluid such as interstitial fluid and blood.
  • interstitial fluid is more preferable.
  • the interstitial fluid has a low solids content and a low non-volatile content. Therefore, when interstitial fluid is used as a sample, the channel is less likely to be clogged with solids and deposited non-volatile components.
  • the sample channel 30 has a single tubular structure, and the sample inflow portion 31 and the driving liquid introduction portion 32 are formed one each.
  • the sample channel may be branched or may be plural.
  • the sample channel may be formed in a straight line, curved line, or curved line. Also, a plurality of sample inlets and drive liquid inlets may be formed.
  • the capillary pump 40 is formed at one location, but the sample suction layer of the sampling sheet of the present invention may have capillary pumps formed at a plurality of locations.
  • Base film preparation step A paper base film is prepared as a base film. After that, the surface forming the flow path is waterproofed.
  • Methods of waterproofing include a method of attaching a waterproof sheet to the base film and a method of applying a hydrophobizing agent to the surface of the base film.
  • Second film lamination step Next, a second film is laminated on the surface of the first film on which the flow paths are formed.
  • the first film and the second film can be laminated by an ordinary method such as an adhesive agent or thermocompression bonding.
  • the sample suction layer of the sampling sheet of the present invention can be manufactured.
  • the first film having the flow path may be manufactured by a resin molding method such as a 3D printer.
  • FIG. 9 is a cross-sectional view schematically showing an example of a cross section perpendicular to the planar direction of the inspection sheet of the present invention.
  • the inspection sheet 3 shown in FIG. 9 is composed of the sampling sheet 2 and a sensing layer 90 laminated on the sample suction layer 1 of the sampling sheet 2 and having a sensor 91 .
  • the sensor connection portion 33 is formed in at least a part of the sample channel 30 of the sample suction layer 1 , and the sensor 91 of the sensing layer 90 is connected to the sensor connection portion 33 of the sample suction layer 1 . It is connected to the.
  • samples in the living body can be continuously collected. Therefore, by analyzing the sample with the sensor 91, the biological biomarkers can be continuously monitored, and the biological information can be confirmed in real time.
  • the biomarkers to be analyzed by the sensor 91 are preferably set appropriately according to the purpose, and may be low-molecular-weight biomarkers such as cortisol and blood sugar, or high-molecular-weight biomarkers such as proteins and nucleic acids. Also, the sensor 91 may be used to analyze pH and odor components.
  • the sensing layer 90 and the sampling sheet 2 can be separated, and the sampling sheet 2 may be disposable. With such a structure, it is possible to repeatedly use the inspection sheet 3 by exchanging the sampling sheet 2 .
  • the inspection sheet 3 may have a communication device that enables communication between the sensor 91 and an external recording device or control device. If the inspection sheet 3 has such a communication device, it is possible to easily monitor the living body and control the sensor 91 .
  • the inspection sheet 3 may have a pseudo skin layer as the outermost layer.
  • the pseudo-skin layer is composed of a pseudo-skin positioned outside and an elastic layer formed inside the pseudo-skin.
  • the artificial skin is preferably made of urethane skin agent, synthetic rubber (such as silicone rubber), natural rubber, or the like.
  • the elastic layer is preferably made of urethane protective layer, polystyrene foam, polymer sponge, or the like. If the test sheet 3 has a pseudo skin layer, the sensing layer 90 and the sampling sheet 2 can be protected against external impact. In addition, the appearance of the inspection sheet 3 can be made to resemble the skin of a living body.
  • the present disclosure (1) includes a sample suction layer, a microneedle formation surface on which sample collection microneedles are formed, and a microneedle having an adhesive surface facing the microneedle formation surface and in contact with the sample suction layer.
  • the sample suction layer includes a first film having a concave channel and a second film laminated on the first film so as to cover the channel.
  • the flow path includes a sample flow path and a capillary pump connected to the sample flow path, and the sample flow path is formed with a sample inflow portion and a driving liquid introduction portion having a sealing function.
  • the driving liquid introduction portion is opened to introduce an amount of the driving liquid that reaches the connection portion between the sample flow channel and the capillary pump, and then When the driving liquid introduction part is closed, the driving liquid moves to the capillary pump due to capillary action, so that the sample flow path becomes in a negative pressure state, and the sample is sucked into the sample flow path in the negative pressure state.
  • the microneedle for sample collection is a sampling sheet communicating with the sample inflow portion of the sample suction layer.
  • the present disclosure (2) is the sampling sheet according to the present disclosure (1), wherein the driving liquid introduction section is formed between the sample inflow section and the connection section.
  • the capillary pump has an end connected to the sample channel and an end not connected to the sample channel, and the end of the capillary pump not connected to the sample channel is the sampling sheet according to (1) or (2) of the present disclosure, in which an atmosphere opening portion and/or a liquid absorbing portion are formed.
  • the present disclosure (4) is the sampling sheet according to the present disclosure (3), wherein the liquid absorbing portion is dispersed with a water absorbing polymer.
  • the present disclosure (5) is the sampling sheet according to any one of the present disclosures (1) to (4), wherein a sensor connection portion is formed in at least a part of the sample channel.
  • the present disclosure (6) comprises the sampling sheet according to the present disclosure (5), and a sensing layer laminated on the sample suction layer of the sampling sheet and having a sensor, wherein the sensor of the sensing layer includes the sample A test sheet connected to the sensor connection portion of the suction layer.
  • the present disclosure (7) uses the sample-collecting microneedle constituting the sampling sheet according to any one of the present disclosure (1) to (5) to allow a sample to flow into the sample inflow portion of the sample suction layer.
  • the driving liquid introduction part is closed, and the driving liquid is moved to the capillary pump by capillary action to put the sample channel in a negative pressure state, and the sample is sucked into the sample channel in the negative pressure state, and the capillary is moved. and a sampling step of reaching the pump.
  • the present disclosure (8) is the sampling method according to the present disclosure (7), in which the samples are continuously collected in the sample collection step.
  • the present disclosure (9) is the sampling method according to the present disclosure (7) or (8), wherein the sampling step is performed continuously for 1 to 30 days.
  • the present disclosure (10) is the sampling method according to any one of the present disclosure (7) to (9), wherein the sample is interstitial fluid.
  • Quick-drying fibers Dry-X (manufactured by Daiichi Boseki Co., Ltd.) and Powered Spun (manufactured by Fine Track Co., Ltd.) were prepared and cut into a size of 100 mm ⁇ 100 mm to obtain a quick-drying fiber test piece. .
  • the time required for the residual water content of the filter paper to reach 10% by weight or less was measured.
  • the quick-drying fiber used is dry-ex, it takes 70 minutes to reach 10% by weight or less.
  • the quick-drying fiber used was a powered spun, it took 75 minutes to reach 10% by weight or less.
  • hydrophilic particles As hydrophilic particles, SNOWTEX 30 (manufactured by Nissan Chemical Co., Ltd.) was dispersed in water to prepare an aqueous dispersion of 30% by weight of hydrophilic particles. Next, a 100 mm ⁇ 100 mm filter paper (circular quantitative filter paper No. 5C) was impregnated with 1 mL of a 30% by weight aqueous dispersion of Snowtex 30, and dried at 130 ° C. for 30 minutes with a circulation dryer. A hydrophilic particle specimen was prepared that was dried and impregnated with hydrophilic particles.
  • a filter paper (circular quantitative filter paper No. 5C) was cut into a size of 10 mm ⁇ 10 mm to obtain a test sample 1. Dry-ex and filter paper (circular quantitative filter paper No. 5C) were cut into pieces of 10 mm ⁇ 10 mm, and these were superimposed to obtain test sample 2. A powered span and filter paper (circular quantitative filter paper No. 5C) were cut into 10 mm ⁇ 10 mm pieces, and these were superimposed to obtain test sample 3. An aqueous dispersion of 3% by weight Snowtex 30 was prepared. Next, filter paper (circular quantitative filter paper No.
  • FIG. 10 is a schematic diagram schematically showing the transpiration test.
  • a capillary 140 was prepared and positioned such that one end 142 of capillary 140 contacted each test sample 144 .
  • 0.5 ⁇ L of water was intermittently added from the other end 141 of the capillary 140 once every 10 minutes. This operation reproduced the state in which the amount of water flowing out from one end 142 per unit time was 0.05 ⁇ m/min.
  • the weight of water in each test sample was measured 1 hour, 2 hours and 3 hours after the start of water addition.
  • the weight of water contained in each test sample was calculated from the weight of each test sample 1 hour, 2 hours and 3 hours after the start of water addition, and the weight of each test sample when dry (before the start of the test). It was calculated as a numerical value after subtracting the weight. Table 1 shows the results.
  • test samples 2 to 4 showed less increase in weight of water contained in the test samples than test sample 1 over time. This is probably because the test samples 2 to 4 have better moisture transpiration properties than the test sample 1.
  • the use of Dry-X, Powered Spun, and Snowtex 30 as the material for the liquid-absorbing portion improves the transpiration of water. Therefore, it is considered that a sampling sheet having a liquid absorbing portion using these materials can be used continuously for a long period of time.
  • the sampling sheet of the present invention By using the sampling sheet of the present invention, it is possible to continuously aspirate samples. Therefore, the sampling sheet of the present invention is useful as a configuration for successively aspirating a sample in a test sheet for successively and instantaneously monitoring biological information.

Abstract

Provided is a small and portable sampling sheet for use as an inspection sheet capable of successively analyzing samples. The sampling sheet according to the present invention comprises a sample suction layer and a microneedle layer having a microneedle formation surface on which sample-collecting microneedles are formed and an adhesive surface facing the microneedle formation surface and in contact with the sample suction layer, wherein the sample suction layer includes a first film having a recessed flow path and a second film laminated on the first film so as to cover the flow path, the flow path includes a sample flow path and a capillary pump connected to the sample flow path, a sample inflow portion and a driving liquid introduction portion having a sealing function are formed in the sample flow path, in a state in which the sample can flow into the sample inflow portion, the driving liquid introduction portion is opened to introduce a driving liquid in an amount that reaches a connection portion between the sample flow path and the capillary pump, and when the driving liquid introduction portion is thereafter closed, the driving liquid moves to the capillary pump due to capillary action, so that the sample flow path becomes in a negative pressure state, the sample is sucked into the sample flow path in the negative pressure state, whereby the capillary pump can be reached, and the sample-collecting microneedles communicate with the sample inflow portion of the sample suction layer.

Description

サンプリングシート、検査用シート及び試料採取方法Sampling sheet, inspection sheet and sampling method
本発明は、サンプリングシート、検査用シート及び試料採取方法に関する。 TECHNICAL FIELD The present invention relates to a sampling sheet, an inspection sheet, and a sample collection method.
生体の状態を確認するために、血液等の試料を用いてバイオマーカーを分析する方法は従来から行われている。このようなバイオマーカーを分析する装置は、一度に処理する試料の数を多くし、分析の処理速度を向上させるため大型化している。 In order to confirm the state of a living body, a method of analyzing biomarkers using a sample such as blood has been conventionally performed. Devices for analyzing such biomarkers are becoming larger in order to increase the number of samples to be processed at one time and improve the processing speed of analysis.
しかし、上記の方法でバイオマーカーを測定する場合、試料採取から分析までに時間がかかり、迅速に生体の状態を確認することは難しかった。
また、バイオマーカーを分析する装置は、大型であるので、スペースが限られている救急現場や手術室等に設置するのは困難であった。さらに、この装置は、洗浄液や廃液の配管が必要なことから、所定の場所に固定的に設置されるため、在宅患者やベッドサイドへ移動・持ち運ぶのは極めて困難であった。 However, when biomarkers are measured by the above methods, it takes time from sample collection to analysis, and it is difficult to quickly confirm the state of the living body.
In addition, since the apparatus for analyzing biomarkers is large, it is difficult to install it in an emergency site, an operating room, or the like, where space is limited. Furthermore, since this device requires piping for the cleaning liquid and the waste liquid, it is installed fixedly at a predetermined location, making it extremely difficult to move or carry it to a patient at home or to the bedside.
特許文献１には、試料採取から試料までを迅速に行うことができ、小型で、可搬で、扱いが容易な検査シートが開示されている。
すなわち、特許文献１には、吸水による膨張性を有するシート状の紙基材と、前記紙基材の表面に設けられた第１の耐液性フィルムと、前記第１の耐液性フィルムが設けられた前記紙基材の面に形成された凹形状の流路を上面から封止する第２の耐液性フィルムと、を備え、前記流路として、一端に液体の試料が導入される開口部が設けられ、他端に大気開放部が設けられ、それらの間に所定の容積を有するサンプリング流路が設けられ、前記第１の耐液性フィルム及び前記第２の耐液性フィルムに設けられた開口を介した吸水による前記紙基材の膨張により駆動される第１の毛細管力及び第１のポンプ圧の少なくとも一方により、前記開口部に導入された液体の試料を前記サンプリング流路に送る送液部が設けられている第１の流路と、一端に開口部が設けられ、他端に大気開放部が設けられ、それらの間に前記サンプリング流路が設けられ、前記第１の耐液性フィルム及び前記第２の耐液性フィルムに設けられた開口を介した吸水による前記紙基材の膨張により駆動される第２の毛細管力及び第２のポンプ圧の少なくとも一方により、前記サンプリング流路に送られた前記試料を下流に送る送液部が設けられている第２の流路と、が形成され、送られた前記試料と液体の試薬とを混合するための混合用セルと、前記混合用セルで前記試薬と混合された前記試料の特性を検出する検出用セルと、が形成されている検査用シートが開示されている。 Patent Literature 1 discloses a small-sized, portable, and easy-to-handle test sheet that enables rapid processing from sample collection to sample collection.
That is, in Patent Document 1, a sheet-like paper substrate having swelling property due to water absorption, a first liquid-resistant film provided on the surface of the paper substrate, and the first liquid-resistant film a second liquid-resistant film that seals from the upper surface a concave-shaped flow path formed on the surface of the paper substrate provided, and a liquid sample is introduced to one end of the flow path. An opening is provided, an air opening is provided at the other end, a sampling channel having a predetermined volume is provided between them, and the first liquid-resistant film and the second liquid-resistant film are provided with At least one of a first capillary force and a first pump pressure driven by expansion of the paper base material due to water absorption through the provided opening causes the liquid sample introduced into the opening to flow through the sampling channel. A first flow path provided with a liquid feeding section for sending to the At least one of a second capillary force and a second pump pressure driven by expansion of the paper substrate due to water absorption through openings provided in the liquid-resistant film and the second liquid-resistant film, and a second flow path provided with a liquid feeding section that feeds the sample sent to the sampling flow path downstream, and is used for mixing the sent sample and a liquid reagent. A test sheet is disclosed in which a cell and a detection cell for detecting characteristics of the sample mixed with the reagent in the mixing cell are formed.
特許第５６８８６３５号公報Japanese Patent No. 5688635
近年、継時的かつ即時的な生体情報のモニタリングも重要になっている。特許文献１に記載の検査用シートは、１度の分析は迅速に行うことができるものの、連続的に分析できないという問題があった。 In recent years, continuous and immediate monitoring of biological information has also become important. The inspection sheet described in Patent Document 1 has the problem that although one-time analysis can be performed quickly, continuous analysis cannot be performed.
本発明は、上記問題点を鑑みてなされた発明であり、本発明の目的は、小型で、可搬であり、かつ、継時的に試料を分析することができる検査用シートに用いるためのサンプリングシート、これらを含む検査用シート、並びに、試料採取方法を提供することである。 The present invention is an invention made in view of the above problems, and an object of the present invention is to provide a test sheet that is small, portable, and capable of continuously analyzing samples. An object of the present invention is to provide a sampling sheet, an inspection sheet containing these sheets, and a method for collecting a sample.
本発明者は、これらの課題を解決するべく鋭意検討した結果、本発明に到達した。
すなわち本発明は、試料吸引層と、試料採取用マイクロニードルが形成されたマイクロニードル形成面、及び、上記マイクロニードル形成面と対向し、上記試料吸引層に接触する接着面を有するマイクロニードル層とからなるサンプリングシートであって、上記試料吸引層は、凹形状の流路を有する第１フィルムと、上記流路を覆うように上記第１フィルムの上に積層された第２フィルムとを備え、上記流路は、試料流路と、上記試料流路に接続するキャピラリーポンプとを備え、上記試料流路には、試料流入部と、密閉機能を有する駆動液導入部とが形成されており、上記試料流入部に試料が流入できるようにした状態で、上記駆動液導入部を開けて、上記試料流路と上記キャピラリーポンプとの接続部まで到達する量の駆動液を導入し、その後、上記駆動液導入部を閉めた際、上記駆動液が、毛細管現象によりキャピラリーポンプに移動することにより上記試料流路が陰圧状態となり、上記試料が陰圧状態の上記試料流路に吸引されることにより、上記キャピラリーポンプまで到達でき、上記試料採取用マイクロニードルは、上記試料吸引層の上記試料流入部に通じているサンプリングシート；
上記本発明のサンプリングシートと、上記サンプリングシートの上記試料吸引層に積層され、センサを有するセンシング層とからなり、上記試料吸引層の試料流路の少なくとも一部にはセンサ接続部が形成されており、上記センシング層の上記センサは、上記試料吸引層の上記センサ接続部に接続されている検査用シート；
上記本発明のサンプリングシートを構成する上記試料採取用マイクロニードルを用いて、上記試料吸引層の試料流入部に試料が流入できるようにする試料流入工程と、上記試料吸引層の駆動液導入部を開けて、上記試料流路と上記キャピラリーポンプとの接続部まで到達する量の駆動液を導入する駆動液導入工程と、上記駆動液導入部を閉め、上記駆動液を、毛細管現象によりキャピラリーポンプに移動させることにより上記試料流路を陰圧状態とし、上記試料を陰圧状態の上記試料流路に吸引させて、上記キャピラリーポンプまで到達させる試料採取方法に関する。 The present inventor arrived at the present invention as a result of intensive studies to solve these problems.
That is, the present invention includes a sample suction layer, a microneedle formation surface on which sample collection microneedles are formed, and a microneedle layer having an adhesive surface facing the microneedle formation surface and in contact with the sample suction layer. wherein the sample suction layer comprises a first film having a concave channel, and a second film laminated on the first film so as to cover the channel, The channel includes a sample channel and a capillary pump connected to the sample channel, and the sample channel is formed with a sample inlet and a driving liquid inlet having a sealing function, In a state in which the sample can flow into the sample inflow portion, the driving liquid introduction portion is opened to introduce an amount of the driving liquid that reaches the connection portion between the sample flow channel and the capillary pump, and then the When the driving liquid introduction part is closed, the driving liquid moves to the capillary pump due to capillary action, so that the sample flow path becomes in a negative pressure state, and the sample is sucked into the sample flow path in the negative pressure state. A sampling sheet that can reach the capillary pump, and the sample-collecting microneedle communicates with the sample inflow portion of the sample suction layer;
It comprises the sampling sheet of the present invention and a sensing layer having a sensor laminated on the sample suction layer of the sampling sheet, and a sensor connection part is formed in at least a part of the sample channel of the sample suction layer. an inspection sheet in which the sensor of the sensing layer is connected to the sensor connection portion of the sample suction layer;
A sample inflow step of allowing the sample to flow into the sample inflow portion of the sample suction layer using the sample-collecting microneedle constituting the sampling sheet of the present invention, and a driving liquid introduction portion of the sample suction layer. a driving liquid introducing step of opening and introducing an amount of the driving liquid that reaches the connecting portion between the sample channel and the capillary pump; and closing the driving liquid introducing portion to introduce the driving liquid into the capillary pump by capillary action. The present invention relates to a sample collection method in which the sample channel is moved to a negative pressure state, and the sample is sucked into the negative pressure sample channel and reaches the capillary pump.
本発明によれば、小型で、可搬であり、かつ、継時的に試料を分析することができる検査用シートに用いるための試料吸引層を提供することができる。 According to the present invention, it is possible to provide a sample suction layer for use in a test sheet that is small, portable, and capable of continuously analyzing samples.
図１は、本発明のサンプリングシートの平面方向に垂直な断面の一例を模式的に示す断面図である。FIG. 1 is a cross-sectional view schematically showing an example of a cross section perpendicular to the plane direction of the sampling sheet of the present invention. 図２Ａは、本発明のサンプリングシートにおける試料吸引層の一例を模式的に示す平面図である。FIG. 2A is a plan view schematically showing an example of the sample suction layer in the sampling sheet of the present invention. 図２Ｂは、図２ＡのＡ－Ａ線断面図である。FIG. 2B is a cross-sectional view taken along line AA of FIG. 2A. 図３は、本発明の試料採取方法における試料吸引層準備工程の一例を模式的に示す断面図である。FIG. 3 is a cross-sectional view schematically showing an example of the sample suction layer preparation step in the sample collection method of the present invention. 図４は、本発明の試料採取方法における試料流入工程の一例を模式的に示す断面図である。FIG. 4 is a cross-sectional view schematically showing an example of the sample inflow step in the sample collection method of the present invention. 図５は、本発明の試料採取方法における駆動液導入工程の一例を模式的に示す平面図である。FIG. 5 is a plan view schematically showing an example of the driving liquid introducing step in the sampling method of the present invention. 図６Ａは、本発明の試料採取方法における試料採取工程の一例を模式的に示す平面図である。FIG. 6A is a plan view schematically showing an example of a sample collection step in the sample collection method of the present invention. 図６Ｂは、本発明の試料採取方法における試料採取工程の一例を模式的に示す平面図である。FIG. 6B is a plan view schematically showing an example of the sampling process in the sampling method of the present invention. 図６Ｃは、本発明の試料採取方法における試料採取工程の一例を模式的に示す平面図である。FIG. 6C is a plan view schematically showing an example of the sampling process in the sampling method of the present invention. 図６Ｄは、本発明の試料採取方法における試料採取工程の一例を模式的に示す平面図である。FIG. 6D is a plan view schematically showing an example of the sampling process in the sampling method of the present invention. 図７Ａは、本発明のサンプリングシートにおける試料吸引層において、大気開放部が形成されたキャピラリーポンプの一例を模式的に示す平面図である。FIG. 7A is a plan view schematically showing an example of a capillary pump in which the sample suction layer of the sampling sheet of the present invention is formed with an atmosphere opening portion. 図７Ｂは、本発明のサンプリングシートにおける試料吸引層において、液体吸収部が形成されたキャピラリーポンプの一例を模式的に示す平面図である。FIG. 7B is a plan view schematically showing an example of a capillary pump in which a liquid absorbing portion is formed in the sample suction layer of the sampling sheet of the present invention. 図８は、センサ接続部を有する本発明のサンプリングシートの一例を模式的に示す平面図である。FIG. 8 is a plan view schematically showing an example of the sampling sheet of the present invention having sensor connections. 図９は、本発明の検査用シートの平面方向に垂直な断面の一例を模式的に示す断面図である。FIG. 9 is a cross-sectional view schematically showing an example of a cross section perpendicular to the planar direction of the inspection sheet of the present invention. 図１０は、蒸散性試験を模式的に示す模式図である。FIG. 10 is a schematic diagram schematically showing the transpiration test.
以下、本発明を詳細に説明する。
本発明のサンプリングシートは、試料吸引層と、試料採取用マイクロニードルが形成されたマイクロニードル形成面、及び、上記マイクロニードル形成面と対向し、上記試料吸引層に接触する接着面を有するマイクロニードル層とからなるサンプリングシートであって、上記試料吸引層は、凹形状の流路を有する第１フィルムと、上記流路を覆うように上記第１フィルムの上に積層された第２フィルムとを備え、上記流路は、試料流路と、上記試料流路に接続するキャピラリーポンプとを備え、上記試料流路には、試料流入部と、密閉機能を有する駆動液導入部とが形成されており、上記試料流入部に試料が流入できるようにした状態で、上記駆動液導入部を開けて、上記試料流路と上記キャピラリーポンプとの接続部まで到達する量の駆動液を導入し、その後、上記駆動液導入部を閉めた際、上記駆動液が、毛細管現象によりキャピラリーポンプに移動することにより上記試料流路が陰圧状態となり、上記試料が陰圧状態の上記試料流路に吸引されることにより、上記キャピラリーポンプまで到達でき、上記試料採取用マイクロニードルは、上記試料吸引層の上記試料流入部に通じている。 The present invention will be described in detail below.
The sampling sheet of the present invention includes a sample suction layer, a microneedle formation surface on which sample collection microneedles are formed, and a microneedle having an adhesive surface facing the microneedle formation surface and in contact with the sample suction layer. wherein the sample suction layer includes a first film having a concave channel and a second film laminated on the first film so as to cover the channel. wherein the flow path includes a sample flow path and a capillary pump connected to the sample flow path, and the sample flow path is formed with a sample inflow portion and a driving liquid introduction portion having a sealing function. In a state in which the sample can flow into the sample inflow portion, the driving liquid introduction portion is opened to introduce an amount of the driving liquid that reaches the connection portion between the sample flow channel and the capillary pump, and then When the driving liquid introduction part is closed, the driving liquid moves to the capillary pump due to capillary action, so that the sample flow path becomes in a negative pressure state, and the sample is sucked into the sample flow path in the negative pressure state. As a result, even the capillary pump can be reached, and the sample-collecting microneedle communicates with the sample inflow portion of the sample suction layer.
本発明のサンプリングシートは、上記構成を有していれば、発明の効果を奏する範囲で、他にどのような構成を有していてもよい。 As long as the sampling sheet of the present invention has the above structure, it may have any other structure as long as the effect of the invention is exhibited.
図１は、本発明のサンプリングシートの平面方向に垂直な断面の一例を模式的に示す断面図である。 FIG. 1 is a cross-sectional view schematically showing an example of a cross section perpendicular to the plane direction of the sampling sheet of the present invention.
図１に示すサンプリングシート２は、上記試料吸引層１と、試料採取用マイクロニードル８０が形成されたマイクロニードル形成面７１、及び、マイクロニードル形成面７１と対向し、試料吸引層１に接触する接着面７２を有するマイクロニードル層７０とからなる。 The sampling sheet 2 shown in FIG. 1 faces the sample suction layer 1, the microneedle formation surface 71 on which the sample collection microneedles 80 are formed, and the microneedle formation surface 71, and contacts the sample suction layer 1. and a microneedle layer 70 having an adhesive surface 72 .
まず、マイクロニードル層７０について説明する。 First, the microneedle layer 70 will be described.
マイクロニードル層７０の材料は特に限定されないが、例えばアルミニウムやステンレス合金などの金属、シリコン、カーボン、セラミック、カルシウム系鉱物を含む各種鉱物材料などの各種無機材料や、有機系の高分子化合物等であることが好ましい。 Although the material of the microneedle layer 70 is not particularly limited, for example, metals such as aluminum and stainless alloys, various inorganic materials such as silicon, carbon, ceramics, various mineral materials including calcium-based minerals, and organic polymer compounds. Preferably.
マイクロニードル層の厚み（図１中、符号Ｔで示す厚み）は、２００～３０００μｍであることが好ましく、５００～１０００μｍであることがより好ましい。 The thickness of the microneedle layer (thickness indicated by symbol T in FIG. 1) is preferably 200 to 3000 μm, more preferably 500 to 1000 μm.
試料採取用マイクロニードル８０は、中空であり、内部を試料が通過できるようになっている。 The sample-collecting microneedle 80 is hollow so that the sample can pass through it.
サンプリングシート２では、試料採取用マイクロニードル８０は、後述する試料吸引層１の試料流入部３１に通じている。 In the sampling sheet 2, the sample-collecting microneedle 80 communicates with the sample inflow portion 31 of the sample suction layer 1, which will be described later.
試料採取用マイクロニードル８０の材料としては、特に限定されないが、例えばアルミニウムやステンレス合金などの金属、シリコン、カーボン、セラミック、カルシウム系鉱物を含む各種鉱物材料などの各種無機材料や、有機系の高分子化合物等であることが好ましい。 The material of the sample-collecting microneedle 80 is not particularly limited, but for example, various inorganic materials such as metals such as aluminum and stainless alloys, silicon, carbon, ceramics, various mineral materials including calcium-based minerals, and organic high-strength materials. It is preferably a molecular compound or the like.
高分子化合物としては、既知の化合物（合成高分子及び天然高分子）を使用することができる。例えばＰＥＴ（ポリエチレンテレフタレート）や、ポリエチレン、ポリプロピレン、アクリル樹脂、エポキシ樹脂、ポリスチレンなど、種々のプラスチック材料の他、生体吸収高分子を使用することができる。 Known compounds (synthetic polymers and natural polymers) can be used as the polymer compound. For example, various plastic materials such as PET (polyethylene terephthalate), polyethylene, polypropylene, acrylic resin, epoxy resin, and polystyrene, as well as bioabsorbable polymers can be used.
生体吸収高分子としては、既知の化合物（合成高分子及び天然高分子）を使用することができる。例えば、ポリ乳酸、ポリグリコール酸、ポリ－εカプロラクトン、ポリ－ρ－ジオキサン、ポリリンゴ酸などのエステル化合物、ポリ酸無水物などの酸無水物、ポリオルソエステルなどのオルソエステル化合物、ポリカーボネートなどのカーボネート化合物、ポリジアミノホスファゼンなどのホスファゼン化合物、合成ポリペプチドなどのペプチド化合物、ポリホスホエステルウレタンなどのリン酸エステル化合物、ポリシアノアクリレートなどの炭素－炭素化合物、ポリ－β－ヒドロキシ酪酸、ポリリンゴ酸などのエステル化合物、ポリアミノ酸、キチン、キトサン、ヒアルロン酸、ヒアルロン酸ナトリウム、ペクチン酸、ガラクタン、デンプン、デキストラン、デキストリン、アルギン酸、アルギン酸ナトリウム、セルロース化合物（エチルセルロース、カルボキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース）、ゼラチン、寒天、ケルトロール、レオザン、キサンタンガム、プルラン、アラビアゴムなどのグリコシド化合物（多糖類）、コラーゲン、ゼラチン、フィブリン、グルテン、血清アルブミンなどのペプチド化合物（ペプチド、タンパク質）、デオキシリボ核酸、リボ核酸などのリン酸エステル化合物（核酸）、ポリビニルアルコールなどのビニル化合物などが挙げられる。 Known compounds (synthetic polymers and natural polymers) can be used as bioabsorbable polymers. For example, ester compounds such as polylactic acid, polyglycolic acid, poly-ε-caprolactone, poly-ρ-dioxane, and polymalic acid, acid anhydrides such as polyanhydrides, orthoester compounds such as polyorthoesters, and carbonates such as polycarbonates. compounds, phosphazene compounds such as polydiaminophosphazene, peptide compounds such as synthetic polypeptides, phosphate ester compounds such as polyphosphoester urethane, carbon-carbon compounds such as polycyanoacrylate, poly-β-hydroxybutyric acid, polymalic acid, etc. Ester compound, polyamino acid, chitin, chitosan, hyaluronic acid, sodium hyaluronate, pectic acid, galactan, starch, dextran, dextrin, alginic acid, sodium alginate, cellulose compounds (ethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose), glycoside compounds (polysaccharides) such as gelatin, agar, keltrol, leozan, xanthan gum, pullulan, gum arabic, peptide compounds (peptides, proteins) such as collagen, gelatin, fibrin, gluten, serum albumin, deoxyribose Phosphate ester compounds (nucleic acids) such as nucleic acids and ribonucleic acids, vinyl compounds such as polyvinyl alcohol, and the like.
試料採取用マイクロニードル８０の外径は１００～１０００μｍであることが好ましく、３００～７００μｍであることがより好ましい。
また、試料採取用マイクロニードル８０の内径は１０～１００μｍであることが好ましく、３０～７０μｍであることがより好ましい。
試料採取用マイクロニードル８０の長さ（図１中、符号Ｌで示す距離）は２００～２０００μｍであることが好ましく、５００～１０００μｍであることがより好ましい。 The outer diameter of the sample-collecting microneedle 80 is preferably 100-1000 μm, more preferably 300-700 μm.
The inner diameter of the sample-collecting microneedle 80 is preferably 10 to 100 μm, more preferably 30 to 70 μm.
The length of the sample-collecting microneedle 80 (distance indicated by symbol L in FIG. 1) is preferably 200 to 2000 μm, more preferably 500 to 1000 μm.
試料採取用マイクロニードル８０は１本のみが形成されていてもよく、複数本が形成されていてもよい。 Only one sample-collecting microneedle 80 may be formed, or a plurality of sample-collecting microneedles 80 may be formed.
図１では、試料採取用マイクロニードル８０はマイクロニードル層７０と一体化して形成されているが、これらは別の部材として形成されていてもよい。
この場合、マイクロニードル層及び試料採取用マイクロニードルの材料は同じであってもよく、異なっていてもよい。 Although the sample-collecting microneedles 80 are integrally formed with the microneedle layer 70 in FIG. 1, they may be formed as separate members.
In this case, the materials of the microneedle layer and the sampling microneedles may be the same or different.
サンプリングシート２では、マイクロニードル形成面７１に、低刺激性皮膚粘着剤（特開２００８－２４７８２０号公報等に記載の粘着剤組成物）等がコーティングされていてもよい。
また、マイクロニードル層は、公知の方法（モールドを使用する方法等）等により、製造することができる。 In the sampling sheet 2, the microneedle forming surface 71 may be coated with a hypoallergenic skin adhesive (adhesive composition described in JP-A-2008-247820, etc.) or the like.
Also, the microneedle layer can be manufactured by a known method (such as a method using a mold).
次に、本発明のサンプリングシートを構成する試料吸引層について説明する。 Next, the sample suction layer constituting the sampling sheet of the present invention will be described.
図２Ａは、本発明のサンプリングシートにおける試料吸引層の一例を模式的に示す平面図である。
図２Ｂは、図２ＡのＡ－Ａ線断面図である。
図２Ａ及び図２Ｂに示す試料吸引層１は、凹形状の流路２０を有する第１フィルム１１と、流路２０を覆うように第１フィルム１１の上に積層された第２フィルム１２とを備える。 FIG. 2A is a plan view schematically showing an example of the sample suction layer in the sampling sheet of the present invention.
FIG. 2B is a cross-sectional view taken along line AA of FIG. 2A.
The sample suction layer 1 shown in FIGS. 2A and 2B comprises a first film 11 having a concave channel 20 and a second film 12 laminated on the first film 11 so as to cover the channel 20. Prepare.
また、流路２０は、試料流路３０と、試料流路３０に接続するキャピラリーポンプ４０とを備え、試料流路３０には、試料流入部３１と、密閉機能を有する駆動液導入部３２とが形成されている。 The channel 20 includes a sample channel 30 and a capillary pump 40 connected to the sample channel 30. The sample channel 30 includes a sample inlet 31 and a driving liquid inlet 32 having a sealing function. is formed.
また、試料吸引層１は、試料流入部３１に試料が流入できるようにした状態で、駆動液導入部３２を開けて、試料流路３０とキャピラリーポンプ４０との接続部２１まで到達する量の駆動液を導入し、その後、駆動液導入部３２を閉めた際、駆動液が、毛細管現象によりキャピラリーポンプ４０に移動することにより試料流路３０が陰圧状態となり、試料が陰圧状態の試料流路３０に吸引されることにより、キャピラリーポンプ４０まで到達できるという機能を有する。 In addition, in the sample suction layer 1, in a state in which the sample can flow into the sample inflow portion 31, the drive liquid introduction portion 32 is opened, and the sample suction layer 1 has an amount that reaches the connection portion 21 between the sample flow path 30 and the capillary pump 40. When the driving liquid is introduced and then the driving liquid introduction part 32 is closed, the driving liquid moves to the capillary pump 40 due to capillary action, and the sample channel 30 is put in a negative pressure state. It has the function of being able to reach the capillary pump 40 by being sucked into the channel 30 .
このような機能を有する本発明のサンプリングシートを用いて本発明の試料採取方法を行うことができる。
本発明の試料採取方法は、（０）試料吸引層準備工程、（１）試料流入工程、（２）駆動液導入工程、及び、（３）試料採取工程を含む。
各工程について、図面を用いて以下に説明する。 The sample collection method of the present invention can be performed using the sampling sheet of the present invention having such functions.
The sample collection method of the present invention includes (0) a sample suction layer preparation step, (1) a sample inflow step, (2) a driving liquid introduction step, and (3) a sample collection step.
Each step will be described below with reference to the drawings.
（０）試料吸引層準備工程
図３は、本発明の試料採取方法における試料吸引層準備工程の一例を模式的に示す断面図である。
本発明の試料採取方法では、まず、図３に示すように、試料吸引層１を備えるサンプリングシート２を準備する。 (0) Sample-Absorbing Layer Preparation Step FIG. 3 is a cross-sectional view schematically showing an example of the sample-absorption layer preparation step in the sample-collecting method of the present invention.
In the sample collection method of the present invention, first, as shown in FIG. 3, a sampling sheet 2 having a sample suction layer 1 is prepared.
（１）試料流入工程
図４は、本発明の試料採取方法における試料流入工程の一例を模式的に示す断面図である。
上記「（０）試料吸引層準備工程」の後、図４に示すように、サンプリングシート２のマイクロニードル形成面７１が生体Ｂの表面に接触するように配置する。
これにより、試料採取用マイクロニードル８０が生体Ｂの表面に刺さり、生体Ｂの内部に入ることになる。 (1) Sample inflow step FIG. 4 is a sectional view schematically showing an example of the sample inflow step in the sample collection method of the present invention.
After the above "(0) sample suction layer preparation step", as shown in FIG.
As a result, the sample-collecting microneedle 80 sticks into the surface of the living body B and enters the inside of the living body B. As shown in FIG.
これにより、試料採取用マイクロニードル８０を通じて、試料吸引層１の試料流入部３１に試料が流入できるようになる。
なお、本明細書において、「試料吸引層の試料流入部に試料が流入できる状態」とは、試料流路３０から吸引等がされると試料が試料流入部３１に流入できる状態を意味し、ポンプ等で能動的に試料を、試料流入部３１に流入させることではない。
また、「試料流路３０から吸引」以外にも、マイクロニードル由来毛細管力、試料５０側からの圧力（体液等の圧力）等によっても、試料５０が試料流入部３１に流入できるようにすることができる。 This allows the sample to flow into the sample inflow portion 31 of the sample suction layer 1 through the sample-collecting microneedle 80 .
In the present specification, "the state in which the sample can flow into the sample inlet of the sample suction layer" means the state in which the sample can flow into the sample inlet 31 when the sample is sucked from the sample channel 30. It is not to actively flow the sample into the sample inlet 31 using a pump or the like.
In addition to "sucking from the sample flow path 30", the sample 50 can be flowed into the sample flow-in part 31 by the microneedle-derived capillary force, the pressure from the sample 50 side (pressure of body fluid, etc.), or the like. can be done.
（２）駆動液導入工程
図５は、本発明の試料採取方法における駆動液導入工程の一例を模式的に示す平面図である。
上記「（１）試料流入工程」の後、図５に示すように、試料吸引層１の駆動液導入部３２を開けて、試料流路３０とキャピラリーポンプ４０との接続部２１まで到達する量の駆動液６０を導入する。
なお、駆動液６０は、毛細管力により、接続部２１に到達させても良い。また、駆動液６０は、外力による変形により、接続部２１に至るまでの流路の体積を収縮させることで、接続部２１に到達させても良い。また、駆動液６０は、駆動液導入部が吸水性部材（特許第５６８５００７号公報等に記載の吸水性樹脂を含む部材等）を有し、吸水性部材が駆動液を吸収することにより膨張して、接続部２１に至るまでの流路の体積を収縮させることにより、接続部２１に到達させても良い。 (2) Driving liquid introducing step FIG. 5 is a plan view schematically showing an example of the driving liquid introducing step in the sampling method of the present invention.
After the above "(1) sample inflow step", as shown in FIG. of the driving liquid 60 is introduced.
Note that the driving liquid 60 may reach the connecting portion 21 by capillary force. Further, the drive liquid 60 may reach the connection portion 21 by contracting the volume of the flow path up to the connection portion 21 by deformation due to an external force. The driving liquid 60 has a water-absorbing member (such as a member containing a water-absorbing resin described in Japanese Patent No. 5685007, etc.) at the driving liquid introduction portion, and the water-absorbing member expands as it absorbs the driving liquid. Alternatively, the liquid may reach the connecting portion 21 by contracting the volume of the flow path leading to the connecting portion 21 .
（３）試料採取工程
図６Ａ～図６Ｄは、本発明の試料採取方法における試料採取工程の一例を模式的に示す平面図である。
図６Ａに示すように、上記「（２）駆動液導入工程」の後、試料流路３０とキャピラリーポンプ４０との接続部２１まで到達した駆動液６０は、キャピラリーポンプ４０の毛細管現象により吸引される。
ここで、駆動液導入部３２を閉めると、図６Ｂに示すように、駆動液６０が、毛細管現象によりキャピラリーポンプ４０に移動することにより、試料流路３０が陰圧状態となる。
そうすると、図６Ｃに示すように試料５０は、陰圧状態の試料流路３０に吸引される。
次に、試料５０が、キャピラリーポンプ４０まで到達すると、図６Ｄに示すように、今度は、試料５０がキャピラリーポンプ４０に吸引されることになる。
なお、図６Ｂ～図６Ｄ中、矢印は吸引方向を示す。 (3) Sampling Process FIGS. 6A to 6D are plan views schematically showing an example of the sampling process in the sampling method of the present invention.
As shown in FIG. 6A , after the “(2) driving liquid introduction step”, the driving liquid 60 reaching the connecting portion 21 between the sample flow path 30 and the capillary pump 40 is sucked by the capillary action of the capillary pump 40 . be.
Here, when the driving liquid introduction part 32 is closed, as shown in FIG. 6B, the driving liquid 60 moves to the capillary pump 40 by capillary action, and the sample channel 30 becomes negative pressure.
Then, as shown in FIG. 6C, the sample 50 is sucked into the sample channel 30 in the negative pressure state.
Next, when the sample 50 reaches the capillary pump 40, the sample 50 is sucked into the capillary pump 40 as shown in FIG. 6D.
Note that the arrows in FIGS. 6B to 6D indicate the direction of suction.
本発明の試料採取方法では、試料採取工程において連続的に試料５０を採取することが好ましく、１～３０日連続して試料採取工程を行うことがより好ましく、１４～３０日連続して試料採取工程を行うことが更に好ましい。
試料５０がキャピラリーポンプ４０に吸引されると、キャピラリーポンプの毛細管力により、試料５０が連続的に試料流入部３１から流れ込む。そのため、試料流路３０のある１点には、常に新しい試料５０が流れることになる。従って、そのある１点において、試料５０を分析することにより、継時的に試料の採取元の状態をモニタリングすることができる。 In the sampling method of the present invention, it is preferable to continuously collect the sample 50 in the sampling step, more preferably to perform the sampling step continuously for 1 to 30 days, and to collect the sample continuously for 14 to 30 days. It is more preferable to carry out the steps.
When the sample 50 is sucked into the capillary pump 40 , the sample 50 continuously flows from the sample inlet 31 due to the capillary force of the capillary pump. Therefore, a new sample 50 always flows to one point of the sample channel 30 . Therefore, by analyzing the sample 50 at that one point, the condition of the source of the sample can be monitored over time.
次に、本発明のサンプリングシートにおける試料吸引層の各構成について説明する。 Next, each configuration of the sample suction layer in the sampling sheet of the present invention will be described.
（第１フィルム及び第２フィルム）
第１フィルム及び第２フィルムの材料は、特に限定されないが、耐液性フィルムであることが好ましく、樹脂フィルム、紙ベースフィルム等であることがより好ましい。
樹脂フィルムとしてはポリオレフィン、ポリウレタン等からなることが好ましい。
紙ベースフィルムとしては、セルロース等からなることが好ましい。
また、紙ベースフィルムでは、表面が防水シート、疎水化剤や、ブロッキング防止剤等でコーティングされていることが好ましい。 (First film and second film)
Materials for the first film and the second film are not particularly limited, but preferably a liquid-resistant film, more preferably a resin film, a paper base film, or the like.
The resin film is preferably made of polyolefin, polyurethane, or the like.
The paper base film is preferably made of cellulose or the like.
Moreover, the surface of the paper-based film is preferably coated with a waterproof sheet, a hydrophobizing agent, an antiblocking agent, or the like.
第１フィルムと第２フィルムとは、同じ材料から形成されていてもよく、異なる材料から形成されていてもよい。 The first film and the second film may be made of the same material or may be made of different materials.
第１フィルムの厚さは、１００～１０００μｍであることが好ましい。
第２フィルムの厚さは、１～５０μｍであることが好ましい。 The thickness of the first film is preferably 100-1000 μm.
The thickness of the second film is preferably 1-50 μm.
上記の通り、第１フィルムには流路が形成されており、第１フィルムには第２フィルムが積層されている。
第１フィルムと第２フィルムとは、流路の試料流路が陰圧状態となった際に、外部から空気が試料流路に入らないように積層されていればその積層方法は特に限定されず、例えば、接着剤により接続されていてもよく、熱圧着により接続されていてもよい。 As described above, the flow path is formed in the first film, and the second film is laminated on the first film.
If the first film and the second film are laminated so that air does not enter the sample channel from the outside when the sample channel of the channel is in a negative pressure state, the lamination method is not particularly limited. Instead, for example, they may be connected with an adhesive, or they may be connected by thermocompression bonding.
（キャピラリーポンプ）
キャピラリーポンプは、毛細管現象により、駆動液及び試料をキャピラリーポンプ内に移動させることができる機能を有する。
本発明のサンプリングシートにおけるキャピラリーポンプは、駆動液及び試料を試料流路から連続的に吸引できればその形状は特に限定されない。
例えば、キャピラリーポンプ４０は、図１に示すように、複数の毛細管が集合して形成されていてもよい。 (capillary pump)
A capillary pump has a function of moving a driving liquid and a sample into the capillary pump by capillary action.
The shape of the capillary pump in the sampling sheet of the present invention is not particularly limited as long as the driving liquid and the sample can be continuously sucked from the sample channel.
For example, the capillary pump 40 may be formed by assembling a plurality of capillaries, as shown in FIG.
キャピラリーポンプが複数の毛細管が集合して形成されている場合、キャピラリーポンプの入口から奥に向かって、毛細管の断面積を次第に小さくすることにより毛細管力を発揮させてもよい。
また、奥に向かっていくに従って表面のぬれ性が高くなるように毛細管の内面の材質を変更することにより毛細管力を発揮させてもよい。 When the capillary pump is formed by gathering a plurality of capillaries, the capillary force may be exerted by gradually decreasing the cross-sectional area of the capillaries from the inlet of the capillary pump toward the back.
Also, the capillary force may be exhibited by changing the material of the inner surface of the capillary so that the wettability of the surface increases as it goes deeper.
また、キャピラリーポンプが複数の毛細管が集合して形成されている場合、毛細管の内径は、２０～５００μｍであることが好ましく、４０～２００μｍであることがより好ましい。
また、毛細管の長さは、４～１００ｍｍであることが好ましく、１０～５０ｍｍであることがより好ましい。
また、毛細管の本数は、２～３０本であることが好ましく、５～１０本であることがより好ましい。 Moreover, when the capillary pump is formed by gathering a plurality of capillaries, the inner diameter of the capillary is preferably 20 to 500 μm, more preferably 40 to 200 μm.
Also, the length of the capillary tube is preferably 4 to 100 mm, more preferably 10 to 50 mm.
The number of capillaries is preferably 2-30, more preferably 5-10.
本発明のサンプリングシートにおける試料吸引層では、キャピラリーポンプは、試料流路に接続する端部と、試料流路に接続しない端部を有し、キャピラリーポンプの試料流路に接続しない端部には、大気開放部及び／又は液体吸収部が形成されていることが好ましい。 In the sample suction layer in the sampling sheet of the present invention, the capillary pump has an end connected to the sample channel and an end not connected to the sample channel, and the end not connected to the sample channel of the capillary pump has , an atmosphere opening portion and/or a liquid absorption portion are preferably formed.
このような態様について図面を用いて説明する。
図７Ａは、本発明のサンプリングシートにおける試料吸引層において、大気開放部が形成されたキャピラリーポンプの一例を模式的に示す平面図である。
図７Ｂは、本発明のサンプリングシートにおける試料吸引層において、液体吸収部が形成されたキャピラリーポンプの一例を模式的に示す平面図である。 Such an aspect will be described with reference to the drawings.
FIG. 7A is a plan view schematically showing an example of a capillary pump in which the sample suction layer of the sampling sheet of the present invention is formed with an atmosphere opening portion.
FIG. 7B is a plan view schematically showing an example of a capillary pump in which a liquid absorbing portion is formed in the sample suction layer of the sampling sheet of the present invention.
図７Ａに示すキャピラリーポンプ４０は、試料流路３０に接続する端部４１と、試料流路３０に接続しない端部４２を有し、キャピラリーポンプ４０の試料流路３０に接続しない端部４２には、大気開放部４３が形成されている。
大気開放部４３とは、キャピラリーポンプ４０を構成する毛細管の端部が閉鎖されておらず、キャピラリーポンプ４０が外気と通じていることを意味する。
キャピラリーポンプ４０が大気開放部４３を有すると、キャピラリーポンプ４０内を移動した駆動液６０や試料５０は、大気開放部４３まで到達する。そして、駆動液６０や試料５０のうちの揮発成分は大気開放部４３から蒸発する。そのため、キャピラリーポンプ４０は絶えず毛細管力を発揮することができる。 The capillary pump 40 shown in FIG. 7A has an end portion 41 connected to the sample flow channel 30 and an end portion 42 not connected to the sample flow channel 30. is formed with an air release portion 43 .
The atmosphere opening portion 43 means that the capillary pump 40 communicates with the outside air without closing the ends of the capillaries constituting the capillary pump 40 .
When the capillary pump 40 has the atmosphere opening portion 43 , the driving liquid 60 and the sample 50 that have moved inside the capillary pump 40 reach the atmosphere opening portion 43 . Volatile components in the driving liquid 60 and the sample 50 evaporate from the atmosphere opening portion 43 . Therefore, the capillary pump 40 can constantly exert capillary force.
キャピラリーポンプ４０内を移動した駆動液６０や試料５０が、試料流路３０に接続しない端部４２から流出する単位時間当たりの液量は０．０１～１μＬ／ｍｉｎであることが好ましい。
なお、上記の通り流出した駆動液６０や試料５０のうちの揮発成分は大気開放部４３から蒸発するが、単位時間当たりの蒸発量は、上記流出する単位時間当たりの液量以上であることが好ましい。
上記流出する単位時間当たりの液量は、上記の試料採取用マイクロニードル８０の内径等を調整することで、好ましい範囲に調整することができる（例えば、流出する単位時間当たりの液量が１μＬ／ｍｉｎを超える場合は、試料採取用マイクロニードル８０の内径を小さくすることで、流出する単位時間当たりの液量を少なくすることができる傾向がある）。 It is preferable that the driving liquid 60 and the sample 50 that have moved in the capillary pump 40 flow out from the end portion 42 that is not connected to the sample channel 30 at a liquid volume of 0.01 to 1 μL/min per unit time.
The volatile components of the driving liquid 60 and the sample 50 that have flowed out as described above evaporate from the atmosphere opening portion 43, but the amount of evaporation per unit time is equal to or greater than the amount of liquid that flows out per unit time. preferable.
The amount of liquid flowing out per unit time can be adjusted to a preferable range by adjusting the inner diameter of the sample-collecting microneedle 80 (for example, the amount of liquid flowing out per unit time is 1 μL/ If it exceeds min, there is a tendency that the amount of liquid flowing out per unit time can be reduced by reducing the inner diameter of the sample-collecting microneedle 80).
図７Ｂに示すキャピラリーポンプ４０は、試料流路３０に接続する端部４１と、試料流路３０に接続しない端部４２を有し、キャピラリーポンプ４０の試料流路３０に接続しない端部４２には、液体吸収部４４が形成されている。
キャピラリーポンプ４０が液体吸収部４４を有すると、キャピラリーポンプ４０内を移動した駆動液６０や試料５０は、液体吸収部４４まで到達する。そして、駆動液６０や試料５０のうちの液体成分は液体吸収部４４に吸収される。そのため、キャピラリーポンプ４０は絶えず毛細管力を発揮することができる。
なお、液体吸収部は液体を吸収することができればその構成は特に限定されないが、吸水性ポリマーや、速乾性繊維や、親水性粒子が分散されていることが好ましい。
吸水性ポリマーは、架橋ポリアクリル酸ナトリウム塩（特許第５６８５００７号公報等に記載の吸水性樹脂）からなることが好ましい。
速乾性繊維は、ポリエステル、綿、レーヨン、キュプラ等の速乾性繊維からなることが好ましい。
親水性粒子としては、コロイダルシリカ、珪藻土化合物（ベントナイト等）等が挙げられる。 The capillary pump 40 shown in FIG. 7B has an end portion 41 connected to the sample channel 30 and an end portion 42 not connected to the sample channel 30. , a liquid absorbing portion 44 is formed.
When the capillary pump 40 has the liquid absorbing section 44 , the driving liquid 60 and the sample 50 that have moved inside the capillary pump 40 reach the liquid absorbing section 44 . Liquid components of the driving liquid 60 and the sample 50 are absorbed by the liquid absorbing section 44 . Therefore, the capillary pump 40 can constantly exert capillary force.
The configuration of the liquid absorbing portion is not particularly limited as long as it can absorb liquid, but it is preferable that a water absorbing polymer, quick-drying fiber, or hydrophilic particles are dispersed.
The water-absorbing polymer is preferably composed of crosslinked polyacrylic acid sodium salt (water-absorbing resin described in Japanese Patent No. 5685007, etc.).
The quick-drying fibers are preferably made of quick-drying fibers such as polyester, cotton, rayon, and cupra.
Examples of hydrophilic particles include colloidal silica and diatomaceous earth compounds (bentonite, etc.).
上記の速乾性繊維としては、長期間連続使用する観点からは、以下の試験を実施し、「残留水分が１０重量％以下になるまでの時間」が、１４５ｍｉｎ以下である繊維が好ましく、１００ｍｉｎ以下である繊維が更に好ましく、９０ｍｉｎ以下である繊維が特に好ましい。
＜速乾性繊維の評価試験＞
速乾性繊維を１００ｍｍ×１００ｍｍの大きさに切断して速乾性繊維試験片とする。
次に、１００ｍｍ×１００ｍｍのろ紙（円形定量ろ紙　Ｎｏ．５Ｃ）に、速乾性繊維試験片を接触させ、その後ろ紙に０．６ｍＬの水を添加し、その後、接触させたろ紙及び速乾性繊維試験片をそのまま、２０℃、６５％ＲＨの環境下で、吊り干ししする。
添加した水の重量に基づいて、ろ紙の残留水分が１０重量％以下になるまでの時間を測定する。
当該時間が、「残留水分が１０重量％以下になるまでの時間」である。 As the quick-drying fiber, from the viewpoint of long-term continuous use, the following test was carried out, and the "time until the residual water content became 10% by weight or less" is preferably a fiber of 145 min or less, and 100 min or less. is more preferred, and fibers with 90 min or less are particularly preferred.
<Evaluation test of quick-drying fiber>
The quick-drying fiber is cut into a size of 100 mm×100 mm to obtain a quick-drying fiber test piece.
Next, the quick-drying fiber test piece is brought into contact with a 100 mm × 100 mm filter paper (circular quantitative filter paper No. 5C), 0.6 mL of water is added to the back paper, and then the contact filter paper and the quick-drying fiber test The piece is hung to dry as it is under an environment of 20° C. and 65% RH.
Based on the weight of added water, measure the time until the residual water content of the filter paper becomes 10% by weight or less.
This time is "the time until the residual water content becomes 10% by weight or less".
上記の親水性粒子としては、長期間連続使用する観点からは、以下の試験を実施し、「残留水分が１０重量％以下になるまでの時間」が、１４５ｍｉｎ以下である粒子が好ましく、１００ｍｉｎ以下である粒子が更に好ましく、９０ｍｉｎ以下である粒子が特に好ましい。
＜親水性粒子の評価試験＞
親水性粒子を水に分散させ、３０重量％の親水性粒子の水分散液を作製する。
次に、１００ｍｍ×１００ｍｍのろ紙（円形定量ろ紙　Ｎｏ．５Ｃ）に、１ｍＬの３０重量％の親水性粒子の水分散液を含浸させ、１３０℃×３０分の条件で、循風乾燥機で乾燥し、親水性粒子が含浸された親水性粒子試験片を作製する。
次に、親水性粒子試験片に０．６ｍＬの水を添加し、その後、親水性粒子試験片をそのまま、２０℃、６５％ＲＨの環境下で、吊り干ししする。
添加した水の重量に基づいて、親水性粒子試験片の残留水分が１０重量％以下になるまでの時間を測定する。
当該時間が、「残留水分が１０重量％以下になるまでの時間」である。 As the above hydrophilic particles, from the viewpoint of long-term continuous use, the following test was carried out, and "the time until the residual water content became 10% by weight or less" is preferably particles of 145 minutes or less, and 100 minutes or less. is more preferred, and particles with 90 min or less are particularly preferred.
<Evaluation test of hydrophilic particles>
Hydrophilic particles are dispersed in water to prepare a 30% by weight aqueous dispersion of hydrophilic particles.
Next, a 100 mm × 100 mm filter paper (circular quantitative filter paper No. 5C) is impregnated with 1 mL of a 30% by weight aqueous dispersion of hydrophilic particles, and dried with a circulating air dryer under the conditions of 130 ° C. for 30 minutes. to prepare a hydrophilic particle test piece impregnated with hydrophilic particles.
Next, 0.6 mL of water is added to the hydrophilic particle test piece, and then the hydrophilic particle test piece is hung and dried as it is under an environment of 20° C. and 65% RH.
Based on the weight of the added water, measure the time until the residual water content of the hydrophilic particle test piece becomes 10% by weight or less.
This time is "the time until the residual water content becomes 10% by weight or less".
（試料流路）
試料流路は、駆動液及び試料が通ることができれば、特に限定されないが、その幅は、２０～５００μｍであることが好ましく、４～２００μｍであることがより好ましい。 (Sample flow path)
The sample channel is not particularly limited as long as the drive liquid and the sample can pass through it, but the width is preferably 20 to 500 μm, more preferably 4 to 200 μm.
試料流路に形成された試料流入部は、１個のみが形成されていてもよく、複数個が形成されていてもよい。 Only one sample inlet portion may be formed in the sample channel, or a plurality of sample inlet portions may be formed.
本発明のサンプリングシートにおいて、試料流入部に試料を流入させる手段としては、上記マイクロニードルを用いる方法が挙げられる。 In the sampling sheet of the present invention, the method of using the microneedles is mentioned as a means for inflowing the sample into the sample inflow part.
（駆動液導入部）
駆動液導入部は、密閉機能を有する。
駆動液導入部は、初期状態では、駆動液を試料流路に導入することができる形状を有する。
「密閉機能」とは、試料流路が陰圧状態となった際に、空気が駆動液導入部から流入しない程度に駆動液導入部を密閉できる機能を意味する。
なお、駆動液導入部は、駆動液を試料流路とキャピラリーポンプとの接続部まで到達させるためのポンプ機能を有していてもよい。
また、駆動液導入部は、試料流入部と、接続部との間に形成されていることが好ましい。
なお、駆動液導入部は、１個のみが形成されていてもよく、複数個が形成されていてもよい。 (driving liquid introduction part)
The driving liquid introduction part has a sealing function.
In the initial state, the driving liquid introduction part has a shape that allows the driving liquid to be introduced into the sample channel.
The "sealing function" means a function that can seal the driving liquid introduction part to such an extent that air does not flow in from the driving liquid introduction part when the sample channel is in a negative pressure state.
In addition, the driving liquid introduction section may have a pumping function for causing the driving liquid to reach the connecting section between the sample channel and the capillary pump.
Moreover, it is preferable that the driving liquid introduction section is formed between the sample inflow section and the connection section.
It should be noted that only one drive liquid introduction portion may be formed, or a plurality of drive liquid introduction portions may be formed.
駆動液導入部の密閉機能の例としては、手動式の弁、電動式の弁により駆動液導入部を密閉できる機能が挙げられる。また、外力により変形し駆動液導入部を密閉できる機能であってもよい。さらに、駆動液導入部が吸水性部材を有し、吸水性部材が駆動液を吸収することにより膨張して駆動液導入部を密閉できる機能であってもよい。 Examples of the sealing function of the driving liquid introduction section include a function of sealing the driving liquid introduction section with a manual valve or an electric valve. Further, it may have a function of being deformed by an external force to seal the driving liquid introducing portion. Furthermore, the function may be such that the driving liquid introduction section has a water absorbing member, and the water absorbing member absorbs the driving liquid and expands to seal the driving liquid introduction section.
なお、本発明のサンプリングシートにおける試料吸引層において、キャピラリーポンプ及び試料流路の形状等の態様は、本発明のサンプリングシートにおける試料吸引層が機能を発揮できるよう、用いる駆動液の種類、試料の種類に応じ、適宜設定することが好ましい。 In the sample suction layer of the sampling sheet of the present invention, aspects such as the shape of the capillary pump and the sample flow channel are selected so that the sample suction layer of the sampling sheet of the present invention can exhibit its function. It is preferable to set appropriately according to the type.
本発明のサンプリングシートにおける試料吸引層では、試料流路の少なくとも一部には、センサ接続部が形成されていることが好ましい。
このような態様について図面を用いて説明する。
図８は、センサ接続部を有する本発明のサンプリングシートの一例を模式的に示す平面図である。
図８に示す試料吸引層１は、試料流路３０にはセンサ接続部３３が形成されている。
センサ接続部３３は、試料流路３０に形成されていれば、その形成位置は特に限定されないが、例えば、試料流入部３１の隣に形成されていてもよく、接続部２１の隣に形成されていてもよい。
センサ接続部３３にセンサを接続することにより、試料流路３０を流れる試料５０を、センサにより分析することができる。
特に、本発明のサンプリングシートにおける試料吸引層では、継時的に試料を吸引することができるので、試料の採取元の状態を継時的にモニタリングすることができる。 In the sample suction layer of the sampling sheet of the present invention, it is preferable that a sensor connection portion is formed in at least a part of the sample channel.
Such an aspect will be described with reference to the drawings.
FIG. 8 is a plan view schematically showing an example of the sampling sheet of the present invention having sensor connections.
The sample suction layer 1 shown in FIG. 8 has a sensor connection portion 33 formed in the sample channel 30 .
The sensor connecting portion 33 is not particularly limited in position as long as it is formed in the sample channel 30 . may be
By connecting a sensor to the sensor connection portion 33, the sample 50 flowing through the sample channel 30 can be analyzed by the sensor.
In particular, since the sample suction layer in the sampling sheet of the present invention can continuously suck the sample, it is possible to continuously monitor the state of the source of the sample.
（駆動液）
本発明のサンプリングシートにおける試料吸引層を用いて試料を採取する際に用いる駆動液は、水、生理食塩水等であることが好ましい。
これらの中では、生理食塩水であることがより好ましい。 (driving fluid)
It is preferable that the driving liquid used when collecting a sample using the sample suction layer in the sampling sheet of the present invention is water, physiological saline, or the like.
Among these, physiological saline is more preferable.
（試料）
本発明のサンプリングシートにおける試料吸引層を用いて採取する試料の採取元は、ヒト等の生体であることが好ましい。
また、採取する試料は、細胞間質液、血液等の体液であることが好ましい。
これらの中では、細胞間質液であることがより好ましい。
細胞間質液は、固形分の含有量が少なく、不揮発成分の含有量も少ない。そのため、細胞間質液を試料とする場合、流路が固形分や、析出した不揮発成分により詰まりにくい。 (sample)
The source of the sample collected using the sample suction layer in the sampling sheet of the present invention is preferably a living body such as a human.
Moreover, the sample to be collected is preferably body fluid such as interstitial fluid and blood.
Among these, interstitial fluid is more preferable.
The interstitial fluid has a low solids content and a low non-volatile content. Therefore, when interstitial fluid is used as a sample, the channel is less likely to be clogged with solids and deposited non-volatile components.
図２Ａに示す試料吸引層１では、試料流路３０が１本の管状の構造であり、試料流入部３１と、駆動液導入部３２が１個ずつ形成されていたが、本発明のサンプリングシートにおける試料吸引層では、試料流路は分岐していてもよく、複数本あってもよい。また、試料流路は、直線状に形成されていてもよく、曲線状に形成されていてもよく、屈曲していてもよい。
また、試料流入部及び駆動液導入部は複数個形成されていてもよい。 In the sample suction layer 1 shown in FIG. 2A, the sample channel 30 has a single tubular structure, and the sample inflow portion 31 and the driving liquid introduction portion 32 are formed one each. In the sample suction layer in , the sample channel may be branched or may be plural. Moreover, the sample channel may be formed in a straight line, curved line, or curved line.
Also, a plurality of sample inlets and drive liquid inlets may be formed.
図２Ａに示す試料吸引層１では、キャピラリーポンプ４０が１か所に形成されていたが、本発明のサンプリングシートにおける試料吸引層では、キャピラリーポンプは複数個所に形成されていてもよい。 In the sample suction layer 1 shown in FIG. 2A, the capillary pump 40 is formed at one location, but the sample suction layer of the sampling sheet of the present invention may have capillary pumps formed at a plurality of locations.
次に、第１フィルムに紙ベースフィルムを用いた試料吸引層の製造方法の一例を説明する。 Next, an example of a method for manufacturing a sample suction layer using a paper base film as the first film will be described.
（１）基体フィルム準備工程
基体フィルムとして、紙ベースフィルムを準備する。その後、流路を形成する面に防水処理を行う。
防水処理の方法としては、基体フィルムに防水シートを貼付する方法や、基体フィルムの表面に疎水化剤を塗布する方法が挙げられる。 (1) Base film preparation step A paper base film is prepared as a base film. After that, the surface forming the flow path is waterproofed.
Methods of waterproofing include a method of attaching a waterproof sheet to the base film and a method of applying a hydrophobizing agent to the surface of the base film.
（２）溝部形成工程
次に、基体フィルムの防水処理した面をプレス機で平坦化する。
その後、基体フィルムの防水処理した面に、流路に対応する凸部が形成された転写板を配置し、熱プレスすることにより流路を形成する。
転写版は、金属板をエッチング等の通常の方法で加工することにより形成することができる。
以上の工程を経て凹形状の流路が形成された第１フィルムを作製することができる。 (2) Groove Forming Step Next, the water-proof surface of the base film is flattened by a press.
After that, a transfer plate having projections corresponding to the flow paths is placed on the waterproof surface of the base film, and heat-pressed to form the flow paths.
A transfer plate can be formed by processing a metal plate by an ordinary method such as etching.
Through the steps described above, the first film in which the concave flow paths are formed can be produced.
（３）第２フィルム積層工程
次に、第１フィルムの流路が形成された面に第２フィルムを積層する。
なお、第１フィルムと第２フィルムとは、接着剤や、熱圧着等の通常の方法により積層することができる。 (3) Second film lamination step Next, a second film is laminated on the surface of the first film on which the flow paths are formed.
In addition, the first film and the second film can be laminated by an ordinary method such as an adhesive agent or thermocompression bonding.
以上の工程を経て、本発明のサンプリングシートにおける試料吸引層を製造することができる。 Through the above steps, the sample suction layer of the sampling sheet of the present invention can be manufactured.
なお、試料吸引層を製造する場合、流路を有する第１フィルムは、３Ｄプリンター等の樹脂を成型する方法で作製してもよい。 When manufacturing the sample suction layer, the first film having the flow path may be manufactured by a resin molding method such as a 3D printer.
次に、上記サンプリングシートを含む本発明の検査用シートについて説明する。
図９は、本発明の検査用シートの平面方向に垂直な断面の一例を模式的に示す断面図である。
図９に示す検査用シート３は、サンプリングシート２と、サンプリングシート２の試料吸引層１に積層され、センサ９１を有するセンシング層９０とからなる。
さらに、検査用シート３では、試料吸引層１の試料流路３０の少なくとも一部にはセンサ接続部３３が形成されており、センシング層９０のセンサ９１は、試料吸引層１のセンサ接続部３３に接続されている。 Next, the inspection sheet of the present invention including the above sampling sheet will be described.
FIG. 9 is a cross-sectional view schematically showing an example of a cross section perpendicular to the planar direction of the inspection sheet of the present invention.
The inspection sheet 3 shown in FIG. 9 is composed of the sampling sheet 2 and a sensing layer 90 laminated on the sample suction layer 1 of the sampling sheet 2 and having a sensor 91 .
Furthermore, in the test sheet 3 , the sensor connection portion 33 is formed in at least a part of the sample channel 30 of the sample suction layer 1 , and the sensor 91 of the sensing layer 90 is connected to the sensor connection portion 33 of the sample suction layer 1 . It is connected to the.
このような検査用シート３を、マイクロニードル形成面７１が生体の表面に接触するように配置すると、試料採取用マイクロニードル８０が生体の表面に刺さり、生体の内部に入ることになる。 When such an inspection sheet 3 is arranged so that the microneedle forming surface 71 is in contact with the surface of the living body, the sample-collecting microneedles 80 stick into the surface of the living body and enter the inside of the living body.
ここで、試料吸引層１に駆動液を導入し、キャピラリーポンプを駆動させると、継時的に生体内の試料を採取することができる。
そのため、センサ９１により試料を分析することにより、生体のバイオマーカーを継時的にモニタリングすることができ、生体の情報をリアルタイムで確認することができる。 Here, by introducing a driving liquid into the sample suction layer 1 and driving the capillary pump, samples in the living body can be continuously collected.
Therefore, by analyzing the sample with the sensor 91, the biological biomarkers can be continuously monitored, and the biological information can be confirmed in real time.
センサ９１で分析するバイオマーカーは、目的に応じ適宜設定することが好ましいが、コルチゾール、血糖等の低分子バイオマーカーであってもよく、タンパク質や核酸等の高分子バイオマーカーであってもよい。
また、センサ９１によりｐＨや臭気成分を分析してもよい。 The biomarkers to be analyzed by the sensor 91 are preferably set appropriately according to the purpose, and may be low-molecular-weight biomarkers such as cortisol and blood sugar, or high-molecular-weight biomarkers such as proteins and nucleic acids.
Also, the sensor 91 may be used to analyze pH and odor components.
検査用シート３において、センシング層９０と、サンプリングシート２とは分離可能であり、サンプリングシート２はディスポーザブルであってもよい。
このような構造であると、サンプリングシート２を取り換えることで、繰り返し検査用シート３を使用することが可能になる。 In the inspection sheet 3, the sensing layer 90 and the sampling sheet 2 can be separated, and the sampling sheet 2 may be disposable.
With such a structure, it is possible to repeatedly use the inspection sheet 3 by exchanging the sampling sheet 2 .
検査用シート３は、センサ９１と外部の記録装置や制御装置とを通信可能にする通信機器を有していてもよい。
検査用シート３が、このような通信機器を有すると、生体のモニタリングやセンサ９１の制御を容易に行うことができる。 The inspection sheet 3 may have a communication device that enables communication between the sensor 91 and an external recording device or control device.
If the inspection sheet 3 has such a communication device, it is possible to easily monitor the living body and control the sensor 91 .
検査用シート３は、最外層に、疑似スキン層を有していてもよい。
また、疑似スキン層は、外部に位置する疑似皮膚と、疑似皮膚の内側に形成された弾性層とからなることが好ましい。
疑似皮膚は、ウレタン表皮剤、合成ゴム（シリコンゴム等）、天然ゴム等からなることが好ましい。
弾性層は、ウレタン保護層、ポリスチレン発泡体、ポリマースポンジ等からなることが好ましい。
検査用シート３が、疑似スキン層を有すると、外部からの衝撃に対し、センシング層９０や、サンプリングシート２を保護することができる。
また、検査用シート３の外観を、生体の皮膚に似せることができる。 The inspection sheet 3 may have a pseudo skin layer as the outermost layer.
In addition, it is preferable that the pseudo-skin layer is composed of a pseudo-skin positioned outside and an elastic layer formed inside the pseudo-skin.
The artificial skin is preferably made of urethane skin agent, synthetic rubber (such as silicone rubber), natural rubber, or the like.
The elastic layer is preferably made of urethane protective layer, polystyrene foam, polymer sponge, or the like.
If the test sheet 3 has a pseudo skin layer, the sensing layer 90 and the sampling sheet 2 can be protected against external impact.
In addition, the appearance of the inspection sheet 3 can be made to resemble the skin of a living body.
本明細書には以下の事項が開示されている。 The following matters are disclosed in this specification.
本開示（１）は、試料吸引層と、試料採取用マイクロニードルが形成されたマイクロニードル形成面、及び、上記マイクロニードル形成面と対向し、上記試料吸引層に接触する接着面を有するマイクロニードル層とからなるサンプリングシートであって、上記試料吸引層は、凹形状の流路を有する第１フィルムと、上記流路を覆うように上記第１フィルムの上に積層された第２フィルムとを備え、上記流路は、試料流路と、上記試料流路に接続するキャピラリーポンプとを備え、上記試料流路には、試料流入部と、密閉機能を有する駆動液導入部とが形成されており、上記試料流入部に試料が流入できるようにした状態で、上記駆動液導入部を開けて、上記試料流路と上記キャピラリーポンプとの接続部まで到達する量の駆動液を導入し、その後、上記駆動液導入部を閉めた際、上記駆動液が、毛細管現象によりキャピラリーポンプに移動することにより上記試料流路が陰圧状態となり、上記試料が陰圧状態の上記試料流路に吸引されることにより、上記キャピラリーポンプまで到達でき、上記試料採取用マイクロニードルは、上記試料吸引層の上記試料流入部に通じているサンプリングシートである。 The present disclosure (1) includes a sample suction layer, a microneedle formation surface on which sample collection microneedles are formed, and a microneedle having an adhesive surface facing the microneedle formation surface and in contact with the sample suction layer. wherein the sample suction layer includes a first film having a concave channel and a second film laminated on the first film so as to cover the channel. wherein the flow path includes a sample flow path and a capillary pump connected to the sample flow path, and the sample flow path is formed with a sample inflow portion and a driving liquid introduction portion having a sealing function. In a state in which the sample can flow into the sample inflow portion, the driving liquid introduction portion is opened to introduce an amount of the driving liquid that reaches the connection portion between the sample flow channel and the capillary pump, and then When the driving liquid introduction part is closed, the driving liquid moves to the capillary pump due to capillary action, so that the sample flow path becomes in a negative pressure state, and the sample is sucked into the sample flow path in the negative pressure state. The microneedle for sample collection is a sampling sheet communicating with the sample inflow portion of the sample suction layer.
本開示（２）は、上記駆動液導入部は、上記試料流入部と、上記接続部との間に形成されている本開示（１）に記載のサンプリングシートである。 The present disclosure (2) is the sampling sheet according to the present disclosure (1), wherein the driving liquid introduction section is formed between the sample inflow section and the connection section.
本開示（３）は、上記キャピラリーポンプは、上記試料流路に接続する端部と、上記試料流路に接続しない端部を有し、上記キャピラリーポンプの上記試料流路に接続しない端部には、大気開放部及び／又は液体吸収部が形成されている本開示（１）又は（２）に記載のサンプリングシートである。 In the present disclosure (3), the capillary pump has an end connected to the sample channel and an end not connected to the sample channel, and the end of the capillary pump not connected to the sample channel is the sampling sheet according to (1) or (2) of the present disclosure, in which an atmosphere opening portion and/or a liquid absorbing portion are formed.
本開示（４）は、上記液体吸収部は、吸水性ポリマーが分散されている本開示（３）に記載のサンプリングシートである。 The present disclosure (4) is the sampling sheet according to the present disclosure (3), wherein the liquid absorbing portion is dispersed with a water absorbing polymer.
本開示（５）は、上記試料流路の少なくとも一部には、センサ接続部が形成されている本開示（１）～（４）のいずれかに記載のサンプリングシートである。 The present disclosure (5) is the sampling sheet according to any one of the present disclosures (1) to (4), wherein a sensor connection portion is formed in at least a part of the sample channel.
本開示（６）は、本開示（５）に記載のサンプリングシートと、上記サンプリングシートの上記試料吸引層に積層され、センサを有するセンシング層とからなり、上記センシング層の上記センサは、上記試料吸引層の上記センサ接続部に接続されている検査用シートである。 The present disclosure (6) comprises the sampling sheet according to the present disclosure (5), and a sensing layer laminated on the sample suction layer of the sampling sheet and having a sensor, wherein the sensor of the sensing layer includes the sample A test sheet connected to the sensor connection portion of the suction layer.
本開示（７）は、本開示（１）～（５）のいずれかに記載のサンプリングシートを構成する上記試料採取用マイクロニードルを用いて、上記試料吸引層の試料流入部に試料が流入できるようにする試料流入工程と、上記試料吸引層の駆動液導入部を開けて、上記試料流路と上記キャピラリーポンプとの接続部まで到達する量の駆動液を導入する駆動液導入工程と、上記駆動液導入部を閉め、上記駆動液を、毛細管現象によりキャピラリーポンプに移動させることにより上記試料流路を陰圧状態とし、上記試料を陰圧状態の上記試料流路に吸引させて、上記キャピラリーポンプまで到達させる試料採取工程とを含む試料採取方法である。 The present disclosure (7) uses the sample-collecting microneedle constituting the sampling sheet according to any one of the present disclosure (1) to (5) to allow a sample to flow into the sample inflow portion of the sample suction layer. a driving liquid introducing step of opening the driving liquid introducing portion of the sample suction layer and introducing an amount of the driving liquid that reaches the connecting portion between the sample channel and the capillary pump; The driving liquid introduction part is closed, and the driving liquid is moved to the capillary pump by capillary action to put the sample channel in a negative pressure state, and the sample is sucked into the sample channel in the negative pressure state, and the capillary is moved. and a sampling step of reaching the pump.
本開示（８）は、上記試料採取工程では、連続的に上記試料を採取する本開示（７）に記載の試料採取方法である。 The present disclosure (8) is the sampling method according to the present disclosure (7), in which the samples are continuously collected in the sample collection step.
本開示（９）は、上記試料採取工程を、１～３０日連続して行う本開示（７）又は（８）に記載の試料採取方法である。 The present disclosure (9) is the sampling method according to the present disclosure (7) or (8), wherein the sampling step is performed continuously for 1 to 30 days.
本開示（１０）は、上記試料は細胞間質液である本開示（７）～（９）のいずれかに記載の試料採取方法である。 The present disclosure (10) is the sampling method according to any one of the present disclosure (7) to (9), wherein the sample is interstitial fluid.
（試験例）
図７Ｂに示すような液体吸収部を有するサンプリングシートについて、液体吸収部として好ましい材料を以下の実験で確認した。 (Test example)
For a sampling sheet having a liquid absorbing portion as shown in FIG. 7B, the following experiments were conducted to confirm preferred materials for the liquid absorbing portion.
（材料の評価基準）
１００ｍｍ×１００ｍｍのろ紙（円形定量ろ紙　Ｎｏ．５Ｃ）に、０．６ｍＬの水を添加し、その後、２０℃、６５％ＲＨの環境下で、吊り干しした。
添加した水の重量に基づいて、ろ紙の残留水分が１０重量％以下になるまでの時間を測定したところ、１４５分であった。 (Material evaluation criteria)
0.6 mL of water was added to a 100 mm×100 mm filter paper (circular quantitative filter paper No. 5C), and then hung to dry under an environment of 20° C. and 65% RH.
Based on the weight of added water, the time required for the residual water content of the filter paper to reach 10% by weight or less was measured and found to be 145 minutes.
（速乾性繊維の評価）
速乾性繊維であるドライエックス（第一紡績（株）製）、及び、パワードスパン（（株）ファイントラック製）を準備し、１００ｍｍ×１００ｍｍの大きさに切断して速乾性繊維試験片とした。
１００ｍｍ×１００ｍｍのろ紙（円形定量ろ紙　Ｎｏ．５Ｃ）を２枚準備し、各速乾性繊維試験片をそれぞれ別のろ紙に接触させ、その後、ろ紙に０．６ｍＬの水を添加し、その後、接触させたろ紙及び速乾性繊維試験片をそのまま、２０℃、６５％ＲＨの環境下で、吊り干しした。
添加した水の重量に基づいて、ろ紙の残留水分が１０重量％以下になるまでの時間を測定した。
使用した速乾性繊維が、ドライエックスの場合、１０重量％以下になるまでの時間は７０分であり、
使用した速乾性繊維が、パワードスパンの場合、１０重量％以下になるまでの時間は７５分であった。 (Evaluation of quick-drying fiber)
Quick-drying fibers Dry-X (manufactured by Daiichi Boseki Co., Ltd.) and Powered Spun (manufactured by Fine Track Co., Ltd.) were prepared and cut into a size of 100 mm × 100 mm to obtain a quick-drying fiber test piece. .
Prepare two pieces of 100 mm × 100 mm filter paper (circular quantitative filter paper No. 5C), contact each quick-drying fiber test piece with another filter paper, then add 0.6 mL of water to the filter paper, and then contact The filter paper and the quick-drying fiber test piece were dried as they were under an environment of 20° C. and 65% RH.
Based on the weight of water added, the time required for the residual water content of the filter paper to reach 10% by weight or less was measured.
When the quick-drying fiber used is dry-ex, it takes 70 minutes to reach 10% by weight or less.
When the quick-drying fiber used was a powered spun, it took 75 minutes to reach 10% by weight or less.
（親水性粒子の評価）
親水性粒子として、スノーテックス３０（日産化学（株）製）を水に分散させ、３０重量％の親水性粒子の水分散液を作製した。次に、１００ｍｍ×１００ｍｍのろ紙（円形定量ろ紙　Ｎｏ．５Ｃ）に、１ｍＬの３０重量％のスノーテックス３０の水分散液を含侵させ、１３０℃×３０分の条件で、循風乾燥機で乾燥し、親水性粒子が含浸された親水性粒子試験片を作製した。
次に、親水性粒子試験片に０．６ｍＬの水を添加し、その後、親水性粒子試験片をそのまま、２０℃、６５％ＲＨの環境下で、吊り干しした。
添加した水の重量に基づいて、親水性粒子試験片の残留水分が１０重量％以下になるまでの時間を測定したところ、８５分であった。 (Evaluation of hydrophilic particles)
As hydrophilic particles, SNOWTEX 30 (manufactured by Nissan Chemical Co., Ltd.) was dispersed in water to prepare an aqueous dispersion of 30% by weight of hydrophilic particles. Next, a 100 mm × 100 mm filter paper (circular quantitative filter paper No. 5C) was impregnated with 1 mL of a 30% by weight aqueous dispersion of Snowtex 30, and dried at 130 ° C. for 30 minutes with a circulation dryer. A hydrophilic particle specimen was prepared that was dried and impregnated with hydrophilic particles.
Next, 0.6 mL of water was added to the hydrophilic particle test piece, and then the hydrophilic particle test piece was hang-dried as it was under an environment of 20°C and 65% RH.
Based on the weight of water added, the time required for the residual water content of the hydrophilic particle test piece to reach 10% by weight or less was measured and found to be 85 minutes.
上記試験において、速乾性繊維であるドライエックス及びパワードスパンを用いた場合、並びに、親水性粒子であるスノーテックス３０を用いた場合の「残留水分が１０重量％以下になるまでの時間」は、評価基準であるろ紙の「残留水分が１０重量％以下になるまでの時間」よりも短かった。
従って、ドライエックス、パワードスパン及びスノーテックス３０は、液体吸収部として好ましい材料であることが判明した。 In the above test, when the quick-drying fibers Dry-X and Powered Spun were used, and when the hydrophilic particles SNOWTEX 30 were used, the "time until the residual water content became 10% by weight or less" was It was shorter than the "time until the residual water content became 10% by weight or less" of the filter paper, which is an evaluation criterion.
Therefore, Dry-X, Powered Spun and Snowtex 30 have been found to be preferred materials for the liquid absorber.
（水分の蒸散性評価）
以下の方法で、液体吸収部の水分の蒸散性を評価した。 (Evaluation of moisture transpiration)
The moisture transpiration property of the liquid absorbing portion was evaluated by the following method.
（試験サンプルの作製）
ろ紙（円形定量ろ紙　Ｎｏ．５Ｃ）を１０ｍｍ×１０ｍｍに切断し、試験サンプル１とした。
ドライエックス及びろ紙（円形定量ろ紙　Ｎｏ．５Ｃ）を１０ｍｍ×１０ｍｍに切断し、これらを重ね合わせ、試験サンプル２とした。
パワードスパン及びろ紙（円形定量ろ紙　Ｎｏ．５Ｃ）を１０ｍｍ×１０ｍｍに切断し、これらを重ね合わせ、試験サンプル３とした。
３重量％のスノーテックス３０の水分散液を準備した。次に、ろ紙（円形定量ろ紙　Ｎｏ．５Ｃ）を１０ｍｍ×１０ｍｍに切断し、上記３重量％のスノーテックス３０の水分散液０．１ｍＬを含浸させ、１３０℃×３０分の条件で、循風乾燥機で乾燥し、試験サンプル４とした。 (Preparation of test sample)
A filter paper (circular quantitative filter paper No. 5C) was cut into a size of 10 mm×10 mm to obtain a test sample 1.
Dry-ex and filter paper (circular quantitative filter paper No. 5C) were cut into pieces of 10 mm×10 mm, and these were superimposed to obtain test sample 2.
A powered span and filter paper (circular quantitative filter paper No. 5C) were cut into 10 mm×10 mm pieces, and these were superimposed to obtain test sample 3.
An aqueous dispersion of 3% by weight Snowtex 30 was prepared. Next, filter paper (circular quantitative filter paper No. 5C) was cut into 10 mm × 10 mm, impregnated with 0.1 mL of the above 3% by weight aqueous dispersion of Snowtex 30, and circulated at 130 ° C. for 30 minutes. It was dried in a drier and used as test sample 4.
（水分の蒸散性試験）
図１０は、蒸散性試験を模式的に示す模式図である。
図１０に示すように、キャピラリー１４０を準備し、キャピラリー１４０の一方の端部１４２が各試験サンプル１４４に接触するように配置した。
次に、キャピラリー１４０の他方の端部１４１から１０分間に１回、断続的に０．５μＬの水を添加した。この操作により、水が一方の端部１４２から流出する単位時間当たりの液量が０．０５μｍ／ｍｉｎである状態を再現した。
水の添加の開始から１時間後、２時間後及び３時間後に、各試験サンプルに含まれる水の重量を測定した。
なお、各試験サンプルに含まれる水の重量は、水の添加の開始から１時間後、２時間後及び３時間後の各試験サンプルの重量から、乾燥時（試験開始前）の各試験サンプルの重量を引いた数値として算出した。
結果を表１に示す。 (Moisture transpiration test)
FIG. 10 is a schematic diagram schematically showing the transpiration test.
As shown in FIG. 10, a capillary 140 was prepared and positioned such that one end 142 of capillary 140 contacted each test sample 144 .
Next, 0.5 μL of water was intermittently added from the other end 141 of the capillary 140 once every 10 minutes. This operation reproduced the state in which the amount of water flowing out from one end 142 per unit time was 0.05 μm/min.
The weight of water in each test sample was measured 1 hour, 2 hours and 3 hours after the start of water addition.
The weight of water contained in each test sample was calculated from the weight of each test sample 1 hour, 2 hours and 3 hours after the start of water addition, and the weight of each test sample when dry (before the start of the test). It was calculated as a numerical value after subtracting the weight.
Table 1 shows the results.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
表１に示すように試験サンプル２～４は、試験サンプル１よりも、時間経過に伴う試験サンプルに含まれる水の重量の増加が少ないことが判明した。
これは、試験サンプル２～４が、試験サンプル１よりも水分の蒸散性が良いためと考えられる。
つまり、ドライエックス、パワードスパン及びスノーテックス３０を、液体吸収部の材料として用いると、水分の蒸散性が向上することが判明した。
従って、これらの材料が用いられた液体吸収部を有するサンプリングシートは、長期間連続使用することができると考えられる。 As shown in Table 1, it was found that test samples 2 to 4 showed less increase in weight of water contained in the test samples than test sample 1 over time.
This is probably because the test samples 2 to 4 have better moisture transpiration properties than the test sample 1.
In other words, it was found that the use of Dry-X, Powered Spun, and Snowtex 30 as the material for the liquid-absorbing portion improves the transpiration of water.
Therefore, it is considered that a sampling sheet having a liquid absorbing portion using these materials can be used continuously for a long period of time.
本発明のサンプリングシートを用いることにより、継時的に試料を吸引することができる。
そのため、本発明のサンプリングシートは、継時的かつ即時的な生体情報のモニタリングを行うための検査シートにおいて、試料を継時的に吸引する構成として有用である。 By using the sampling sheet of the present invention, it is possible to continuously aspirate samples.
Therefore, the sampling sheet of the present invention is useful as a configuration for successively aspirating a sample in a test sheet for successively and instantaneously monitoring biological information.
１　試料吸引層
２　サンプリングシート
３　検査用シート
１１　第１フィルム
１２　第２フィルム
２０　流路
２１　接続部
３０　試料流路
３１　試料流入部
３２　駆動液導入部
３３　センサ接続部
４０　キャピラリーポンプ
４１　試料流路に接続する端部
４２　試料流路に接続しない端部
４３　大気開放部
４４　液体吸収部
５０　試料
６０　駆動液
７０　マイクロニードル層
７１　マイクロニードル形成面
７２　接着面
８０　試料採取用マイクロニードル
９０　センシング層
９１　センサ
１４０　キャピラリー
１４１　キャピラリーの一方の端部
１４２　キャピラリーの他方の端部
１４４　試験サンプル
Ｂ　生体
  1 Sample suction layer 2 Sampling sheet 3 Inspection sheet 11 First film 12 Second film 20 Channel 21 Connection part 30 Sample channel 31 Sample inflow part 32 Driving liquid introduction part 33 Sensor connection part 40 Capillary pump 41 In the sample channel Connected end 42 End 43 not connected to the sample channel Air release portion 44 Liquid absorption portion 50 Sample 60 Driving liquid 70 Microneedle layer 71 Microneedle forming surface 72 Adhesive surface 80 Microneedle for sampling 90 Sensing layer 91 Sensor 140 capillary 141 one end of capillary 142 the other end of capillary 144 test sample B organism

Claims (10)

  1. 試料吸引層と、
    試料採取用マイクロニードルが形成されたマイクロニードル形成面、及び、前記マイクロニードル形成面と対向し、前記試料吸引層に接触する接着面を有するマイクロニードル層とからなるサンプリングシートであって、
    前記試料吸引層は、凹形状の流路を有する第１フィルムと、
    前記流路を覆うように前記第１フィルムの上に積層された第２フィルムとを備え、
    前記流路は、試料流路と、前記試料流路に接続するキャピラリーポンプとを備え、
    前記試料流路には、試料流入部と、密閉機能を有する駆動液導入部とが形成されており、
    前記試料流入部に試料が流入できるようにした状態で、前記駆動液導入部を開けて、前記試料流路と前記キャピラリーポンプとの接続部まで到達する量の駆動液を導入し、その後、前記駆動液導入部を閉めた際、前記駆動液が、毛細管現象によりキャピラリーポンプに移動することにより前記試料流路が陰圧状態となり、前記試料が陰圧状態の前記試料流路に吸引されることにより、前記キャピラリーポンプまで到達でき、
    前記試料採取用マイクロニードルは、前記試料吸引層の前記試料流入部に通じているサンプリングシート。     a sample suction layer;
    A sampling sheet comprising a microneedle formation surface on which sample collection microneedles are formed, and a microneedle layer having an adhesive surface facing the microneedle formation surface and in contact with the sample suction layer,
    The sample suction layer includes a first film having a concave channel;
    a second film laminated on the first film so as to cover the flow channel;
    The channel comprises a sample channel and a capillary pump connected to the sample channel,
    A sample inlet and a driving liquid inlet having a sealing function are formed in the sample channel,
    In a state where the sample can flow into the sample inflow portion, the driving liquid introduction portion is opened to introduce an amount of the driving liquid that reaches the connection portion between the sample flow channel and the capillary pump. When the driving liquid introduction part is closed, the driving liquid moves to the capillary pump due to capillary action, so that the sample flow path becomes in a negative pressure state, and the sample is sucked into the sample flow path in the negative pressure state. can reach the capillary pump,
    A sampling sheet in which the sample-collecting microneedle communicates with the sample inflow portion of the sample suction layer.
  2. 前記駆動液導入部は、前記試料流入部と、前記接続部との間に形成されている請求項１に記載のサンプリングシート。 2. The sampling sheet according to claim 1, wherein the driving liquid introducing portion is formed between the sample inflow portion and the connecting portion.
  3. 前記キャピラリーポンプは、前記試料流路に接続する端部と、前記試料流路に接続しない端部を有し、
    前記キャピラリーポンプの前記試料流路に接続しない端部には、大気開放部及び／又は液体吸収部が形成されている請求項１又は２に記載のサンプリングシート。     The capillary pump has an end connected to the sample channel and an end not connected to the sample channel,
    3. The sampling sheet according to claim 1 or 2, wherein an air release portion and/or a liquid absorption portion are formed at the end of the capillary pump that is not connected to the sample channel.
  4. 前記液体吸収部は、吸水性ポリマーが分散されている請求項３に記載のサンプリングシート。 4. The sampling sheet according to claim 3, wherein the liquid absorbing portion has a water absorbing polymer dispersed therein.
  5. 前記試料流路の少なくとも一部には、センサ接続部が形成されている請求項１又は２に記載のサンプリングシート。 3. The sampling sheet according to claim 1, wherein a sensor connecting portion is formed in at least part of the sample channel.
  6. 請求項５に記載のサンプリングシートと、
    前記サンプリングシートの前記試料吸引層に積層され、センサを有するセンシング層とからなり、
    前記センシング層の前記センサは、前記試料吸引層の前記センサ接続部に接続されている検査用シート。     A sampling sheet according to claim 5;
    A sensing layer laminated on the sample suction layer of the sampling sheet and having a sensor,
    The inspection sheet, wherein the sensor of the sensing layer is connected to the sensor connection portion of the sample suction layer.
  7. 請求項１に記載のサンプリングシートを構成する前記試料採取用マイクロニードルを用いて、前記試料吸引層の試料流入部に試料が流入できるようにする試料流入工程と、
    前記試料吸引層の駆動液導入部を開けて、前記試料流路と前記キャピラリーポンプとの接続部まで到達する量の駆動液を導入する駆動液導入工程と、
    前記駆動液導入部を閉め、前記駆動液を、毛細管現象によりキャピラリーポンプに移動させることにより前記試料流路を陰圧状態とし、前記試料を陰圧状態の前記試料流路に吸引させて、前記キャピラリーポンプまで到達させる試料採取工程とを含む試料採取方法。     A sample inflow step of allowing the sample to flow into the sample inflow portion of the sample suction layer using the sample-collecting microneedle constituting the sampling sheet according to claim 1;
    a driving liquid introducing step of opening a driving liquid introducing portion of the sample suction layer and introducing an amount of the driving liquid that reaches a connecting portion between the sample channel and the capillary pump;
    The driving liquid introduction part is closed, and the driving liquid is moved to a capillary pump by capillary action to put the sample channel in a negative pressure state, and the sample is sucked into the sample channel in the negative pressure state. and a sampling step of reaching the capillary pump.
  8. 前記試料採取工程では、連続的に前記試料を採取する請求項７に記載の試料採取方法。 8. The sample collection method according to claim 7, wherein in said sample collection step, said samples are collected continuously.
  9. 前記試料採取工程を、１～３０日連続して行う請求項７又は８に記載の試料採取方法。 The sampling method according to claim 7 or 8, wherein the sampling step is performed continuously for 1 to 30 days.
  10. 前記試料は細胞間質液である請求項７又は８に記載の試料採取方法。
          9. The sampling method according to claim 7 or 8, wherein the sample is interstitial fluid.
PCT/JP2022/035338 2021-09-24 2022-09-22 Sampling sheet, inspection sheet, and sample collection method WO2023048214A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5688635B2 (en) * 2010-08-26 2015-03-25 国立大学法人 東京大学 Inspection sheet, chemical analyzer, and method for manufacturing inspection sheet
WO2019176126A1 (en) * 2018-03-16 2019-09-19 国立大学法人東京大学 Inspection chip and inspection device
JP2021506391A (en) * 2017-12-22 2021-02-22 ブリテル アクチエボラグ パブリークＢｒｉｇｈｔｅｒ Ａｂ （Ｐｕｂｌ） Diagnostic skin patch

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5688635B2 (en) * 2010-08-26 2015-03-25 国立大学法人 東京大学 Inspection sheet, chemical analyzer, and method for manufacturing inspection sheet
JP2021506391A (en) * 2017-12-22 2021-02-22 ブリテル アクチエボラグ パブリークＢｒｉｇｈｔｅｒ Ａｂ （Ｐｕｂｌ） Diagnostic skin patch
WO2019176126A1 (en) * 2018-03-16 2019-09-19 国立大学法人東京大学 Inspection chip and inspection device

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