WO2016017591A1 - Instrument de test, dispositif de test, kit de test, et procédé de mesure - Google Patents

Instrument de test, dispositif de test, kit de test, et procédé de mesure Download PDF

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Publication number
WO2016017591A1
WO2016017591A1 PCT/JP2015/071271 JP2015071271W WO2016017591A1 WO 2016017591 A1 WO2016017591 A1 WO 2016017591A1 JP 2015071271 W JP2015071271 W JP 2015071271W WO 2016017591 A1 WO2016017591 A1 WO 2016017591A1
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Prior art keywords
liquid
substance
particulate matter
binding
measurement target
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PCT/JP2015/071271
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English (en)
Japanese (ja)
Inventor
倫久 川田
直美 富田
中野　郁雄
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シャープ株式会社
日本光電工業株式会社
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Priority to JP2016538342A priority Critical patent/JPWO2016017591A1/ja
Publication of WO2016017591A1 publication Critical patent/WO2016017591A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/02—Investigating particle size or size distribution

Definitions

  • the present invention relates to an inspection instrument for measuring particulate matter present in a liquid and a measurement method.
  • Measurement of particulate matter suspended in a liquid is widely performed in the fields of environmental surveys and medical examinations.
  • the particulate matter is counted or the size is measured.
  • Patent Document 1 discloses a hemocytometer (counting chamber) that is a device for holding a liquid (measuring liquid) in which particulate matter is suspended.
  • This hemocytometer is composed of an upper plate and a lower plate.
  • a space is defined between both plates by (i) forming a groove in one of the plates, or (ii) providing a spacer between the two plates.
  • the measurement target liquid is injected into the space, and the particulate matter in the measurement target liquid is counted.
  • Patent Document 1 does not consider the movement of particulate matter due to Brownian motion.
  • Patent Document 1 has a problem that a measurement error occurs due to Brownian motion of the particulate matter.
  • the present invention has been made to solve the above problems, and an object of the present invention is to provide an inspection instrument, a measurement method, and an inspection kit that can reduce the measurement error of particulate matter caused by Brownian motion of the particulate matter. There is to do.
  • an inspection instrument is an inspection instrument that includes a holding unit that holds a measurement target liquid, and the holding unit includes two opposing surfaces that face each other.
  • the two opposing surfaces form a gap for filling the measurement target liquid, and a distance between the two opposing surfaces is defined to be constant, and the measurement target liquid is separated from the measurement target.
  • the sample liquid containing the particulate matter and the flow reducing substance that increases the viscosity of the sample liquid are mixed.
  • a measurement method is a method for measuring a particulate matter in a sample liquid, and the particulate matter is added to the sample solution containing the particulate matter.
  • the inspection instrument includes a sample liquid containing a particulate substance and a binding substance that binds to the particulate substance, thereby combining the particulate substance and the binding substance.
  • a liquid to be measured by mixing a first mixing unit that generates a conjugate-containing liquid containing the fluid, a conjugate-containing liquid generated in the first mixing unit, and a flow reducing substance that reduces the movement of the conjugate.
  • a second mixing unit that holds the measurement target liquid in a state where the conjugate in the measurement target liquid can be measured.
  • a measurement method measures the particulate matter using an inspection instrument that holds a measurement target liquid containing the particulate matter to be measured.
  • a gap for holding the measurement target liquid is formed in the inspection instrument, and by adding a flow reducing substance to the sample liquid containing the particulate substance, the particulate matter
  • the flow reducing substance is a substance that imparts Newtonian viscosity, pseudoplastic viscosity, or Bingham viscosity to the sample liquid.
  • a test kit includes a flow reducing substance that reduces the movement of the particulate matter in a sample liquid containing the particulate matter to be measured, and the flow reducing substance is added to the sample liquid.
  • a test kit including a test tool in which a gap for holding a liquid to be measured generated by the process is formed, wherein the flow reducing substance has Newtonian viscosity, pseudoplastic viscosity, or Bingham viscosity in the sample liquid. It is a substance to be granted.
  • the inspection instrument has an effect of reducing the measurement error of the particulate matter caused by the Brownian motion of the particulate matter (conjugate). Further, when the particulate substance and the binding substance are combined before the step of adding the flow reducing substance, the two can be efficiently combined. Furthermore, when the flow reducing substance is a substance that imparts Newtonian viscosity, pseudoplastic viscosity, or Bingham viscosity to the sample liquid, the sample liquid to which the flow reducing substance is added can be easily introduced into the gap.
  • Embodiment 1 The following describes Embodiment 1 of the present invention with reference to FIGS.
  • FIG. 1 is a diagram illustrating a configuration of an inspection chip 1 (inspection instrument) according to the present embodiment.
  • the inspection chip 1 is an instrument for optically capturing an image of a minute particulate substance suspended in a measurement target liquid (inspection target liquid) and analyzing the image.
  • the inspection chip 1 can be suitably used as an instrument for measuring the number or size of particulate matter contained in a predetermined amount of the liquid to be measured.
  • the inspection chip 1 may be used to chemically or physically measure the amount, shape, size, or characteristics of the particulate matter present in the measurement target liquid.
  • the inspection chip 1 includes a base material 11 and a cover 12.
  • the base material 11 is composed of a plate-like member, and the sample liquid 90 and the flow reducing substance 91 are mixed on one surface (referred to as the upper surface) of the wide surfaces (plate surfaces) of the base material 11. Is provided with a recess 13 (holding portion) for holding the liquid to be measured.
  • the cover 12 is a translucent member that covers most of the upper surface of the substrate 11.
  • the cover 12 has two openings (introduction ports 14). These openings are located at both ends of the recess 13, and both ends of the recess 13 are not covered by the cover 12. Both end portions serve as introduction ports 14 for introducing the liquid to be measured into the recess 13.
  • the concave portion 13 may be manufactured by processing the base material 11 such as cutting or molding.
  • the concave portion 13 is formed in a concave shape on the planar base material 11 (for example, the shape seen from the normal direction of the plate surface of the base material 11 forms a square shape and has a cross-sectional shape perpendicular to the plate surface of the base material 11. May be manufactured by attaching a tape or a film or the like having a concave shape.
  • a minute space defined by the bottom surface 13a of the recess 13 and the back surface of the cover 12 is formed.
  • the back surface of the cover 12 is the surface of the cover 12 on the side facing the bottom surface 13a.
  • the minute space has a function of holding the liquid to be measured.
  • the bottom surface 13a of the recess 13 is rectangular, and the inlet 14 is provided as a substantially rectangular slit.
  • the shapes of the recess 13 and the introduction port 14 are not particularly limited, and may be appropriately determined by the designer of the inspection chip 1.
  • inlet 14 may be provided, in that case, it is preferable to form a passage for air when the liquid to be measured flows into the recess 13.
  • the height of the recess 13 is defined as the distance of the gap between the two opposing surfaces described above (between the bottom surface 13a of the recess 13 and the back surface of the cover 12).
  • the height of the concave portion 13 is regulated to a certain value so that a capillary force acts by the gap.
  • the height is, for example, not less than 50 ⁇ m and not more than 100 ⁇ m.
  • the two opposing surfaces (the bottom surface 13a of the recess 13 and the back surface of the cover 12) are maintained parallel to each other.
  • the measurement target liquid is dropped into the introduction port 14
  • the measurement target liquid is introduced into the recess 13 by capillary force. For this reason, the measurement target liquid can be easily introduced into the recess 13.
  • the head pressure (self-weight) of the measurement target liquid dropped on the introduction port can be used together with the capillary force, so that the measurement target liquid can be easily introduced.
  • the height of the recess 13 is defined to be constant.
  • a predetermined amount of the measurement target liquid can be set as the measurement target by filling the recess 13 with the measurement target liquid and using the measurement target liquid existing within the predetermined area as the measurement target. Therefore, it is not necessary to measure a predetermined amount of the measurement target liquid, and quantitative measurement of the measurement target liquid can be easily performed.
  • the height of the recess 13 may be appropriately determined by the designer of the test chip 1 according to the volume of the liquid to be quantified as long as the capillary force is configured to work. The same applies to the inspection chip of each embodiment described later.
  • a pressure may be applied to the measurement target liquid using a power device such as a pump.
  • a power device such as a pump is used to move to the recess 13 of the liquid to be measured. May be promoted.
  • the capillary force generated between the bottom surface 13a and the cover 12 for introducing the liquid to be measured into the recess 13 may not necessarily be used.
  • the height of the recess 13 may be larger than the above-described 50 ⁇ m, and may be appropriately determined by the designer of the inspection chip 1.
  • the material of the base material 11, the cover 12, and the recess 13 is not particularly limited as long as it does not interfere with the measurement of the particulate matter contained in the measurement target liquid.
  • the material of the cover 12 and the recess 13 is polycarbonate, polystyrene, COP (cycloolefin polymer), COC (cycloolefin copolymer), PET (polyethylene terephthalate). ), PMMA (polymethylmethacrylate), ABS (acrylonitrile-butadiene-styrene), or a known glass material may be used.
  • a known metal material such as aluminum or stainless steel may be used.
  • sample solution 90 The sample liquid 90 is a liquid containing particulate matter that is a measurement target using the inspection chip 1.
  • the measurement is optically performed by, for example, an inspection apparatus 100 shown in FIG.
  • the optical measurement for example, the particulate matter is counted and / or the particle size of the particulate matter is measured.
  • the sample solution 90 may be, for example, water (specifically, a river, the sea, the number of drinks, industrial washing water, water for plant cultivation, or the like).
  • examples of the particulate material include sand, metal particles, bacteria, pollen, and microorganisms.
  • sample liquid 90 may be, for example, a body fluid (specifically, blood, saliva, urine, etc.).
  • a body fluid specifically, blood, saliva, urine, etc.
  • examples of the particulate matter include white blood cells, red blood cells, platelets, microorganisms, bacteria, cells, or fragments thereof.
  • the types of the liquid component and the particulate matter of the sample liquid 90 are not particularly limited.
  • the flow reducing substance 91 is a substance added to the sample liquid 90 in order to increase the viscosity of the sample liquid 90. By increasing the viscosity of the sample liquid 90, the Brownian motion of the particulate matter can be reduced. This effect will be described later.
  • the flow reducing substance 91 may be, for example, a thickener, a gelling agent, a photocurable resin (UV curable resin), a two-component mixed curing agent, or the like.
  • the flow reducing substance 91 may be added to the sample solution 90 as a solution, or may be added to the sample solution 90 as a powder.
  • Thickener has the property of imparting viscosity to the liquid.
  • thickeners for example thickening polysaccharides or suitable synthetic compounds may be used.
  • thickeners such as xanthan gum, carrageenan, locust bean gum, guar gum, gellan gum, gum arabic, tara gum, tamarind seed gum, psyllium seed gum, gati gum, porphyran, starch, and mannan as thickeners. May be used.
  • mucopolysaccharide hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratan sulfate, etc.
  • polymer water-soluble cellulose [methylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, carboxymethylcellulose, etc.]
  • PEG Polyethylene glycol
  • glycerin, amorphous silica, etc. may be used as a thickener.
  • the viscosity can be added to the sample liquid only by adding the thickener to the sample liquid 90. Further, by adjusting the concentration of the thickener added to the sample liquid 90, the desired viscosity of the liquid to be measured can be obtained.
  • Gelling agent has the property of gelling a liquid.
  • a suitable chemical gel or physical gel may be used as the gelling agent. Specifically, agarose (agar), pectin, alginic acid, carrageenan and the like may be used as a gelling agent.
  • a desired viscosity of the liquid to be measured can be obtained by adjusting a ratio of adding the gelling agent to the sample liquid 90.
  • the photo-curing resin has a property of being cured when irradiated with light having a predetermined wavelength.
  • the gelling agent for example, a UV curable epoxy resin material that cures when irradiated with UV (ultraviolet) light may be used.
  • the user of the inspection chip 1 can increase the viscosity of the measurement target liquid at a desired timing. For this reason, by performing the step of irradiating the measurement target liquid with UV light after the step of introducing the measurement target liquid into the recess 13, the time required for the step of introducing the measurement target liquid into the recess 13 is shortened.
  • the two-component mixed curing agent has a property of being cured by mixing the main agent and the curing agent.
  • a two-component mixed curing agent for example, a known two-component mixed epoxy curing agent may be used.
  • the curing rate of the liquid to be measured can be adjusted.
  • FIG. 2 is a diagram illustrating the inspection apparatus 100 (measurement apparatus) of the present embodiment.
  • the inspection apparatus 100 is an apparatus that optically measures the measurement target liquid held on the inspection chip 1.
  • the inspection apparatus 100 includes an inspection chip 1, a light source 31, a beam splitter 32, a collimator lens 33a, an objective lens 33b, a condenser lens 33c, and a light receiving element 34 (light receiving unit).
  • the inspection chip to be inspected by the inspection apparatus 100 is not limited to the inspection chip 1 and may be an inspection chip according to each embodiment described later. The same applies to the inspection apparatus 300 (see FIG. 7) described later.
  • the light source 31 emits measurement light for performing optical measurement on the particulate matter contained in the measurement target liquid held on the inspection chip 1.
  • the light source 31 is, for example, a semiconductor laser.
  • the measurement light emitted from the light source 31 may be visible light or invisible light such as infrared light or ultraviolet light.
  • the beam splitter 32 is an optical element that splits light by reflecting part of incident light and transmitting other light.
  • the measurement light emitted from the light source 31 enters the beam splitter 32 via the collimating lens 33a. A part of the measurement light is reflected by the beam splitter 32 and reaches the measurement target liquid held on the inspection chip 1 via the objective lens 33b. And inspection light arises as a result of particulate matter or a flow reducing substance contained in a liquid to be measured receiving measurement light.
  • the inspection light is (i) light (reflected light) generated by the measurement light reflected on the particulate matter, and (ii) light scattered by the particulate matter (scattered light). And (iii) means at least one of fluorescence emitted from the particulate matter or the flow reducing substance as a result of the particulate matter receiving the measurement light.
  • Part of the measurement light is transmitted by the beam splitter 32 and reaches the light receiving element 34 via the condenser lens 33c.
  • Each of the collimator lens 33a, the objective lens 33b, and the condenser lens 33c is an optical element that condenses light that has passed through a predetermined optical path.
  • the collimating lens 33 a is disposed between the light source 31 and the beam splitter 32.
  • the collimating lens 33a converts the measurement light from the light source 31 toward the beam splitter 32 into parallel light.
  • the objective lens 33 b is disposed between the beam splitter 32 and the inspection chip 1.
  • the objective lens 33 b condenses the measurement light traveling from the beam splitter 32 toward the inspection chip 1 and makes the inspection light traveling from the inspection chip 1 toward the beam splitter 32 into parallel light.
  • the condenser lens 33 c is disposed between the beam splitter 32 and the light receiving element 34.
  • the condensing lens 33c condenses the inspection light from the beam splitter 32 toward the light receiving element 34.
  • the light receiving element 34 outputs an electrical signal (for example, voltage or current) having a magnitude corresponding to the amount of received light. That is, the light receiving element 34 is a photoelectric conversion element that converts an optical signal into an electrical signal. The light receiving element 34 functions as a light receiving unit in the inspection apparatus 100.
  • the light receiving element 34 is a photodiode. For this reason, the light receiving element 34 outputs a current as an electrical signal.
  • a photoelectric conversion element other than a photodiode such as a phototransistor, an avalanche photodiode, or a photomultiplier tube, may be used.
  • the light receiving element 34 When the light receiving element 34 receives the inspection light from the inspection chip 1, the light receiving element 34 outputs a current having a magnitude corresponding to the received light quantity. Therefore, a current value corresponding to the position of the point where the measurement light is incident on the measurement target liquid contained in the test chip 1 is obtained in the light receiving element 34.
  • the current value obtained in the light receiving element 34 is converted into a voltage, and then converted into a voltage by an AD (Analog-Digital) converter provided outside the inspection apparatus 100 in order to facilitate data processing. May be applied. Further, the AD converter may be provided inside the inspection apparatus 100.
  • the optical system for measurement (that is, the light source 31, the beam splitter 32, the collimating lens 33a, the objective lens 33b, the condensing lens 33c, and the light receiving element 34) is relatively set with respect to the fixed inspection chip 1. By moving, the position of the point where the measurement light is incident on the measurement target liquid contained in the test chip 1 is changed.
  • the position of the point where the measurement light is incident on the measurement target liquid contained in the test chip 1 may be changed by moving the test chip 1 relative to the fixed optical system.
  • the position of the point where the measurement light is incident on the measurement target liquid contained in the test chip 1 is By changing over the entire region in which the liquid to be measured is held in the inspection chip 1, a current value mapping result (that is, a current value data series) indicating the overall aspect of the region is obtained.
  • the particulate matter contained in the liquid to be measured can be optically measured by numerically analyzing the mapping result of the current value.
  • the type of the particulate matter can be specified by detecting the fluorescence emitted from the particulate matter as the inspection light. Further, the size of the particulate matter can be measured by detecting scattered light generated by the particulate matter.
  • the number of specific particulate matter present within a predetermined area on the bottom surface 13a of the recess 13 is counted. can do.
  • the two-dimensional (ie, planar) distribution of the particulate matter suspended in the liquid to be measured can be expressed numerically. It can also be calculated as data. Further, by performing numerical processing on the numerical data, image data indicating a two-dimensional distribution of the particulate matter can be obtained.
  • FIG. 2 illustrates a configuration in which the upper surface of the inspection chip 1 is irradiated with measurement light.
  • the substrate 11 is made of a material that transmits measurement light and inspection light
  • the lower surface of the inspection chip 1 may be irradiated with measurement light.
  • the case where optical measurement is performed on the measurement target liquid using the inspection apparatus 100 is illustrated, but the measurement target liquid is measured by any other method. Also good.
  • the method for measuring particulate matter using the inspection chip 1 includes the following first to third steps.
  • the measurement target liquid is prepared by mixing the sample liquid 90 and the flow reducing substance 91.
  • the flow reducing substance 91 a case where a xanthan gum aqueous solution is used as the flow reducing substance 91 will be described as an example.
  • an aqueous xanthan gum solution as the flow reducing substance 91 is prepared. Specifically, 97.5 mL of distilled water is added to 2.5 g of xanthan gum. Then, the xanthan gum is dissolved in distilled water by sufficiently stirring the aqueous solution using a stirrer. Thereby, 100 g of xanthan gum aqueous solution having a concentration of 2.5% by mass is prepared.
  • xanthan gum aqueous solution immediately after preparation contains air, bubbles are mixed therein. For this reason, it is preferable to deaerate xanthan gum aqueous solution using an aspirator or a vacuum pump.
  • the degassed xanthan gum aqueous solution is used as the flow reducing substance 91.
  • the sample solution 90 is 50 ⁇ L of water containing cells as particulate matter. Further, as the flow reducing substance 91, 12.5 ⁇ L of the above xanthan gum aqueous solution is used. Therefore, the volume ratio between the sample liquid 90 and the flow reducing substance 91 is 4: 1.
  • a liquid to be measured is obtained by mixing the sample liquid 90 and the flow reducing substance 91. The liquid to be measured is a 0.5% by mass xanthan gum aqueous solution.
  • the concentration of xanthan gum in the flow reducing substance 91 and the measurement target liquid is not limited to the above values, and is appropriately changed so as to obtain a suitable viscosity according to the specification of the inspection apparatus 100 or the volume of the recess 13. May be.
  • the viscosity of the liquid to be measured obtained in the first step (that is, 0.5 mass% xanthan gum aqueous solution) was measured with a B-type viscometer under the conditions of a temperature of 20 ° C. and a rotation speed of 60 rpm. ⁇ The value is from s to 400 mPa ⁇ s.
  • xanthan gum has pseudoplastic viscosity (pseudoplastic viscosity)
  • the viscosity of the liquid to be measured at rest is greater than the above-described measured value.
  • the measurement target liquid prepared in the first step is filled in the recess 13 of the test chip 1. Specifically, the measurement target liquid is dropped into the introduction port 14. Thereby, the liquid to be measured is introduced into the recess 13 by the capillary force generated in the gap between the bottom surface 13 a and the cover 12.
  • the measurement target liquid may be dropped into the introduction port 14 until the measurement target liquid is filled almost entirely inside the recess 13.
  • the third step (Third step: measurement of particulate matter)
  • measurement is performed on the particulate matter contained in the measurement target liquid filled in the recess 13 in the second step.
  • the measurement for the particulate matter is performed using, for example, the inspection apparatus 100 described above. Thereby, for example, the particulate matter can be counted.
  • 3 and 4 are diagrams illustrating the relative positional relationship between the laser spot and the particle.
  • the particle movement distance x due to Brownian motion is expressed by the following equation (1).
  • D is a diffusion coefficient
  • t is a measurement time (that is, an elapsed time from the start of particle observation).
  • ⁇ X 2 > represents the root mean square of the movement distance x.
  • the diffusion coefficient D is expressed by the following equation (2).
  • k B is a Boltzmann constant
  • T is an absolute temperature
  • a is a particle radius
  • ⁇ is a viscosity (viscosity coefficient).
  • the diffusion coefficient D increases as the particle radius a decreases. Therefore, when the measurement time t of the equation (1) is considered as a constant value, it can be seen that the movement distance x increases as the particle size becomes smaller.
  • the viscosity ⁇ required to keep the particle movement distance x within a predetermined range may be determined according to the size of the particle to be measured.
  • the particles to be measured are scanned by a laser (measurement light).
  • the measurement time t may be determined by the particle diameter (particle diameter), the particle moving distance, the laser beam diameter, and the laser scanning speed.
  • the moving distance x of the particles needs to satisfy the following formula (5).
  • FIG. 3 exemplifies the relative positional relationship between the laser spot and the particle in the direction in which scanning with the laser is performed.
  • the viscosity ⁇ only needs to satisfy the formula (4) at the maximum value of the measurement time t in the formula (7). That is, the viscosity ⁇ is derived by applying the formula (4) to the formula (7), and satisfies the following formula (8). Of 10% or less.
  • the measurement time t is also determined by the beam diameter of the laser, the feed pitch for scanning the laser, and the scanning time of one cycle of the laser.
  • the beam diameter orthogonal to the laser scanning direction is represented as b2, and the feed pitch is represented as L.
  • the number of times the laser passes through one arbitrary point is represented by an integer n.
  • n is an integer obtained by rounding up the value of b2 / L.
  • FIG. 4 illustrates the relative positional relationship between the laser spot and the particles when the light source is moved in a direction perpendicular to the laser scanning direction.
  • the laser scanning may be performed once, so the time t corresponds to one period of the scanning time t ′.
  • the viscosity ⁇ is determined by the equation (4).
  • the viscosity ⁇ of the liquid to be measured is higher than the range determined by the equations (8) and (10).
  • the moving distance x of the particle can be kept within a range of 10% or less of the diameter of the particle.
  • the viscosity ⁇ may be determined according to the size of the particle to be measured, the specifications of the apparatus used for measurement, and the required measurement accuracy.
  • a 0.25 ⁇ m
  • b 6 ⁇ m
  • b2 12 ⁇ m
  • L 2 ⁇ m
  • T 293.15 K
  • V 0.565 m / s
  • t ′ 0. If 333 sec, ⁇ ⁇ 3433 mPa ⁇ s.
  • pedia is the minimum value of the radius of the particle to be measured, which is assumed when a thickener is used as the flow reducing substance 91.
  • b, b2, L, T, V, and t ′ are values given by standard specifications of the light source 31 included in the inspection apparatus 100.
  • the exposure time corresponds to the measurement time t, so the value of the viscosity ⁇ can be determined by equation (4).
  • the value of the viscosity ⁇ may be appropriately set according to the size of the particle to be measured, the specification of the apparatus used for the measurement, and the required measurement accuracy.
  • the viscosity ⁇ of the measurement target liquid may be set as ⁇ ⁇ 700 mPa ⁇ s or more.
  • the upper limit value of the viscosity of the flow reducing substance 91 may be set within a range in which the liquid to be measured can be introduced into the recess 13.
  • the Brownian motion of the particulate matter present in the measurement target liquid is significantly suppressed as compared with the case where the particulate matter is present in the sample liquid 90 in which the flow reducing substance 91 is not mixed. Is possible. For this reason, when the measurement target liquid introduced into the recess 13 is measured, the influence of the Brownian motion of the particulate matter on the measurement result is measured for the sample liquid 90 in which the flow reducing substance 91 is not mixed. This can be reduced as compared with the case of performing.
  • test chip 1 of the present embodiment it is not necessary to (i) suppress the Brownian motion of the particulate matter contained in the measurement target liquid and (ii) quantify the measurement target liquid in advance. And (iii) The effect that the introduction of the liquid to be measured into the recess 13 can be facilitated can be realized at the same time.
  • an inspection kit including the inspection chip 1 and the flow reducing substance 91 may be provided.
  • the flow reduction substance 91 according to the kind of the particulate matter which a user makes a measurement object with the test
  • a reactive substance that specifically reacts with the particulate matter for example, a dye-labeled antibody that stains the particulate matter by reacting with the particulate matter
  • a reactive substance that specifically reacts with the particulate matter for example, a dye-labeled antibody that stains the particulate matter by reacting with the particulate matter
  • FIG. 5 is a diagram showing a configuration of the inspection chip 2 (inspection instrument) of the present embodiment.
  • the inspection chip 2 includes a base material 21 and a cover 22.
  • the cover 22 is disposed on two substantially rectangular spacers 23 provided on the upper surface 21 s of the base material 21.
  • the cover 22 covers a part of the upper surface 21s.
  • the upper surface 21s is formed as a flat surface not provided with a recess. Therefore, the test chip 2 according to the present embodiment is different from the test chip 1 according to the first embodiment in that the concave portion 13 as a holding portion is not provided.
  • a gap 25 is defined between the upper surface 21s and the back surface of the cover 22 (the surface facing the base material 21). In the inspection chip 2, the measurement target liquid is held in the gap 25.
  • the inspection chip 2 a space defined by two opposing surfaces of the base material 21 and the cover 22 facing each other and two opposing surfaces (side surfaces) of the two spacers 23 facing each other.
  • the liquid to be measured is retained. Therefore, the holding portion is configured by the base material 21, the cover 22, and the spacer 23.
  • the cover 22 is substantially square.
  • the shape of the cover 22 is not particularly limited and may be determined as appropriate by the designer of the inspection chip 2.
  • the height of the gap 25 is defined as the distance between the upper surface 21s and the cover 22. This height is defined such that a capillary force acts by the gap 25, and the height is, for example, 50 ⁇ m.
  • the measurement target liquid is dropped in the vicinity of the gap 25 on the upper surface 21s, the measurement target liquid is introduced into the gap 25 by capillary force. For this reason, the liquid to be measured can be easily introduced into the gap 25.
  • the height of the gap 25 is defined to be constant, a predetermined value on the upper surface 21s that defines the gap 25 when the measurement target liquid filled in the gap 25 is viewed from a direction perpendicular to the upper surface 21s. The amount of the liquid to be measured existing within the area is constant.
  • a predetermined amount of the measurement target liquid can be set as the measurement target. Therefore, it is not necessary to measure a predetermined amount of the measurement target liquid, and quantitative measurement of the measurement target liquid can be easily performed.
  • the inspection chip according to one embodiment of the present invention can introduce (i) a measurement target liquid to which a viscosity is given, and (ii) quantitatively measure the measurement target liquid.
  • the configuration is not limited to the configuration shown in the first and second embodiments.
  • the inspection chip may be configured as an inspection chip 2a as a modified example shown below.
  • FIG. 6 is a diagram showing a configuration of an inspection chip 2a (inspection instrument) as a modified example of the inspection chip according to the first or second embodiment.
  • the inspection chip 2a includes a base material 21a and a cover 22a.
  • a concave portion 26 (holding portion) that holds the measurement target liquid is provided on the upper surface of the base material 21a.
  • the cover 22 a is disposed so as to cover the entire upper surface of the recess 26.
  • an introduction groove 24 for introducing the liquid to be measured into the recess 26 is provided in a portion not covered with the cover 22a.
  • the recess 26 has a substantially square bottom surface 26a, and the introduction groove 24 is provided as a groove having a substantially circular recess.
  • the shapes of the recess 26 and the introduction groove 24 are not particularly limited, and may be determined as appropriate by the designer of the inspection chip 2a.
  • the height of the concave portion 26 (distance between the bottom surface 26a and the cover 22a) is defined so that a capillary force works by a gap between the bottom surface 26a and the cover 22a, and the height is, for example, 50 ⁇ m. .
  • the measurement target liquid is dropped into the introduction groove 24
  • the measurement target liquid is introduced into the recess 26 by capillary force. For this reason, the measurement target liquid can be easily introduced into the recess 26.
  • the height of the concave portion 26 is defined to be constant, a predetermined amount of the measurement target liquid filled in the concave portion 26 can be set as the measurement target, similarly to the test chips 1 and 2. Therefore, it is not necessary to measure a predetermined amount of the measurement target liquid, and quantitative measurement of the measurement target liquid can be easily performed.
  • FIG. 7 is a diagram illustrating an inspection apparatus 300 according to the present embodiment. Similar to the inspection apparatus 100 of the first embodiment, the inspection apparatus 300 of the present embodiment is an apparatus that performs optical measurement on the measurement target liquid held on the inspection chip 1.
  • the inspection apparatus 300 includes an inspection chip 1, a light source 31, a beam splitter 32, a collimator lens 33a, an objective lens 33b, a condensing lens 33c, and an image sensor 35 (light receiving unit).
  • the inspection apparatus 300 according to the present embodiment has a configuration obtained by replacing the light receiving element 34 with the imaging element 35 in the inspection apparatus 100 according to the first embodiment.
  • the image sensor 35 outputs image data (for example, a color image or a monochrome image) corresponding to the received light.
  • the image sensor 35 is a CCD (Charge Coupled Device) image sensor.
  • the image pickup device 35 another image pickup device such as a CMOS (Complementary Metal Oxide Semiconductor) image sensor may be used.
  • CMOS Complementary Metal Oxide Semiconductor
  • the imaging element 35 is an element configured by arranging a plurality of light receiving elements (for example, the light receiving elements 34) in a matrix. For this reason, the image pickup element 35 also functions as a light receiving unit, similarly to the light receiving element 34.
  • the image sensor 35 When the image sensor 35 receives the inspection light from the inspection chip 1, the image sensor 35 outputs image data corresponding to the received inspection light. Accordingly, image data corresponding to the position of the point where the measurement light is incident on the measurement target liquid contained in the test chip 1 is obtained in the image sensor 35.
  • the position of the point where the observation light is incident on the measurement target liquid included in the inspection chip 1 is extended over the entire region where the measurement target liquid is held in the inspection chip 1.
  • the image data obtained in the imaging device 35 of the inspection apparatus 300 is information with higher visibility than the current value mapping result obtained in the inspection apparatus 100 of the first embodiment. Therefore, by optically coupling an instrument such as an optical microscope to the image sensor 35, it is possible to allow the user to visually confirm the entire region where the measurement target liquid is held.
  • the number of particulate matter suspended in the measurement target liquid can be counted.
  • a two-dimensional (ie, planar) distribution of the particulate matter can be calculated as numerical data.
  • Embodiment 4 The following describes Embodiment 4 of the present invention with reference to FIGS.
  • FIG. 8 is a diagram showing a configuration of the inspection chip 1 (inspection instrument) of the present embodiment.
  • the inspection chip 1 used in the present embodiment is the same as the inspection chip 1 shown in FIG.
  • the sample liquid 90 and the flow reducing substance 91 may have the same composition as in the first embodiment.
  • the recessed part 13 provided in the upper surface of the base material 11 is for hold
  • the height of the recess 13 in this embodiment is, for example, 50 ⁇ m.
  • the liquid to be measured in the present embodiment is prepared by mixing the sample liquid 90 and the binding substance 92 and adding the flow reducing substance 91 to the mixed liquid.
  • a pressure may be applied to the measurement target liquid using a power device such as a pump.
  • a power device such as a pump.
  • the capillary force or the water head pressure (self-weight) rather than the pump because the liquid to be measured can be introduced with a simple configuration.
  • the capillary force generated between the bottom surface 13a and the cover 12 for introducing the liquid to be measured into the recess 13 does not necessarily have to be used.
  • the binding substance 92 is a substance that binds (interacts) with the particulate matter contained in the sample liquid 90, and facilitates detection of the particulate matter.
  • the binding substance 92 may be a solution or a powder.
  • binding substance 92 examples include staining dyes (Gram staining, Giemsa staining, PAS (Periodic® acid-Schiff) staining, NAP (neutrophil alkaline phosphatase) staining, PO (Peroxidase) staining, iron staining, etc.), fluorescence Examples include dyes for staining (such as DAPI (diamidino-2-phenylindole)), fluorescently labeled antibodies, enzyme-labeled antibodies, and antibody-bound beads (such as latex aggregation beads and magnetic beads).
  • staining dyes such as DAPI (diamidino-2-phenylindole)
  • fluorescently labeled antibodies such as enzyme-labeled antibodies, and antibody-bound beads (such as latex aggregation beads and magnetic beads).
  • the binding liquid 90a (a binding body-containing liquid) is a liquid in which the sample liquid 90 and the binding substance 92 are mixed, and includes a binding body of the particulate matter and the binding substance 92. By binding the particulate matter to the binding material 92, the particulate matter can be labeled.
  • An antigen-antibody reaction may be used for the production of the conjugate. By using the antigen-antibody reaction, the conjugate can be specifically bound to the particulate matter, and the detection accuracy of the particulate matter can be increased.
  • the sample liquid 90 is a plasma component
  • the particulate matter to be measured contained in the sample liquid 90 is platelets
  • the binding substance 92 is FITC (fluorescein isothiocyanate) labeled anti-CD41. It is an antibody.
  • the FITC-labeled anti-CD41 antibody binds to CD41, which is a marker protein present on the surface of platelets, and platelets and FITC A conjugate with the labeled anti-CD41 antibody is generated.
  • CD41 which is a marker protein present on the surface of platelets
  • platelets and FITC A conjugate with the labeled anti-CD41 antibody is generated.
  • the concentration of platelets can be measured.
  • the flow reducing substance 91 is a substance added to the binding liquid 90a in order to increase the viscosity of the binding liquid 90a, and the same substance as the flow reducing substance 91 described in the first embodiment can be used.
  • the flow reducing substance 91 may be added as a solution to the binding liquid 90a, or may be added as a powder to the binding liquid 90a.
  • the inspection apparatus used in the present embodiment is the same as the inspection apparatus 100 and the inspection apparatus 300 described in the first and third embodiments (see FIGS. 1 and 7).
  • FIG. 9 is a flowchart illustrating an example of a measurement method using the inspection chip 1. This measuring method includes the following first to fourth steps.
  • a binding substance 92 is added to the sample liquid 90 to generate a bound body in which the particulate matter and the binding substance 92 are bound (S11).
  • a binding substance 92 is added to the sample liquid 90 as a binding substance 92 and left for a predetermined time.
  • a pH adjusting agent such as a buffer may be added to the sample solution 90 in order to increase the specificity of the antigen-antibody reaction.
  • FITC Fluorescein isothiocyanate
  • the whole blood is centrifuged and the plasma component (supernatant) is collected.
  • a FITC-labeled anti-CD41 antibody solution is added and allowed to stand for a predetermined time, thereby binding CD41 present on the surface of platelets to the FITC-labeled anti-CD41 antibody.
  • This reaction produces a conjugate between platelets and FITC-labeled anti-CD41 antibody (antigen-antibody reaction).
  • the binding liquid 90a conjugate containing liquid
  • the flow reduction substance 91 are mixed to prepare a measurement target liquid (S12).
  • a measurement target liquid S12
  • a case where a xanthan gum aqueous solution is used as the flow reducing substance 91 will be described as an example.
  • an aqueous xanthan gum solution as the flow reducing substance 91 is prepared. Specifically, 97.5 mL of distilled water is added to 2.5 g of xanthan gum. Then, the xanthan gum is dissolved in distilled water by sufficiently stirring the aqueous solution using a stirrer. Thereby, 100 g of xanthan gum aqueous solution having a concentration of 2.5% by mass is prepared.
  • xanthan gum aqueous solution immediately after preparation contains air, bubbles are mixed therein. For this reason, it is preferable to deaerate xanthan gum aqueous solution using an aspirator or a vacuum pump.
  • the degassed xanthan gum aqueous solution is used as the flow reducing substance 91.
  • the sample solution 90 is 50 ⁇ L of water containing cells as particulate matter.
  • As the flow reducing substance 91 12.5 ⁇ L of the above xanthan gum aqueous solution is used. Since the volume of the binding substance 92 is usually very small, the volume of the binding liquid 90a is also approximately 50 ⁇ L. Therefore, the volume ratio of the binding liquid 90a and the flow reducing substance 91 is 4: 1.
  • a measurement target liquid is obtained.
  • the liquid to be measured is a 0.5% by mass xanthan gum aqueous solution.
  • the concentration of xanthan gum in the flow reducing substance 91 and the measurement target liquid is not limited to the above values, and is appropriately changed so as to obtain a suitable viscosity according to the specification of the inspection apparatus 100 or the volume of the recess 13. May be.
  • the viscosity of the liquid to be measured obtained in the second step (that is, 0.5 mass% xanthan gum aqueous solution) was measured with a B-type viscometer under the conditions of a temperature of 20 ° C. and a rotation speed of 60 rpm. ⁇ The value is from s to 400 mPa ⁇ s.
  • xanthan gum has pseudoplastic viscosity (pseudoplastic viscosity)
  • the viscosity of the liquid to be measured at rest is greater than the above-described measured value.
  • the measuring solution prepared in the second step is filled into the recess 13 of the test chip 1 (S13). Specifically, the measurement target liquid is dropped into the introduction port 14. As a result, the liquid to be measured dropped into the introduction port 14 is introduced into the recess 13 by the capillary force generated in the gap between the bottom surface 13 a and the cover 12.
  • the measurement target liquid may be dropped into the introduction port 14 until the measurement target liquid is filled almost entirely inside the recess 13.
  • the fourth step (particulate matter measurement step)
  • measurement is performed on the particulate matter (strictly, a conjugate) contained in the measurement target liquid filled in the recess 13 in the third step.
  • the measurement for the combined body is performed using, for example, the inspection apparatus 100 described above. Thereby, for example, the particulate matter can be counted.
  • the measurement liquid in order to measure the conjugate, the measurement liquid is prepared by mixing the binding liquid 90a and the flow reducing substance 91. For this reason, the viscosity of the liquid to be measured increases more than the viscosity of the binding liquid 90a.
  • the process of adding the binding substance 92 to the sample liquid 90 is performed prior to the process of adding the flow reducing substance 91 to the sample liquid 90.
  • the efficiency of the binding between the particulate matter and the binding substance 92 decreases as the viscosity of the solvent (or dispersion medium) containing them increases.
  • the binding substance 92 is an antibody, the molecular weight of the binding substance 92 is large, so that it is strongly influenced by the viscosity of the solvent.
  • the binding efficiency between the particulate matter and the binding substance 92 is reduced. Can be prevented.
  • an inspection kit including the inspection chip 1, the flow reduction substance 91, and the binding substance 92 may be provided.
  • This test kit assumes measurement of a predetermined particulate matter, and a binding substance 92 that specifically binds to the particulate matter is included in the test kit.
  • FIG. 10 is a top view showing the configuration of the inspection chip 4 (inspection instrument) of the present embodiment.
  • the inspection chip 4 includes a cover 42 on the upper surface.
  • the cover 42 is made of a translucent material so that the liquid inside the first minute space 43 and the second minute space 45 described later can be seen from the outside.
  • the cover 42 has three openings (introduction port 44, first air hole 51, and second air hole 52).
  • the inspection chip 4 is provided with two spaces (a first minute space 43 and a second minute space 45), and these two spaces and the three openings are a flow path (first flow path). 46, the second flow path 47, the third flow path 48, and the fourth flow path 49).
  • the inspection chip 4 of the present embodiment is greatly different from the inspection chip 1 of Embodiment 1 described above in that two spaces (a first micro space 43 and a second micro space 45) are provided.
  • the first minute space 43 (first mixing unit) holds a binding material 92 in a predetermined amount of powder (solid) in advance, and mixes the sample liquid 90 dropped from the inlet 44 and the binding material 92. It is a space for.
  • the second micro space 45 (second mixing unit) holds a predetermined amount of powder reducing (solid) flow reducing substance 91 in advance, and the binding liquid 90a generated in the first micro space 43 and the flow reducing substance.
  • 91 is a space for mixing 91.
  • the second minute space 45 holds the measurement target liquid generated by mixing the binding liquid 90a and the flow reduction substance 91 in a state in which the conjugate in the measurement target liquid can be optically measured. .
  • the binding substance 92 and the flow reduction substance 91 are held in a powder state (dry state), the degree to which the sample liquid 90 and the binding liquid 90a are diluted can be reduced. Therefore, even when the concentration of the particulate matter in the sample liquid 90 is low, the detection sensitivity of the particulate matter can be maintained.
  • the inlet 44 is an opening for dropping the sample liquid 90.
  • the first flow path 46 is a flow path that connects the inlet 44 and the first minute space 43.
  • the first minute space 43 is a space for mixing the sample liquid 90 dropped from the introduction port 44 and the binding substance 92 held in advance (binding step).
  • the second flow path 47 is a flow path that guides the gas in the first minute space 43 to the first air hole 51.
  • the first air hole 51 is an opening for discharging the gas guided from the second flow path 47 to the outside of the inspection chip 4.
  • the three openings (introduction port 44, first air hole 51, and second air hole 52) shown in FIG. 10 are circular. However, the shapes of the three openings are not particularly limited, and may be determined as appropriate by the designer of the test chip 4.
  • the third flow channel 48 is a flow channel that connects the first micro space 43 and the second micro space 45, and a valve 50 that controls the solution in the first micro space 43 flowing into the second micro space 45. Is provided. Details of the valve 50 will be described later with reference to FIGS.
  • the second minute space 45 mixes the binding liquid 90a that has flowed in from the first minute space 43 via the third flow path 48 and the flow reducing substance 91 that is held in advance. This is a space for (addition process).
  • the fourth flow channel 49 is a flow channel that guides the gas in the second minute space 45 to the second air hole 52.
  • the second air hole 52 is an opening for discharging the gas guided from the fourth flow path 49 to the outside of the inspection chip 4.
  • the liquid mixed in the second minute space 45 is held in the second minute space as a measurement target liquid. Thereafter, the measurement target liquid is optically measured by the inspection apparatus 100 shown in FIG.
  • the first minute space 43 may not hold the binding substance 92 in advance.
  • the binding substance 92 is added in advance to the liquid dropped to the introduction port 44 to form the above-described conjugate.
  • the bottom surfaces of the two spaces (the first minute space 43 and the second minute space 45) shown in FIG. 10 are substantially rectangular.
  • the area of the bottom surface of the second minute space 45 is smaller than the area of the bottom surface of the first minute space 43.
  • the sample liquid 90 that is not the binding liquid 90a but remains in the area other than the first microspace 43 is mixed into the second microspace 45. Become.
  • the concentration of particulate matter in the sample solution 90 it is necessary to accurately measure the number of particulate matter (conjugate) to be measured with respect to the amount of the sample solution 90 to be measured.
  • the concentration of the particulate matter (conjugate) cannot be accurately measured when the binding liquid 90a is diluted by mixing unreacted particulate matter that has not become a conjugate.
  • the shape and size of the two spaces need not be particularly limited, and may be determined as appropriate by the designer of the inspection chip 4.
  • the height of the gap is set so that the sample liquid 90 is introduced by the capillary force generated in the gap between the upper surface and the lower surface of the first minute space 43.
  • the height of the gap is set so that the binding liquid 90a is introduced by the capillary force generated in the gap between the upper surface and the lower surface of the second minute space 45.
  • the height of the gap between the first minute space 43 and the second minute space 45 is, for example, 50 ⁇ m.
  • the sample solution 90 in which the sample solution 90 is dropped into the introduction port 44 is introduced into the first minute space 43 by capillary force.
  • the binding liquid 90 a that has flowed into the third flow path 48 by opening the valve 50 is introduced into the second minute space 45 by capillary force. Therefore, the introduction of the sample liquid 90 into the first micro space 43 and the introduction of the binding liquid 90a into the second micro space 45 can be easily performed only by the operation of dropping the sample liquid 90 into the introduction port 44. Can do.
  • the sample liquid 90 when introducing the sample liquid 90, since the water head pressure at the time of dripping at the inlet along with the capillary force can be used, the sample liquid 90 can be introduced more easily.
  • the height of the second minute space 45 (the height of the gap) is defined to be constant.
  • FIG. 11 (Configuration example of inspection chip 4) (A) to (c) of FIG. 11 are exploded views showing specific examples of the configuration of the test chip 4 of this embodiment.
  • the inspection chip 4a shown in FIG. 11 (a) is composed of three plates, and each of the inspection chips 4b and 4c shown in FIGS. 11 (b) and 11 (c) has two plates. It is the composition which consists of.
  • the inspection chip 4a is assembled by overlapping the first base material 40, the second base material 41a, and the cover 42a from below.
  • a valve 50 is provided on the upper surface of the first base material 40 (the surface on the second base material 41a side). The valve 50 is installed at a position facing the third flow path 48a in the second base material 41a.
  • the cover 42 a is formed with three openings, that is, an inlet 44, a first air hole 51, and a second air hole 52.
  • the second base material 41a is formed with an introduction recess 44a, a first air hole recess 51a, and a second air hole recess 52a. These recesses are formed at positions corresponding to the introduction port 44, the first air hole 51, and the second air hole 52.
  • the introduction recess 44 a constitutes a recess for introducing the sample liquid 90 into the first minute space 43 together with the introduction port 44.
  • the first air hole recess 51 a and the first air hole 51 constitute an air passage that communicates the first minute space 43 and the external space.
  • the second air hole recess 52a, together with the second air hole 52, constitutes an air passage that communicates the second minute space 45 and the external space.
  • first recess 43a and the second recess 45a are formed in the second base material 41a.
  • the first recess 43a defines the first minute space 43 together with the lower surface of the cover 42a (the surface on the second base material 41a side).
  • the second recess 45a defines the second minute space 45 together with the lower surface of the cover 42a.
  • a first channel 46a to a fourth channel 49a are formed in the second base material 41a.
  • a hole is formed at a predetermined location on the bottom surface of the third channel 48a so that the valve 50 provided in the first base member 40 is inserted.
  • the sample liquid 90 dropped into the introduction port 44 flows into the first micro space 43 via the first flow path 46 a by capillary force, and the binding liquid in the first micro space 43. 90a is generated.
  • the binding liquid 90a flows into the second microspace 45 from the first microspace 43 via the third flow path 48a by the opening of the valve 50 and the capillary force, and the measurement target liquid is generated.
  • FIG. 11B shows an inspection chip 4b assembled from two plates.
  • the inspection chip 4b includes a first base material 40 and a cover 42b.
  • the cover 42b has three openings (introduction port 44b, first air hole 51b and second air hole 52b), two recesses (first recess 43b and second recess 45b), and four flow paths (first A first flow path 46b to a fourth flow path 49b) are formed.
  • the two concave portions and the four flow paths are formed on the lower surface (the surface on the first base material 40 side) of the cover 42b.
  • the first minute space 43 is formed by the first recess 43b and the upper surface of the first base material 40 (the surface on the cover 42b side), and the second minute space 45 is formed by the second recess 45b and the upper surface of the first base material 40. Formed from.
  • the introduction port 44b, the first air hole 51b, and the second air hole 52b are each formed as a hole penetrating the cover 42b.
  • the sample liquid 90 dropped onto the introduction port 44b flows into the first micro space 43 via the first flow path 46b by capillary force, and the binding liquid is generated in the first micro space 43. 90a is generated.
  • the valve 50 is opened, the binding liquid 90a flows into the second microspace 45 from the first microspace 43 via the third flow path 48b by capillary force, and a measurement target liquid is generated.
  • FIG. 11C shows an inspection chip 4c assembled from two plates.
  • the inspection chip 4c includes a first base material 40c and a cover 42c.
  • the upper surface (the surface on the cover 42c side) of the first base material 40c has five recesses (introduction recess 44c, first air hole recess 51c, second air hole recess 52c, first recess 43c, and second recess 45c). ) And four flow paths (the first flow path 46c to the fourth flow path 49c).
  • the first minute space 43 is formed from the first recess 43c and the lower surface of the cover 42c (the surface on the first base material 40c side), and the second minute space 45 is formed from the second recess 45c and the lower surface of the cover 42c. Is done.
  • the width of the third flow path 48c is designed to be a width that allows the valve 50 provided on the lower surface of the cover 42c to be inserted.
  • the cover 42c has three openings (introduction port 44, first air hole 51, and second air hole 52).
  • the introduction port 44, the first air hole 51, and the second air hole 52 are formed at positions facing the introduction recess 44c, the first air hole recess 51c, and the second air hole recess 52c in the first base material 40c. Has been.
  • a valve 50 is provided on the lower surface of the cover 42c (the surface on the first base material 40c side). The valve 50 is installed at a position facing the third flow path 48c in the first base material 40c.
  • the sample liquid 90 dropped onto the introduction port 44 flows into the first micro space 43 via the first flow path 46 c by capillary force, and the binding liquid is generated in the first micro space 43. 90a is generated.
  • the valve 50 is opened, the binding liquid 90a flows into the second microspace 45 from the first microspace 43 via the third flow path 48c by capillary force, and a measurement target liquid is generated.
  • the valve 50 shown in FIG. 10 is for controlling the inflow of liquid from the first minute space 43 to the second minute space 45.
  • the valve 50 is closed after the sample liquid 90 starts to flow into the first minute space 43 until the binding liquid 90a is generated. Thereby, the valve 50 prevents the sample liquid 90 and the binding liquid 90a from flowing out from the first minute space to the second minute space. Then, after the binding liquid 90a is generated in the first minute space 43, the valve 50 is opened.
  • the valve 50 is opened, the liquid can pass through the third flow path 48. In this state, the binding liquid 90a flows from the first minute space into the second minute space by capillary force.
  • the valve 50 may be opened and closed at a timing desired by the user.
  • FIG. 12 is a diagram illustrating an example of the configuration of the valve 50a according to the present embodiment.
  • a valve 50a shown in FIG. 12 is a microvalve (electrowetting valve) using electrowetting, and is a device that switches the transfer of the solution (opens and closes the flow of the solution) by applying a voltage.
  • 12A is a schematic diagram showing a state where no voltage is applied in the valve 50a
  • FIG. 12B is a schematic diagram showing a state where a voltage is applied.
  • a valve 50a including a working electrode 53 and a reference electrode 54 is provided in the third flow path 48.
  • a hydrophobic film 53 a is formed on the surface of the working electrode 53. For this reason, the binding liquid 90 a that has moved in the third flow path 48 due to the capillary force stops when it reaches the working electrode 53.
  • the surface of the working electrode 53 is hydrophobic when no voltage is applied, and becomes hydrophilic when a voltage is applied. For this reason, the stop and movement of the binding liquid 90a can be switched by applying a voltage.
  • the hydrophobicity of the valve 50a stops the binding liquid 90a from flowing out from the first micro space 43 to the second micro space 45.
  • the binding liquid 90a is urged to flow out from the first micro space 43 to the second micro space 45 due to the hydrophilicity of the valve 50a.
  • FIG. 13 (A) and (b) of Drawing 13 are figures showing an example of the composition of the valve concerning this embodiment, respectively.
  • the hydrophobic valve 50b shown in FIG. 13 (a) is a highly hydrophobic valve
  • the hydrophilic valve 50c shown in FIG. 13 (b) is a highly hydrophilic valve.
  • the cross-sectional areas of the hydrophobic valve 50b and the hydrophilic valve 50c are both designed to be smaller than the cross-sectional area of the third flow path 48.
  • the hydrophobic valve 50b is disposed at the center of the third flow path 48, and acts as a stop valve for blocking the flow of the binding liquid 90a.
  • the binding liquid 90a is filled in the third flow path 48 on the first minute space 43 side, which is divided by the hydrophobic valve 50b, in the vicinity of the inlet of the hydrophobic valve 50b (on the first minute space 43 side in the hydrophobic valve 50b).
  • the binding liquid 90a flows due to the surface tension of the binding liquid 90a, the hydrophobicity (contact angle) of the hydrophobic valve 50b, and the pressure due to the decrease in the flow path width.
  • the binding liquid 90a In order for the binding liquid 90a to flow out from the first microspace 43 to the second microspace 45, it is necessary to apply an external force fw in the direction from the first microspace 43 to the second microspace 45 to the binding liquid 90a.
  • the magnitude of the external force fw may be such that the sum of the external force fw and the capillary force exceeds the pressure generated in the direction from the second minute space 45 toward the first minute space 43.
  • the method of applying the external force fw is a method of sucking the binding liquid 90 a by a pump, a method of sucking a gas in contact with the binding liquid 90 a, or the second micro space 45 from the first micro space 43 in the third flow path 48.
  • hydrophobic treatment of the hydrophobic valve 50b application of a hydrophobic resin material, application of a fluorine-based hydrophobic agent, surface treatment with a fluorine-based gas, or the like can be used.
  • the degree of hydrophobicity of the hydrophobic valve 50b is arbitrarily set so that the contact angle exceeds 90 °.
  • the third flow path 48 connected to the hydrophobic valve 50b is preferably hydrophilic with a contact angle of less than 90 °.
  • the hydrophilic valve 50c shown in FIG. 13B will be described.
  • the hydrophilic valve 50c is arranged at the center of the third flow path 48 or at a position connecting the first minute space 43 and the third flow path 48, and acts as a stop valve for blocking the flow of the binding liquid 90a.
  • the interface of the binding liquid 90a is near the outlet of the hydrophilic valve 50c (the connecting portion between the hydrophilic valve 50c and the third flow path 48 on the second minute space 45 side). Tension is generated.
  • the concave surface 93 of the hydrophilic valve 50c changes to a convex surface 93a at the center. Then, by continuously applying the external force f, the inside of the hydrophilic valve 50c is filled with the binding liquid 90a, and the shape of the surface 93a is changed to the surface 93b having a convex shape with a low mountain with respect to the second minute space 45 side. Change. Further, when the external force f is continuously applied, the surface 93b changes to a surface 93c further protruding toward the second minute space 45, and finally the binding liquid 90a present in the hydrophilic valve 50c It flows out from the first minute space 43 to the second minute space 45.
  • the method of applying the external force f includes a method of sucking the binding liquid 90a by a pump, a method of sucking a gas in contact with the binding liquid 90a, or a direction from the first micro space 43 to the second micro space 45 in the third flow path 48. There is a method of rotating the inspection chip 4 so that a centrifugal force is generated in the direction.
  • Embodiment 6 of the present invention will be described below with reference to FIG.
  • the measurement accuracy of the particulate matter is improved, and the viscosity of the liquid to be measured increases, so that the liquid to be measured is hardly introduced into the inspection chip 1.
  • the purpose is to eliminate the disadvantages.
  • the inspection chip 1 used in this embodiment is the same as the inspection chip 1 shown in FIG.
  • the sample liquid 90 and the flow reducing substance 91 may have the same composition as in the first embodiment.
  • the measurement target liquid is a liquid generated by adding the flow reducing substance 91 to the sample liquid 90.
  • the inspection chip 1 includes a base material 11 and a cover 12. On the upper surface of the base material 11, there is provided a recess 13 (holding part) that holds the measurement target liquid prepared by mixing the sample liquid 90 and the flow reducing substance 91.
  • a minute space (gap) defined by the bottom surface 13 a of the recess 13 and the back surface of the cover 12 is formed.
  • the back surface of the cover 12 is a surface of the cover 12 on the side facing the bottom surface 13a.
  • the minute space has a function of holding the liquid to be measured. Therefore, it can be said that the recess 13 and the cover 12 form a gap for holding the liquid to be measured.
  • the height of the recess 13 is, for example, 50 ⁇ m.
  • a pressure may be applied to the measurement target liquid using a power device such as a pump.
  • a power device such as a pump.
  • the capillary force or the water head pressure (self-weight) rather than the pump because the liquid to be measured can be introduced with a simple configuration.
  • the capillary force generated between the bottom surface 13a and the cover 12 for introducing the liquid to be measured into the recess 13 does not necessarily have to be used.
  • the height of the recess 13 may be larger than the above-described 50 ⁇ m, and may be appropriately determined by the designer of the inspection chip 1.
  • the flow reducing substance 91 in the present embodiment is a substance added to the sample liquid 90 in order to increase the viscosity of the sample liquid 90 (reduce the fluidity). By increasing the viscosity of the sample liquid 90, the Brownian motion of the particulate matter can be reduced. Therefore, it can be said that the flow reducing substance 91 is a substance that reduces the movement of the particulate matter in the sample liquid 90 containing the particulate matter to be measured.
  • the flow reduction material 91 for example, the same material as the flow reduction material 91 described in the first embodiment can be used.
  • the flow reducing substance 91 may be added to the sample solution 90 as a solution, or may be added to the sample solution 90 as a powder.
  • the inspection apparatus used in the present embodiment is the same as the inspection apparatus 100 and the inspection apparatus 300 described in the first and third embodiments (see FIGS. 1 and 7).
  • the measurement method in the present embodiment is the same as the measurement method described in the first embodiment.
  • the shear stress generated when the measurement target liquid is introduced into the inspection chip will be described. As shown in FIG. 1, the measurement target liquid dropped from the introduction port 14 is introduced into the recess 13 by the capillary force generated in the gap between the bottom surface 13 a and the cover 12.
  • the liquid to be measured flows through the recess 13 after the liquid to be measured is dropped into the introduction port 14, the liquid between the liquid to be measured and the bottom surface 13 a and the lower surface of the cover 12 (surface on the base material 11 side).
  • a frictional force is generated in a direction opposite to the capillary force.
  • the velocity distribution of the flow of the measurement target liquid is generated in the droplet of the measurement target liquid according to the distance from the bottom surface 13a or the lower surface of the cover 12 (the velocity of the measurement target liquid is uniform in the droplet).
  • the presence of molecules that move at different speeds in the droplets of the measurement target liquid flowing in the recesses 13 generates shear stress in the measurement target liquid.
  • the measurement target liquid does not flow due to the capillary force, and therefore the degree of flow of the measurement target liquid becomes small. And since the velocity distribution of the flow generated in the droplet of the measurement target liquid flowing in the recess 13 is reduced, the shear stress generated in the measurement target liquid is also reduced.
  • a fluid containing a substance that reduces fluidity there is a fluid having a property of changing the viscosity of the fluid according to the magnitude of an applied force.
  • a fluid having a property of changing the viscosity of the fluid according to the magnitude of an applied force There are Newtonian fluids and non-Newtonian fluids.
  • a Newtonian fluid has a viscous property in which the flow shear stress and the flow velocity gradient are proportional
  • a non-Newtonian fluid has a viscous property in which the relationship between the flow shear stress and the flow velocity gradient is not linear.
  • Non-Newtonian fluids are roughly classified into dilatant fluids, pseudoplastic fluids (pseudoplastic fluids), and Bingham fluids.
  • FIG. 14 is a conceptual diagram showing changes in the viscosity of the fluid with respect to the magnitude of the applied force for each property of the fluid.
  • FIG. 14A is a conceptual diagram showing the change in the viscosity of the fluid with respect to the magnitude of the applied force when the fluid is a dilatant fluid.
  • the viscosity of the fluid increases as the magnitude of the applied force increases.
  • the measurement target liquid has a dilatant fluid property (dilatant viscosity)
  • the measurement target liquid flowing in the recess 13 in the test chip 1 shown in FIG. Larger shear stress is generated than the target liquid. For this reason, the viscosity of the liquid to be measured flowing inside the recess 13 is higher than the viscosity of the liquid to be measured after filling the recess 13. Therefore, the liquid to be measured having the property of a dilatant fluid is unsuitable for eliminating the above-mentioned dilemma.
  • FIG. 14B is a conceptual diagram showing a change in the viscosity of the fluid with respect to the magnitude of the applied force when the fluid is a Newtonian fluid.
  • the viscosity of the fluid is constant regardless of the magnitude of the applied force.
  • the viscosity of the liquid to be measured flowing inside the recess 13 and the liquid to be measured after filling the recess 13 The viscosity is equal to each other without depending on the magnitude of the shear stress generated in the liquid to be measured.
  • FIG. 14C is a conceptual diagram showing a change in the viscosity of the fluid with respect to the magnitude of the applied force when the fluid is a pseudoplastic fluid.
  • the viscosity of the fluid decreases as the magnitude of the applied force increases.
  • the viscosity of the liquid to be measured flowing in the recess 13 in the inspection chip 1 shown in FIG. The viscosity of the liquid to be measured after filling the recess 13 is lower.
  • FIG. 14D is a conceptual diagram showing a change in the viscosity of the fluid with respect to the magnitude of the force applied when the fluid is a Bingham fluid.
  • the viscosity of the fluid decreases as the magnitude of the force increases until the magnitude of the applied force reaches a predetermined value. After reaching the predetermined value, the viscosity of the fluid is constant regardless of the magnitude of the force. For this reason, when the liquid to be measured has the properties of Bingham fluid (Bingham viscosity), when the shearing stress has reached a predetermined value, the measurement target is measured by the capillary force and the water head pressure (self-weight) when dripping into the inlet. It becomes easy for the liquid to flow. On the other hand, when the shear stress does not reach the predetermined value, the flow of the measurement target liquid tends to be suppressed.
  • the measurement target liquid is more easily introduced into the inspection chip 1 than the measurement target liquid having the property of a dilatant fluid. Therefore, in the case of a measurement target liquid having the properties of Newtonian fluid, pseudoplastic fluid, or Bingham fluid, the time during which the measurement target liquid is introduced into the inspection chip 1 is compared with that of the measurement target liquid having the properties of a dilatant fluid. Can be shortened.
  • the measurement time of the liquid to be measured can be shortened, and the convenience for the user can be improved. Moreover, when the particulate matter contained in the liquid to be measured is easily altered, the possibility of the alteration can be reduced.
  • Examples of the flow reducing substance 91 that imparts Newtonian viscosity to the sample liquid 90 include locust bean gum, tamarind seed gum, and carrageenan.
  • Examples of the flow reducing substance 91 that imparts pseudoplastic viscosity to the sample liquid 90 include xanthan gum, guar gum, and gellan gum.
  • Examples of the flow reducing substance 91 that imparts Bingham viscosity to the sample solution 90 include amorphous silica.
  • the viscosity of the measurement target liquid is constant or increases after the measurement target liquid is filled in the inspection chip 1. For this reason, in the measurement target liquid, the Brownian motion of the particulate matter contained in the measurement target liquid is suppressed as compared with the measurement target liquid of the dilatant fluid whose viscosity decreases after filling. Also from this viewpoint, it is preferable that the liquid to be measured is a Newtonian fluid, a pseudoplastic fluid, or a Bingham fluid.
  • the measurement target liquid has the property of pseudoplastic fluid or Bingham fluid
  • the viscosity of the measurement target liquid increases after the measurement target liquid is filled in the inspection chip 1.
  • the Brownian motion of the particulate matter contained in a measuring object liquid is suppressed. Therefore, the measurement accuracy of the particulate matter can be improved.
  • the lower the height of the recess 13 within the above-described range the more the above-described effect that is achieved when the measurement target liquid has the property of a pseudoplastic fluid, that is, the Brownian motion of the particulate matter contained in the measurement target liquid is suppressed.
  • the effect that the measurement accuracy of the particulate matter can be improved is increased.
  • the height of the recess 13 is set to a height (for example, 50 ⁇ m or more and 100 ⁇ m or less) that allows the measurement target liquid to be easily affected by the generated shear stress, and the measurement target liquid is a pseudoplastic fluid. It is possible to more reliably realize the purpose of “facilitating introduction of the liquid to be measured into the recess 13 while suppressing Brownian motion of the particulate matter”.
  • the liquid to be measured has a viscosity within a predetermined range (for example, 200 mPa ⁇ s or more and 700 mPa ⁇ s or less) and has properties of Newtonian fluid, pseudoplastic fluid, or Bingham fluid.
  • the height of the recess 13 may be defined so that the assumed target liquid can be introduced into the recess 13 within a predetermined time (for example, within 5 seconds).
  • an inspection kit including the inspection chip 1 and the flow reducing substance 91 may be provided.
  • the flow reduction substance 91 according to the kind of the particulate matter which a user makes a measurement object with the test
  • the particulate matter is labeled using a binding substance 92 to facilitate the detection of the particulate matter.
  • the measurement liquid is prepared by mixing the sample liquid 90 and the binding substance 92 and adding the flow reducing substance 91 to the mixed liquid. Therefore, in the present embodiment, the flow reducing substance 91 can be expressed as a substance added to the binding liquid 90a in order to increase the viscosity of the binding liquid 90a.
  • the inspection chip 1 used in the present embodiment is the same as the inspection chip 1 of the first embodiment.
  • the sample liquid 90 and the flow reducing substance 91 may have the same composition as in the first embodiment.
  • the binding liquid 90a can also be regarded as a sample liquid containing particulate matter to be measured.
  • the measurement method in the present embodiment is the same as the measurement method shown in FIG. 9 described in the fourth embodiment.
  • an xanthan gum aqueous solution is used as the flow reducing substance 91, and 50 ⁇ L of water containing cells as particulate substances is used as the sample liquid 90.
  • the step of adding the binding substance 92 is performed prior to the step of adding the flow reducing substance 91.
  • the efficiency of the binding between the particulate matter and the binding substance 92 decreases as the viscosity of the solvent (or dispersion medium) containing them increases.
  • the binding substance 92 is an antibody, the molecular weight of the binding substance 92 is large, so that it is strongly influenced by the viscosity of the solvent.
  • the particulate substance and the binding substance 92 can be efficiently combined.
  • the present invention can also be expressed as follows.
  • the inspection tool includes a base material that holds a sample for inspecting fine particles in a liquid sample, and a flow reduction substance, and mixes the flow reduction substance and the liquid sample. Fine particles are measured.
  • the flow reducing substance is a thickener.
  • the flow reducing substance is a gelling agent.
  • the flow reducing substance is a photocurable resin.
  • An inspection tool is an inspection tool for measuring the particle diameter of fine particles in a liquid sample, and includes a base material having a space for holding the sample and a flow reducing substance. Then, after mixing the flow reducing substance and the liquid sample, the sample is introduced into the base material, and the sample is quantified in the minute space of the base material, and then the fine particles are measured.
  • the inspection apparatus optically measures the size of the fine particles in the sample and counts the number using the inspection tool according to one aspect of the present invention.
  • the particle detection method is a particle detection method for measuring particulate matter in a sample solution, and includes adding a reactant that specifically reacts with the particulate matter to the sample solution.
  • the flow reducing substance adding step is a step of mixing the reaction liquid and the flow reducing substance solution.
  • the flow reduction substance addition step is a step of adding the reaction liquid to a container holding a solid flow reduction substance.
  • the flow reducing substance adding step is a step of developing the reaction liquid on a measurement unit holding a solid flow reducing substance.
  • the flow reducing substance is a thickener (which increases the viscosity of the sample liquid).
  • the flow reducing substance has at least one of xanthan gum, sodium polyacrylate, and carboxymethylcellulose.
  • the particulate detection method is a particulate detection method for measuring particulates in a sample liquid, and the fluid reduction substance mixing step of mixing the fluid reduction substance in the sample liquid to suppress the particulate flow. And an inflow process for flowing the sample liquid mixed with the flow reducing substance into the micro space, and an optical detection step for optically measuring the size of the fine particles in the sample liquid with suppressed flow, and the flow reducing substance Is a material having at least one of Newtonian viscosity, pseudoplastic viscosity, and Bingham viscosity.
  • the measurement method is a microparticle detection method for detecting the size of microparticles in a sample liquid, and a reactive substance that specifically reacts with the particles in the sample liquid is added to the sample liquid
  • the flow reducing substance is a material having a pseudo plastic viscosity.
  • the flow reduction substance is at least one of xanthan gum and guar gum.
  • the inflow step is a step of flowing into the micro space using at least one of capillary force and gravity.
  • the present invention can be used for an inspection instrument and a measurement method for measuring particulate matter existing in a liquid.

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  • Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Materials By Optical Means (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)

Abstract

　L'invention concerne un instrument de test (1) pourvu d'un évidement (13) pour contenir un liquide ciblé pour la mesure. L'évidement (13) est pourvu de deux surfaces en vis-à-vis qui se font mutuellement face. Les deux surfaces en vis-à-vis forment un espace destiné à être rempli avec le liquide ciblé pour la mesure, la distance prescrite comprise entre les deux surfaces en vis-à-vis étant constante. Le liquide ciblé pour la mesure est un mélange d'un échantillon liquide (90) qui contient une substance particulaire ciblée pour la mesure, et d'une substance de réduction de fluidité (91) permettant d'augmenter la viscosité de l'échantillon liquide.
PCT/JP2015/071271 2014-08-01 2015-07-27 Instrument de test, dispositif de test, kit de test, et procédé de mesure WO2016017591A1 (fr)

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