WO2005116662A1 - 生体情報検出ユニット - Google Patents
生体情報検出ユニット Download PDFInfo
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- WO2005116662A1 WO2005116662A1 PCT/JP2005/010305 JP2005010305W WO2005116662A1 WO 2005116662 A1 WO2005116662 A1 WO 2005116662A1 JP 2005010305 W JP2005010305 W JP 2005010305W WO 2005116662 A1 WO2005116662 A1 WO 2005116662A1
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- Prior art keywords
- flow path
- liquid
- sample
- operation area
- blood
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- 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
- G01N35/00029—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor provided with flat sample substrates, e.g. slides
- G01N35/00069—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor provided with flat sample substrates, e.g. slides whereby the sample substrate is of the bio-disk type, i.e. having the format of an optical disk
Definitions
- the present invention relates to a biological information detection unit, and more specifically, to a biological fluid information detection unit for measuring, for example, biological fluid component information.
- the present invention also relates to a liquid operation tool used in such a biological information detecting unit, a biological substance information detecting unit, a biological sample mixing method, a liquid measuring chamber, and the like.
- a device was proposed to measure multi-component components such as blood components and urine components using the dry chemistry method, and has been used in many medical institutions.
- a glucose meter has been provided as a device that patients themselves can handle due to the rapid increase in the number of diabetic patients.
- cerebral infarction, myocardial infarction, and other diseases that are deeply related to lifestyles are increasing rapidly, increasing the need for familiar multiple blood component tests. Testing is needed.
- Japanese Patent Publication No. 5-62304 a unique blood analyzer was proposed.
- This blood analyzer uses centrifugation and capillary force as driving force, and measures the color reaction produced by quantitatively supplying serum and plasma obtained by separating blood cells into a well containing a lyophilized reagent.
- the blood analyzer proposed in Japanese Examined Patent Publication No. 5-6 234 is intended for blood tests in space and can be used under zero gravity by using only centrifugal force and capillary force. ing.
- US Pat. No. 5,160,702 discloses a blood analysis unit using a rotor. This US patent describes a liquid handling area having various shapes, and a mode of transporting liquid using capillary action on a rotor.
- centrifugation can collect and collect high specific gravity components in blood in an aggregating manner. Therefore, in Japanese Patent Application Laid-Open No. 2001-239183, blood cells and blood clots are separated after centrifugation. A configuration that separates by sedimentation is disclosed. However, in the case of this patent publication, there is only disclosure to the extent that it is limited to the use of a centrifuge alone.
- Japanese Patent Publication No. 5-62304 discloses that after centrifugation, a fixed blood cell separation blood is supplied to the reagent storage well to cause a color-forming reaction and to check the color-forming value. Although it is possible to perform a series of operations, it takes a certain amount of time to perform sufficient separation by centrifugation, and the separated serum components must be transferred to the next processing step. Must. In analyzing the biochemical components in serum by the color reaction between serum and reagent, the color development time between reagent and serum may greatly affect the test accuracy. Control of operating process time is considered an important factor.
- the blood analysis unit that attempts to effectively use the capillary force and the centrifugal force has a small flow path diameter, so that the capillary force and the surface tension are reduced.
- the effect is stronger and the liquid does not move in the desired direction, and if surface treatment is applied, the liquid depends on whether the treatment is performed hydrophobic or hydrophilic. The state of the liquid changes greatly, and the movement of the liquid tends to be more difficult.
- Potential problems include the suspension of liquid movement due to the inflow of air into the capillary, the retention of the liquid for a certain period of time when wettability is ensured, and the centrifugal force and capillary force antagonizing Excessive movement and minute movement of the liquid caused by the difference in the capillary force due to the difference in the viscosity of the liquid in the immersed state.
- Stopping the movement of liquid due to the inflow of air into the capillary causes a problem as an increase in the required amount of liquid due to the stoppage of movement of the liquid, that is, a reduction in the recovery rate. In a severe situation, malfunction may be caused by stopping the liquid.
- the liquid moves to an unexpected space through the wall surface due to the wettability in the flow path and the surface tension of the liquid, etc. This is a problem when it is necessary to maintain a fixed space, for example, when measuring an object.
- the use of a low-cost motor is considered to contribute more to the user economically, but a certain space is narrowed. In a system in which liquid is moved by centrifugal force through a flow path, the motor's operating performance is not sufficiently satisfied. It may be impossible to obtain.
- the wettability of the surface state can be eliminated by chemically or physically treating the wettability of the surface state as a method of adjusting the excessive movement or minute movement of the liquid.However, these methods are easy and cost effective in the manufacturing process. As a result, it suggests that it may not be possible to provide users with the desired inexpensive mechanism.
- hemoglobin Ale when a useful measurement item such as hemoglobin Ale and a serum biochemical component in particular, such as hemoglobin Ale, are measured simultaneously in the same measurement unit, it is necessary to control the blood cell separation time on the test sequence. In some cases. In this case, it is necessary to control not only to shorten the time but also to increase the time.
- an additional step of mixing an auxiliary solution such as a diluting solution or a cell modifying solution is added.
- mixing is not performed simply by pouring two liquids, and it is difficult to simply rotate the liquid, so that a rotation in a different direction (a shaking motion) is given. Work is required. For this purpose, the performance of the drive motor is required, and therefore, an expensive servomotor with high performance is required.
- the final region is often considered to be a region for the purpose of quantifying the liquid, and errors in the quantification of the liquid due to the incorporation of air or the like may cause the mechanism to be hindered.
- Japanese Unexamined Patent Publication No. Hei 9-1504732 discloses means for solving these problems.
- the flow path leading to the operation area must be long in order to hold the liquid in the operation area for a certain period of time, and the introduction flow path should use as little liquid as possible.
- quantification of a sample is an indispensable element.
- the blood used as a sample has a large content component and is divided into blood cells and plasma or serum components. Of these, most are plasma or serum components. Therefore, when preparing a sample quantitatively, it is necessary to perform two types of steps: a blood cell separation step and a plasma or serum quantification step. Because of the large number of measurements, there was the inconvenience of increasing the size of the measurement and inspection tools and increasing the processing time.
- the present invention has been made in view of the above-described various problems in the related art, and in one aspect, is for detecting biological information.
- a disk-shaped rotor-type analysis means including a combination of a flow path for transferring a sample and an operation area for operating the sample, and a sample placement portion in the operation area is in an outer peripheral direction, and
- the biological information detection unit is characterized in that the distance between the outer edge and the center is longer than the other outer edges.
- the present invention provides, in another aspect, a method for detecting biological information. Because
- the biological information detection unit is characterized in that a cross-sectional area of a connection surface is smaller than a cross-sectional area of a connection between the output channel and the operation region.
- the present invention further provides, in another aspect, a flow path for transferring a liquid by capillary action, and an operation area for temporarily or continuously storing and operating the liquid, and at least an object.
- the liquid operation tool is characterized in that it has a configuration in which a thinner flow path is arranged around the periphery to hold the liquid at a portion where the liquid is to be held.
- the present invention provides a centrifugal separator comprising, on one surface, a bodily fluid storage portion provided on a rotating body and a particle accommodating portion having a connection port continuous in an outer peripheral direction of the bodily fluid storage portion.
- the biological substance information detection unit is characterized in that the mouth is provided with a centrifugal separation means having a convex structure at the boundary between the body fluid storage part and the particle storage part.
- the present invention provides a means for mixing two or more types of liquids on another surface, the two or more supply channels for introducing two or more types of liquids, and the liquid mixing means. And one or more output channels for recovering the mixed liquid, and one or more of the output channels or the two or more supply channels generates a capillary force.
- the liquid in the storage chamber is changed by using a liquid mixing means having a capillary tube having at least one of air pressure, gravity, centrifugal force, and inertia force to change the amount of liquid introduced into the capillary tube.
- the method is characterized by performing an operation of changing the amount according to the amount of liquid introduced into the capillary.
- the present invention provides a method for mixing two or more liquids.
- Means comprising two or more supply channels for introducing two or more liquids, a reservoir for mixing the liquids, and one or more output channels for collecting the mixed liquids
- Liquid mixing means in which one or more of the output flow path and the two or more supply flow paths form a capillary having a micro cross-sectional area for generating a capillary force; and air pressure, gravity, centrifugal force, and inertial force.
- the present invention provides, in one aspect, a storage chamber provided on a rotating body for storing together a biological sample and at least two liquids for mixing with the biological sample.
- Transfer power supply means for applying a force opposing the centrifugal force of the rotating body to the liquid in the storage chamber in a direction outward of the chamber, and rotating the rotating body about a rotation speed center axis, and rotating the rotating body at a predetermined number of times.
- the biological information detection unit is characterized by having a driving means capable of changing the number of times.
- a storage chamber provided on a rotating body for storing together a biological sample and at least two of a mixing liquid for mixing with the biological sample, and a liquid in the storage chamber.
- Moving force supply means for applying a force in a direction opposite to the centrifugal force, and driving means capable of rotating the rotating body around a central axis and changing the rotating number a predetermined number of times. It is in the characteristic biological information detection unit.
- a biological information detection unit comprising: a small chamber that is opened at an outermost periphery in a negative direction of a primary reaction tank that receives a force in one direction; and an additive is placed in the small chamber.
- the present invention provides an operation region having a predetermined depth on one surface, a preliminary region for preliminarily storing a sample, and a capillary tube connecting the operation region and the preliminary region.
- the biological information detection unit includes a flow path having a force, and a pressure generating unit that presses or sucks a fluid in the flow path and applies a force in a direction to supply the fluid to an operation area.
- an operation area for operating a liquid for operating a liquid
- a supply flow path for supplying a sample liquid to the operation area for supplying a sample liquid to the operation area
- an output flow path for removing a sample after the operation from the operation area.
- the biological information detection unit is characterized in that a sample solution is quantified by providing a deaeration port between the supply flow path and the output flow path in the operation area.
- an operation area provided on a rotating body for operating a liquid, a supply flow path for supplying a sample liquid to the operation area, and a sample operated from the operation area.
- the biological information detection unit is characterized in that a sample solution is quantified by providing a biological information detection unit.
- an operation area provided on a rotating body for operating a liquid, a supply flow path for supplying a sample liquid to the operation area, and removing an operated sample from the operation area.
- the supply flow path is disposed in the centrifugal center direction with respect to the operation area, and a deaeration port is provided between the supply flow path and the output flow path in the operation area.
- the biological information detection unit is characterized in that a sample liquid is quantified by arranging the deaeration port position inside the centrifugal direction with respect to the output flow path.
- the present invention provides, in one aspect, at least a quantitative chamber provided with an output channel in an outer peripheral direction, wherein the quantitative chamber is connected to an overflow channel in which overflowing liquid flows in a central direction, An output flow path for outputting a liquid to the outside is connected, a projection is provided in a connection surface between the overflow path and the quantitative chamber, and a region interposed between the output flow path and the connection portion of the quantitative chamber. It is located in the liquid metering chamber.
- the present invention also provides, in another aspect, at least a metering chamber provided with an output channel in an outer peripheral direction, wherein the metering chamber is connected to an overflow channel in which overflowed liquid flows in a central direction, and is provided in an outer peripheral direction.
- An output flow path for outputting a liquid to the outside is connected, and a projection is provided in a connection surface between the overflow path and the measurement chamber, and in a region interposed between the output flow path and the connection section between the measurement chamber and the overflow.
- the liquid metering chamber is characterized in that the metering is performed based on the volume between the channel and the projection.
- FIG. 1 is a schematic diagram showing one embodiment of the present invention
- FIG. 2 is a schematic diagram showing the operation of one embodiment of the present invention
- FIG. 3 is a schematic view showing another embodiment of the present invention.
- FIG. 4 is a schematic view showing another embodiment of the present invention.
- FIG. 5 is a schematic diagram showing another embodiment of the present invention.
- FIG. 6 is a schematic diagram showing another embodiment of the present invention.
- FIG. 7 is a schematic view showing another embodiment of the present invention.
- FIG. 8 is a schematic view showing another embodiment of the present invention.
- FIG. 9 is a schematic diagram for explaining the operation of the embodiment shown in FIG.
- FIG. 10 is a schematic diagram showing another embodiment of the present invention.
- FIG. 11 is a schematic diagram illustrating the operation of the embodiment illustrated in FIG. 10, and FIG. 12 is a schematic diagram illustrating another embodiment of the present invention.
- FIG. 13 is a schematic diagram for explaining the operation of the embodiment shown in FIG. 12, and FIG. 14 is a schematic diagram showing the entire embodiment of the present invention.
- FIG. 15 is a schematic diagram showing a part of the embodiment shown in FIG. 14,
- FIG. 16 is a schematic diagram showing a part of the embodiment shown in FIG. 14,
- FIG. FIG. 18 is a schematic diagram for explaining the operation of the embodiment shown in FIG. 14,
- FIG. 18 is a schematic diagram for explaining the operation of the embodiment shown in FIG. 14,
- FIG. 20 is a schematic diagram illustrating the operation of the embodiment illustrated in FIG. 14,
- FIG. 21 is a schematic diagram illustrating the operation of the embodiment illustrated in FIG. 14.
- FIG. 22 is a schematic diagram showing one embodiment of the quantitative configuration of the present invention.
- FIG. 23 is a schematic diagram showing one embodiment of the quantitative configuration of the present invention.
- 23 is a schematic diagram for explaining the operation of the embodiment shown in FIG. 23,
- FIG. 25 is a schematic diagram for explaining the operation of the embodiment shown in FIG. 23, and
- FIG. 26 is an embodiment of the present invention. It is a schematic diagram showing an example,
- FIG. 27 is a schematic diagram for explaining the operation of the embodiment shown in FIG. 26,
- FIG. 28 is a schematic diagram for explaining the operation of the embodiment shown in FIG. 26, and
- FIG. 26 is a schematic diagram illustrating the operation of the embodiment shown in FIG. 26, and
- FIG. 30 is a schematic diagram illustrating the operation of the embodiment shown in FIG. BEST MODE FOR CARRYING OUT THE INVENTION
- the inventor of the present invention has a disk-shaped rotor-type analysis means comprising a combination of a flow path for transferring a sample and an operation area for operating the sample, wherein a desired indwelling portion is located in an outer circumferential direction. And the outer edge and the middle The present inventors have found that the position of the sample in the operation area can be set to a specific position by setting the operation area such that the distance of the heart is longer than other outer circumferences. Came to reach.
- a sample is transferred to a specific site within one operation area without a shield or a configuration for guiding the sample, and a measurement area, a quantitative
- a flow path port for moving to another operation area such as a structural member for use, it is possible to obtain an effect such that a target sample can be efficiently transferred.
- the present invention focuses on the fact that the liquid in the container forms a liquid surface having an equal distance from the substantially circumferential center due to centrifugal force, and has a different radius with respect to the outer peripheral shape of the container.
- the liquid stays at a farther part of the outer peripheral side. Therefore, in the present invention, it is sufficient that the diameter from the center of the desired portion for collecting the sample in the operation area is longer than the other diameters, and the difference is, for example, 0:! It is not limited to this, since it differs depending on the amount of the sample.
- the liquid in the container forms a liquid surface whose distance from the substantially circumferential center is equal due to centrifugal force
- the centrifugal force is reduced, the liquid sample is placed on the wall of the space where the liquid sample is held. It has been found that this effect is improved by using a material that improves wettability, or by reducing the contact angle with the wall surface of the liquid sample by performing chemical surface treatment or physical surface treatment. Obtained.
- the present invention provides an operation area for operating a liquid, A supply flow path for supplying a liquid, an output flow path for taking out the sample after the operation from the operation area, and a cross-sectional area of a connection surface between the supply flow path and the operation area, the output flow path, and the operation.
- Combination configuration that makes the cross-sectional area smaller than the connection area with the area, even in the operation area where multiple flow paths on the supply side and output side are connected, output or supply flow path such as centrifugal force, gravity, etc. It is possible to hold the sample liquid in the operation area under the condition where the force repulsive to the capillary force acts.
- the hole diameter of the supply port in the present invention is, for example, 0.04 to lmm 2
- the hole diameter of the output port is, for example, 0.99 to 2.25 mm 2 .
- the arrangement of the supply port and the output port is not particularly limited, but in the case of a configuration such as a rotor that can use centrifugal force, the supply port should be located near the center, after the operation of the liquid in the operation area. This is advantageous in that the liquid can be moved to the next operation area by centrifugal force.
- a liquid operating tool having a flow path for transferring liquid by capillary action and an operating area for temporarily or continuously storing and operating the liquid
- the liquid is transferred to at least a target portion.
- the liquid can be retained in the operation area for a certain period of time, and the amount of liquid can be measured by the space in the operation area. Even if the space has a structure in which a solid water-soluble substance such as a coloring reagent is held in advance, a force such as centrifugal force or air pressure can be introduced into the liquid.
- the solid water-soluble substance can be filled without escaping into the external space.
- the specified amount of liquid can be agitated and mixed only by changing the rotation speed of centrifugal force, for example.
- the air-concentration operation of the oxygen-saturated liquid is performed only by a simple operation of changing the rotation speed of centrifugal force. It has made it possible to supply the required reactive oxygen in the region.
- the narrow channel cross-sectional area which connects the operation area provided on the outlet 0. In 0. 4 to 0. 2 5 mm 2, was filled in a space in contact with isotonic solution and narrow channel input Ri mouth In this case, it was found that the liquid in the operation area did not move to the external space.
- the liquid having a higher specific gravity than the gas is sufficient, and almost no liquid is contained in the operation area. It is possible to fill without air infiltration. For example, when a force of 500 to 10,000 G is applied, it has been found that filling can be performed in about 100 to 60 seconds. It should not be limited because it changes greatly depending on the liquid volume. Also, for example, when a surfactant such as TWEEN TM 20 (trade name) is used to improve the wettability of the surrounding space of the present invention and the change in the amount of liquid transferred to the wall surface is measured.
- a surfactant such as TWEEN TM 20 (trade name) is used to improve the wettability of the surrounding space of the present invention and the change in the amount of liquid transferred to the wall surface is measured.
- the present invention provides a rotating body for performing centrifugal separation, wherein the body fluid storing portion includes a body fluid supply port and a separated body fluid extracting port provided on a predetermined circumference of the rotating body; It is a centrifugal separation method comprising a particle container having a connection port having a continuous convex structure (hereinafter also referred to as a convex section).
- a centrifugal separation method comprising a particle container having a connection port having a continuous convex structure (hereinafter also referred to as a convex section).
- the present invention includes a body fluid storage section including a body fluid supply port and a separated body fluid extraction port provided on a predetermined circumference of a rotating body, and a convex portion continuous to a connection portion between the body fluid storage section and the particle storage section.
- Centrifugal separation means consisting of a particle storage section having a connection port, and the predetermined circumference of the rotating body only needs to be at least an area where a centrifugal force acts, and the body fluid storage section has a centrifugal force. This is an area where acts, and its size is appropriately adjusted depending on the amount of sample to be handled.
- connection port is a connection connection port between the bodily fluid storage section and the particle storage section, and the size thereof is any one of the distance and height of the outer circumference of the body fluid storage section and the inner circumference of the particle storage section. The smaller area is the maximum area.
- the speed of blood cell separation may be adjusted by adjusting either the inner distance or the height, or both.
- the height of the cross section of the separated body fluid extraction port is lower than the height of the connection connection port as compared with the cross section of the separated body fluid extraction port.
- connection port needs to secure the surface tension within the cross-sectional area to hold the separated blood cells, so the connection port height is up to about 2 mm, Preferred It should be adjusted between 0.3 and 1.5 mm.
- the bodily fluid reservoir has a shape such that the distance between the central axis and the outermost position on both sides of the outer peripheral edge is different as shown in Fig. 6 in order to concentrate the internal bodily fluid on the target site. It is preferable that the circumference of the bodily fluid concentration site on the outer peripheral edge of the bodily fluid reservoir is set to be outside the circumference of the other sites.
- liquids or particles will collect more outwardly under centrifugal force than the specific gravity of the body, and thus, in the body fluid component, the body fluid that contains the component to be analyzed This is effective when separating blood and manipulating blood before and after the separation.
- the particle container is a space for storing particles such as blood cells and blood clots that are separated and separated, and is connected to the periphery of the body fluid storage unit at least in the direction in which centrifugal force acts. What is necessary is just to arrange
- the particle storage area is a place for storing unnecessary materials, but when measuring the physical properties of blood cells, etc., transfer the blood cells, etc. to another operation area. A transfer path may be newly provided.
- the convex portion in the connection port having the continuous convex portion is such that particles such as blood cells easily enter the particle storage portion, but once entering the particle storage portion, if the structure does not easily go out to the outside. Often, when used under gravity, it may only be necessary to make the depth of the particle storage section in the bottom direction greater than the depth of the bodily fluid storage section.
- the relationship between the depth of the particle container and the distance from the connection port is desirably that the distance from the connection port is larger than the depth of the particle container.
- the shape of the projection inside the particle storage section can be increased by forming an angle in the centrifugal direction from the upper side of the projection. This is when the shape of the convex part is long in the depth direction. If the centrifugal force acts to accommodate particles with a higher specific gravity, it becomes an obstacle because the vector direction of the force due to the centrifugal force cannot work in the vertical direction with respect to the accommodation part. Because there are times.
- the depth between the body fluid storage part and the particle storage part is larger in the particle storage part than in the body fluid storage part. This is because, in the stationary state where gravity is dominant and the gravity is dominant, the deeper the container, the more efficiently the material with a higher specific gravity can be contained below.
- a continuous convex portion having a height of the connection port of about 0.3 to 2 mm and a width of about 1 to 200 mm is preferable.
- these are usually more preferably about 0.5 to lmm in height and about 5 to 2 Omm in width.
- Separation time 10 / cross-sectional area (mm 2 )
- the determination of the completion time of separation varies depending on the viscosity, water content, etc. of the patient's blood, but should be applicable when separating less than 60% of blood in terms of hematocrit.
- the constant 10 here fluctuates between about 8 and 12. This is caused by factors other than those described by the present invention, such as wettability, material, and processing roughness of the surface of the rotating body for processed measurement.
- the centrifugal force at this time is also a number that should be greatly influenced by this constant. This centrifugal force is a result in the range of 500 to 600 G in the experiment of the present invention.
- the positions of the body fluid supply port and the separated body fluid extraction port are appropriately selected, but it is sufficient if there is at least a body fluid supply port. , That The reagent storage well may be connected as it is.
- the body fluids handled are blood, urine, sweat, bacterial fluid, medium after cell culture, fluid after physical destruction of tissue cells, lymph fluid, interstitial lymph fluid, bone marrow fluid, tissue fluid, saliva, gastric fluid, and synovial fluid.
- Pleural effusion, semen, bile, ascites, amniotic fluid, etc., and the particles to be separated include red blood cells, white blood cells, blood clots, bacteria, cells, tissue sections, contaminants, and interfering substances. It is appropriately selected according to the purpose.
- the present invention is a means for mixing two or more liquids, wherein two or more supply flow paths for introducing two or more liquids, a storage chamber for mixing, and a recovery of the mixed liquid
- One or more output flow paths for the liquid crystal display, and one or both of the output flow path and the two or more liquid supply flow paths have a minute cross-sectional area that generates a capillary force.
- the amount of liquid introduced into the capillary is changed by using one or more of air pressure and gravity or gravity and Z or centrifugal force and / or inertia force.
- a stirring and mixing means by a method of performing an operation of changing according to the amount of liquid to be introduced; a storage chamber for storing a biological sample provided on a rotating body and a mixing liquid for mixing with the biological sample in one space; Outwardly with respect to the reservoir, Moving force supply means for applying a force for moving the liquid in the direction of the center of the body to the liquid in the storage chamber; rotating the rotation body about a rotation center axis, and changing the rotation number a predetermined number of times.
- the combination with the driving means enables quick mixing while reducing the load on the rotary motor.
- the present invention includes a centrifugal force generated when, for example, the rotating body rotates, and a liquid moving force for generating another force for moving the liquid, and the liquid moving force and the centrifugal force are opposed to each other. Adjust the centrifugal force This reciprocates the movement of the liquid introduced into the capillary and mixes the liquid in the storage chamber.
- the biological sample according to the present invention includes blood, urine, semen, interstitial fluid, sweat, blood components such as serum and plasma, bacterial fluid, medium after cell culture, solution after physical destruction of tissue cells, lymph solution, Interstitial lymph fluid, bone marrow fluid, tissue fluid, saliva, gastric fluid, synovial fluid, pleural effusion, semen, bile, ascites, amniotic fluid, etc. are exemplified.
- Examples include an activator solution, a medium, an environmental hormone solution, a specific saturated gas solution, a cell disruption solution, a DNA extract, a color reagent, a marker substance, and a coagulation substance.
- the moving force used in the moving force supply means includes, for example, capillary force, other porous materials such as non-woven fabric and cotton cloth, suction force generated by volume change, gravity, air pressure, and mixing. It shows the force such as gas pressure that is generated more.
- the moving force supply means has a part for moving the liquid from the storage part to the outside at least once in the direction opposite to the centrifugal force, but the opposition at that time is not necessarily the centrifugal direction.
- the direction does not need to be 0 degrees, and at least a direction in which the movement of the liquid stops due to centrifugal force or moves more slowly. It goes without saying that it is basically toward the centrifugal center.
- a capillary tube having a bent portion extending toward the central portion is preferable in that the centrifugal force can stop the advance of the liquid, but is not limited thereto.
- the operation of changing the amount of liquid introduced into the capillary and changing the amount of liquid in the result storage chamber according to the amount of liquid introduced into the capillary is, for example, As described above, a force is applied in a direction that impedes the movement of the liquid due to the capillary force of the capillary, indicating an operation of restricting the movement of the liquid in the capillary, and the force for restricting the liquid in the capillary. In addition to the centrifugal force described above, gravity, air pressure, etc. may be used.
- a combination of a storage part having a greater depth and a flow path extending from the centrifugal direction may be used.
- the flow path is in a state of having a force for sucking the liquid in the storage portion in a direction opposite to the centrifugal force due to the capillary force, the suction force of a separately provided suction member, and the like.
- the fluid that has entered the storage section is attracted to the flow path by the attraction force of the flow path and is attracted to the flow path, but the rotation speed is increased and the fluid flows. Even if the fluid is mixed by repeating this operation by separating from the path, reducing the rotation speed again, drawing the fluid into the flow channel, increasing the rotation speed again, separating the fluid from the flow channel, and repeating this operation good.
- the present invention comprises, in an intermediate step, a small chamber opened in the outermost periphery in one direction of a primary reaction tank which receives a force in one direction, and a configuration in which an additive is placed in the small chamber in an intermediate step.
- an additive in the present invention, it is possible to sufficiently cope with the case where no water can be obtained or other processing is required.
- the additive in the present invention include mutarotase, gnorecose, and the like.
- Oxidase penoleoxidase, vasconolevate oxidase, phenol, 1-naphthol-3,6-disulfonic acid sodium, catalase, L-aspartic acid, ⁇ -ketodaltaric acid, thiamine pyrophosphate, Magnesium chloride hexahydrate, HEPES, lipoprotein lipase, adenosine-5, -triammonium triphosphate trihydrate, PIPES (buffer) peranine, carbonate buffer , Hydroxide diisocyanato Li um P - two Torofueniruri phosphate Nina Application Benefits um, click Reachinaze, Zarukoshi Oxidase, good buffer, creatininase, sodium azide, 3,5-dinitrobenzoic acid, lithium hydroxide monohydrate, cholesterol oxidase, hexokinase, j8 NAD, nitrote Trazolium blue, L-lithium lactate,
- the force in one direction is a centrifugal force, air pressure, gravity, or the like, and the outermost circumference in one direction is the peripheral portion of the primary reaction tank farthest from the direction in which the force is applied.
- An open small chamber is a small chamber connected inside the peripheral part of the primary reaction tank, and the form of the additive disposed therein is contained in a solid, liquid, or soluble capsule. And those carried on porous particles.
- the opening an acute angle, when the additive is a liquid, it can be held inside the small chamber by surface tension. In the case of a solid form, it is also possible to prevent the additive from coming out of the compartment by making the opening smaller than the size of the solid.
- the present invention provides an operation area having a predetermined depth and a spare area for preliminarily storing a sample (a specimen), and has a capillary force connecting the operation area and the spare area. Press the fluid in the flow channel With a combination of pressure generating means that applies pressure or suction and applies a force in the direction to supply to the operation area, the liquid passes through the operation area while the flow path with capillary force is connected to the operation area After that, the liquid in the operation region is stabilized by the holding force of the liquid held in the capillary, here, the capillary force.
- an operation region having a predetermined depth, a preliminary region for preliminarily storing a sample are provided, and the operation region; a flow channel having a capillary force connecting between the preliminary regions;
- the capillary force of the flow path and the flow path of the flow path in the flow path where the capillary force is generated By transporting the filling liquid by surface tension, it is possible to seal the liquid that has been moved to the operation area in advance.
- the operation region in the present invention is, for example, a region that reacts with a cell modifying element, such as a region that reacts with a reagent, and indicates a final operation region in biological measurement such as a marker substance detection site.
- a cell modifying element such as a region that reacts with a reagent
- indicates a final operation region in biological measurement such as a marker substance detection site.
- a marker substance detection site There are some cases where it is applicable even for a fixed-quantity tank.
- it may be a final room for transporting samples or a storage unit for keeping samples for a certain period of time or longer.
- the strong capillary force of the present invention is When accuracy is taken into account, a flow path having a diameter cross section of 0.04 to 0.25 mm 2 is exemplified.
- hydrophilic treatment examples include application of a wetting agent or a surfactant, plasma treatment, application of an excipient, treatment with a mixed solution of chromic sulfate, adjustment of surface roughness, removal of a water-phobic film, and the like.
- the biological sample in the present invention includes whole blood, serum, plasma, blood components, and various blood components such as blood cells, blood clots, and platelets, as well as urine, semen, breast milk, sweat, interstitial fluid, bacterial fluid, Various types of body fluids such as a medium after cell culture, a fluid after physical destruction of tissue cells, an interstitial lymph fluid, a bone marrow fluid, a tissue fluid, saliva, a gastric fluid, a synovial fluid, a pleural effusion, a bile fluid, an ascites fluid, an amniotic fluid, etc. are exemplified.
- the pressure generating means is, for example, air pressure, water pressure, gravity, or inertial force that gives a force parallel to the traveling direction of the flow path.
- centrifugal force is preferable when the whole is incorporated in the rotor. However, it is not limited to the centrifugal force.
- the sample liquid is used in such an amount that all the liquid is not supplied to the operation area, or that the amount of the sample liquid includes the inside of the channel in which the capillary force is generated.
- the spare area is formed much deeper than the capillary channel, and 1.5 to 3 mm deeper compared to 0.2 to 0.5 mm in the capillary channel is hydrophilic. Is particularly suitable when the wettability of the liquid is improved by a chemical treatment, etc., but there is no concern that the liquid moves due to the surface tension of the liquid, and the sample holding stability in the operation area is improved. Is preferred.
- the filling liquid in the present invention is mainly used for sealing a fixed amount or a semi-quantitative amount or more of a liquid which has been sent into the operation area, and is used for an extra sample or water which does not affect the sample.
- an aqueous solution such as physiological saline, a liquid having a high boiling point and which is not easily evaporated even in a small amount
- aromatic solvents such as DMS0, DMF, AN, xylene, etc., self-solidifying adhesives, sealants, and substances dissolved by drying of moisture are solid at room temperature, and thus have the above-mentioned capillary force.
- the filling solution is preferably filled quickly and preferably in the channel, and the configuration for that purpose is not limited.
- the sample When the filling liquid fills the flow path, the sample is filled in the operation area, causing a mixing reaction with reagents, etc., so that the liquid does not move to other areas during the measurement stage.
- the capillary force of this flow path does not affect the surrounding area or the liquid in the flow path, before the operation area is introduced, After performing the pretreatment steps necessary for the measurement to prevent the contents of the sample from being altered or deactivated due to the effects of storage, retain the sample until measurement, hold it enough to withstand transportation, and evaporate If you need to be resistant to, you can also indicate.
- the present invention relates to a method for quantifying a liquid sample, comprising: an operation area provided on a rotating body for operating a liquid; a supply flow path for supplying a sample liquid to the operation area; An output flow path for removing the sample after the operation; a deaeration port disposed between the supply flow path and the output flow path in the operation area; a flow path to the deaeration port
- the cross-sectional area has a configuration larger than the supply flow path and the output flow path, and when the sample supplied from the supply flow path is filled with the sample in the operation area with respect to the supply, If no more than a certain pressure is applied to the supply of the sample to the supply channel when the air no longer flows out of the vent,
- the inventor of the present invention focused on the inability to supply the materials. According to the present method, it is possible to quantify even a small amount of liquid by utilizing the difference in specific gravity from gas, regardless of the inherent viscosity of the liquid.
- the sample when the sample is supplied using gravity, centrifugal force, air pressure, inertia force, or the like as a supply means for supplying the sample to the operation area, If the structure or the distribution of force is set so that the pressure per unit area of the above-mentioned force on the liquid sample is smaller than the interface where the supply flow path and the operation area are in contact with each other, In particular, when liquid is supplied from the supply flow path to the operation area using centrifugal force, in a configuration in which a part of the supply flow path has an elbow-shaped structure extending to the center of the centrifugation, the supply flow path is not provided.
- the centrifugal force is configured to be the weakest at this elbow.However, when such a structure or a mechanical vector can be set, the deaeration port uses, for example, centrifugal force. In some cases, supply to centrifugal center When the flow path is set inside and the output flow path is set outside, it is arranged between the supply flow path and the output flow path.
- the operation region is filled with the liquid sample.
- the gas component located in the space within the operation area to which the liquid sample is supplied in the supply channel is lost.
- the increase in the pressure in the operation area includes a force required for supplying the liquid sample, such as gravity, centrifugal force, air pressure, and inertia force, which are proportional to the force exerted on the operation liquid. I do.
- the inflow of the liquid is stopped, and the stoppage of the inflow of the liquid allows the amount of the liquid supplied to the operation area to be determined.
- the liquid in the supply channel is moved to the operation area using centrifugal force, for example.
- the supply channel has an elbow structure, because it is necessary to convey the liquid using the capillary force and siphon force of the liquid.
- the supply force is minimized even if the elbow is used, the liquid retained in the pre-supply chamber or the operation area flows out to this portion, and the liquid is discharged from the supply passage. It becomes possible.
- the present invention has an operation area for operating a sample by centrifugal force, and the outer peripheral shape of the operation area is located at a distance from the center with respect to a target outer peripheral portion.
- the sample can be collected in a certain space around the lengthened area, which can be an obstacle in moving to the operation area next to the sample, for example, stopping the movement of liquid due to air mixing, It is possible to eliminate the fluctuation factor of the recovery rate of the required sample due to contamination and to make the liquid transfer more stable, and to further improve the hydrophilicity of the material forming this configuration. The effect can be improved.
- the present invention relates to a case where blood cells are separated by centrifugal force.
- the control of the amount of the protolysate, including the supplied blood, and the processing time in the measurement sequence are performed on a rotating body that integrates the separation unit and the measurement chamber.
- the present invention has an effect that blood cells can be separated in a time suitable for the measurement, and can form a separation section suitable for automatic blood processing.
- the present invention relates to a method of adding an auxiliary substance such as a diluent for measuring a large number of components from a small amount of a body fluid in a component analysis of a body fluid sample using a rotating body, or a method of dissolving a solid with a biological sample.
- an automatic analyzer can be realized with a simple configuration by simply giving strength to the rotation speed without using special parts.
- mixing for realizing chemical reactions mixing for adjusting components in liquids such as pH, mechanism for separating specific substances by binding with affinity substances, marking of minute amount of biological substances, 2 or more types
- Method for calculating the mixing ratio of unknown liquids in liquids, separation of oil-water-aqueous solution, etc. Neutralization, method for preparing saturated gas solution, cell aggregation, coagulation of chemical substances, kit for preparing dilution series, dilution method for introduction of cells, mixing of cells derived from living organisms, liquids with bacteria, etc., extraction of internal substances, component analysis
- This technology can be used in a wide range of applications such as pretreatment processes. It can also be used for organic chemical reactions, inorganic chemical reactions, coordination reactions, ionic reactions, redox reactions, etc. with chemical substances other than biological substances.
- an operation area in which an external drive force is suppressed and a fluid transfer operation can be performed is set by using a strong capillary force in order to hold a measurement sample for obtaining biological information for a certain period or more in the operation area.
- a biological information detection unit having a space that can be used for measurement, reaction, retention, transfer, and storage is realized.
- the present invention provides a means for quantifying a liquid in a rotating body, and in an environment where surface tension or capillary force is dominant regardless of the viscosity of the liquid.
- accurate quantification can be realized.
- This is particularly useful when a biological sample is used as a liquid sample.For example, even if the sample has the same structure, quantitative accuracy can be improved for samples with different viscosities, blood, saliva, etc.
- the centrifugal force to form the quantitative ridge in the operation area for example, sufficiently overcome the surface tension derived from viscosity.
- the movement of a fluid can be controlled by adjusting the shape of the operation area.
- At least the outer radius of a portion where a sample is to be collected in one operation area may be made longer than that of a series of continuous outer circumferences.
- FIG. 3 (a) shows a case in which liquid is to be collected in the output flow path 43, in which the outer radius r1 is longer than the other radius r2.
- FIG. 2 is similar, but shows the area where the operation is performed on the rotating rotor.
- the movement of the liquid is controlled by the size of the area of the supply channel and the output channel connected to the operation area.
- the centrifugal force and the gravity are reduced by making at least the flow diameter of the supply flow path supplied into the operation area smaller than the particle diameter of the output flow path for outputting the sample to the next operation area.
- the liquid is supplying a force that antagonizes or exceeds the capillary force, it is necessary to keep the liquid in the operation area for a certain period of time.
- the centrifugal force is generated, excessive specification may be required for the specification of the motor that is the source of the centrifugal force.
- the difference between the particle diameters of the supply channel and the output channel is that the area of the supply channel is 0.04 to 0.64 mm 2 , and the area of the output channel is 0.16 to: L mm It is preferably 2 , but is not limited to this.
- the present invention has been made based on the finding that although the area of the flow passage is smaller, the capillary force exerts a stronger liquid suction force.
- the area of the flow path is preferably smaller.
- one or more flow paths having an area of about 0.04 to 0.25 mm 2 are provided. This is a condition for holding about 3 to 10 ⁇ l of liquid in the operation area. It should be defined by the viscosity of the liquid and the processing space.
- this effect is remarkable when the cross-sectional area of this flow path is the smallest among the flow paths existing in the same structure, and there is almost no liquid movement even after 4 hours, and it depends on the room temperature of the liquid. It has been found that evaporation has a greater effect.
- the channel having a strong capillary force is disposed at the end in the direction in which the liquid is to be moved, or is provided in a region where the liquid is to be drawn.
- the system may be configured to perform optical, electrochemical, physical chemistry, or biophysical measurements, and may require longer processing times or mechanical systems that may cause liquid transfer to fail. It is effective in cases such as Since the wettability of the liquid is hardly affected, it is effective in that it can be applied to various materials.
- the present invention relates to a centrifugal separator for adjusting the separation speed by adjusting the area of a connection port that connects a region for storing a bodily fluid to be subjected to centrifugation and a region for storing separated particles through a continuous head.
- a connection port that connects a region for storing a bodily fluid to be subjected to centrifugation and a region for storing separated particles through a continuous head.
- the maximum value of the area of the connection port is appropriately adjusted by using the smaller one of the size of the outer peripheral surface of the bodily fluid storage region and the size of the inner peripheral surface of the particle storage region as the maximum value. Just do it.
- the area may be adjustable.
- one or more input channels and output channels are provided in the bodily fluid storage unit, and the position may be at least such that the output channel is connected to the outer circumferential side surface of the bodily fluid storage unit.
- the direction of the output flow path to be connected preferably coincides with the vertical direction of the direction of the opening of the connection port for separation.
- This has a higher specific gravity than each separated liquid component by arranging the opening vertically with respect to the direction in which capillary force, air pressure, gravity, and other forces required to move the liquid are applied.
- the containment walls are arranged in the direction of the vector in which the substance is to be transferred, to ensure containment. This effect also enables stable separation and recovery without giving a complicated structure such as a physical mechanism, and is expected to be economically effective.
- the body fluid storage unit and the particle storage unit usually have a larger surface area in the body fluid storage unit and a deeper structure in the particle storage unit, but are not particularly limited.
- a storage space for temporarily or continuously storing a biological sample and a mixing body for mixing with the biological sample on a rotor (rotating body) and a flow path extending from the storage space are provided. And outward from the storage space Thus, a fluid moving force is applied, and the moving force is applied to at least a part of the flow path in a direction opposite to the centrifugal force direction.
- a configuration in which they are arranged in the centrifugal force direction is exemplified. It is preferable that the storage section and the flow path are formed by forming a concave portion on the rotating body and then covering the surface with a lid-like body.
- the configuration according to the present invention may be used, for example, for mixing a blood component after blood cell separation with a diluent for diluting and increasing the volume of the blood component to measure a large number of blood components, a solid reagent, and a quantitative serum.
- a diluent for diluting and increasing the volume of the blood component to measure a large number of blood components, a solid reagent, and a quantitative serum.
- the surface of the mixing chamber in the present invention which is suitably used to sufficiently mix both, is preferably subjected to a hydrophilic treatment.
- the present invention relates to an operation area for performing operations such as quantification of a sample, a color reaction with a reagent, mixing, storage, and the like, and an area before supplying the sample to the operation area.
- a sufficient sample is supplied to the spare area so that the sample is supplied to the operation area and the process moves to the measurement stage.
- the sample input to the spare area is moved and filled around and inside the capillary force of the flow path
- the pressure generating means applies pressure to the sample in the state of being moved and filled in the vicinity of the flow path to move the sample to the operation area
- the pressure generating means applies pressure to the flow path until the sample is filled also in the flow path.
- the liquid in the operation area is released from external forces and mixed with reagents. Colors are combined, allowing external colorimetry. Since the sample is filled in the operation area where the operation area has a sufficient distance in the direction of the optical path, the sample can be sufficiently taken without changing the optical path length in colorimetry. Stable optical measurement becomes possible.
- the spare area is subjected to a hydrophobic treatment.
- FIG. 21 shows one embodiment of the quantitative configuration of the present invention.
- reference numeral 261 is a flow path for quantification
- 262 is a quantification chamber
- 260 is a flow path between the quantification chamber 262 and the flow path for quantification 26.1. It is a connection port to connect.
- Reference numeral 263 denotes a blood cell storage unit. The trajectory drawn by the radius 26 R 2 connecting the portion of the connection port 260 in the center O direction and the center O to the inside of the fixed volume chamber 26 2 becomes the liquid level in the fixed volume chamber 26 2. Since the quantification chamber 262 has a blood cell separating function, the blood cell storage part 263 has a deeper bottom than the quantification chamber 262.
- Reference numeral 264 denotes an input-side flow path, which has a configuration in which a bent portion is formed in the center O direction in order to control the flow of liquid due to centrifugal force.
- Reference numeral 265 denotes an output channel having a bent portion for controlling the movement of liquid using centrifugal force.
- the flow path for quantitative determination 26 1 extends so as to be inside the circular locus 26 A formed by the radius 26 R 1 connecting the bent portion of the output flow path 2 65 and the center O.
- the degree of the inside may be the same as or the inside of the locus 26 A. 2 6 6 It is a vent.
- the opening direction may be any of up, down, left, and right.
- the liquid is supplied from the input side channel due to the siphon phenomenon or the like, and is accumulated in the quantitative chamber 262. At this time, the liquid is rotated around the center O, and the liquid gradually accumulates from the outer circumference in the quantification chamber 262 and the blood cell storage section 2663, and the liquid reaches the connection port 260. In a state in which the liquid fills the flow path 261, which is near the connection port 260, and the liquid blocks the entire connection port 260, that is, in a state in which the liquid reaches the locus 26B, The supply of the liquid supplied from the input side flow path 264 is stopped by the saturation of the gas generated when the connection port 260 is closed with the liquid. At this point, the fixed volume of the liquid determined by the volume in the fixed volume chamber and the volume in the blood cell storage unit 263 partitioned by the locus 26B is determined.
- the blood cells are separated and stored in the blood cell storage part 263 by rotation, and the blood cells are stored in the blood cell storage part 263 that has descended further toward the bottom.
- This blood cell separation ability is required when the target is blood, and is unnecessary when quantifying a diluent.
- connection port 260 By moving the connection port 260 in the radial direction of the quantitative chamber, the circumference locus 26 A determined by the distance between the center portion of the connection port 260 and the center O and the quantitative chamber 26 2 The liquid having a volume determined by the distance to the outermost periphery of the blood cell (here, including the outermost periphery of the blood cell container 263) is quantified.
- FIG. 1 is a view showing one embodiment of the present invention, and shows a configuration of a rotating body R.
- Rotating body R is made of polypropylene, polycarbonate, acryl, ABS, polystyrene, polyethylene, polyethylene terephthalate, PVDF, PTFE, Posi-Shidari Bininore, TPX, P0M, UF, SAN, PSU , PPS, PP0, PPA, PEN, PAR, PA, MF, FEP, DAP, ASA, AS, AES, silicon, glass, aluminum plate, etc.
- the channel to be formed is formed by a concave portion, and is formed by bonding a sheet as a lid from above using an adhesive, laser, ultrasonic welding, or the like.
- the manufacturing method is, for example, the base material is formed by cutting using the CADZCAM method, and precision processing is performed by using technology such as electric power.In addition, precision processing using semiconductor technology, processing using stereolithography, etc. It is also possible to create in.
- the rotating body R is rotated about the central axis O, and a centrifugal force is applied to each operation area. Although only the centrifugation step is shown in FIG. 1, the supply port for supplying blood from outside and the mixing step shown in other figures are connected as a whole.
- Reference numeral 1 1 1 denotes a blood cell storage section, which is a concave tank connected to the outer peripheral surface of the storage section 1 21, and is preferably formed with a deeper bottom than the storage section 1 2 1 .
- the storage section 121 is formed in a fan shape in the outer peripheral direction, and is connected to the supply flow path 141 and the output flow path 151.
- the combination of the blood cell storage unit 111 and the storage unit 122 forms an operation area.
- the outer peripheral surface of the storage section 1 2 1 forms a fan shape, but the diameter rl on the output flow path 1 5 1 side is longer than the other diameter r 2 by 0.3 mm or more.
- connection port for connecting the blood cell storage section 1 1 1 and the storage section 1 2 1, and preferably, the connection port 13 1 contains blood cells stored in the blood cell storage section 1 1 1 , Do not disperse to storage unit 1 2 1
- a convex portion is formed along the connection side of the connection port 13 1.
- the supply flow path 14 1 is for supplying the sample liquid to the storage section 121.
- the output channel 15 1 is for supplying the sample liquid after the operation to the next operation area.
- the output flow path 15 1 is connected at the outer peripheral surface of the storage section 12 1, and the form of the output flow path 15 1 is on a circular arc or a convex section led out from the outer peripheral surface of the storage section 12 1 It is preferable to extend in a direction perpendicular to the shape from the viewpoint of improving the liquid recovery rate. This is due to the vertical placement of the force vector that must be accommodated against the vector on the liquid to be moved, thereby reducing the vertical and force vector. For example, it is based on the theory that the liquid is left in the storage unit by being used as a force applied to the wall surface of the storage unit and, as a result, the movement of the liquid in the storage unit is inhibited as the stress on the wall surface.
- forming the output port at an angle of 180 degrees or more with respect to the storage section is a means for preventing the substance present in the storage section from flowing out to the output port, and depends on the amount of the processing solution. 1 0 0 ⁇ 4 0 0 ⁇ 1 in our Itewa when processing liquid, Ri by the placing the convex shape 0. 1 to 1. an outlet 5 mm about the output port away Ri by protrusions However, it is possible to prevent the substance from flowing out of the storage section.
- the liquid is not supplied from the supply channel 14.1 to the storage unit 121, and when supplied, the centrifugal force is stronger than the capillary force generated in the output channel 15 1. Since the force has already been generated, the liquid can continue to exist in the output channel.
- the whole blood ZK remaining in the reservoir 1 21 is centrifuged by the rotation of the rotating body (rotor) R, and the blood cells in the whole blood ZK are projected at the connection port 13 1 (see FIG. 1). And is stored in the blood cell storage unit 1 1 1.
- the whole blood ZK contains almost all blood cells in the blood cell storage unit 111, and blood components such as serum or plasma remain. This blood component behaves as if it gathers in a part with a long radius r1, especially when the wettability of the surface of the storage part 121 is improved. Gather around one.
- the blood cells KK are stored in the blood cell storage unit 1 1 1, and the separation is almost completed.
- the rotation speed of the rotating body R is reduced, the capillary force, which was suppressed by the centrifugal force and increased, increases the capillary force. Then, it moves to the outside via the output channel 15 1 (see Fig. 2 (b)).
- serum and plasma after blood cell separation can be formed without leaving any serum or the like in the storage section and without waste. This is because the effect of the present invention, which has the effect of collecting the liquid in a certain space, prevents the incorporation of air, which is the most important factor in reducing the recovery.
- FIGS. 3 (a) and 3 (b) each show an operation unit constituted by a concave portion provided on the rotating body.
- reference numeral 41 denotes a supply channel
- reference numeral 42 denotes an operation unit.
- 4 3 is an output flow path, but the connection surface d 2 between the operation section 4 2 and the output flow path 4 3 is clearly wider than the connection surface d 1 between the supply flow path and the operation section 4 2. It has become.
- d1 and d2 indicate the area of the connection port between each flow path and the operation area.
- the radius of the outer periphery of the operation area and the radius of the central axis O are such that the radius r 1 of the portion where the sample is to be collected is longer than the other radius r 2.
- the capillary force generated by the material is not uniform even at the same cross-sectional area.
- the generated capillary force was about 0.4 G (in the case of centrifugal force, the radius of gyration was 11.8 mm and the number of revolutions was 280 rpm)
- the cross-sectional area of the supply channel of the same material and the same wettable material is 0.0 4 If mm 2 and set, this (if the centrifugal force generated, the rotation radius 4. 3 cm, rotation speed 9 0 0 rpm equal force is generated) the capillary force of about 4 0 G by that, the operation of the sample
- the output flow path 43 may be connected in the vicinity thereof.
- a capillary It can be introduced by using the principle of the siphon and the centrifugal force while the liquid is filled in the output circuit with the force, and introducing it to other areas, or by using the air pushing pressure, depressurizing force, and the like.
- the structure is such that the mechanism is not affected even when the air portion exists in the operation area, a structure that does not allow the operation liquid to flow in the vicinity of the supply flow path is provided based on the method of the present invention. By doing so, the capillary forces in the supply flow path do not interfere with the movement of liquid to the output circuit.
- d 1 is preferable in that 0.04 to 1 mm 2 can exhibit the maximum capillary force, due to problems in production technology that can be manufactured precisely by current molding or cutting.
- This minimum cross-sectional area is not limited in a processing region where the development of technology is expected, such as when a manufacturing method using semiconductor technology is used.
- FIG. 3 (b) shows an embodiment in which the present invention is applied to the mixing operation area.
- reference numeral 4 2 1 denotes a mixing tank, and the radius r 1 of the outer periphery and the center of the portion where liquid is to be collected is set to be longer than the other radius r 2.
- 41 a is a blood component supply flow path for supplying blood components such as serum and plasma
- 4 lb is a diluent supply flow path
- 43 is an output flow path for supplying and outputting the mixed liquid after mixing to the next operation area.
- Reference numeral 44 is a convex portion for containing particles unnecessary for measurement separated by centrifugal force, such as blood cells. This part is used to separate the remaining blood cells in the blood cell separation process before mixing. If the unnecessary particles are sufficiently removed in the previous stage, the convex portion 44 may not be necessary.
- the blood component is supplied from the blood component supply channel 41 a to the mixing tank 42 1, and the diluent is supplied from the diluent supply channel 41 b to the mixing tank 42 1.
- the mixing tank 4 21 is rotated and shaken about the central axis O of the port, and mixed in the mixing tank 4 21. At this time, the internal solution is attracted by the capillary force of the supply channels 41a and 41b, and is not output from the output channel 43 to the outside.
- the mixing is performed by changing the amount of liquid present in the capillary by changing the rotation speed of the rotating body and by changing the amount of liquid present in the capillary according to the centrifugal force generated according to the rotation speed.
- This is a method in which a turbulent flow is generated in the mixing tank 421 by moving the liquid from the passage 43 or to mix.
- the mixture After mixing to some extent, in order to use the principle of siphon, the mixture is rotated at a low speed for a certain period of time, and after the capillary is sufficiently filled with liquid, the rotation speed is further increased and the mixed liquid is output from the output flow path 43. .
- the sample liquid can be retained in the operation area by attracting the liquid by the capillary force on the supply channel side, and the liquid can be held and output with a simple configuration.
- the area d1 of the supply flow path 41 connected to the operation unit 42 and the area d2 of the output flow path 43 have a relationship of d1 ⁇ d2.
- the output flow path 43 is as shown in FIG. 3 (c)
- the output flow path 43 is connected to the bottom of the operation section 42, and in FIG. 3 (d), the output flow path 43 is arranged above the operation section 42. Examples are given for each.
- the arrangement of the output flow path 43 is changed up and down with respect to the operation section 42. Even if the area d1 of the supply flow path 41 is reduced, the sample liquid can be attracted to the supply flow path 41 side.
- Reference numeral 45 denotes a distribution channel, which is a channel connected to the previous operation area.
- H is a lid, which has a sheet shape, and is connected to the base material of the rotor by an adhesive or ultrasonic welding. .
- reference numeral 71 denotes an operation area, and in the case of a reagent reaction tank, a reagent is contained, and it is a portion where it is preferable to form a final object to which a liquid for operation reaches. is there.
- a dummy space formed only for connecting the other end of the capillary (capillary channel) 72 may be used.
- the capillary channel 72 is preferably a channel having a cross-sectional area of KA: 0.04 to 0.25 mm 2 in terms of the current processing accuracy. However, with the improvement of machining accuracy in the future, the possibility of shifting in the direction of smaller numbers is shown. Five capillary channels having the same cross-sectional area KA were provided radially. Even if the reaction reagent requires oxygen, by changing the rotation speed, oxygen at the KA interface between the distribution channel 73 and the capillary channel 72 is introduced into the operation area 71 to perform the reaction. It is possible to proceed. It has been found that setting the cross-sectional area KA to a minimum value in all other cross-sectional areas in the same structure is more effective.
- the distribution channel 73 is for moving the blood and the diluent between the operation areas.
- the depth of the distribution channel 73 is desirably sufficiently larger than the cross-sectional area of the capillary channel 72.
- the depth is preferably 1 to 3 mm.
- 1-3 mm is preferable. That's right.
- each capillary channel 72 has a strong capillary force, by providing five of them, a stronger capillary force is obtained. Since it is possible to realize a configuration that can be pulled to a certain area, it can be used as a fluid drive source.
- FIG. 4 (b) shows a configuration in which the operation region 74 and the distribution channel 73 are connected without using a capillary channel.
- the area KB of the coupling surface 75 is, for example, 0.44 to 0.8 mm 2, and the contact angle S between the operation region 74 and the distribution channel 73 is, for example, 5 to 30 degrees.
- the coupling surface 75 holds the liquid by the surface tension generated by the contact angle S between the operation area 74 and the distribution channel 73, the sample passing through the distribution channel 73 is This is held on the coupling surface 75. Since the surface tension changes due to the viscosity of the liquid, the contact angle between the operation area and the distribution channel is adjusted appropriately within the range of 5 to 30 degrees.
- Fig. 4 (b) The configuration of Fig. 4 (b) is simpler, and can form a sample operation area with reduced cost when forming a fluid chip.
- the embodiment shown in FIG. 4 is preferably used for a drive source or a function for quantifying and stopping a fluid or simply for stopping or slowing down a flow. This is also effectively used when performing operations on polymer liquids.
- FIG. 5 (e) is a top view of a centrifugal configuration showing one embodiment of the present invention.
- the present embodiment is a blood test unit having a centrifugal separator as one component, and has a supply channel 14 for supplying blood for processing, An output channel 15 for outputting blood to the next step is provided.
- Reference numeral 12 is a bodily fluid reservoir, the size of which depends on the amount of blood to be processed, but the hematocrit value when processing 20 to 500 ⁇ l of blood. In order to enhance the measurement of 60% of the sample, 8 to 200 mm 3 is exemplified.
- 11 is a particle storage unit. It is mainly used to accommodate blood cells, and its size is large enough to process samples with a hematocrit value of 60% when processing 20 to 500 ⁇ l of blood. For example, the position of 12 to 300 mm 3 is exemplified.
- Reference numeral 13 denotes a projection, which is uniformly formed at a height (cc) of 0.5 to 2 mm at the bottom of a connection port connecting the particle storage section 11 and the body fluid storage section 12. I have.
- Fig. 5 (a) is a cross section of X-X in Fig. 5 (e).
- the convex portion 13 is formed in a roughly trapezoidal or triangular shape. This is because the blood cells present in the body fluid storage portion at the start of separation are quickly and efficiently introduced into the particle storage portion. This is to provide a gentle slope from the air to the particle storage. It is preferable that the blood cells can easily get over and not move easily in the opposite direction due to the centrifugal force in the direction from the particle storage unit 11 to the body fluid storage unit 12. However, as shown in FIG. Even if the shape of the part 13 is not characterized, it may be better to make the particle storage part 11 deeper than the body fluid storage part 12. However, even if the depth is simply increased, the above-described problem occurs.
- the ratio of the distance from the connection port to the outermost part of the particle container and the depth is preferably 1 or more: 1.
- the substance stored in the particle storage unit has a higher specific gravity than the substance stored in the body fluid storage unit, it is necessary to consider that the particle storage chamber is deeper than the body fluid storage unit in consideration of the storage efficiency. Desirable but not limiting.
- FIG. 5B is a view of the front of the connection port K. It has a roughly rectangular shape (a is 10 mm and b is 0.5 mm), but is not limited to this, and any shape may be used as long as it is a connection port. In this case, the area of the connection port K was made into a rectangular shape for easy calculation.
- FIG. 5B is a view of the front of the connection port K. It has a roughly rectangular shape (a is 10 mm and b is 0.5 mm), but is not limited to this, and any shape may be used as long as it is a connection port. In this case, the area of the connection port K was made into
- 5 (c) is a diagram in which the state provided with the blood cell storage unit 11 and the connection port K is taken as a perspective space.
- the projections 13 do not have to be arranged in a straight line, and do not have to have a uniform height cc when the connection surface is curved.
- the blood cell component can be more efficiently stored in the blood cell storage unit.
- the supply flow path 14 has a supply section IN which is a connection part with the storage section 12, and is a flow path to which a mixture of the original blood, the diluent, and the original blood is supplied.
- the other end of the supply channel 14 is connected to, for example, an external blood input port or a diluent mixing unit.
- the other end of the output flow path 15 is connected to a quantification unit for quantifying a sample liquid after separation of serum or the like, a reagent chamber equipped with a reagent, and the like.
- the cross section is, for example, 1 mm 2 or less, and is formed in a size that allows a capillary force to act.
- the output flow path 15 has a supply port OUT forming a connection surface with the storage section 12 and has the same size as the supply flow path 14, but the output flow path 15 is located at the center C. It may have a bent shape toward it.
- FIG. 5D is a diagram showing an example of the positional relationship of the embodiment of the present invention on the rotor R.
- Rotor R is made of PP (polypropylene) polycarbonate, acrylic, ABS, polystyrene, polyethylene, polyethylene terephthalate, PVDF, PTFE, Positive Shiraidani, TPX, P0M, UF, SAN, PSU, PP S, PP0, PPA, PEN, PAR, PA, MF, FEP, DAP, ASA, AS, AES, Si]) Easy to form shapes such as concrete, glass, aluminum plate, etc. shape Channels, storage sections, and blood cell storage sections are formed in a disk that can be made of unchanged industrial materials by carving grooves, and in some cases, the formed channel surface can be subjected to hydrophobic or hydrophilic treatment. Good.
- the analysis rotor is formed by joining the lid H made of PPS, PP0, PPA, PEN, PAR, PA, MF, FEP, DAP, ASA, AS, AES, silicon, glass, aluminum plate, etc.
- the driving source for supplying the raw blood G to the reservoir 12 is, for example, centrifugal force, gravity, or capillary force.
- the rotor R is rotated at 1,000 to 30,000 rpm with respect to the raw blood supplied to the reservoir 12.
- the rotation speed should be determined based on the distance between the storage part 12 and the centrifugal center C and the separation time. However, considering the economical problems and the safety aspects of the user, the number of rotations is 3, 000. It is desirable to perform the separation at about 6,000 rotations, but it is not limited.
- centrifugal force is specified by the centrifugal force obtained at that number of rotations rather than by specifying the rotation of the rotor. Not something.
- the centripetal force at this time was generally calculated from a value that can be given by the following equation.
- Blood cells GK in the original blood G move in the direction of the convex portion 13 due to the centrifugal force ⁇ .
- the blood cell GK receives a stronger force in the direction of the projection 13 than other liquids, and the blood cell G gets over when the rotation speed exceeds a certain value. By repeating such an operation, only the blood cell GK is stored in the blood cell storage unit 11.
- Blood components such as serum and plasma, from which the blood cells GK have moved to the blood cell storage unit 11 attempt to move to the outside from the output port OU via the output channel 15 by capillary force, but at a certain level. Due to the centrifugal force described above, the blood component reaching the bending portion is prevented from proceeding, and therefore does not move outward.
- the blood cell GK in the blood G is moved to the blood cell storage unit 11 by continuing for a predetermined time. Then, blood cells are separated into blood components such as serum, and then centrifugal force is reduced by reducing the rotation speed. The separated blood components are transferred to the outside by the capillary force in the output channel 15. Move.
- the centrifugation time is 2.5 to 5 mm2 in the diameter of the connection port, the number of rotations is 3, 000 to 5, 000 rpm, and the original blood supplied from the supply section IN is used. If the volume is 0.14 to 0.25 ml, 1.5 to 3 minutes is exemplified.If you want to increase the separation time, narrow the pore size of the connection port or reverse to separate. If you want to make the time faster, adjust it by making it wider.
- the determination of the completion time of separation varies depending on the viscosity, water content, etc. of the patient's blood, but should be applicable when separating less than 60% of blood in terms of hematocrit.
- the constant 10 here fluctuates between about 8 and 12 depending on the contents of the components of the processing liquid. This is due to factors other than those described by the present invention, for example, It can also be attributed to the wettability, material, processing roughness, etc. of the surface of the rotating body for processed measurement.
- the centrifugal force at this time is also a number that should be greatly affected by this constant, but this centrifugal force is a result at 500 to 600 G in the experiment of the present invention, but at 900 G However, almost the same result was obtained.
- This number is also affected by the ratio of the depth of the blood cell storage part to the distance from the connection port to the outermost part of the blood cell storage part.
- this ratio is in the range of 1: 1 to 1: 3.5. It is valid. When this ratio decreases when the depth is set to 1, the number decreases, and when the ratio increases, the constant increases.
- reference numeral 61 denotes a mixing storage chamber, which has a small chamber 65 in an outer peripheral direction and an output flow path 63 extending outward. Further, a sample supply flow path 62 and an auxiliary liquid supply flow path 64 are connected to the inner peripheral side of the mixing storage chamber 61.
- the mixing storage chamber 61 is installed such that the distance rl between the outer peripheral surface at the connection portion with the output flow path 6.3 and the center OK is longer than the distance r2 between the other outer peripheral portion and the center OK.
- the sample supply channel 62 is a channel for supplying a blood component solution such as serum or plasma
- the auxiliary solution supply channel 64 is for dilution of, for example, a diluent and amplification for measurement. This is a flow path for supplying an auxiliary liquid for performing the following.
- the output flow path 63 is bent once in the center direction and extends to the next operation area.
- connection port (0.04 to 0.64 mm 2 ) between the sample supply channel 62 and the auxiliary liquid supply channel 64 and the mixing storage chamber 61 is the same as the output channel 63. It is preferable that the area is set to be smaller than the area of the connection surface with the mixing storage chamber 61 (0.25 to lmm 2 ).
- This connection cross section is It is set within the above range according to the current processing conditions.However, if the value is reduced in accordance with the progress of processing technology in the future, it is possible to handle a smaller amount of liquid, and it is not specified. Absent.
- the small chamber 65 is a part for containing unnecessary components remaining in the sample by centrifugation. This may not be necessary if there is no unnecessary component in the sample supplied from the sample supply channel 62.
- the size is, for example, approximately 0.3 to 6.5 mm 3, but is not limited thereto.
- the size of the mixing storage chamber 61 in the present embodiment differs depending on the supplied sample and the amount of the auxiliary liquid, but approximately 1.5 times or more the value of the combined sample and auxiliary liquid. If a certain force, the depth near the connection port is increased, the liquid mixing section is set shallower than that depth, and a structure is provided to prevent the liquid from returning to the connection port once introduced. It can be even smaller. Also, when the depth of the introduction portion is changed, a convex shape is formed at the boundary and a structure is set so that the surface tension is further increased, so that a liquid having a lower surface tension, such as an organic material, is formed. It is effective when a solvent or the like is used, but is not limited to this ratio.
- these components are incorporated in a disc having a center axis OK, and that a drive device for rotating the disc is also provided.
- the sample solution 6 KS is supplied from the sample supply channel 62 without rotating or rotating the rotor (see FIG. 6 (b)) ′.
- the auxiliary liquid 6KK is supplied from the auxiliary liquid supply flow path 64 (see FIG. 6 (c)). These introductions may be simultaneous.
- the sample liquid 6 KS and the auxiliary liquid 6 KK are attracted by the capillary force of the sample supply flow path 62 and the auxiliary liquid supply flow path 64 when the rotation of the rotor is small or stationary. Is trying to form a closed state.
- Reference numeral 51 denotes a reagent reaction tank, which is a cylindrical body having a depth of 5 t, and a supply capillary (flow channel) 52 is connected to an upper portion thereof.
- Supply bristle pipe 5 that the diameter area, and 0. 0. 4 to 0. 2 5 mm 2
- a plurality of supply capillaries may be arranged in parallel.
- the depth 5 t of the reagent reaction vessel 51 is 0.3 to 5 mm, which is important for both the mixing operation by repeatedly moving the liquid by the capillary force of the sample supply channel and the centrifugal force, and also for securing the optical path length. I like it.
- Reference numeral 53 is a distribution channel for distributing the sample solution to other reagent reaction tanks ⁇ and other operation areas, and has a caliber area of about 1 to 4 mm 2 as an example. Is done.
- Reference numeral 54 denotes a coloring reagent which dissolves in the sample solution to cause a coloring reaction.
- Reference numerals 55 and 56 denote translucent portions for measurement, which are formed of members transmitting external light. The upper measuring light transmitting part 55 and the lower measuring light transmitting part 56 need both for the measurement by the transmitted light, but may be one for the measurement of the reflected light.
- This configuration shows an example of a configuration in which a lid is formed as a concave portion on a rotor and a cover H is joined from above with a bonding agent, and FIG. 7 shows a part of this configuration.
- FIG. 7B A cross-sectional view showing a cross section taken along line X-X 'in FIG. 7A is shown in FIG. 7B and thereafter.
- the sample 5S1 flowing through the distribution channel 53 is held by the capillary force of the supply channel 52 (see FIG. 7 (b)). With the sample flowing through the distribution channel 53 interrupted, the sample 5S2 is held in the supply channel 52, and is in effect a quantified sample.
- the number of rotations of the rotor R is set to 5, and the sample 5S2 in the supply channel 52 is pushed into the reagent reaction vessel 51 (see FIGS. 7 (c) and 7 (d)).
- the extruded sample 5 S 3 comes into contact with the reagent 54, and dissolution starts. After 10 to 60 seconds, when the rotation speed is reduced and the centrifugal force (5 CC 1) is reduced, the mixed liquid flows between the supply channel 52 and the reagent reaction tank due to the capillary force of the supply channel 52. Move so that it is drawn to the connection port, 5S4 (see Fig. 7 (e)).
- the reagent and sample are thoroughly mixed, and a state suitable for measurement is formed.
- the measurement is performed, for example, using an optical path HS in which one of the upper and lower directions is selected as shown in FIG. 7 (f).
- reference numeral 91 denotes a primary reaction tank, which is disposed on a rotor that rotates about a central axis O 9, and is a distance r between the outermost peripheral edge on the outermost output side. 2 and the distance r 1 from the center of the other part,
- Reference numeral 92 denotes a cell, in which, for example, mutarotase, dalcosoxidase, peroxidase, ascorbate oxidase, phenol, phenol, sodium 1-naphthol-3,6-disulfonate, phosphoric acid, Pyruvate oxidase, oxa-acetate decarboxylase, catalase, N-ethyl-N- (2-hydroxy-3--3-sulfop-pill) -m-toluidine sodium, 4-aminoantipyrine, L-aspartic acid, poly-keto d'tartaric acid, thiamine pyrophosphate, magnesium chloride hexahydrate Hydrate, HEPES, lipoprotein lipase, adenosine_5, -ninatrinium triphosphate trihydrate, gnoresellonolekinase, gnoresellonole-3-phosphate oxidas
- the primary reagent 95 is, for example, a freeze-dried one, or a state in which a liquid is impregnated in a porous particle made of ceramics or a polymer, or a liquid state.
- a small chamber 92 and a primary reaction tank 9 are shown. By making the connection portion 96 with 1 an acute angle, the liquid reagent in the small chamber stays inside due to surface tension.
- Reference numeral 93 denotes an input flow path for inputting a sample liquid
- 94 denotes an output flow path for outputting a mixed and reacted sample in the primary reaction tank 91 to another reaction tank. It is.
- the output flow path 94 has a so-called siphon form, and has a function of adjusting the movement of the solution in the primary reaction tank 91 to the outside by controlling the rotation speed.
- the configuration is preferably disposed on a rotor, but may not be disposed on a rotating body such as a rotor as long as a unidirectional force is applied to a sample or the like.
- FIG. 8 Next, the operation of FIG. 8 will be described in detail with reference to FIGS. 9 (a) and 9 (b).
- the distance r2 between the outermost peripheral portion on the output flow path 94 side and the central axis O9 is made longer than the distance r1 of the other outermost peripheral portion.
- the mixed solution M 9 tends to collect on the output channel 94 side without leaving the mixed solution M 9 of the reagent in the primary reaction tank 91, and the mixed solution M 9 is output from the output channel 94 to the outside. Can be output.
- Reference numeral 71 denotes an operation tank in which a lyophilized reagent 76 is disposed.
- the reagent include an enzyme such as glucose oxidase, but are not particularly limited as long as it is necessary for measurement.
- As the depth Tb 0.3 to 5 mm is exemplified.
- Reference numeral 722 is a group of flow channels having the same cross-sectional area, and has the same length, but is not particularly limited. This channel group is merely an example, and a single channel may be used in some cases.
- the existing air and gas in the operation tank 7 1 This is effective in that it becomes an air vent channel that passes through at least one of the two channels to the outside.
- the force relationship which changes variously due to the gravity generated from the height of the capillary channel, the specific gravity of the liquid to be handled, the surface wettability of the structure, etc. Multiple introductions may be necessary to set the capillary force for holding the body to a maximum.
- Reference numeral 73 denotes a distribution channel for transporting the supplied sample to various operation tanks.
- Reference numeral 74 denotes a spare chamber, whose cross-sectional area is 91 to 601 as compared with the cross-sectional area S2 of the capillary channel.
- Reference numeral 75 denotes a first supply channel, and the cross-sectional area S 1 of the first channel is 2 to 25 times larger than the cross-sectional area S 2 of each channel of the channel group 72 2.
- the spare chamber 74 has a configuration in which the connecting surface with the flow path group 72 2 is drawn in an arc so as to make the length of the flow path group equal.
- Reference numeral 77 denotes an upper light-transmitting portion
- reference numeral 78 denotes a lower light-transmitting portion, which is formed of a light-transmitting member for externally measuring a mixed and colored state of the reagent 76 and the sample.
- Specific examples include, but are not limited to, polystyrene, PET, acrylic, polycarbonate, transparent plastics such as resin materials for contact lenses, and glass.
- R is a rotating body, is a disc-shaped body that rotates around a central axis (not shown), and the arrangement of the capillaries preferably extends in the direction of centrifugal force.
- the sample K S flowing through the distribution channel 73 is supplied to the preliminary chamber 74 via the first supply channel 75 (see FIG. 11A).
- the sample KS stored in the preliminary chamber 74 is drawn to the flow channel group 722 by capillary force, flows into each flow channel, and is filled (see FIG. 11B).
- the flow channel group 722 is filled with the sample (KSG), and the sample (KSG) remains around the flow channel group 722 in the spare area.
- the centrifugal force E 1 is increased by increasing the rotational force of the rotor.
- the sample in 7 22 is pushed out to operation tank 7 1.
- the sample in the preparatory chamber 74 moves to the flow channel group 722 by capillary force sequentially, and the sample in the flow channel group 722 is operated by centrifugal force. It is pushed out into the tank 71 (see Fig. 11 (c)).
- the sample in the operation tank 71 and the sample in the flow channel group 722 are held by the capillary force of the flow channel group and the surface tension in the preparatory chamber 74 to maintain a stable state.
- the quantitative sample KS in the operation tank 71 can be formed in a stable state without being attracted to the flow path group.
- the quantitative sample K S is determined by the sum of the volume of the operation tank 71 and the total volume of the channel group 722.
- the quantitative sample K S in the operation tank 71 is mixed (K S M) with the reagent 78 and undergoes a color-developing reaction, and the color value is measured by transmission of the external measurement light K H.
- the embodiment described above includes a reagent reaction tank for securing the measurement optical path length, This shows a state in which the flow channel group is fully filled with the sample (see Fig. 11 (d) '), but the amount of the sample to be introduced is set to be sufficiently small with respect to the operation tank 71. May be.
- the sample may be desirably quantified or semi-quantified in the operation area before the preparatory room, but may be quantified in the flow channel group 722.
- a first supply channel 75 is provided in the reserve room 74 so as to extend in the direction of the centrifugal center as close as possible and at least a certain distance from the channel group 722, and upstream of the first supply channel 75.
- the supply of the filler is performed immediately after the sample is introduced into the operation area, before the rotation speed is reduced, and before the sample is drawn to the flow channel group 722 and refilled.
- the filler is guided to the boundary between the first supply channel 75 and the preliminary chamber 75 by capillary force, surface tension, gravity, or the like, and further, The distance from the first supply channel 75 to the channel group 722 is moved at a moving speed determined by the surface wettability of the preliminary chamber 74.
- the filler after the movement is filled in the flow channel group 722 by the capillary force of the flow channel group 722.
- the input flow path cross-sectional area is sufficiently larger than one flow path cross-sectional area of the flow path group 7222. Need to be taken.
- the cross-sectional area of the input flow path depends on the type of the filler, but is, for example, about 30 to 300 times that of DMSO for the cross-sectional area of one flow path in the flow path group. Is appropriate.
- Example 10 shows a liquid holding kit for the purpose of temporarily holding and storing liquid.
- Reference numeral 80 denotes a substrate, which has an effect on a biological sample having a thickness of l to 10 mm, for example. Inexpensive production is possible with a small amount of resin.
- it consists of polystyrene, polypropylene, polyethylene, ABS, polycarbonate, acrylic, and glass.
- the size of the substrate 80 is, for example, about several mm 2 to several tens mm 2, but is not limited.
- Reference numeral 81 denotes a storage area, which is formed by a cylindrical concave portion.
- Reference numeral 8 2 denotes a plug-constituting flow path group, in which one or more flow paths (cross-sectional area: 0.09 to 2.25 mm 2 ) have the same length, and the storage area 8 1 and the spare area 8 3 And connect.
- Reference numeral 84 denotes an input port, which is a flow path for externally inputting a storage solution and a stopper solution.
- Reference numeral 85 denotes a supply channel, which is a channel for supplying a storage solution and a plug solution from outside.
- the supply flow path 8.5 is curved along the curved surface of the contact surface with the plug-constituting flow path group 82 in the preliminary area 83, and further extends outside the preliminary area 83. I have.
- Sectional area of the supply channel 8 5 is larger Ri by the cross-sectional area of the plug arrangement channel groups 82, the difference is, 0. 2 1 ⁇ 2.
- 2 mm 2 is to plug configuration channel group of the liquid It is preferable because the movement is smooth.
- Reference numeral 86 denotes a lid, which is formed of, for example, the same member as the substrate 81, and covers the plug-constituting flow channel group 82, the operation area 81, and the like formed as a groove on the substrate 81. .
- a lid which is formed of, for example, the same member as the substrate 81, and covers the plug-constituting flow channel group 82, the operation area 81, and the like formed as a groove on the substrate 81.
- an adhesive bonding method using an adhesive a method such as welding, or a close contact method using a silicon-containing sheet is used.
- the lid 86 is preferably transparent so that the internal state can be grasped. Next, the operation of FIG. 12 will be described in detail with reference to FIG.
- the storage liquid 8B is input from the input port 84 (see 8A). At this time, it is preferable to use a liquid equivalent to the storage amount or slightly larger.
- the storage liquid 8B is pulled by the strong capillary force of the plug-constituting flow channel group 82, and is filled in each of the plug-constituting flow channel groups 82.
- the storage liquid examples include enzyme reagents and other reagents, body fluids such as blood, plasma, and serum, tissues such as cells and bacteria, and in vivo chemical substance solutions such as DNA and RNA.
- body fluids such as blood, plasma, and serum
- tissues such as cells and bacteria
- in vivo chemical substance solutions such as DNA and RNA.
- gas may be used in some cases.
- the storage liquid 8B flows along the curved surface, and sequentially. Fill the plug-constituting flow channel group 82.
- a force (8E) is applied from the outside as shown in FIG. 13 (c).
- This force is exemplified by, for example, centrifugal force, air pressure, gravity, inertia force, and the like. Due to this force (8E), the storage liquid 8B in the plug-constituting flow channel group 82 moves to the storage area 81. This is a timing to apply this force. At least when the storage liquid 8B moves to the storage area 81, the stopper liquid 8D is input from the input port 84 (8C See).
- the stoppering liquid 8D is supplied to the spare region 83 via the supply passage 85, and is filled in the empty stopper-constituting flow passage group 82.
- As the stoppering liquid 8D for example, an inert and stable solution is preferable.
- At least the input from the input port 84 of the stoppering liquid 8D is supplied at least before the storage liquid 8B in the stopper-constituting flow path group 82 moves to the storage area 81. preferable.
- the plug-constituting flow channel group 82 is filled with the plug liquid 8D, and the storage liquid 8B in the storage area 81 is stored in a state where it is shut off from the outside.
- the lid 86 is opened or the stopper liquid 8D in the stopper-constituting flow path group 82 is released by suction, etc., and the internal storage solution is used.
- the storage liquid 8B in the stopper-constituting flow path group 82 is withdrawn without opening the lid 86, the storage liquid 8B is emptied and the capillarity is restored. 82 is refilled and held. In this state, it is set on a measuring device or the like, and mosquito is added to the plug-constituting flow channel group 82, whereby the internal storage liquid is taken out.
- the configuration may be such that the cassette is fitted into the reagent reaction tank in a cassette form.
- Such a storage solution body is suitable, for example, when a small amount of collected body fluid is held in a remote place.
- Fig. 14 shows a disc-shaped rotor structure made of Ataryl with a radius of 35 mm and a depth of 4 mm. As shown in the figure, the rotor structure was used for measuring undiluted serum components.
- the region 23 X is divided into a first diluted serum component measurement region 23 Y and a second diluted serum component measurement region 23 Z different in the degree of dilution from the first diluted serum component measurement region.
- Reference numeral 201 denotes a diluent reservoir, which is previously sealed and enclosed, and preferably has a configuration in which, when used, the sealed state is released by an external pressure and flows out to the outside. It is not limited.
- Reference numeral 202 denotes a first blood storage unit, which stores blood collected from a patient or the like. The first blood reservoir 202 has triple side walls, with no extra space between the side walls. It has a storage section 202 a for storing the excess blood.
- Reference numeral 203 denotes a first flow path, which is composed of two flow paths, and connects the first blood storage section 202 with the blood cell separation / distribution section 203a.
- the blood cell separation / distribution unit 203 a connects the first blood cell separation unit 204 and the second blood cell separation unit 206 to the second flow path 208.
- the first blood cell separation section 204 is connected to the first blood cell storage section 205 via the first continuous projection section 250, and the specific configuration thereof is centrifugation as shown in FIG. Having a configuration.
- the second blood cell separation section 206 is connected to the second blood cell storage section 207 via the second continuous projection section 251, and its specific configuration is a centrifugal separation configuration as shown in FIG. Have.
- the second blood cell separation section 206 is connected to one end of the fifth flow path 215 having the bent portion L4. Serum component measurement area 2 3 X
- the second flow path 208 is connected to the first fixed amount section 219.
- the first quantification section 219 is connected to the third blood cell separation section 217, and is connected to the excess blood storage section 219a, and the excess blood storage section 219a is connected to the deaeration channel 2 Connect to one end of 20.
- the other end of the degassing channel 220 is connected to the first degassing port 222.
- FIG. 16 specifically shows the periphery of the third blood cell separation unit 2 17.
- the distance DD4 between the outermost right edge of the third blood cell separation section 2 17 and the central axis O is longer than the other edges DD3, and a configuration for efficient movement of the separated serum is provided. Has become.
- the third blood cell separation unit 2 17 is configured to be connected to the third blood cell storage unit 2 18 via the third continuous protrusion 250.
- Reference numeral 2 16 denotes a third flow path, which includes a bent portion L 8 and a connection point with the third blood cell separation portion 2 17 as shown by a dotted line EO in FIG. It is set so as to be present on the circumference where the distance between the left connection point of the blood cell separation part 2 17 and the third continuous projection part 250 and the center axis O is the same.
- the third flow path 2 16 is further connected to the fourth blood cell separation section 222, and the fourth blood cell separation section 222 is connected to the fourth blood cell storage section 222.
- the depth of the fourth blood cell separation section 222 is shallower than that of the fourth blood cell storage section 222, and the residual blood cells stored in the fourth blood cell storage section 222 are separated by the fourth blood cell separation section 222. It has a configuration that does not flow out to 2.
- the fourth blood cell separation section 222 is connected to a sixth flow path 222 having a bent portion L6.
- the fourth blood cell separation unit 222 is used when sufficient blood cell separation cannot be performed in the third blood cell separation unit 217, and the capacity or measurement of the third blood cell separation unit 217 is used.
- the sixth flow path 2 24, which may be unnecessary depending on components, etc., is connected to the first distribution flow path 2 41, and the outer side surface of the first distribution flow path 2 41 is equally spaced, Six first reagent reaction sections 242 each having a channel group 243 having the same shape and the same size are arranged in six places.
- Flow passage group 2 4 3 strong consists in a state of being arranged at equal intervals in the radial microchannels with FIGS. 4 (a) of the sea urchin same by showing the cross-sectional area 0. 0 4 ⁇ 0. 0 9 mm 2 It has a configuration that exerts capillary force.
- Reference numeral 242 denotes a first reagent reaction section, in which different freeze-dried reagents are stored.
- Reference numeral 244 denotes a first recovery area, and the specific configuration is shown in FIG. FIG. 15 shows the second collection area 239, which has the same size and shape.
- the first recovery area 244 includes a grid network having the same cross-sectional area SS 1, and the cross-sectional area SS 1 of the flow network corresponds to each of the flow channels of the flow channel group 243.
- the cross-sectional area is at least three times larger than SS2. 2 4 5 is the second vent.
- the flow path group 243 has a configuration directed from the first distribution flow path 241 to centrifugal light.
- 'Serum component measurement area 23 X is for measuring the color reaction by diluting the serum after blood cell separation into each reagent reaction tank without dilution and measuring the color reaction. If the sample is sufficient, it may be sufficient for use as a component measurement configuration. All vents penetrate upward and communicate with the atmosphere.
- the fourth flow path 2 12 having the bent portion L 1 connects the first blood cell separation section 204 with the first mixing section 2 25.
- Reference numeral 247 denotes a first dilution channel, which is composed of two channels having the same size and shape, and each of which is connected to the diluting liquid distributor 247a.
- the diluent dispensing section 247a is connected to the first diluent quantifying section 210 and the second diluent quantifying section 209, respectively. It is preferable that both corners in the outer peripheral direction of the first diluent.
- Quantifying portion 210 are formed as gentle curved surfaces.
- One end of a second dilution flow path 2 11 1 is connected to the center axis direction of the first dilution and quantitative section 2 10, and the other end is a surplus liquid storage section 2 for storing the surplus diluent. 4 6 are formed.
- the surplus liquid storage section 24 6 is connected to the third deaeration port flow path 2 48 for connection with the third deaeration port 2 49.
- a fourth dilution channel 2 13 having a bent portion L2 is connected in the direction.
- the connection between the first diluent quantitative section 2 10 and the fourth dilution channel 2 13 is based on the connection relationship between the third blood cell separation section 2 17 and the third channel 2 16 shown in FIG. 16. It is preferable to make the same connection as described above.
- the fourth dilution channel 2 13 is connected to the first mixing section 2 25.
- the first mixing section 225 forms a first storage chamber 226 in the outer peripheral direction and is formed so as to draw an arc around the first storage chamber 226.
- the left edge of the outer periphery of the first mixing section 222 has a bent section L5 One mixing channel 2 27 is connected.
- the distance between the outer peripheral edge of the first mixing section 2 25 near the connection with the first mixing flow path 2 27 and the central axis O is larger than the distance between the other outer peripheral edge and the central axis O. It's getting longer.
- the other end of the first mixing channel 227 is connected to the second distribution channel 236.
- On the outer side surface of the second distribution channel 2 36 there are 6 second reagent reaction sections 2 3 7 provided at equal intervals and having a channel group 2 3 8 of the same shape and size. Are arranged.
- the flow channel group 238 is constructed by arranging fine flow channels having the same cross-sectional area of 0.04 to 0.09 mm 2 at equal intervals radially. It has a configuration that exerts capillary force.
- Reference numeral 237 denotes a second reagent reaction section, in which different lyophilized reagents for diluted serum are stored.
- Reference numeral 239 denotes a second collection area, and the specific configuration is shown in FIG.
- the second recovery area 239 is composed of a grid network having the same cross-sectional area SS 1, and the cross-sectional area SS 1 of the flow network is the cross-sectional area of the individual flow channels of the flow channel group 238. It is three times larger than the cross-sectional area SS2.
- 240 is a fourth deaeration port.
- the first diluted component measurement area 23 Y is configured such that the diluent determined by the volume of the first dilution area and the serum are mixed, and the second reagent reaction section 237 performs a color reaction with the reagent.
- the degree of dilution may differ depending on the reagent.
- a dilution system that has a different dilution step from the dilution performed in the first dilution component measurement area is referred to as the second dilution component measurement in Fig. 14. This is shown in region 23Z, and its configuration will be described. '
- both corners in the outer peripheral direction are formed as gentle curved surfaces, like the first diluting liquid quantifying section 210.
- the volume of the second diluent quantitative unit 209 is different from that of the first diluent quantitative unit 210, and the diluent corresponding to the volume of the second diluent quantitative unit 209 is quantified.
- One end of a second dilution flow path 211 is connected to the center axis direction of the second diluting liquid quantitative section 209.
- a fifth dilution channel 2 14 having a bent portion L3 is connected to the outer peripheral direction of the second diluent quantitative section 209.
- the connection between the second diluent quantitative section 209 and the fifth dilution flow path 2 14 is based on the connection relationship between the third blood cell separation section 2 17 and the third flow path 2 16 shown in FIG. Preferably, a similar connection is made.
- the fifth diluent flow path 2 14 is further connected to the second mixing section 2 28.
- the second mixing section 228 is formed so as to form a second storage chamber 229 in the outer peripheral direction and to draw an arc around the second storage chamber 229.
- a second mixing channel 230 provided with a bent portion L7 is connected to the outer peripheral left edge.
- the other end of the second mixing channel 230 is connected to the third distribution channel 231.
- the distance between the central axis O and the vicinity of the connection with the second mixing flow path 230 at the outer peripheral edge of the second mixing section 228 is longer than the distance between the other outer peripheral edge and the central axis 0. I'm familiar.
- the flow path group 2 32 is composed of micro flow paths having the same cross-sectional area of 0.04 to 0.09 mm 2 arranged radially at equal intervals. It has a configuration that exerts strong capillary force.
- Reference numeral 233 denotes a third reagent reaction section, in which different lyophilized reagents for diluted serum are stored.
- Reference numeral 234 denotes a third recovery area, and the specific configuration is shown in FIG.
- the third recovery area 2 3 4 is composed of a grid network having the same cross-sectional area SS 1, and the cross-sectional area SS 1 of the flow network is defined by the individual flow paths of the flow path group 2 32. It is three times larger than the cross-sectional area SS2. 2 3 5 is the 5th deaeration port is there.
- the rotor R is provided with fitting ports T1 and T2 for fitting the rotor R to the mounting projection on the measuring device when the rotor R is mounted on the measuring device.
- the fitting ports T1 and T2 may be formed to penetrate the rotor R up and down, or may be formed as convex portions on the lower surface.
- the rotor R is formed by forming recesses in each area on the substrate, then attaching a freeze-dried reagent to the square reagent reaction tank, and bonding a lid made of a transparent sheet, film, or hard plate from above. Used in a bonded state by chemicals, self-adhesive, or other means.
- the lid (for example, H shown in Fig. 3 (c)) has a deaeration port, a blood supply port, a fitting port, and a diluent discharge operation member formed on the substrate. And the like are formed.
- blood 35 to 250 collected in the first blood reservoir 202 is provided.
- ⁇ 1 is supplied by a dropper and a pipe.
- the supply amount is approximately sufficient, and the excess amount is held in the accommodating portion 202a formed by the peripheral groove.
- the blood 22A in the first blood reservoir 202 moves so as to be drawn to the first channel 203.
- the blood is transferred to the blood cell distribution / separation section 203a and the first blood cell separation section 204, the second blood cell separation section 204 Go to 6.
- the overflowed part is passed through the second flow path 208 and the first fixed amount section 219.
- the third blood cell separation unit 217 is filled with blood, and the surplus is stored in the adjacent excess blood storage unit 219a via the first fixed amount unit 219 (22E).
- the blood cells 22 J separated by the first blood cell separation section 204 are stored in the first blood cell storage section 205 and the first blood cell separation section 2 Within 24, the serum gradually becomes 22 A1 state.
- the blood cells 22 I separated by the second blood cell separation unit 206 are stored in the second blood cell storage unit 206, and the inside of the second blood cell separation unit 206 is in a state of serum 22 A 2. It becomes.
- the blood cells 2 2D separated by the third blood cell separation unit 2 17 are stored in the third blood cell storage unit 2 18, and the inside of the third blood cell separation unit 2 17 is in the state of the serum 22 C. It becomes.
- the so-called siphon phenomenon causes centrifugal force in the vicinity of the bent portion L1 of the fourth flow path 212.
- the serum 22 A 1 whose movement has been suppressed by the above, flows into the first mixing section 225 over the bending section L 1.
- the serum 22 A 2 whose movement was suppressed by the centrifugal force in the vicinity of the bent portion L 4 of the fifth flow path 2 15, passes through the bent portion L 4 and becomes second mixed. Enter part 2 2 8.
- the number of rotations of the rotor R is raised to 2,000 to 6,000 rpm again when each serum crosses each bend, so that the formation in each blood cell separation section is performed in the first mixing section 2 2 5. Move all to the second mixing section 228 and the fourth blood cell separation section 222.
- the residual blood cells in the serum flowing into the first mixing section 225 are stored in the first storage chamber 226, and the residual blood cells in the serum flowing into the second mixing section 228.
- the blood is stored in the second storage chamber 229, and more precise blood cell separation is performed, and sufficient blood cell separation is also performed for the serum 22 L flowing into the fourth blood cell separation unit 222.
- the residual blood cells are stored in the fourth blood cell storage part 222.
- the number of rotations is repeatedly increased and decreased in a cycle of 5 to 40 seconds in the range of 50,000 to 1,500 rpm and 3, 000 to 6,000 rpm.
- the quantitative serum and the quantitative diluent in the first mixing section 225 are moved between the bent portion L5 of the first mixing flow path 227 and the first mixing section 225. Reciprocating, stirring operation is performed, and sufficient mixing is performed.
- the quantitative serum and the quantitative diluent in the second mixing section 228 are bent by the bending portion L 7 of the second mixing channel 230 and the second mixing section 228.
- the mixture is reciprocated, and the stirring operation is performed, and sufficient mixing is performed.
- the blood cell separation is performed on 22 L of the serum that has flowed into the fourth blood cell separation section 222, and the operation of storing the residual blood cells in the fourth blood cell storage section 222 is repeated. Specifically, the operation shown in FIG. 6 is performed.
- the rotation speed of the rotor is reduced to 100 to 300 rpm.
- the serum in the fourth blood cell separation section 222 crosses the bent portion L6 of the sixth flow path 222, and then rotates again, depending on the case. By increasing to rpm, it flows into the first distribution channel 2 4 1.
- the fourth blood cell storage section 222 stores residual blood cells (22Y).
- the serum 22 T is attracted and filled by the capillary force of each channel group 24 3 (22 U), and further, the capillary force of the first collection area 24 4. Is also attracted, and the mixed solution is filled in each flow path of the first recovery area 244 (22 V).
- the rotation may be increased again to 3,000 to 6,000 rpm in some cases.
- the mixed solution 22Q is supplied to the second distribution channel 2336, and as shown in FIG. 19, is attracted by the capillary force of each channel of the channel group 2338, and The mixed solution is filled in each flow path group 23 (22R), and is further attracted by the capillary force of the second recovery area 239 to be mixed into each flow path of the second recovery area 239.
- the liquid is filled (22S).
- the first storage small chamber 222 stores the rotated residual blood cells 22 W
- the second storage small chamber 222 stores the rotated residual blood cells 22 X.
- the rotation may be increased again to 3,000-6,000 rpm in some cases. And is supplied to the third distribution channel 2 3 1 as shown in FIG.
- the mixed solution 22 N is attracted and filled by the capillary force of each channel group 232 (220), and is further attracted by the capillary force of the third recovery area 234. Then, the mixed solution is filled in each flow path of the third recovery area 234 (22P).
- each collection section Although the serum or mixed serum to be filled in each collection section is an excess, if a part of each flow path group becomes a void, the capillary force of each flow path group is strong, so that it is retained in each collection section. The excess surplus moves there, and always keeps each channel group filled with serum or a mixture thereof. Thereafter, the number of revolutions is again increased to 3, 000 to 6, OOOrpm.
- the serum filled in the flow channel group 2443 in the serum component measurement area 23X is supplied to the first reagent reaction section 2442 so as to be pushed out by centrifugal force.
- the serum in the first collection area 244 is moved and filled by capillary force in the flow path group 243, and is pushed out by centrifugal force. The rotation is continued until the flow path group 2443 is filled with the serum 22U.
- the serum that has flowed into the first reagent reaction section 242 dissolves and mixes the internal reagent (22Z), causing a color-forming reaction and causing the measurement light from above and below or from the outer circumference of the reagent reaction tank.
- the color value is measured by irradiating.
- the shape of the reagent reaction section is tapered in the upper direction, which is more effective against air escape.
- the diluted mixed serum filled in the channel group 238 is supplied to the second reagent reaction section 237 so as to be pushed out by centrifugal force.
- the diluted mixed serum in the second collection area 239 is moved and filled by capillary force in the flow path group 238, and is pushed out by centrifugal force. Inside is diluted mixed blood The rotation is continued until the flow is filled with the serum and the flow path group 238 is filled with the serum 22R.
- the serum that has flowed into the reagent reaction tank 237 becomes a mixed state (23B) by dissolving the reagent inside, causing a color-forming reaction, and measuring light is emitted from above, below, or around the reagent reaction tank. The color value is measured by irradiation.
- the diluted mixed serum filled in the flow path group 2332 is supplied to the third reagent reaction section 2333 so as to be pushed out by centrifugal force.
- the diluted mixed serum 22 P in the third collection area 2.34 in the flow path group 2 32 2 is moved and filled by capillary force, and is pushed out by centrifugal force. This rotation is continued until the inside of the reagent reaction section 233 is filled with the diluted mixed serum, and the flow path group 232 is filled with the serum 22O.
- the serum that has flowed into the third reagent reaction section 233 becomes a state in which the reagent inside is dissolved and mixed (23A), causing a color-forming reaction and measuring light from above and below or from the outer periphery of the reagent reaction tank. The color value is measured by irradiating.
- the time from when blood is first supplied to the first blood reservoir 202 until it comes into contact with the reagent in each reagent reaction section and the color reaction measurement is performed is, for example, 180 to 300 seconds. However, it is appropriately adjusted depending on the amount of blood, test items, and the like.
- FIG. 22 (a) is a cross section of Z l —Z l of FIG. 22 (b).
- the 2R is a rotor composed of a disk having a radius of 25 to 50 mm and a thickness of 3 to 7 mm.
- the rotor 2R is made of a transparent plastic such as polystyrene, PET, acrylic, polycarbonate, resin material for contact lenses, etc., or a transparent plastic such as glass.
- the structure is formed by grooves as shown in FIG.
- the rotor R shown in FIG. 14 has the same configuration.
- reference numeral 301 denotes a diluent storage unit, which may have the same configuration and operation as those shown in FIG.
- Reference numeral 302 denotes a first buffer area, which is a part for temporarily storing a diluent.
- the size of the first buffer region 302 should be at least larger than the quantitative value, but is preferably a volume close to the quantitative value.
- Reference numeral 303 is a reference flow path for flowing a diluent corresponding to the reference into the reference storage section 304.
- Reference numeral 30 denotes a deaeration channel, and reference numeral 30 denotes a deaeration port.
- Reference numeral 307 denotes a first fixed-quantity deaeration section, which is formed by a flow path extending in the middle direction and a deaeration port arranged in the center direction.
- Reference numeral 308 denotes a first flow path, which is a flow path connecting the first buffer area 302 and the first diluting liquid quantitative section 309, and is directed toward the center in order to exert a siphon action. A bent portion is formed.
- Reference numeral 309 denotes a first diluting liquid quantification unit, and a first quantification deaeration unit 307 is connected to a side surface in the center direction.
- Reference numeral 310 denotes a second flow path, which connects the first diluent quantitative section 309 with the first mixing chamber 319.
- the flow path also forms a bent portion with respect to the center direction.
- Reference numeral 311 denotes a blood reservoir, which supplies blood temporarily collected from the outside and temporarily stores the blood.
- Reference numeral 312 denotes a blood distribution path, which is a flow path for distributing necessary blood to the blood cell separation section according to the reagent and the dilution factor.
- Reference numeral 313 denotes a first blood cell separation section, which is connected to the first blood cell storage section 314 in the outer peripheral direction, and has an internal structure as shown in FIG.
- 3 1 4 is the first blood cell storage unit, at least The first blood cell separation part is formed deeper than the first blood cell separation part, and its size may be equal to or smaller than that of the first blood cell separation part 313.
- Reference numeral 315 denotes a third flow path, which connects the first blood cell separation unit 313 and the first quantification unit 316, and has a bent portion toward the center.
- Reference numeral 316 denotes a first quantification unit, which is connected to the first quantification deaeration unit 317 because it has the same configuration as that of FIG.
- the first fixed quantity degassing section 3 17 has the same configuration as the first fixed quantity degassing section 3 07, and the flow path is closer to the center than the bent portion of the fourth flow path 3 18. It extends and has a vent at its end.
- Reference numeral 318 denotes a fourth flow path, which connects the first quantification unit 316 with the first mixing chamber 319.
- Reference numeral 319 denotes a first mixing chamber, which has a curved shape in the outward direction and a blood cell storage section 3222 provided in the center for accommodating residual blood cells and the like during mixing and stirring.
- the reference numeral 320 provided is a deaeration port for the first mixing chamber, which is a part communicating with the outside, and which is combined with the flow path 3221 at the center side of the first mixing chamber 319. It is formed by combination. 3 2 3 is a fifth flow path, which connects the first mixing chamber 3 19 and the first distribution path 3 2 4, and has a bent portion formed in the middle toward the center. Have been. 3 2 4
- Reference numeral 325 denotes a flow channel group, which has a configuration as shown in FIG. 326 is a reagent reaction tank, which forms an elliptical cylindrical body whose major axis is in the radial direction. The reason for the elliptical shape is to deal with physical deviations when attaching the rotating body to the rotating motor and to minimize measurement errors due to centrifugal deviations.
- Reference numeral 327 denotes a first recovery area, in which a flow path larger than the diameter of the flow path of the flow path group 325 is formed in a grid. They are arranged side by side and connected to the first collection area deaeration port 3 2 8. The specific configuration and operation are as described in FIG.
- Reference numeral 329 is a second buffer area, which temporarily stores the diluent.
- the size of the second buffer area 329 may be at least larger than the quantitative value, but preferably a volume close to the quantitative value.
- Reference numeral 330 denotes a blood discharge channel for collecting blood overflowing from the first and second blood cell separation sections and flowing the blood to the excess blood storage section 331. In consideration of the user's ease of use during blood spotting, blood spotting within a certain range can be used, contributing to a mechanism for eliminating troublesome quantitative spotting.
- Reference numeral 332 denotes a deaeration port for an excess blood reservoir, which is configured by combining a flow path extending in the center direction and a deaeration port.
- Reference numeral 335 denotes a second quantitative deaeration section, which is formed by a flow path extending in the center direction and a deaeration port arranged in the center direction.
- Reference numeral 33 denotes a sixth flow path, which is a flow path connecting the second buffer area 329 and the second diluting liquid quantifying section 334, and is directed toward the center in order to exert a siphon action. A bent portion is formed.
- Reference numeral 334 denotes a second diluting liquid quantification unit, and a second quantification deaeration unit 335 is connected to a side surface in the center direction.
- Reference numeral 3442 is a 10th flow path, which connects the second diluent quantitative section 3334 with the second mixing chamber 3336.
- the flow path also forms a bent portion with respect to the center direction.
- Reference numeral 337 denotes a second blood cell separation unit, which is connected to the second blood cell storage unit 338 in the outer peripheral direction, and has an internal structure as shown in FIG.
- Reference numeral 338 denotes a second blood cell storage section, which is formed at least deeper than the second blood cell separation section 33 7 and has a size equal to or smaller than that of the second blood cell separation section 33 7. I just need.
- Reference numeral 339 denotes an eighth flow path, which connects the second blood cell separation section 337 and the second fixed quantity section 340, and has a bent portion toward the center.
- 340 is the second quantitative section In order to have the same configuration as that of FIG. 21, it is connected to the second quantitative degassing unit 35 2.
- the second fixed volume degassing section 352 has the same configuration as the first fixed quantity degassing section 307, and the flow path is closer to the center than the bent portion of the ninth flow path 3441. It extends and has a vent at its end.
- Reference numeral 341 denotes a ninth flow path, which connects the second quantitative section 340 with the second mixing chamber 336.
- Reference numeral 336 denotes a second mixing chamber, which has a curved shape in the outward direction and a blood cell storage section provided in the center, and is provided for accommodating residual blood cells and the like during mixing and stirring. .
- Reference numeral 3442 denotes a 10th flow path, which connects the second diluent quantitative section 3334 and the second mixing chamber 3336 while having a bent portion in the middle direction on the way.
- Reference numeral 343 denotes a first first flow path, which has a bent portion in the middle and in the center direction, and is used to connect the second mixing chamber 3336 with the second distribution flow path 3444.
- Reference numeral 344 denotes a second distribution channel, which forms a circular arc extending on the circumference, and has a channel length twice as long as the first distribution channel 324.
- a channel group 3 4 5 having one end connected to the reagent reaction tank 3 4 6 is provided at equal intervals.
- a second recovery area 347 and a third recovery area 350 are connected to both ends, respectively.
- the second recovery area 347 is connected to the second recovery area deaeration port 348, and the third recovery area 350 is connected to the third recovery area deaeration port 351.
- the configuration of the second recovery area 347 and the third recovery area 350 is the same as that of the first recovery area 327, and thus the description of the specific configuration is omitted.
- a second collection area 347 and a third collection area 350 are connected to both ends of the second distribution channel 344, respectively. It is suitably used when more flow path groups are connected, and enables more rapid and sufficient replenishment of liquid to each flow path group.
- blood is supplied to the blood reservoir 3 1 1.
- the amount of blood to be supplied may be an approximate standard, and blood may be supplied using a dropper or the like.
- the lid After supplying the blood to the blood reservoir 3 1 1, the lid is closed or otherwise shut off from the outside, and the diluent stored in advance or newly supplied is stored in the diluent reservoir 310. Open to 1. In this state, the rotor
- 2R is rotated at a rotational speed of 3,000 to 6,000 rpm.
- the blood in the blood reservoir 311 moves to the blood distribution path 312 by centrifugal force, and the blood in the first blood cell separation section 312, respectively.
- the overflowing blood is stored in the excess blood storage unit 331 via the blood discharge channel 330.
- the air existing in the surplus blood reservoir 331 in advance flows out of the surplus blood reservoir deaeration port 332 to the outside.
- the diluent released in the diluent storage unit 301 moves to the first buffer region 302 and the second buffer region 329 by centrifugal force.
- the diluent supplied to the first buffer area 302 and the second buffer area 329 becomes full and overflows, and the overflowed part is stored in the reference storage section 304 via the discharge channel 303. Is stored in At this time, the air in the reference storage section 304 is discharged to the outside from the deaeration port 303 via the deaeration flow path 305.
- the blood moved to the first blood cell separation section 3 13 Rotate at a rotation speed of 00 O rpm to perform blood cell separation.
- Blood cells having a high specific gravity are stored in the first blood cell storage section 314.
- the same centrifugation is performed in the second blood cell separation unit 337, and the blood cells are stored in the second blood cell storage unit 338.
- the rotation speed is reduced to 100 to 150 rpm.
- the serum from which the blood cells have been separated is supplied to the first diluent quantitative section 309 via the bent portion of the third flow path 315 due to a decrease in centrifugal force.
- the serum of the second blood cell separation section 337 is supplied to the second quantitative section 340 via the bent portion of the eighth channel 339.
- the diluent is supplied to the first diluent quantitative section 309 via the first flow path 308 and is supplied to the second diluent quantitative section 340 via the sixth flow path 333 Increase the number of rotations to 1,000 to 4,000 rpm to supply serum to the first quantification unit 316, supply serum to the second quantification unit 340, and first dilution
- the supply of the diluent to the liquid metering section 309 and the supply of the diluent to the second diluent metering section 334 are accelerated.
- the serum supplied to the first quantification section 3 16 is supplied until the first quantification section 3 17 and the connection port of the first quantification section 3 16 are closed, the serum is supplied to the third flow path.
- the serum in the first quantification unit 3 16 whose supply has been stopped is in effect a quantified substance.
- serum is quantified in the second quantification section 340, and quantification is also performed in the first diluent quantification section 309 and the second diluent quantification section 334.
- separation of residual blood cells is also preferably performed by blood cell separation.
- the rotation speed was reduced to 100 to 150 rpm, and the quantified serum was passed over the bent portion of the fourth flow path 3 18, and the serum was increased by increasing the rotation speed, whereby the serum was mixed in the first mixing chamber 3 1 Supply to 9. Similarly, through the ninth flow path, the serum Supply to mixing chamber 3 3 6.
- the diluent in the first diluting liquid quantifying section 309 is supplied to the first mixing chamber 319 through the second flow path 310, and the diluting liquid in the second diluting liquid quantifying section 334 is diluted.
- the liquid moves to the second mixing chamber via the 10th flow path 342 and is supplied.
- the serum and diluent transferred to each mixing chamber have a rotation speed of 3,000 to 6,000 rpm, preferably 1,000 to 2,000 rpm.
- the mixture is changed by reciprocating between the fifth flow path 3 2 3 and the first mixing chamber 3 19 while being changed in a cycle of 5 seconds, and similarly, the first flow path 3 4 3 and the second mixing chamber 3 are mixed. It is mixed by reciprocating between 36. After a lapse of 4 to 30 seconds, by lowering the rotation speed, the liquid mixture in the first mixing chamber 3 19 is moved to the first distribution path 3 24 via the fifth flow path 3 23, The liquid mixture in the second mixing chamber 336 is moved to the second distribution channel 344 via the first channel 343, and the rotation speed is increased again to promote the movement.
- the mixed solution that has moved to the first distribution channel 3 2 4 is sequentially filled into the channel group 3 25 having strong capillary force, and the excess mixed solution is filled into the capillary of the first recovery area 3 27. You.
- the mixed solution that has moved to the second distribution channel 344 also fills the next channel group while filling the channel group 345 near the first channel.
- the 2nd recovery area 347 and the 3rd recovery area 350 are filled with an excess liquid mixture.
- the internal A coloring reaction is caused by dissolving and mixing a part of the reagent and the mixed solution.
- the developed color value in the reagent reaction tank is measured by measuring transmitted light and reflected light from outside. Also, by arranging a collection area on both sides of the second distribution channel 344 and supplying the liquid from the center, the liquid can be uniformly filled into the channel group from the center to both sides. As a result, the timing for filling the sample solution in the flow channel group into the reagent reaction tank can be easily set.
- two diluted sera having different dilution rates were formed, but two or more sera may be defined and selected.
- FIG. 23 shows a blood quantitative separation section of a disk-shaped rotor.
- reference numeral 401 denotes a blood reservoir, which is constituted by a concave portion formed on the rotor R.
- Reference numeral 402 denotes a first flow path, which connects the blood reservoir 410 to the blood distribution flow path 422.
- Reference numeral 403 denotes a second flow path, which connects the blood reservoir 410 with the blood distribution flow path 422.
- These flow paths are formed on the left and right sides of the blood distribution flow path 422, and are first formed in the direction in which the blood quantitative distribution section for supplying blood is disposed.
- the first blood quantitative separation section which is connected to the blood distribution channel 4 2 2 and connects the first convex sections 4 0 4 a and 4 0 4 b formed at an acute angle in the outer circumferential direction (in the figure,
- the space separated by the connecting surface between the blood distribution channel 4 and the blood distribution channel 4 2 2 is the quantitative space.
- the first convex portions 404a and 404b are preferably acute-angled, and their tips are preferably directed, for example, toward the outer periphery.
- the first convex portions 404 a and 404 b are configured so that the blood cells stored in the first blood cell storage portion After the liquid moves using the principle of siphon, the liquid moves in the capillary direction due to the surface tension generated in the liquid when the rotation speed of the motor is reduced, when the serum moves through 10 It acts as a stopper so that it does not move together. Therefore, the first convex portion 404a provided on the opposite side of the capillary channel may not be necessary.
- Reference numeral 405 is a first blood cell storage section, which is connected to the first blood quantitative separation section 404, and has a continuous projection on the connection surface as shown in FIG. 5 (a). And accommodates blood cells separated by centrifugation based on the rotation of the rotor R.
- Reference numeral 406 denotes a second blood quantitative separation section, which is connected to the blood distribution flow path 422, and has second convex portions 406a and 406b formed at an acute angle in the outer circumferential direction.
- the space defined by the surface connecting the two (shown by the broken line in the figure) and the connection surface with the blood distribution channel 422 is the quantitative space.
- the second convex portions 406a and 406b are preferably rectangular in shape, and their tips are preferably directed, for example, in the outer peripheral direction.
- the second convex portions 406a and 406b serve as siphons.
- the stopper moves the liquid in the capillary direction due to the surface tension generated in the liquid when the motor speed is reduced, so that the stopper does not move together. It has the function of Therefore, the second convex portion 406b provided on the opposite side of the capillary channel may not be necessary.
- Reference numeral 407 is a second blood cell storage unit, which is connected to the second blood quantitative separation unit 406, and has a continuous projection on the connection surface as shown in FIG. 5 (a). And accommodates blood cells separated by centrifugation based on the rotation of the rotor R.
- Reference numeral 408 is a third blood quantitative separation section, 2 2, a surface (shown by a broken line in the figure) connecting the third convex portions 408 a and 408 b formed at an acute angle in the outer circumferential direction, and a blood distribution flow path 4 2 2
- the space divided by the connecting surface of is the quantitative space.
- the third projections 408 a and 408 b are preferably acute-angled, and their tips are preferably directed, for example, in the outer peripheral direction.
- the third convex portions 408 a and 408 b use the siphon principle when the blood cells accommodated in the third blood cell accommodating portion 409 move the serum through the third curved flow path 412.
- the stopper After moving the liquid, the stopper stops the liquid from moving along the capillary direction due to the surface tension generated in the liquid when the motor speed is reduced. It has all the functions. Therefore, the third part 408a installed on the opposite side of the capillary channel may not be necessary.
- Reference numeral 409 is a third blood cell storage unit, which is connected to the third blood quantitative separation unit 408, and has a continuous projection on the connection surface as shown in FIG. 5 (a). And accommodates blood cells separated by centrifugation based on the rotation of the rotor R.
- Reference numeral 410 denotes a first bent flow path, which is formed with a bent part directed toward the center, one end of which is connected to the upper part of the first convex part 400 b, and the other end of which is the first bent part. Connect to the surface of the processing section 4 14 in the center direction.
- Reference numeral 411 denotes a second bent flow path, which is formed with a bent part directed toward the center, one end of which is connected to the upper part of the second convex part 406a, and the other end thereof is Connected to the surface of the second processing unit 4 16 in the center direction.
- Reference numeral 4122 denotes a third bent flow path, which is formed with a bent portion directed toward the center, one end of which is connected to the upper part of the third convex portion 408b, and the other end of which is the third bent flow passage. 3 Connects to the center of the processing section 4 18.
- each flow path When moving serum, etc., in each of these flow paths, 410, 411, and 412, the edge of each flow path should be rounded to prevent liquids from running ahead. And prevent air from being mixed in. Satisfied, but not limited.
- Reference numeral 413 denotes an excess blood storage unit, which stores the blood overflowing from the third blood quantitative separation unit 408 via the excess blood distribution channel 413a.
- the excess blood distribution channel 413a is connected to the center of the third blood quantitative distribution section 408, and the excess blood distribution channel 413a is connected to the third blood quantitative distribution section 408.
- the connection surface becomes a boundary surface for quantifying the blood in the third blood quantitative distribution section 408.
- Reference numeral 414 denotes a first processing unit, which performs processing such as mixing of the separated blood quantified by the first blood quantitative separation unit 404 with a diluent, secondary blood cell separation, and reagent reaction. .
- the circumferential direction of the first processing section has a curved shape, and a convex portion 414a for accommodating blood cells and reagent is formed at the center.
- Reference numeral 415 denotes a deaeration unit, which is formed by a deaeration port having one end connected to the outside, and a flow path connected to the first processing unit 414 at the other end.
- Reference numeral 416 denotes a second processing section, which performs processing such as mixing of the separated blood quantified by the second blood quantitative separation section 406 with a diluent, secondary blood cell separation, and reagent reaction. is there.
- the circumferential direction of the second processing section has a curved shape, and a convex portion 416a for accommodating blood cells and reagents is formed at the center.
- Reference numeral 417 denotes a deaeration section, which is formed by a deaeration port having one end connected to the outside and a flow path connected to the second processing section 416 at the other end.
- Reference numeral 418 denotes a third processing section, which performs processing such as mixing of the separated blood quantified by the third blood quantitative separation section 408 with a diluent, secondary blood cell separation, and reagent reaction. is there.
- the circumferential direction of the third processing section has a curved shape, and a convex portion 418a for accommodating blood cells and reagent is formed at the center.
- Reference numeral 419 denotes a deaeration section, which is formed by a deaeration port having one end connected to the outside and a flow path connected to the third processing section 418 at the other end.
- Reference numeral 420 denotes a supply channel, and at one end, a third processing unit 4 1 8 and the other end, not shown, is connected to a reaction tank containing a reagent.
- Reference numeral 421 denotes a degassing part, which is formed at one end with a degassing port connected to the outside and the other end with a flow path connected to the surplus blood storage part 413.
- the blood cell storage section 401 After blood is supplied to the blood cell storage section 401, a sealed state is formed so as not to leak outside.
- the rotor R When the rotor R is rotated at a rotation speed of 2,500 to 6,000 rpm after sealing, the blood BL1 in the blood reservoir 401 is supplied with the first flow path 402, the second flow path.
- the blood is supplied to the first blood quantitative separation section 404 and the second blood quantitative separation section 406, respectively (see FIG. 24 (a)).
- the blood supplied to the first blood cell quantitative separation section 404 is further filled into the first blood cell storage section 405, and the blood supplied to the second blood cell quantitative separation section 406 is supplied to the second blood cell
- the container 407 is filled (BL 3).
- the blood first overflows from the first blood quantitative separation section 404, and the overflowing blood BL 4 flows into the blood distribution channel 4 22.
- the blood is supplied to the third blood quantitative separation section 408 via the excess blood distribution channel 413a.
- the second blood quantitative separation section 406 becomes full of blood (BL 2), and the blood overflowing from the second blood quantitative separation section 406 is supplied to the blood distribution flow path 422, the excess blood distribution flow.
- the blood is supplied (BL 4) to the third blood quantitative separation section 408 via the path 413 a (see FIG. 24 (b)).
- the blood supplied to the third blood quantitative separation section 408 flows into the third blood cell storage section 409 and is filled therein, and as shown in FIG.
- the overflowing blood is stored in the excess blood storage unit 4 13 while the storage unit is full of blood.
- centrifugation is performed with the rotation speed set to 3,000 to 7000 rpm, and blood cells with a large specific gravity are stored in the blood cell separation section in the outer peripheral direction, and blood cells are separated. .
- the rotation speed of the rotor R is reduced to 50 to 200 rpm.
- the blood, plasma, or serum filled in the first curved flow path 410 flows in the direction of the first processing section 414. It moves by the so-called siphon phenomenon.
- the volume from the connection surface between the first blood quantitative separation section 404 and the blood distribution flow path 422 to the surface connecting the first convex sections 404a and 404b is determined.
- the blood has moved to the first processing unit.
- the blood, plasma, or serum filled in the first bending flow path 410 flows in the second processing section 416 direction. They move by the so-called siphon phenomenon.
- the blood, plasma, or serum filled in the first curved flow path 410 is displaced in the direction of the third processing section 418. It moves by the so-called siphon phenomenon.
- BL 9 indicates the blood cells stored in the first blood cell storage unit 405
- BL 10 indicates the blood cells stored in the second blood cell storage unit 40'7
- BL 11 indicates the third blood cell storage unit
- the blood cells contained in 409 are shown.
- BL12 is the serum quantified in the first blood quantification section 404
- BL13 is the serum quantified in the second blood quantification section 406
- BL14 is the sera quantified in the second blood quantification section 406.
- B L 15 is excess blood.
- each processing unit is performed, for example, in a state in which the operations shown in FIGS.
- Such a quantification method can be used for quantification of a diluent and other liquids without requiring a combination with a blood cell separation unit. That is, if a flow path (preferably having a bent portion directed toward the center direction) having an opening is arranged in the outer peripheral direction of the liquid storage section, The space between the circumferential line passing through the outermost circumferential portion of the surface of the storage part in the center direction and the opening surface of the flow path can form a fixed area.
- Example 12 Example 12:
- reference numeral 501 denotes a disc-shaped carrier, which is made of a transparent or translucent polyacrylic resin.
- the carrier 501 is provided with grooves or recesses to store the diluent. Parts and flow paths can be configured.
- the carrier 501 is bonded to a concave portion thereof using a transparent sheet as a lid.
- Reference numeral 502 denotes a diluent storage portion, which is formed as a concave portion, has a shape that becomes shallower toward the outside, and is connected to the first flow path 50 5.
- Reference numeral 503 denotes a diluting liquid quantitative chamber, and a preliminary chamber 504 is formed outward, and a second flow path is provided at a connection portion between the dilution chamber quantitative chamber 503 and the preliminary chamber 504. One end of 506 is connected.
- the second flow path 506 extends parallel to the diameter, passes near the center, and is connected to the downstream mixing chamber 507 at the opposing portion while having two bent portions. The two bent portions of the second flow path 506 are appropriately adjusted depending on the arrangement of the mixing chamber, and may be one or no at all.
- Reference numeral 510 denotes an excess liquid storage tank, which is connected to the diluent quantitative chamber 503 and the third flow path 506.
- Reference numeral 511 denotes a degassing port, which is connected to a flow path extending from the surplus liquid storage tank 5110 toward the center.
- the deaeration port 5 1 1 is for pushing out the air that resists the flow of the diluent to the outside, and is arranged in the center direction to prevent the diluent from flowing out.
- the diluent in the diluent storage chamber 502 is supplied so as to be opened.
- the diluent is supplied by, for example, breaking a patch containing the diluent and filling the diluent storage chamber 502 with the diluent K1 (see FIG. 27).
- the carrier 501 is rotated about the center point O.
- the diluent is supplied to the quantitative chamber 503 via the first flow path 505 by centrifugal force, and the preliminary chamber 504 and the quantitative chamber 503 are filled with the diluent K2 and
- the surplus K 3 of the diluent flows into the surplus chamber 5 10 (see FIG. 28) (see FIG. 29).
- the diluent also flows into the second flow path 506, and the liquid moves to fill the second flow path 506 by capillary force.
- the diluent stops flowing at the part that works effectively on the surface.
- the rotation speed is reduced.
- the diluent in the second flow path 506 starts to advance due to the capillary force and flows into the mixing chamber 507 at a high rotational speed.
- the flow of the diluent in the liquid mixture 06 is promoted without obstructing the flow of the diluent, and the measured diluent flows into the mixing chamber 507 (see FIG. 30).
- a flow having a high linearity without a bent portion in the center direction is provided.
- the arrangement of the channels can be arranged and a more compact carrier can be provided.
- the biological information analysis unit of the present invention proposes a device that enables more simple and quicker testing of body fluids for multiple items, and has an accuracy that can be used at home, including in medical institutions. Makes a good body fluid testing device feasible.
- the biological information analysis unit of the present invention has a shape suitable for being used as a blood cell separation unit when blood components are measured by separating blood cells when integrated with a blood analyzer. Having. .
- the biological information analysis unit of the present invention enables a simpler and more rapid body fluid test, for example, for multiple items, and provides a highly accurate body fluid test that can be used at home, including in medical institutions.
- the device is feasible.
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- Investigating Or Analysing Biological Materials (AREA)
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Abstract
Description
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JP2004162523A JP2005345160A (ja) | 2004-05-31 | 2004-05-31 | 生体情報分析ユニット |
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