WO2011058655A1 - Système d'analyse de propriétés du sang - Google Patents

Système d'analyse de propriétés du sang Download PDF

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Publication number
WO2011058655A1
WO2011058655A1 PCT/JP2009/069433 JP2009069433W WO2011058655A1 WO 2011058655 A1 WO2011058655 A1 WO 2011058655A1 JP 2009069433 W JP2009069433 W JP 2009069433W WO 2011058655 A1 WO2011058655 A1 WO 2011058655A1
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WO
WIPO (PCT)
Prior art keywords
blood
flow path
flow
microchip
analysis system
Prior art date
Application number
PCT/JP2009/069433
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English (en)
Japanese (ja)
Inventor
正彰 高間
福室　郁
貴紀 村山
Original Assignee
コニカミノルタオプト株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by コニカミノルタオプト株式会社 filed Critical コニカミノルタオプト株式会社
Priority to PCT/JP2009/069433 priority Critical patent/WO2011058655A1/fr
Publication of WO2011058655A1 publication Critical patent/WO2011058655A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood
    • G01N33/4915—Blood using flow cells
    • 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
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1095—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices for supplying the samples to flow-through analysers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502746—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means for controlling flow resistance, e.g. flow controllers, baffles

Definitions

  • the present invention relates to a blood characteristic analysis system.
  • blood vessels in a living body are constantly pulsating, and fluctuating stress due to the pulsation is applied to blood in the blood vessels.
  • the present invention has been made in view of the above circumstances, and it is an object of the present invention to provide a blood characteristic analysis system capable of measuring blood characteristics in a state closer to the living body than in the past.
  • a blood characteristic analysis system for measuring blood characteristics A microchip having at least one flow path through which blood passes; Imaging means for imaging the blood flow in at least one of the internal region, the inlet region, and the outlet region of the flow path; Analysis means capable of calculating blood characteristics by analyzing a blood flow image by the imaging means; A pressure control means capable of changing the blood pressure difference between the upstream side and the downstream side of the flow path at a predetermined cycle or a variable cycle; It is characterized by providing.
  • the invention according to claim 2 is the blood characteristic analysis system according to claim 1,
  • the pressure control means can change a blood pressure difference between the upstream side and the downstream side of the flow path by changing the cross-sectional area of the flow path.
  • the pressure control means generates the blood pressure difference between the upstream side and the downstream side of the flow path by at least one of pressurization and decompression.
  • the blood pressure difference between the upstream side and the downstream side of the flow path through which blood passes can be changed at a predetermined cycle or a variable cycle.
  • Blood characteristics can be measured by simulating pulsation. Therefore, blood characteristics in a state close to the living body can be measured as compared with the conventional measurement in which the pressure difference applied to the blood passing through the flow path is constant.
  • FIG. 1 It is a block diagram which shows the whole structure of the blood characteristic analysis system which concerns on this invention. It is a figure which shows a microchip, (a) is a top view, (b) is an exploded side view, (c) is the elements on larger scale of (a). It is a figure for demonstrating the flow path of a microchip, the upper figure is a top view, and the lower figure is a side view. It is a figure for demonstrating the movable part of the flow path of a microchip. It is a figure which shows the pressure difference of the blood in the upstream and downstream of a flow path, (a) is a figure which is changing with a predetermined period, (b) is a figure which is changing with a variable period. is there.
  • FIG. 1 is a block diagram showing an overall configuration of a blood characteristic analysis system 1 in the present embodiment.
  • the blood characteristic analysis system 1 guides blood from a supply tank 10 to a discharge tank 11 through a microchip (filter) 2 and measures a plurality of types of blood characteristics from information acquired in the process. To do.
  • the blood characteristic analysis system 1 is mainly based on the microchip 2, the TV camera 3 that captures the blood flow in the microchip 2, and the blood flow image captured by the TV camera 3.
  • a personal computer 7 that measures characteristics
  • a display 8 that displays a blood flow image
  • a blood flow control unit 9 that controls blood flow in the microchip 2 are provided.
  • a plurality of liquids such as physiological saline and physiologically active substances are connected to the flow path via the mixer 12 so as to be mixed with blood and guided to the microchip 2.
  • a solution bottle 13 or the like is further provided.
  • the blood mixed with a liquid such as physiological saline or a physiologically active substance is micro-controlled by the differential pressure control unit 91 in the blood flow control unit 9 by controlling the pressurization pump 15 and the decompression pump 16. By adjusting the differential pressure across the chip 2, a desired amount flows through the microchip 2.
  • the valve 10 a of the supply tank 10 and the like are integrated and controlled by the sequence control unit 17.
  • FIG. 2A is a view (plan view) of the microchip as viewed from above
  • FIG. 2B is a side view
  • FIG. 2C is a partially enlarged view of a part of the microchip.
  • the microchip 2 is formed by overlapping a rectangular glass flat plate 20 and a base plate 21 as shown in FIG.
  • the glass flat plate 20 is formed in a flat plate shape and covers the inner side surface of the base plate 21 (the upper surface in FIG. 2B).
  • the base plate 21 has depressions 210 and 211 at both ends, and a plurality of grooves 212 and so on between the depressions 210 and 211.
  • the hollow part 210 has a through-hole 210 a communicating with the supply tank 10 on the bottom surface, and an upstream storage part 22 for storing blood is formed between the glass flat plate 20.
  • the recess 211 has a through hole 211 a communicating with the discharge tank 11 on the bottom surface, and forms a downstream storage 23 for storing blood between the flat glass plate 20.
  • the plurality of grooves 212 are arranged so as to extend in parallel to the direction (X direction in the drawing) connecting the recess 210 and the recess 211, and extend in the X direction described above. It is in a state of being partitioned by the portion 213.
  • the plurality of grooves 212,... Alternately communicate with the depression 210 or the depression 211, whereby the upstream blood circuit 24 that allows blood to flow from the upstream reservoir 22 and the downstream reservoir 23.
  • a downstream blood circuit 25 that allows blood to flow into the glass plate 20 is formed.
  • FIGS. 3A and 3B are diagrams for explaining the flow path of the microchip 2.
  • the upper diagram is a plan view of the terrace portion 213 as viewed from above.
  • the lower diagram is a cross-sectional view of FIGS. 3A and 3B as viewed from the side.
  • a plurality of hexagonal bank portions 214 are arranged in the X direction on the upper end portion of the terrace portion 213, and the glass flat plate 20 is formed on the top surface. Abut.
  • the upstream blood circuit 24, and the downstream blood circuit 25 are cut at the positions indicated by virtual lines AA and BB in FIG.
  • the cross-sectional area is narrower than the inside of the side blood circuit 24 and the downstream blood circuit 25. More specifically, the cross-sectional shape of the flow path 26 is a flat rectangle in accordance with the shape of red blood cells (the shape of a disk with a hollow center and an elliptical shape with a flat cross section). The size is smaller than the size of red blood cells. As a result, it is possible to observe a state in which red blood cells pass through a thin blood vessel such as a capillary blood vessel while deforming its own shape, and it is possible to simulate the degree of dryness of blood in the blood vessel.
  • a thin blood vessel such as a capillary blood vessel while deforming its own shape
  • FIG. 4 is a diagram for explaining the movable part of the microchip 2.
  • the bank portion 214 includes a movable portion 214 a that can move in the X direction and a stationary portion 214 b that is formed integrally with the base plate 21.
  • the movable portion 214a is formed in a square shape including a flow path wall portion 26a at the center in the Y direction among flow path walls parallel to the Y direction forming the flow path 26, and is moved by a predetermined range in the X direction by the actuator 27. It is possible. By the movement of the movable portion 214a, the cross-sectional area of a part of the flow path 26 can be arbitrarily changed.
  • the movable portion 214a is not limited to the above configuration, and may be configured to be movable in the X direction including the flow channel wall in at least a part of the flow channel 26. Furthermore, the cross-sectional shape of the flow channel 26 may be changed. The configuration may be changed. As a configuration for changing the cross-sectional shape, for example, a configuration in which the upper end of the flow path wall portion 26a is inclined in the X direction or a shape in which the flow path wall portion 26a is curved by using a shape memory material or the like can be used. Further, the movable portion 214a, the stationary portion 214b, and the actuator 27 are not shown in FIGS. 2 and 3 for simplification of illustration.
  • Actuators 27 for driving the movable portion 214a are respectively embedded in the base plate 21 corresponding to the movable portion 214a, and are connected to a drive control portion 92, which will be described later, so as to be driven and controlled (FIG. 1). reference).
  • the actuator 27 is not particularly limited, but is a piezoelectric actuator or a piezoelectric ultrasonic linear actuator. As such an actuator 27, for example, those disclosed in JP-A-7-298656, JP-A-2006-66976, or JP-A-2007-57581 can be used.
  • the blood introduced from the supply tank 10 is stored in the upstream storage section 22, and after passing through the flow path 26 and the downstream blood circuit 25 from the upstream blood circuit 24, is stored in the downstream storage section 23 and discharged into the discharge tank 11. It will be discharged from.
  • blood cells in blood flowing through the flow path 26, such as red blood cells first pass through the inlet region A upstream of the gate 215 and then deform the inner region B of the gate 215.
  • pressure sensors E1 and E2 are provided before and after the microchip 2, and the pressure sensors E1 and E2 output the measured chip upstream pressure P1 and chip downstream pressure P2 to the blood flow control unit 9. (See FIG. 1).
  • these pressure sensors E1 and E2 only need to be able to measure the blood pressure in the vicinity of the inlet and outlet of the microchip 2.
  • pressure adjusting containers are provided before and after the microchip 2, and the pressure in each container is measured. You may make it measure.
  • the TV camera 3 is, for example, a digital CCD camera, and a high-speed camera for photographing a blood flow or a camera capable of photographing a moving image is used.
  • the TV camera 3 is installed facing the glass flat plate 20 in the microchip 2 and photographs the blood flow passing through the flow path 26 through the glass flat plate 20.
  • the imaging range is a range including an entrance area A to an exit area C in the plurality of gates 215. However, this imaging range may be a range including at least one of the entrance area A, the internal area B, and the exit area C in each gate 215 shown in FIGS.
  • the blood flow image obtained by the TV camera 3 is output to the personal computer 7 and displayed on the display 8.
  • the personal computer 7 is connected to the TV camera 3 and includes an arithmetic processing unit 70 capable of calculating a plurality of types of blood characteristics from image information output from the TV camera 3.
  • the blood characteristics are various characteristic values indicating blood properties and the like, and include those related to fluidity such as blood coagulation ability in addition to blood pressure and velocity.
  • Aggregation capacity is a quantitative value indicating the ease of occurrence of the aggregation phenomenon in which blood cells stay and bind together, and the area, number, and area ratio of each blood cell type contained in the blood cell retention part consisting of the retained blood cells. Or the number ratio.
  • an arithmetic processing part 70 a conventionally well-known thing can be used.
  • the display 8 is connected to the personal computer 7 and displays a photographed image output from the TV camera 3 and blood characteristics calculated by the personal computer 7.
  • the blood flow control unit 9 includes a differential pressure control unit 91 that controls the differential pressure across the microchip 2 and a drive control unit 92 that controls the drive of the actuator 27, and according to a control command from the sequence control unit 17.
  • the differential pressure control unit 91 and the drive control unit 92 perform predetermined control.
  • the blood flow control unit 9 and the sequence control unit 17 may be configured integrally with the personal computer 7, and the personal computer 7 may perform the predetermined control.
  • the differential pressure control unit 91 controls the pressurization pump 15 upstream of the microchip 2 and the decompression pump 16 downstream of the microchip 2 so that the chip upstream pressure P1 and the chip downstream pressure P2 become predetermined pressures.
  • the drive control unit 92 controls the drive of the actuator 27 so that the distance w (see FIG. 4) between the opposed flow path wall portions 26a in the flow path 26 of the microchip 2 becomes a predetermined value.
  • the operation of the blood characteristic analysis system 1 when measuring blood characteristics will be described below.
  • the sequence controller 17 adds physiological saline or the like to the solution bottle 13 as necessary while injecting blood to be measured into the supply tank 10.
  • the sequence control unit 17 controls the pressurization pump 15 and the decompression pump 16 via the differential pressure control unit 91 to apply a predetermined differential pressure to the microchip 2 to flow blood through the microchip 2,
  • the TV camera 3 images the blood flow in the flow path 26.
  • the distance w between the flow path wall portions 26a in the microchip 2 shown in FIG. 4 is set by the drive control unit 92 so as to repeatedly change at a predetermined cycle.
  • the cross-sectional area of the flow path 26 is changed by changing the distance w.
  • the predetermined period T at this time for example, a value (60 / 65 ⁇ 0.92 sec) simulating an average pulse rate of 65 times / minute at the time of resting modern people may be used, but it is not limited to this value. It can be set as appropriate according to age, gender, health status, and the like.
  • the blood pressure difference ⁇ P is controlled so that the speed of the blood flowing through the flow path 26 is within a range of 0.1 to 30 mm / sec. This is a condition that mainly depends on the shooting capability of the TV camera 3. For example, if the TV camera 3 is a high-speed camera with a frame rate of 1000 fps or higher, the blood speed may be 10 to 30 mm / sec.
  • the pressure difference ⁇ P that periodically changes in this way is generated by increasing and / or decreasing the tip upstream pressure P1 and / or the tip downstream pressure P2 by the pressurizing pump 15 and / or the decompressing pump 16. Also good. Furthermore, you may combine the drive of these pressurization pumps 15 and / or the pressure reduction pump 16, and the fluctuation
  • the period of the pressure difference ⁇ P is not limited to a predetermined value, and may be a variable period T ′ as shown in FIG. Although this figure shows a cycle that becomes shorter with the passage of time, for example, it may be a cycle that becomes longer with the passage of time or a cycle that changes randomly.
  • the personal computer 7 calculates blood characteristics by performing image processing on the captured image
  • the calculation result and the captured image itself are displayed on the display 8.
  • the blood pressure difference ⁇ P between the upstream side and the downstream side of the flow path 26 is changed at a predetermined cycle T or a variable cycle T ′. Therefore, blood characteristics can be measured by simulating blood vessel pulsation in a living body. Therefore, blood characteristics in a state close to the living body can be measured as compared with the conventional measurement in which the pressure difference applied to the blood passing through the flow path is constant.
  • blood is allowed to pass through the flow path 26 by applying the pressure difference ⁇ P.
  • the pressure difference is applied to the blood.
  • a method using electrophoresis may be used without providing ⁇ P.
  • Blood characteristic analysis system 2 Microchip 3 TV camera (photographing means) 9 Blood flow control unit (pressure control means) 26 flow path 70 arithmetic processing unit (analysis means) A Inlet area B Inner area C Outlet area T, T 'Period ⁇ P Pressure difference

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Abstract

L'invention porte sur un système d'analyse de propriétés du sang permettant la mesure d'une propriété du sang dans des conditions proches de celles dans les corps vivants. Spécifiquement, l'invention porte sur un système d'analyse de propriétés du sang (1) destiné à mesurer une propriété du sang, comprenant : une micro-puce (2) possédant au moins une voie d'écoulement (26) par laquelle passe le sang, une caméra de télévision (3) pouvant prendre une image du débit sanguin dans au moins une zone sélectionnée à partir d'une zone interne (B), une zone d'entrée (A) et une zone de sortie (C) dans la voie d'écoulement (26), une unité de traitement arithmétique (70) pouvant analyser l'image du débit sanguin prise par la caméra de télévision (3) et calculer la propriété du sang, et une unité de commande de débit sanguin (9) pouvant modifier la différence de pression sanguine (ΔP) entre un côté amont et un côté aval de la voie d'écoulement (26) selon un cycle prédéterminé (T) ou un cycle de fluctuation (T').
PCT/JP2009/069433 2009-11-16 2009-11-16 Système d'analyse de propriétés du sang WO2011058655A1 (fr)

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PCT/JP2009/069433 WO2011058655A1 (fr) 2009-11-16 2009-11-16 Système d'analyse de propriétés du sang

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001264318A (ja) * 2000-03-15 2001-09-26 Japan Science & Technology Corp 白血球接着現象の解析装置及び解析方法
WO2006095615A1 (fr) * 2005-03-07 2006-09-14 Kuraray Co., Ltd. Dispositif microcanaux, procede de production et procede d’analyse du sang l’utilisant
WO2007046450A1 (fr) * 2005-10-18 2007-04-26 Fujimori Kogyo Co., Ltd. Appareil et méthode pour contrôler la formation de thrombus
JP2008304376A (ja) * 2007-06-08 2008-12-18 Tokyo Metropolitan Univ 試料導入マイクロデバイス

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001264318A (ja) * 2000-03-15 2001-09-26 Japan Science & Technology Corp 白血球接着現象の解析装置及び解析方法
WO2006095615A1 (fr) * 2005-03-07 2006-09-14 Kuraray Co., Ltd. Dispositif microcanaux, procede de production et procede d’analyse du sang l’utilisant
WO2007046450A1 (fr) * 2005-10-18 2007-04-26 Fujimori Kogyo Co., Ltd. Appareil et méthode pour contrôler la formation de thrombus
JP2008304376A (ja) * 2007-06-08 2008-12-18 Tokyo Metropolitan Univ 試料導入マイクロデバイス

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