JP5178224B2 - Analytical device and analyzer using the same - Google Patents

Description

  The present invention relates generally to the field of multi-item biological fluid analyzers (multi-biosensors) as applied to the analysis of various biological and chemical compositions. More specifically, the present invention relates to an analysis device and an analysis apparatus that perform analysis by measuring and transferring a liquid by using a centrifugal force applied and a capillary force generated by a surface characteristic of a passage and a surface tension of the liquid.

2. Description of the Related Art Conventionally, an analyzer for analyzing the characteristics of a sample solution has been put into practical use by using an analysis device that collects the sample solution therein and rotating the analysis device around its axial center.
In recent years, there have been many demands from the market, such as sample volume reduction, device miniaturization, short time measurement, multi-item simultaneous measurement, etc., reacting sample liquids such as blood with various analytical reagents, detecting the mixture, There is a demand for a more accurate analyzer that can examine the progress of various diseases in a short time.

FIG. 9 is a conventional analytical device including a capillary metering segment and a hydrophilic stopper.
This analytical device is composed of air holes V1, V2, V3, V4 communicating with the atmosphere, sample reservoirs R1, R2, R3, a measuring segment L formed by a capillary tube, and a hydrophilic stopper S1.

  The metering segment L ensures that the correct amount of liquid sample is dispensed so that the analytical accuracy is improved. The liquid sample injected into the sample reservoir R1 flows through the measuring segment L by capillary force from the sample reservoir R1, and fills the U-shaped measuring segment L.

  Both ends of the measuring segment L communicate with the air atmosphere through the air holes V1 and V2. The sample liquid moves to the position of the hydrophilic stopper S1 by the capillary force, but stops at the connecting portion between the measuring segment L and the hydrophilic stopper S1.

  This is because by making the hydrophilic stopper S1 wider than the measuring segment L, the capillary force stops because the liquid sample cannot touch the wall surface of the hydrophilic stopper S1. .

  When this analytical device is placed on a rotating platform and rotated at a speed sufficient to overcome the resistance of the hydrophilic stopper S1, the liquid contained in the metering segment L passes through the stopper S1 and is subjected to centrifugal and capillary forces. Enter reagent reservoir R2. When the sample liquid passes through the hydrophilic stopper S1 by centrifugal force, air enters from the air holes V1 and V2, thereby determining the length of the liquid column of the measuring segment L, and hence the amount of sample sent to the reagent reservoir R2. .

Below the sample reservoir R2 is a further reagent reservoir R3, which can react with the sample liquid or be used to prepare the sample liquid for later analysis. The liquid injected into the sample reservoir R2 moves from the sample reservoir R2 to the sample reservoir R3 by centrifugal force.
Japanese translation of PCT publication No. 2005-518531 (FIG. 2)

  However, in the conventional configuration, when the sample liquid moves along the hydrophilic surface of the measuring segment L, the sample liquid does not completely stop at the connecting portion between the measuring segment L and the hydrophilic stopper S1, and thus a part of the sample liquid is used. Overflows the hydrophilic stopper S1, and the weighing segment L has a problem that accurate weighing cannot be performed.

  An object of the present invention is to solve the above-mentioned conventional problems, and to provide an analytical device capable of accurately stopping the flow of liquid due to capillary force.

  According to a first aspect of the present invention, there is provided an analytical device comprising a capillary channel and a sample metering unit for metering only a sample liquid to be analyzed, and a metering unit connected to the sample metering unit and metered by the sample metering unit. An analysis device provided with a microchannel having a receiving portion for receiving a sample liquid and reacting with a reagent, wherein a capillary channel of a connection portion of the sample measuring portion with the receiving portion faces the receiving portion. An inclined surface is formed so as to be wide.

  The analysis device according to claim 2 of the present invention is the analysis device according to claim 1, wherein the height of the sample weighing unit and the height of the receiving unit at the connection surface of the sample weighing unit and the receiving unit are the same as those of the sample weighing unit. The height of the receiving part is higher than the height.

The analytical device according to claim 3 of the present invention is characterized in that, in claim 1, a part or all of the wall surfaces of the sample measuring section and the receiving section are subjected to hydrophilic treatment. .
The analytical device according to claim 4 of the present invention is characterized in that, in claim 1, the hydrophilic treatment is performed on a surface of the microchannel facing the inclined surface.

  According to a fifth aspect of the present invention, there is provided an analyzing apparatus comprising: a rotating disk on which the analyzing device according to the first aspect is set; a rotation driving means for rotating the rotating disk; and a quantitative measurement measured by the sample measuring unit. And control means for controlling the rotation driving means so as to transfer the sample liquid to the receiving portion by centrifugal force generated by rotation of the rotating disk.

  The analyzer according to claim 6 of the present invention is the analyzer according to claim 5, wherein the control means moves the rotating disk clockwise and counterclockwise before executing the reading by accessing the reactant in the receiving portion. The reagent and the sample liquid installed in the receiving portion are alternately swung to stir the sample solution.

  According to this configuration, the flow of liquid due to the capillary force can be accurately controlled by the shape of the flow path, and accurate measurement by the capillary can be performed.

Hereinafter, embodiments of the present invention will be described with reference to FIGS.
(Embodiment 1)
1 to 5 show an analysis device according to Embodiment 1 of the present invention.

  FIG. 1 is an exploded view of the analysis device 104 of the present invention, and FIGS. 2A, 2B, and 2C are a plan view and a cross-sectional view of the analysis device 104 of the present invention, and a front view seen from the inlet 206a. It is.

  The analysis device 104 includes a base substrate 203 having a thickness of 1 mm to 7 mm in which concave portions are formed, and a cover substrate 204 having a thickness of 1 mm to 7 mm attached to the base substrate 203. For example, both the base substrate 203 and the cover substrate 204 are made of a transparent base material.

  A microchannel 105 is formed between the base substrate 203 and the cover substrate 204 bonded together with an adhesive. The microchannel 105 is composed of a capillary channel and receives a sample measuring unit 201 that measures only a fixed amount of sample liquid to be analyzed, and a fixed amount of sample liquid that is connected to the sample measuring unit 201 and is measured by the sample measuring unit 201. And a receiving portion 202 that reacts with the. Specifically, the reagent is accommodated in the receiving part 202 so as to react immediately when the sample liquid moves to the receiving part 202. This reagent may be a solid reagent or applied to the wall surface. For example, glucose oxidase and glucose dehydrogenase for measuring glucose, cholesterol esterase and cholesterol hydrogenase for measuring cholesterol, etc. are used as reagents.

  An inlet 206 a is formed in the sample collection unit 206 at one end of the sample measurement unit 201, and the other end of the sample measurement unit 201 is connected to the receiving unit 202. The shape of the sample collection unit 206 is formed in an arc shape having a width Wc as a diameter.

  The sample weighing unit 201 is provided between the main section 207a of the capillary channel with a uniform gap in the direction from the sample collection section 206 to the receiving section 202 (arrow F direction), and between the receiving section 202 and the terminal position P1 of the main section 207a. The connecting portion 207b. More specifically, the connecting portion 207b of the sample measuring portion 201 has a bottom surface of the concave portion of the base substrate 203 formed into an inclined surface 205 having a circular arc shape, and a capillary channel is widened toward the receiving portion 202. Yes.

  In FIG. 2, the length of the sample weighing unit 201 is Lc, the gap on the side of the injection port 206a of the sample measurement unit 201 is Dc1, the width of the injection port 206a is Wc, the length of the sample collection unit 206 is Rc, and the sample measurement unit 201, the gap between the connection surface P2 of the receiving portion 202 (the end position of the inclined surface 205) P2 is Dc2, and the length of the connection portion 207b is L. The gap of the receiving portion 202 is uniformly shown as Dp in the direction of the arrow F. Further, the height (= Dc2) of the sample measuring unit 201 from the cover substrate 204 and the height (= Dp) of the receiving unit 202 from the cover substrate 204 at the connection surface P2 of the sample measuring unit 201 and the receiving unit 202 are: “Dc2 <Dp”.

  The base substrate 203 and the cover substrate 204 are subjected to hydrophilic treatment on a part or all of the wall surfaces in order to reduce the viscous resistance in the microchannel 105 and facilitate fluid movement. Specifically, either the bottom surface (base substrate 203 side) or the ceiling surface (cover substrate 204 side) of the sample measuring unit 201 and the receiving unit 202 is formed as a continuous surface subjected to hydrophilic treatment.

  Here, hydrophilic means that the contact angle with water is less than 90 °, more preferably less than 40 °. Specifically, examples of the hydrophilic treatment method include a surface treatment method using an active gas such as plasma, corona, ozone, and fluorine, and a surface treatment with a surfactant. Alternatively, a hydrophilic material such as glass is used for at least one of the base substrate 203 and the cover substrate 204, or a hydrophilic powder such as a surfactant, a hydrophilic polymer, or silica gel when molding at least one of the base substrate 203 and the cover substrate 204. A hydrophilizing agent such as may be added to impart hydrophilicity to the material surface.

FIGS. 3A to 3C show the steps of collecting the sample solution in the analytical device 104 thus created and measuring the quantitative amount.
In FIG. 3A, first, a needle is punctured to the fingertip 501 using a blood sampling puncture device or the like to create a blood pool. Therefore, the sample collection unit 206 at the tip of the sample measurement unit 201 is brought into contact with the blood pool. Generally, the capillary force works when part or all of the wall surfaces are hydrophilic and the distance between the facing wall surfaces is 1 mm or less. Further, when the distance is 0.3 mm or less, the capillary force is dominant with respect to the surface energy acting on the sample solution and the wall surface, and the blood that becomes the sample solution 502 does not apply an external force to the sample measuring unit 201. Suction to the capillary channel is started.

Next, as shown in FIG. 3B, the sample liquid 502 is sucked up by the capillary force acting on the sample measuring unit 201, is filled to the starting end position P1 of the inclined surface 205, and stops.
This is because a part of the wall surface that is continuous in the direction in which the sample liquid 502 flows in the sample measuring unit 201 is cut off by the inclined surface 205, so that the wetting interface for allowing the sample liquid 502 to flow in the direction of the receiving unit 202. This is because the tension component is reduced and the capillary force that has been dominant until now is cut off. Further, as shown in FIG. 3C, the sample liquid 502 is sucked up by the connecting portion 207b, and the cross-sectional area at the connecting surface (end position of the inclined surface 205) P2 between the sample measuring portion 201 and the receiving portion 202 is maximized. By the surface tension acting at the interface of the sample liquid 502, a force that returns the sample liquid 502 toward the inside of the sample measuring unit 201 is generated, so that the overflow flow rate of the sample liquid 502 to the receiving unit 202 can be suppressed.

In this embodiment, the surface of the microchannel 105 facing the inclined surface 205 is subjected to the hydrophilic material or hydrophilic treatment for imparting hydrophilicity.
Next, based on specific dimensions, the effect of the first embodiment of the present invention will be described.

  In the analyzing device 104, in order to measure the absorbance in the receiving unit 202 by reacting with the reagent arranged in the receiving unit 202, it is necessary to collect 10 μL of the sample solution by the sample measuring unit 201. Furthermore, in order to improve the measurement accuracy, the quantitative variation in the sample weighing unit 201 needs to be within ± 5%, that is, the sample liquid should be 9.5 to 10.5 μL. Here, the shape of the sample measurement part 201 was Lc = 9.8 mm, Wc = 4.0 mm, and Dc = 0.3 mm. Further, as shown in FIG. 4B, the inclined surface 205 of the connecting portion 207b is inclined so as to be a part of an elliptical arc of L = 1.0 mm and short diameter: Dc2-Dc1 = 0.3 mm. .

As a result, the amount of the sample liquid 502 overflowing to the receiving unit 202 was 0.12 μL, which sufficiently satisfied ± 5%, which is a quantitative variation of the sample liquid 502.
FIG. 5 shows the relationship between the shape of the elliptical arc of the inclined surface 205 arranged in the sample measuring unit 201 and the overflow flow rate of the sample liquid 502 overflowing the receiving unit 202.

  The major axis of the elliptic arc: L = 1.0 mm, and the length of the minor axis: Dc2-Dc1 was changed. For example, when there is no inclined surface 205, the overflow flow rate of the sample liquid 502 to the receiving unit 202 is 0.68 μL, whereas by arranging the inclined surface 205, the sample liquid 502 overflowing the receiving unit 202 It can be seen that the amount is 0.2 μL or less. Furthermore, it turns out that the overflow flow volume to the receiving part 202 can be suppressed by enlarging the short axis: Dc2-Dc1 of an elliptical arc.

  From this result, it is possible to accurately measure the sample liquid by using only the shape of the sample weighing unit 201 by disposing the inclined portion 205 in the connecting portion 207b between the sample weighing unit 201 and the receiving unit 202. In this state, the collection of the sample liquid 502 measured by the sample measuring unit 201 is completed, and the sample liquid can be analyzed with high accuracy.

  The shape of the inclined portion 205 is a part of an arc having a radius L as shown in FIG. 4A, or an elliptical arc having a major axis L and a minor axis: Dc2-Dc1 as shown in FIG. As long as the inclined surface 205 of the connecting portion 207b and the bottom surface of the main section 207a are formed continuously, it is not necessary to limit to an elliptical arc or arc, and it is a straight inclined surface. May be.

(Embodiment 2)
6 to 8 show an analysis apparatus 100 of the present invention that uses the analysis device 104 of the first embodiment.

This analyzer is configured as shown in FIG.
A disc-shaped rotating disk 102 that is rotated around a rotation center 107 by a rotation driving means 106 such as a motor is formed with a recess 103 in which an analysis device 104 that collects a sample solution is set. The concave portion 103 is provided with a hole 114 penetrating in correspondence with the position of the receiving portion 202 of the set analytical device 104.

  The optical measurement unit 108 that accesses the receiving unit 202 of the analysis device 104 set on the turntable 102 is a laser disposed around the turntable 102 so that light can be received through the hole 114 of the turntable 102. A light source 112 and a photodetector 113 are included.

  The control means 109 controls the rotation speed and rotation direction of the turntable 102, the measurement timing of the optical measurement unit 108, and the like. More specifically, the control means 109 not only controls the rotation drive means 106 to rotate the analysis device 104 around the rotation center 107 in a given direction at a predetermined rotation speed via the turntable 102. The analyzing device 104 can be swung by reciprocating left and right at a predetermined amplitude range and a predetermined period around the rotation center 107 at a predetermined stop position.

  The detection light 115 emitted from the laser light source 112 passes through the reaction product of the receiving unit 202 of the analytical device 104 set with the hole 114 of the turntable 102, is received by the photodetector 113, and is input to the calculation unit 110. ing. The calculation unit 110 analyzes the characteristics of the sample solution from the result of the absorbance measurement, and displays it on the display unit 111.

Based on FIG. 7, the centrifugal transfer process and the reagent reaction process of the sample liquid 502 weighed by the sample weighing unit 201 will be described.
After the analysis device 104 filled with the sample liquid 502 in the sample measuring unit 201 is set and fixed in the concave portion 103 of the rotating disk 102, the rotating disk 102 is rotated in the direction of the arrow as shown in FIG. Thus, centrifugal force is generated in the sample liquid 502 filled in the sample measuring unit 201 in the analysis device 104. As a result, the sample liquid 502 stopped at the connection portion 207b starts to move toward the receiving portion 202. Further, by keeping the rotation speed constant, the sample liquid 502 weighed by the sample weighing unit 201 moves to the receiving unit 202 as shown in FIG. 7B.

  The turntable 102 is swung to accelerate the reaction with the reagent. This rocking is performed by repeatedly changing the rotation direction of the turntable 102. Specifically, with the microchannel 105 of the analysis device 104 in the 9 o'clock direction as shown in FIG. 7 (c), it swings alternately by ± 1 ° in the clockwise and counterclockwise directions. By doing so, the sample liquid 502 and the reagent that have moved to the receiving unit 202 are stirred, and a reaction liquid can be finally generated inside the receiving unit 202. The rocking angle and the rocking frequency at this time may be ± 1 ° or more and 22 Hz or more, and the reaction with the reagent is performed in a short time by performing rocking satisfying this condition. be able to. That is, the sample liquid 502 and the reagent can be reliably mixed by swinging the analyzing device 104 at a minute angle at a frequency of about 22 Hz.

The analyzer 100 processes the result of absorbance measurement by the optical measurement unit 108 with the calculation unit 110 and displays the analysis result of the characteristics of the sample solution on the display unit 111.
As described above, since the control means 109 commands the rotation driving means 106 to swing the analysis device 104 via the rotating disk 102, it is possible to analyze the sample liquid 201 with very high accuracy.

FIG. 8 shows an analysis apparatus in operation with two analysis devices 104 set on the turntable 102.
In each of the above embodiments, the base substrate 203 and the cover substrate 204 are formed with a thickness of 1 mm to 7 mm, but there is no particular limitation as long as the microchannel 105 can be formed. The shapes of the base substrate 203 and the cover substrate 204 are not particularly limited, and may be a shape according to the purpose of use, for example, a fan shape, a disk shape, a plate shape, or other complicated shapes.

  In each of the above embodiments, plastic is used as the material of the base substrate 203 and the cover substrate 204 from the viewpoint of easy moldability, high productivity, and low cost. However, glass, silicon wafer, metal, ceramic There is no particular limitation as long as the material can be joined.

  In the above embodiment, the cover substrate 204 and the base substrate 203 are bonded using an adhesive, but may be bonded by a bonding method such as fusion bonding, anodic bonding, or laser bonding depending on the material to be used.

  The present invention can be applied to a medical analysis / inspection apparatus that analyzes components of biological fluids such as blood, saliva, and urine.

The exploded perspective view of the analytical device of the present invention Plan view, sectional view and front view of the same embodiment Explanatory drawing of the sample liquid collection process of the same embodiment Enlarged sectional view of the connection part of the microchannel in the same embodiment Relationship diagram between the sample liquid overflowing the receiving portion and the inclined surface shape in the same embodiment Configuration diagram of analyzer according to the present invention Explanatory drawing of the sample liquid transfer process in the same embodiment Top view when two analytical devices are set on a rotating disk Explanatory drawing of sample control and weighing of conventional analytical device

Explanation of symbols

DESCRIPTION OF SYMBOLS 100 Analyzing apparatus 102 Turntable 103 Recessed part of turntable 102 Analysis device 105 Micro channel 106 Rotation drive means 107 Rotation center 108 Optical measurement part 109 Control means 110 Calculation part 111 Display part 112 Laser light source 113 Photo detector 114 Hole of the turntable 102 DESCRIPTION OF SYMBOLS 115 Detection light 201 Sample measurement part 202 Receiving part 203 Base board 204 Cover board 205 Inclined surface 206 Sample collection part 206a Inlet 207a Main area 207b Connection part 502 Sample liquid (blood)
F Direction from the sample collection unit 206 toward the receiving unit 202 P1 End position of the main section 207a Lc Length of the sample measurement unit 201 Dc1 Clearance on the inlet 206a side of the sample measurement unit 201 Wc Width of the injection port 206a Rc Sample collection unit 206 length P2 Connection surface of the sample measuring unit 201 to the receiving unit 202 (end position of the inclined surface 205)
L Length of connecting portion 207b Dc2 Height of sample weighing unit 201 from cover substrate 204 Dp Height of receiving unit 202 from cover substrate 204

Claims (6)

A sample metering unit configured by a capillary channel for measuring a sample solution to be analyzed only in a fixed amount; a receiving unit connected to the sample metering unit for receiving a sample solution measured by the sample metering unit and reacting with the reagent; An analytical device provided with a microchannel having
An analytical device in which an inclined surface is formed so that a capillary channel of a connection portion of the sample measuring portion with the receiving portion becomes wider toward the receiving portion. The height of the said sample measurement part in the connection surface of the said sample measurement part and the said reception part and the height of the said reception part are for analysis of Claim 1 whose height of the said reception part is higher than the height of the said sample measurement part. device. The analytical device according to claim 1, wherein a hydrophilic treatment is applied to a part or all of the wall surfaces of the sample measuring unit and the receiving unit.   The analysis device according to claim 1, wherein the hydrophilic treatment is performed on a surface of the microchannel facing the inclined surface. A turntable on which the analysis device according to claim 1 is set;
A rotation driving means for rotating the rotating disk;
An analyzer provided with a control means for controlling the rotation driving means so as to transfer a fixed amount of sample liquid measured by the sample measuring section to the receiving section by a centrifugal force generated by rotation of the rotating disk. The control means;
Prior to accessing the reactants in the receiving unit and executing reading, the rotating disk is alternately swung clockwise and counterclockwise to stir the reagent and the sample solution installed in the receiving unit. The analyzer according to claim 5 configured as described above.

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