JP3781709B2 - Chemical analyzer - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a chemical analysis apparatus having a fine flow path such as a specimen test apparatus used for μ-TAS or blood test for performing reaction and synthesis analysis of a trace amount of chemical substances.
[0002]
[Prior art]
In order to efficiently perform biochemical analysis such as gene analysis and blood test, or chemical reaction, a chemical analysis apparatus having a fine channel with a width and depth of an opening cross section of several tens to several hundreds of μm may be used.
[0003]
Also, in recent years, chemical and biochemical analysis integration that integrates functional parts such as liquid feeding, mixing, reaction, and analysis on a glass or silicon chip of about several centimeters square called μ-TAS (Micro Total Analysis System). A system has been proposed (for example, see Non-Patent Document 1). FIG. 10 shows one conventional example of μ-TAS. As shown in FIG. 10, in μ-TAS, a microchannel 100 is formed in a channel substrate 101, and a sample (reagent) is mixed, reacted, detected, etc. in the microchannel 100, thereby creating a drug. And preliminary experiments for medical diagnosis. When a sample is injected from the sample insertion hole 113, the sample passes through the inflow channel 100e and is mixed by the mixing unit 100a. Then, a chemical reaction of the sample occurs in the reaction unit 100b, and the sample after the reaction is separated in the separation unit 100c. The sample after the reaction is detected by the detection unit 100d, and the unnecessary sample is collected by the waste liquid unit 116.
[0004]
In addition, the mixing unit 100a includes a T-shaped fine channel (for example, see Non-Patent Document 2) and a chemical analysis in which the merging angle of the mixing unit 100a is adjusted (for example, see Non-Patent Document 3). There is also a device.
[0005]
[Non-Patent Document 1]
"Production Research" vol.52, no.7, July 2000, P304-311
[0006]
[Non-Patent Document 2]
“New Technology Briefing Material Microreactor Innovation Technology” sponsored by the Japan Science and Technology Agency, March 4, 2002 at Science Plaza B1F Hall, P10
[0007]
[Non-Patent Document 3]
"Chemical Engineering Society 67th Meeting Abstract Document" C201
[0008]
[Problems to be solved by the invention]
As described above, the conventional mixing unit 100a is usually Y-shaped, and since different samples are often mixed in almost equal amounts, the cross-sectional area of each inflow channel 100e does not change. . Therefore, when different samples are mixed at different mixing ratios, the velocity of the sample flowing from each flow path is different, so the interface where the different samples come into contact becomes unstable and uniform with respect to the axial direction of the flow path. There was a problem that hindered proper mixing.
[0009]
In view of the above problems, an object of the present invention is to provide a chemical analyzer that enables stable and uniform mixing of different samples when different samples are mixed at different mixing ratios.
[0010]
[Means for Solving the Problems]
In order to achieve the above object, the first feature of the present invention is that in a chemical analyzer having a mixing section having a groove width of 10 to 900 μm for mixing two different samples at different ratios, (a) one sample flows in (B) a second inflow channel having a cross-sectional area different from that of the first inflow channel, and (c) a first inflow channel. The gist of the present invention is a chemical analysis device including an outflow channel for flowing out a sample after mixing two different samples flowing in from the second inflow channel. Here, the “inflow channel” refers to a groove through which a sample having a width and depth of an opening cross section of several tens μm to several hundreds μm is passed. Further, the outflow channel of the chemical analyzer according to the first feature may have a cross-sectional area equal to the sum of the cross-sectional area of the first inflow channel and the cross-sectional area of the second inflow channel. .
[0011]
According to a second aspect of the present invention, in the chemical analyzer including a mixing section having a groove width of 10 to 900 μm for mixing two different samples at different ratios, (a) a first inflow channel into which one sample flows. And (b) a second inflow channel into which another sample flows, and (c) a central axis that does not intersect at one point with the central axis of the first inflow channel and the central axis of the second inflow channel. The gist of the present invention is a chemical analysis apparatus including an outflow channel that flows out a sample after mixing two different samples.
[0012]
According to a third aspect of the present invention, in the chemical analyzer having a mixing section having a groove width of 10 to 900 μm for mixing two different samples at different ratios, (a) a first inflow channel into which one sample flows. And (b) a second inflow channel into which another sample flows in, and (c) an outflow channel through which the sample after mixing two different samples flows out, and the outflow flow of the first inflow channel The gist is that the chemical analyzer is different from the angle of the second inflow channel with respect to the outflow channel.
[0013]
According to the chemical analyzers according to the first to third features, the mixing section can provide stable mixing by providing inflow channels with different cross-sectional areas, inflow channels with different crossing positions, and inflow channels with different angles. Can be.
[0014]
In addition, the chemical analyzer according to the first to third features includes a sample insertion hole for flowing a sample into the first inflow channel and the second inflow channel filled with the sample, and a sample insertion hole. You may further provide the sheet | seat adhere | attached on the upper part. According to this chemical analyzer, there is no need for means for supplying a sample from the outside, and the flow path substrate can be transported and sold in a state including the sample. Further, in this chemical analyzer, the sample may flow through the first inflow channel and the second inflow channel by inserting a convex pushing rod from the upper part of the sheet into the sample insertion hole. This chemical analyzer has an advantage that the sample does not adhere to the extrusion rod when the sample is extruded through the sheet.
[0015]
The chemical analyzer according to the first to third features includes a sample insertion for inserting a sample while controlling a flow rate in a sample insertion hole for flowing a sample through the first inflow channel and the second inflow channel. And a device.
[0016]
Furthermore, the chemical analysis device according to the first to third features further includes a detection channel for detecting the mixed sample, and a cover made of a material having excellent optical properties, which is installed on the end face of the detection channel. May be. According to this chemical analyzer, since the end face of the detection flow path does not become an obstacle to the entrance / exit of parallel light, detection of color change or the like due to parallel light is performed with high accuracy.
[0017]
DETAILED DESCRIPTION OF THE INVENTION
Next, embodiments of the present invention will be described with reference to the drawings. In the following description of the drawings, the same or similar parts are denoted by the same or similar reference numerals. However, it should be noted that the drawings are schematic.
[0018]
As shown in FIG. 1, the chemical analyzer according to the embodiment of the present invention is a flow path substrate in which a sample insertion hole 13 for inserting a sample and a micro flow path that is a groove of several tens of μm to several 100 μm are formed. 1, an extruding device 2 for extruding a sample placed in the sample insertion hole 13, a light source device 3 for injecting parallel light 31 parallel to the detection flow path 12, and a detection device 4 for detecting the parallel light 31. Prepare. The fine channel on the channel substrate 1 includes a mixing unit 11 that mixes different samples, an outflow channel 20 that flows out the mixed sample, and a detection channel 12 that detects the mixed sample.
[0019]
As the material of the flow path substrate 1, a glass material such as quartz, silicon rubber such as polydimethylsiloxane (PDMS), or an acrylic resin such as polymethyl methacrylate (PMMA) can be considered. Furthermore, a glass epoxy resin, a fluorine resin such as polypropylene (PP) or polytetrafluoroethylene (PTFE), a semiconductor material such as silicon, a metal, or the like may be used.
[0020]
In the embodiment of the present invention, a description will be given using a reagent and a sample as different samples. Here, the specimen refers to a sample to be examined, and the reagent refers to a sample added to examine the specimen. It is assumed that the reagent and the sample are mixed at different mixing ratios.
[0021]
In FIG. 1, the extrusion device 2 is used as the sample insertion device, but a pump or the like may be used in addition to the extrusion device 2. In FIG. 1, the extrusion device 2 inserts a reagent into the reagent insertion hole 13a and inserts a sample into the sample insertion hole 13b. The extrusion device 2 includes a movable part driven by a geared stepping motor or a differential solenoid, a piezoelectric element, and the like as drive means, and can flow different samples at different flow rates. The sample inserted by the extrusion device 2 may be supplied from the outside, or may be inserted and sealed in the sample insertion hole 13 in advance. The case where the sample is sealed in the sample insertion hole 13 will be described in detail later with reference to FIG. The sample pushed out from the sample insertion hole 13 flows to the mixing unit 11, where it is mixed at an appropriate mixing ratio, and then passes through the outflow channel 20 and flows to the detection channel 12. The light source device 3 has its optical axis and the like adjusted so that the parallel light 31 can enter the detection flow channel 12, and the detection device 4 detects the parallel light 31 that has passed through the detection flow channel 12.
[0022]
Next, the fine channel according to the embodiment of the present invention will be described in detail with reference to FIG. The reagent inserted from the reagent insertion hole 13a passes through the first inflow channel 19a and is mixed with the sample in the mixing unit 11. On the other hand, the sample inserted from the sample insertion hole 13b passes through the second inflow channel 19b and is mixed with the reagent in the mixing unit 11. The mixed sample passes through the outflow channel 20 and flows from the channel switching unit 15 to the detection channel 12. The structure of the flow path switching unit 15 will be described in detail later in FIG. The detection flow path 12 is filled with the mixed sample, and the parallel light 31 enters the detection flow path 12 and passes through the mixed liquid in the detection flow path 12 for each time zone in which the chemical reaction after mixing proceeds. The mixed solution is inspected by detecting the emitted light. By providing a plurality of mixing sections 11 and detection flow paths 12 on one flow path substrate 1, a plurality of inspections can be performed sequentially or in parallel on a single flow path substrate 1 in the same process. . In FIG. 2, mixing before detection is performed only once. However, it is also possible to perform detection after mixing a plurality of times by arranging a plurality of sample insertion holes 13 in the flow path toward the detection flow path 12. is there.
[0023]
Next, the case where the sample inserted by the extrusion device 2 is inserted and sealed in the sample insertion hole 13 in advance will be described with reference to FIG. As shown in FIG. 3B, a sample insertion hole 13 which is a through hole for inserting a sample at a position matching one end of the inflow channel 19 is formed on the channel substrate on which the inflow channel 19 is formed. The provided flow path substrate is bonded together. After the sample is inserted into the sample insertion hole 13, a sheet 6 made of a material that can be deformed greatly, such as latex rubber, is adhered to the upper surface of the sample insertion hole 13 by an appropriate bonding member 7. The bonding method is not limited to bonding by the bonding member 7, and mechanical pressing, heat fusion, ultrasonic vibration, or the like may be used. The sample insertion hole 13 has a diameter and depth of 20 mm or less because a sample amount that can be flowed into the fine channel is inserted. In design, about several mm is appropriate.
[0024]
When the sheet 6 is pasted, as shown in FIG. 3A, the sample insertion hole 13 is provided on the lower surface of the sheet, and the adhesive member 7 surrounds the sample insertion hole 13. In addition, the inflow channel 11 exists below the sample insertion hole 13. The seat 6 may be provided with a seat removing portion 6a for the convenience of removing the seat. Alternatively, a flow path substrate in which a sample is inserted in advance and a sheet is attached to the upper surface thereof may be used.
[0025]
The flow path substrate in which the sample insertion hole 13 is filled with the sample is disposed under the convex extrusion bar 21 provided in the extrusion device 2. The extruding device 2 controls the position of the extruding rod 21 to extrude the sample sealed in the sample insertion hole 13 to the inflow channel 19 through the sheet 6. By controlling the force and speed that the extrusion device 2 pushes out, the sample can flow through the inflow channel 19 at an arbitrary flow rate. As a control means for the extrusion rod 21, the extrusion device 2 includes a stepping motor with a gear, a movable part driven by a differential solenoid, or a piezoelectric element.
[0026]
The flow path substrate in which the sample is sealed in the sample insertion hole 13 has an advantage that the sample does not adhere to the extrusion rod 21 when the sample is extruded through the sheet. Further, according to this flow path substrate, there is no need for means for supplying a sample from the outside, and the flow path substrate can be transported and sold in a state including the sample.
[0027]
Next, three types of the mixing unit 11 in FIG. 2 will be described with reference to FIGS.
[0028]
FIG. 4 is an enlarged view of the mixing portion 11 in which the cross-sectional areas of the first inflow channel 19a and the second inflow channel 19b are different. By changing the width and depth of the first inflow channel 19a and the second inflow channel 19b, the opening cross-sectional areas of the first inflow channel 19a and the second inflow channel 19b are made different. Can do. When the reagent supplied through the first inflow channel 19a and the sample supplied through the second inflow channel 19b are mixed at a volume ratio of m: n, the first inflow channel 19a and the second inflow The cross-sectional area ratio of the path 19b is m: n. Although FIG. 4 shows a case where the cross-sectional area is a square, it is needless to say that the cross-sectional area may be a rectangle, a semicircle, or other shapes. According to this fine channel, the inflow rate of the reagent and the sample becomes substantially constant, and samples with different mixing ratios can be mixed uniformly. Further, the cross-sectional areas of the first inflow channel 19a and the second inflow channel 19b are different even if the inflow speeds of different samples flowing in from the left and right are not set to m: n. By changing, the speed difference becomes smaller than when the cross-sectional areas of the first inflow channel 19a and the second inflow channel 19b are equal, and a stable flow can be supplied.
[0029]
The cross-sectional area ratio of the first inflow channel 19a, the second inflow channel 19b, and the outflow channel 20 may be m: n: m + n. That is, the cross-sectional area of the outflow path 20 is equal to the sum of the cross-sectional areas of the first inflow channel 19a and the second inflow channel 19b. According to this fine channel, a stable flow can be supplied without stagnation of the flow of the sample mixed in the mixing section.
[0030]
FIG. 5 shows an enlargement of the mixing section 11 where the central axis of the first inflow channel 19a and the central axis of the second inflow channel 19b do not intersect with the central axis of the outflow channel 20 at one point. FIG. Here, the “center axis” refers to an axis passing through the center of the flow path width. In the normal mixing section 11, as shown in FIG. 4, the central axis of the first inflow channel 19a, the central axis of the second inflow channel 19b, and the central axis of the outflow channel 20 are at one point. Intersect. As shown in FIG. 5, by shifting the first inflow channel 19a from the central axis, the sample flowing through the second inflow channel 19b can have a larger volume ratio than the sample flowing through the first inflow channel 19a. Can be mixed. According to this fine channel, stable and uniform mixing of different samples is possible when different samples are mixed at different mixing ratios.
[0031]
FIG. 6 is an enlarged view of the mixing unit 11 in which the angle α of the first inflow channel 19 a with respect to the outflow channel 20 and the angle β of the second inflow channel 19 b with respect to the outflow channel 20 are different. According to this fine channel, stable and uniform mixing of different samples is possible when different samples are mixed at different mixing ratios.
[0032]
Next, an example of the structure of the flow path switching unit 15 in FIG. 2 will be described with reference to FIG. When performing detection using the parallel light 31 in the detection flow path 12, the detection flow path 12 and the outflow flow path 20 are arranged so as to cross three-dimensionally. This is to prevent the mixed liquid (detection liquid) from flowing into the detection flow path 12 where the outflow flow path 20 intersects the detection flow path 12 that is not the target. Although FIG. 7A shows an example in which the outflow channel 20 and the detection channel 12 intersect perpendicularly, they may be provided so as to intersect in an oblique direction or the same direction. Here, when a large number of detections are performed with one flow path substrate 1, a large number of crossing flow paths cannot be arranged on one flow path substrate 1, so the outflow flow path 20 and the detection flow path 12 are different. They may be formed on the flow path substrate 1, layered on top of each other, and connected therebetween through the through holes 22. In FIG. 7B, the first flow path substrate 1 a provided with the outflow flow path 20, the second flow path substrate 1 b provided with the through hole 22, and the third flow path provided with the detection flow path 12. The substrates 1c are hierarchically overlapped, and the detection channel 12 and the outflow channel 20 are arranged so as to cross three-dimensionally.
[0033]
Next, the shape of the end face of the detection flow path 12 in FIG. 2 will be described with reference to FIG. Irregularities remain on the end face of the detection flow path 12 by any manufacturing method, which obstructs the entrance / exit of the parallel light 31. Therefore, as shown in FIG. 8A, the detection flow path 12 is formed as a through hole, and covers 5 made of quartz or the like having excellent optical characteristics such as light transmittance are bonded to both ends thereof. Examples of the bonding method include heat bonding, heat fusion, optical contact, and mechanical tightening. According to this detection flow path 12, the end face of the detection flow path 12 does not become an obstacle to the entrance / exit of the parallel light 31, so that a change in color or the like by the parallel light 31 is detected with high accuracy. Further, at one end of the detection channel 12, a channel for escaping is formed on the end surface so that the sample is filled up to the end surface of the detection channel 12, and a drain 16 for storing the sample is formed at the end. To do. As shown in FIG. 8B, the drain 16 is provided with an air vent hole 23. In FIG. 8A, the escape flow path and the drain are provided in the horizontal direction, but the present invention is not limited to this and may be provided in the vertical direction. The drain 16 can also be used when the initial portion of the sample flowing through the detection flow channel 12 is not used as a detection target and the sample in the initial portion is removed from the detection flow channel 12. Furthermore, the sample in the detection flow path 12 or the drain 16 can be easily taken out by removing the cover 5.
[0034]
Next, with reference to FIG. 9, a description will be given of a method in which the parallel light 31 is incident on the detection flow path 12 from the light source device 3 and the detection device 4 performs detection. The specimen to which the reagent is added is projected with parallel light 31 in the detection flow path 12. The detection device 4 measures the color of the specimen that changes due to a reaction or the like. Usually, when performing detection using light in the detection flow path 12, the detection light is incident on the detection flow path 12 perpendicularly. Here, by making the parallel detection light 31 incident on the detection flow path 12 provided on the flow path substrate 1, the distance through which the parallel light 31 passes through the sample in the detection flow path 12 is increased. The signal / noise ratio (S / N ratio) can be greatly improved. As the light source of the light source device 3, a laser, a light emitting diode, a light, a lamp light source, or the like can be used, and the light from the light source may be narrowed by an optical fiber or the like.
[0035]
According to the chemical analyzer according to the embodiment of the present invention, by providing inflow channels having different cross-sectional areas, inflow channels having different crossing positions, and inflow channels having different angles, it is possible to achieve stable and uniform mixing in the mixing unit. Can be possible. In particular, in a field where the mixing ratio is as large as 1:10 to 1: 100 and strict accuracy of the ratio is required, the flow in the mixing section is stable and accurate even with different mixing ratios. Mixing can be enabled.
[0036]
(Other embodiments)
Although the present invention has been described according to the above-described embodiments, it should not be understood that the descriptions and drawings constituting a part of this disclosure limit the present invention. From this disclosure, various alternative embodiments, examples and operational techniques will be apparent to those skilled in the art.
[0037]
For example, the fine channel mixing unit 11 according to the embodiment of the present invention has different inflow channels with different cross-sectional areas shown in FIG. 4, inflow channels with different crossing positions shown in FIG. 5, and different angles shown in FIG. You may have the structure which combined each difference of the inflow flow path. For example, the cross-sectional area ratio of the first inflow path 19a and the second inflow path 19b is changed, and the angle of the first inflow path 19a with respect to the outflow path 20 is α, and the second inflow with respect to the outflow path 20 The angle of the flow path 19b can be set to β. Many combinations are conceivable depending on the mixing volume ratio, specific gravity, amount, and the like of the sample to be mixed.
[0038]
As described above, the present invention naturally includes various embodiments not described herein. Therefore, the technical scope of the present invention is defined only by the invention specifying matters according to the scope of claims reasonable from the above description.
[0039]
【The invention's effect】
According to the present invention, it is possible to provide a chemical analyzer that enables stable and uniform mixing of different samples when different samples are mixed at different mixing ratios.
[Brief description of the drawings]
FIG. 1 is a perspective view of a chemical analysis apparatus according to an embodiment of the present invention.
FIG. 2 is a top view of a flow path substrate according to an embodiment of the present invention.
3A is a top view of a reagent insertion hole according to an embodiment of the present invention, and FIG. 3B is a cross-sectional view taken along line AA in FIG. 3A.
FIG. 4 is an enlarged view of a mixing unit according to the embodiment of the present invention (No. 1).
FIG. 5 is an enlarged view of a mixing unit according to the embodiment of the present invention (part 2).
FIG. 6 is an enlarged view of a mixing unit according to the embodiment of the present invention (No. 3).
7A is a top view of a flow path switching unit according to an embodiment of the present invention, and FIG. 7B is a cross-sectional view taken along line BB in FIG. 7A.
8A is a top view of a drain portion according to an embodiment of the present invention, and FIG. 8B is a cross-sectional view taken along the line CC of FIG. 8A.
FIG. 9 is a cross-sectional view of a detection flow channel according to the embodiment of the present invention.
FIG. 10 is a perspective view of a conventional μ-TAS.
[Explanation of symbols]
DESCRIPTION OF SYMBOLS 1,101 Flow path board | substrate 1a 1st flow path board | substrate 1b 2nd flow path board | substrate 1c 3rd flow path board | substrate 3 Light source device 4 Detection apparatus 5 Cover 6 Sheet 6a Sheet removal part 11 Mixing part 12 Detection flow path 13, 113 Sample insertion hole 13a Reagent insertion hole 13b Specimen insertion hole 15 Channel switching unit 16 Drain 19 Inflow channel 19a First inflow channel 19b Second inflow channel 20 Outflow channel 21 Extruding rod 22 Through hole 23 For air venting Hole 31 Parallel light 100 Fine channel 100a Mixing unit 100b Reaction unit 100c Separation unit 100d Detection unit 100e Inflow channel 116 Waste liquid unit

Claims (7)

A first inflow channel formed on the channel substrate and into which one sample flows;
A second inflow channel formed on the channel substrate and into which another sample flows;
A mixing unit for mixing the two different samples flowing in from the first inflow channel and the second inflow channel;
An outflow channel for flowing out the sample to be mixed in the mixing section;
Sample flowing out in the outflow channel is flowed, is arranged to cross the outflow channel, the detection flow path through the flow exiting the flow passage from the end face of the channel substrate,
A cover that is attached to the detection flow path at an end surface of the flow path substrate and has light transmittance;
A first sample insertion hole formed on the flow channel substrate for flowing the one sample through the first inflow channel and a second for flowing the other sample through the second inflow channel. A sample insertion hole;
A deformable first sheet adhered to an upper portion of the first sample insertion hole and a deformable second sheet adhered to an upper portion of the second sample insertion hole;
From the upper part of the first sheet, a convex first extruding rod narrower than the first sample inserting hole is inserted into the first sample inserting hole, and the first extruding rod is used to insert the first extruding rod. The one sample is allowed to flow through the sheet by being pushed out into the first inflow channel, and a convex second extruding rod that is narrower than the second sample insertion hole is further formed from the upper part of the second sheet. A sample insertion device that is inserted into the second sample insertion hole, and flows by pushing the other sample through the second sheet through the second sheet by the second push-out rod,
A chemical analysis device comprising:   2. The chemical analysis according to claim 1, wherein the outflow channel has a cross-sectional area equal to a sum of a cross-sectional area of the first inflow channel and a cross-sectional area of the second inflow channel. apparatus.   The point where the center axis of the first inflow channel and the center axis of the second inflow channel intersect is the point where the center axis of the second inflow channel and the center axis of the outflow channel intersect The chemical analysis apparatus according to claim 1, wherein the chemical analysis apparatus is deviated from the chemical analysis apparatus.   The chemistry according to any one of claims 1 to 3, wherein an angle of the first inflow channel with respect to the outflow channel is different from an angle of the second inflow channel with respect to the outflow channel. Analysis equipment. The detection flow path sterically intersects the outflow flow path, and the detection flow path and the outflow flow path are connected by a through hole formed in the flow path substrate. Item 5. The chemical analysis device according to any one of Items 1 to 4 . The chemistry according to any one of claims 1 to 5 , further comprising a drain for filling the sample from the outflow channel to the end surface of the detection channel on an end surface of the detection channel. Analysis equipment. Chemical analysis apparatus according to any one of claims 1 to 6 wherein the drain, characterized by further comprising a vent hole.

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