WO2007055151A1

WO2007055151A1 - Microreactor and microanalysis system

Info

Publication number: WO2007055151A1
Application number: PCT/JP2006/321965
Authority: WO
Inventors: Akihisa Nakajima; Kusunoki Higashino; Yasuhiro Sando; Youichi Aoki
Original assignee: Konica Minolta Medical & Graphic, Inc.
Priority date: 2005-11-11
Filing date: 2006-11-02
Publication date: 2007-05-18
Also published as: JPWO2007055151A1

Abstract

A microreactor and a microanalysis system enabling a high-reliability analysis. The microreactor which is a chip type microreactor for performing reaction by allowing fluid to flow through micro flow paths, and which comprises a chip substrate formed with micro flow paths, and a coated thin sheet having an adhesive layer on a pasting surface, the surface on the flow path side of the chip substrate and the pasting surface of the coated thin sheet being pressure bonded together which is the simplest way of bonding. The coated thin sheet may be the same in material as the chip substrate, or may have characteristics different from those of the chip substrate, for example, may be provided with a strong water repellency. The microanalysis system comprises a specimen-based chip mounting thereon a reagent and a liquid feed system element, and a device body which consists of separate control/detection components. When performing microanalysis, cross contamination, or carry over contamination is not likely to occur.

Description

Technical field

The present invention relates to a microreactor and a microanalysis system, and more particularly to a microreactor in which a plurality of substrates are bonded with a silicone-based adhesive material and a microanalysis system including the microreactor.

Background art

[0002] In recent years, by making full use of micromachine technology and ultrafine processing technology, devices and means (for example, pumps, valves, flow paths, sensors, etc.) for performing conventional sample preparation, chemical analysis, chemical synthesis, etc. have been developed. A system that has been miniaturized and integrated on a single chip has been developed. This is also called TAS (Micro total Analysis System), bioreactor, lab 'on-chips', biochip, and is used in medical examination' diagnostic field, environmental measurement field, agricultural production field. Its application is expected. When complex processes, skilled procedures, and instrumentation are required, automated, accelerated and simplified microanalysis systems are not only cost, required sample volume, and time, but also time Analysis is possible anywhere.

[0003] In the field where various tests such as clinical tests are performed, results are obtained quickly regardless of the location. Even in the measurement using these analysis chips, the quantitativeness, accuracy of analysis, etc. are important. Since the analysis chip has severe restrictions on its size and shape, establishing a highly reliable liquid delivery system with a simple configuration is an issue. Therefore, there is a need for a microfluidic control element that has high accuracy and excellent reliability. The present inventors have already proposed a microphone pump system suitable for this (Patent Documents 1 and 2).

[0004] Specific problems and demands that should be solved as actual problems have been raised for microreactors that provide simple and rapid analysis means, and their solutions are desired. For example, in order to manufacture a chip-shaped microreactor, plastics having excellent processability and mechanical characteristics are often used as materials. In this case, at least two substrates are bonded to form a chip, and various techniques such as a welding method using an organic solvent are applied in the bonding. It is.

[0005] For example, in the heat fusion method, the surface state of the hot plate portion in contact with the substrate is transferred as it is, so that an optically smooth hot plate is often required. Filling a biological material as a target molecule capture molecule is a process after fusion. In ultrasonic fusion, it is not easy to weld the entire substrate without distortion. Adhesion with adhesives takes a long time to obtain sufficient bonding strength, and there are concerns about the effects of residual solvents and the like. There is also a welding method of irradiating laser light, but special equipment is required for that (Patent Document 3).

Patent Document 1: Japanese Patent Laid-Open No. 2001-322099

Patent Document 2: JP 2004-108285 A

Patent Document 3: Japanese Patent Laid-Open No. 2005-74775

Patent Literature 4: Japanese Translation of Special Publication 2005-513196

Disclosure of the invention

Problems to be solved by the invention

[0006] The present invention made in view of the above-described actual situation can be easily bonded to each other when a plurality of substrates having plastic material strength are bonded to each other, and can be manufactured into a chip with good adhesion. A microreactor composed of substrates is proposed.

Means for solving the problem

[0007] The microreactor of the present invention comprises:

A chip-type microreactor that performs a reaction by flowing a fluid in a microchannel, and at least a chip substrate on which the microchannel is formed;

A coated thin plate having an adhesive layer on the bonding surface;

And a microreactor in which the surface on the fine flow path side of the chip substrate and the bonding surface of the coated thin plate are bonded to each other.

[0008] The coated thin plate may be a sheet or film.

[0009] It is desirable that the adhesive layer of the coated thin plate is an adhesive layer in which a pressure-sensitive adhesive material is applied to the bonding surface, and a silicone-based adhesive material is preferable.

[0010] The silicone pressure-sensitive adhesive material comprises a polydiorganosiloxane polyurea copolymer and a silicone tackifier resin. [0011] The silicone tackifier resin is a silicone resin having a molecular weight of about 100 to about 50,000 and a silanol (S-OH) content of about 1.5 mass% or less.

[0012] The chip substrate is preferably made of a resin material selected from polystyrene, polyolefin, polypropylene, and polycarbonate.

[0013] Each of the fine channels is individually connected to a micropump separate from the chip substrate, and each fluid is fed to each channel force mixing channel by driving the micropump. It is the flow path which carries out.

[0014] The microreactor of the present invention comprises:

Branched microchannels,

A liquid feed control unit that blocks passage of fluid at a lower pressure than a preset pressure, and allows passage of fluid at a pressure higher than a preset pressure;

A backflow prevention unit for preventing backflow of fluid in the flow path;

Consisting of

It is characterized in that it is provided with a quantitative liquid feeding mechanism for controlling the liquid feeding and the amount of the liquid feeding in the branched flow path.

[0015] In addition, the microreactor of the present invention,

A sample receiving part, a reagent containing part, a waste liquid storing part, a micropump connecting part, and a fine flow path that connects each part,

Furthermore, the sample in the sample receiving unit and the reagent storing unit are passed through a fine channel by the action of a separate micro pump connected to the micro pump connecting unit provided downstream from the sample receiving unit and the reagent storing unit. And a detection unit for measuring a reaction product obtained by reaction in the reaction unit.

[0016] Further, the present invention provides the microreactor described above,

The device body;

Comprising at least the device body.

A base body,

A channel opening disposed in the base body for communicating with the microreactor A micro pump unit including the chip connection part, the micro pump, and a detection device that optically detects a reaction product,

A control device that controls at least the function and temperature of the micropump unit, and

Also included is a microanalysis system characterized in that measurement is performed by mounting the microreactor on an apparatus main body in which these components are integrated.

[0017] The micropump comprises:

A first flow path provided in the flow path, the flow path resistance changing according to the differential pressure;

A second flow path provided in the flow path and having a flow rate resistance change ratio with respect to a change in differential pressure smaller than that of the first flow path;

A pressurization chamber provided in the flow path and connected to the first flow path and the second flow path; an actuator for changing the internal pressure of the pressurization chamber;

A driving device for driving the actuator;

Desirable to be a micropump with

The invention's effect

[0018] The microreactor of the present invention can be produced more easily than other bonding methods by simply pressing a coated thin plate having an adhesive layer on the bonding surface to the surface of the chip substrate on which the fine channel is formed. The coated thin plate may be made of the same material as the chip substrate, but can provide characteristics different from the chip substrate, such as strong water repellency.

[0019] The microanalysis system of the present invention has a configuration in which a microreactor for each specimen and a control 'detection component that is a main body of the apparatus are separated. Cross-contamination and carry-over contamination problems are avoided for trace analysis, and a highly reliable and highly sensitive analysis is possible with a quantitative liquid feeding mechanism based on fluid motion control. Brief Description of Drawings

[0020] [Fig. 1] Fig. 1 is a schematic diagram of a micro-analysis system including a microreactor, an apparatus main body, and force.

FIG. 2 is a schematic view of a microreactor (chip). The micropump belongs to a separate device from the micro-mouth reactor. [FIG. 3] FIG. 3 shows a microphone-mouth reactor (chip) structure formed using a groove-formed substrate and a basic substrate that is a coated thin plate.

[Fig. 4] Fig. 4 illustrates the wettability of fluid when a water-repellent coated thin plate is used.

[FIG. 5] FIG. 5 shows a configuration around the pump connection portion of the microreactor when the micropump 11 is separated from the microreactor. (a) is a diagram showing a configuration of a pump unit for feeding a driving liquid, and (b) is a diagram showing a configuration of a pump unit for feeding a reagent.

FIG. 6 shows a piezo pump, (a) is a sectional view showing an example of the pump, and (b) is a top view thereof. (C) is a sectional view showing another example of a piezo pump.

FIG. 7 shows a water repellent valve.

[FIG. 8] FIG. 8 shows a quantitative liquid feeding mechanism.

Explanation of symbols

1 Main unit

2 Microreactor (inspection chip)

3 Penolech element

4 Heater

5 photodiode

6 LED

7 Fluid reservoir

10 Drive fluid tank

11 Micro pump (piezo pump)

12 Pump connection

13 Liquid feed controller

13a Water repellent valve

15 flow path

15A fluid filling channel

15B branch flow path 18 Reagent storage

19 specimens

20 Sample receiver

24 Drive fluid storage

25 Sealing liquid container

26 Air vent flow path

31 Reagents

41 Upper board

42 PCB

43 ¾S¾ plate

44 Piezoelectric element

45 Pressurization chamber

46 1st channel

47 Second flow path

48 1st liquid chamber

49 Second chamber

54 Sample flow path

60 Fluid (reagent solution)

70 Driving fluid

71 Silicon substrate

72 ports

73 ports

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, a microreactor of the present invention and a microanalysis system including the microreactor, a micropump, various control devices, and a detection device will be described. In the present specification, “fluid” refers to a fluid that is sent out by a force micropump such as a fluid container and flows through a flow path in a microphone-mouth reactor 'chip, and a liquid, a fluid, a gas as a fluid to be applied. It may be. In particular, the target fluid is actually a liquid. And various reagents, sample liquids, denaturant liquids, cleaning liquids, driving liquids, and the like.

The “fine channel” is a minute groove-like channel formed in the microreactor, and may be simply referred to as “channel”. Even when the container for the reagents, the reaction unit, or the detection unit is formed in the shape of a wide liquid reservoir, these may be referred to as a “fine channel”. “Element” means a functional component installed in a microreactor.

Microreactor · Microreactor chip

The microreactor of the present invention is equivalent to what is generally called an analysis chip, a microreactor chip, a microfluidic chip and the like. The chip has a vertical and horizontal size force of usually several tens of mm and a height of about several mm, and a fine channel having a width and height of a micro-order size is formed thereon by a fine processing technique.

The microreactor of the present invention is used for chemical analysis, various inspections, sample processing / separation, chemical synthesis, and the like. Various molding materials can be used as the material of the chip, and it is used according to the characteristics of each material.

• Flow path

The flow path of a chip as a microreactor is formed on a substrate according to a flow path arrangement designed in advance according to the purpose. The flow path through which the fluid flows is, for example, a micrometer-order width fine formed with a width and depth of several tens to several hundreds of μm, preferably a width of 50 to 200 μm and a depth of about 25 to 300 μm. It is a flow path. If the channel width is less than 50 m, the channel resistance increases, which is inconvenient for fluid delivery and detection. The advantage of micro-scale space diminishes in channels over 500 m wide. The forming method is based on a conventional fine processing technique. Typically, it is preferable to transfer a fine structure by a photosensitive resin using a photolithography technique, and an unnecessary portion is removed, a necessary portion is added, and a shape is transferred using the transfer structure. A pattern that models the constituent elements of the chip is produced by photolithography, and this pattern is transferred and molded onto a resin. Therefore, the basic substrate material for forming the fine flow path of the microreactor is preferably a plastic having good mechanical properties that can accurately transfer the sub-micron structure and hardly cause deformation of the flow path due to water absorption. For example, polystyrene and polydimethylsiloxane are excellent in shape transferability. If necessary, processing by injection molding or extrusion molding may be used. [0025] In the relationship between the flow path and the fluid in the micrometer region, in general, the behavior of the fluid is dominated by the viscous force rather than the inertial force. The narrower the flow path, the smaller the Reynolds number (= density X speed X typical dimension ÷ viscosity), which is a dimensionless parameter that represents the ratio of the viscous force to the inertial force. For example, this effect is significant in regions where the width is less than lmm. If this Reynolds number is small, the flow becomes stable, and the Reynolds number force can be used to infer whether the fluid flow is laminar. In general, if the Reynolds number is 2000 or less, the flow is laminar.

[0026] When flowing in a micro flow channel of such a microreactor in a laminar flow form with a small fluid force Reynolds number, the flow velocity of the fluid flowing in the center portion of the flow channel is faster than the flow velocity of the fluid flowing near the flow channel wall. There is a general characteristic. The powerful characteristics also affect the mixing efficiency when mixing multiple fluids.

[0027] Further, in the fine space, when the inner surface of the flow path is hydrophobic, it is convenient for controlling the fluid movement when the flow of the fluid is stopped, loosened, or the liquid feeding direction is changed. Therefore, if hydrophobic and water-repellent plastic resin is used so that a small amount of sample liquid can be sent to the substrate that forms the fine channel without any loss in the middle, the water-repellent coating is especially applied to the inside of the channel. Is not required. Examples of such materials include resin such as polystyrene, polyolefin, polypropylene, polyethylene terephthalate, polyethylene naphthalate, polyethylene butyl alcohol, and polycarbonate. These plastics are particularly suitable for chip substrates.

• Chip structure and fabrication

The microreactor of the present invention is a chip-type microreactor in which a fluid flows in a fine channel and performs a reaction, and its basic structure is manufactured by appropriately combining one or more molding materials, and the main body is composed of at least two substrates. This is a chip type microreactor (microfluidic chip) (Fig. 3). Specifically, the microreactor of the present invention includes a chip substrate having at least a fine channel formed thereon and a coated thin plate having an adhesive layer on a bonding surface, and the surface on the fine channel side of the chip substrate and the coated thin plate. This is a microreactor made by laminating the laminated surfaces of each other.

[0028] Preferably, in such a chip, the structure includes a chip substrate (groove forming substrate) in which a fine channel is formed and a basic substrate that is a coated thin plate. A base and a liquid reservoir (reagent storage unit, specimen storage unit, waste liquid storage unit, etc.) are formed, and a flow path is formed on the groove forming substrate. The detection section, or at least the detection section, is covered with a light-transmitting coated thin plate.

[0029] In the microreactor of FIG. 3A illustrating a specific embodiment of the present invention, a chip formed by laminating two substrates of a groove-formed substrate and a coated thin plate having an adhesive layer on the bonding surface is shown. Has been. In FIG. 3 (B), the waste liquid storage part is formed on the surface opposite to the surface on which the fine channel is formed, so that the coated thin plate and the coated substrate are bonded to both surfaces of the groove forming substrate, respectively. Force A coated thin plate having an adhesive layer is bonded to the bonded surface at least on the surface on the fine channel side. In this case, the material of the two coated thin plates may be the same or different.

[0030] To produce the microreactor of the present invention,

On one side of the coated thin plate, which may be a sheet or film, a silicone tackifier resin (molecular weight of about 100 to about 50,000, silanol (Si-OH) content of about 1.5 mass) %)) And a polydiorganosiloxane polyurea copolymer and a pressure-sensitive adhesive material that can also be applied uniformly to form a pressure-sensitive adhesive layer as a bonding surface, and the surface of this pressure-sensitive adhesive layer and a fine substrate on which fine channels are formed The side of the channel

Just stick together and stick them together in place!

[0031] The chip substrate, which is the chip body in which the fine channel is formed, is bonded to the coated thin plate, thereby sealing the fine channel and sealing the waste liquid reservoir. The coated thin plate is a coated thin plate having an adhesive layer on the bonding surface as a cover plate that covers the fine flow path formed on the chip substrate. For this reason, it is a cover plate having a flat surface that is in close contact with the chip substrate, but if there is no problem in terms of adhesion, strength, etc., a thin plate having an adhesive layer that may be a sheet or film, That is, it may be in the form of an adhesive sheet or an adhesive film. Therefore, the thickness is not particularly limited and can be set to the required thickness as required.

[0032] When the chip is manufactured, the two substrates can be firmly bonded together simply by pressure bonding. For example, pressing both sides with a pair of coated thin plate and chip substrate sandwiched between two pressure plates May be. Since the adhesive layer of the coated thin plate is pushed onto the surface to be contacted of the chip substrate and is in close contact with the surface, this state is maintained, so that no leakage occurs.

[0033] In order to simplify this operation, the pressure-sensitive adhesive layer is desirably a pressure-sensitive pressure-sensitive adhesive material. Pressure sensitive adhesives use pressure to provide tackiness, but can be performed at room temperature (approximately 20-30 ° C) and do not require the use of heating equipment. Thus, since heating is not required for crimping, there is no possibility of deformation of the substrate made of resin, plastic, distortion of the flow path, or the like. Adhesion does not require additional equipment such as laser irradiation equipment or ultrasonic generators as long as there is a pressurizing tool, and can be carried out easily.

[0034] The production of such a chip is easy and simpler than other bonding methods. The base material of the coated thin plate may be the same base material as the chip substrate. According to the method of the present invention, it is possible to impart characteristics different from those of the chip substrate and water repellency enhancement described later.

[0035] A method of bonding two or more substrates together using an adhesive is also used, but the adhesive is a solvent used for dissolving the adhesive immediately after the excess portion protrudes from between the substrates, or for bonding. Part of the agent may remain in the substrate or dissolve in the fluid in the flow path, contaminating the inner wall of the flow path and adversely affecting reaction and detection. Or there is a risk that the excess adhesive will enter the microchannel and clog it. In the method of bonding using an adhesive layer as in the present invention, such a concern does not require time for drying and hardening required when pasting with an adhesive. Can be glued.

If necessary, “undercoating” may be applied between the coated thin plate and the adhesive layer to force-bond. Useful chemical primer agents include solvent solutions of acrylonitrile butadiene rubber, epoxy resin and polyamide resin. In addition to such chemical undercoats, mechanical undercoatings may be used.

[0037] The coated thin plate having the adhesive layer on the bonding surface can be produced by applying an adhesive material to form the adhesive layer on the coated thin plate. The material of the coated thin plate is not particularly limited, but a material that can form an adhesive layer is preferable. The pressure-sensitive adhesive layer is formed by applying a pressure-sensitive adhesive material to the coated thin plate, and the coating may be performed uniformly on the surface of the coated thin plate or by applying only to some necessary portions.

The thickness of the adhesive layer may be 50 to 5000 μm, preferably 100 to 1000 μm. In the present invention, in consideration of the above-described method for bonding both substrates, it is desirable that the adhesive layer of the coated thin plate is an adhesive layer coated with a pressure-sensitive adhesive material that can be easily bonded. . The pressure-sensitive adhesive material suitable for the present invention is a silicone-based adhesive material having water repellency, which is a pressure-sensitive adhesive containing a polydiorganosiloxane polyurea copolymer and a compatible tackifier. is there.

[0039] A typical silicone-based pressure-sensitive adhesive is composed of a polydiorganosiloxane polyurea copolymer and a silicone-tackifying resin added to enhance its pressure-sensitive adhesive properties. The content of silicone tackifying resin is desirably present at least about 55% by weight based on the weight of the resin and the polydiorganosiloxane polyurea copolymer. Useful polydi-noreganosiloxane polyurea copolymers comprise two or more different monomers having polydi-noreganosiloxane units, polyisocyanate residue units, and optionally organic polyamine residue units and Z or polyol residue units. Including polymer. This polymer is a product of a polycondensation reaction of polydionoreganosiloxane polyamine and polyisocyanate, and may be a product obtained by reacting with addition of a polyfunctional chain extender.

[0040] On the other hand, the silicone tackifier resin does not substantially contain silanol (Si-OH) having a molecular weight of about 100 to about 50,000! /, (The total mass of the silicone tackifier resin is (Based on the standard, silanol content of about 1.5% by mass or less) Silicone resin, and typical examples include MQ silicone tackified resin, MQD silicone tackified resin, MQT silicone Examples thereof include tackifying rosin.

[0041] The specific composition, adhesive properties, production method, and the like of the above-mentioned pressure-sensitive adhesive that can be combined with the segmented copolymer and the silicone tackifying resin are described in detail in JP-A-2005-513196 (Patent Document 4). And preparations using the same are commercially available as adhesives.

[0042] Needless to say, the above-mentioned adhesive layer has a well-balanced aspect in terms of adhesive strength, adhesion, elasticity and strength required for adhesion of two substrates. In addition to improving the flow characteristics of the fine flow path, improving the function of the water-repellent valve disposed as a flow path element as described later has extremely advantageous characteristics.

[0043] The flow path and flow path elements (water repellent valve, etc.) in the microreactor of the present invention are: The movement of the fluid is controlled using the fact that the material of the substrate is hydrophobic. In other words, the response on the fluid side is improved with respect to control from pumps, valves, etc. acting on the fluid flowing through the flow path (changes in liquid supply pressure, liquid supply timing, changes in liquid supply direction, etc.). In addition, it becomes easier to control the movement.

[0044] The water repellency of the flow path is represented by a larger contact angle indicating the wettability of the fluid flowing through the flow path, as shown in FIG. Therefore, the chip substrate is preferably made of a resin selected from polystyrene, polyolefin, polypropylene, and polycarbonate. For example, the contact angle that indicates the wettability of water to polyolefin is close to 90 degrees, which is the boundary of the occurrence of fluid “wetting”.

FIG. 4 shows a state in which a channel is formed by bonding a chip substrate and a coated thin plate having a pressure-sensitive adhesive layer (a substrate serving as a lid of the channel), and a fluid flows through the channel. Of the adhesive layer of the silicone-based adhesive material, the portion remaining without being directly bonded to the chip substrate comes into contact with the fluid as the water repellent inner surface, so that the wettability of the inner surface of the flow path is lowered. Therefore, the contact angle Θ of the fluid in contact with the coated thin plate can be made larger than the contact angle Θ with respect to the chip substrate. As described above, the flow path having such a structure has high water repellency on the flow path surface, which is convenient for controlling the fluid motion, and improves flow path characteristics such as prevention of loss of adsorption of a specimen substance. .

[0046] In order to impart water repellency as described above, there is also a method in which the inside of the flow path is particularly water-repellent. However, appropriately performing water-repellent coating on a chip on which a fine and complicated flow path pattern is formed is more complicated than the method of using a water-repellent adhesive layer when manufacturing a chip as in the present invention. It is doubtful that there is.

[0047] According to the bonding method of the present invention, even a chip substrate having a complicated and fine flow path pattern formed on the surface as described above may cause obstruction such as blocking, deformation, or damage to the pattern. The surface of the chip substrate on the flow path side can be easily bonded to the coated thin plate by bonding.

[0048] Micropump and pump connection

In the microreactor of the present invention, the fluid in each storage unit such as various reagent storage units and specimen storage unit is connected by a pump connection unit having a channel opening for communicating with the micropump. Then, the liquid is fed by a micropump communicated with each of these accommodating portions. A plurality of fluids sent from a plurality of channels are combined at a single junction and mixed in a downstream mixing channel, and each of the plurality of channels is individually provided in a micropump separate from the chip. Each fluid is fed to each flow path force confluence by driving the micropump.

• Micro pump

In the present embodiment, a micropump 11 is provided for each of the sample receiving unit 20, the reagent storage unit 18, and, if necessary, the control storage unit, to feed the content liquid in these storage units. The micropump 11 is connected to the upstream side of the reagent storage unit 18, and supplies the driving liquid to the reagent storage unit side by the microphone port pump 11, thereby pushing out the reagent into the flow path and feeding the liquid. The micropump unit is built in a device body (microanalysis system) that is separate from the microreactor. By attaching the microreactor to the device body, the micropump unit can be connected to the microreactor from the pump connection part 12. (Figure 5).

[0049] In this embodiment, a piezo pump is used as a micro pump. That is,

A second flow path provided in the flow path, wherein a ratio of a change in flow path resistance to a change in differential pressure is smaller than the first flow path;

A pressurization chamber provided in the flow path and connected to the first flow path and the second flow path; an actuator for changing a pressure inside the pressurization chamber;

This is a piezo pump equipped with (Fig. 6).

[0050] As the micropump, it is preferable to use a force piezo pump that can use various types of pumps such as a check valve type pump provided with a check valve in an inlet / outlet hole of a valve chamber provided with an actuator. FIG. 6 (a) is a cross-sectional view showing an example of a piezo pump, and FIG. 6 (b) is a top view thereof. The micropump includes a substrate 42 on which a first liquid chamber 48, a first flow path 46, a pressurization chamber 45, a second flow path 47, and a second liquid chamber 49 are formed, and is laminated on the substrate 42. Upper substrate 41, diaphragm 43 laminated on upper substrate 41, piezoelectric element 44 stacked on the side of diaphragm 43 facing pressure chamber 45, and drive unit for driving piezoelectric element 44 (Not shown) It has been. The drive unit and the two electrodes on the surface of the piezoelectric element 44 are connected by wiring such as a flexible cable, and a voltage of a specific waveform is applied to the piezoelectric element 44 by the drive circuit of the drive unit through the open connection. It becomes a configuration to apply. Details thereof are described in Patent Documents 1 and 2 above.

[0051] It is also possible to form a plurality of pumps on one silicon substrate. In this case, it is desirable that the driving fluid tank 10 is connected to the port opposite to the port connected to the chip. If there are multiple pumps, their ports may be connected to a common drive fluid tank.

[0052] The relationship between the micropump and the microfluidic system of the present invention will be described below. In the example of FIG. 1 showing a preferred embodiment of the present invention, the micropump belongs to the system main body as an apparatus different from the chip constituting the microreactor, and communicates with the driving liquid tank. When the micro-port pump and the chip constituting the microreactor are joined together in a predetermined state, they are connected to the pump connection portion on the chip and communicate with the flow path of the chip.

FIG. 5 shows the configuration of the periphery of the pump connection part on the chip communicating with the piezo pump as the micropump. In this figure, the flow path downstream from the pump connection portion 12 connecting from the fluid delivery port of the micro pump to the flow path of the chip is on the chip constituting the micro reactor. FIG. 5 (a) shows the configuration of the pump section for feeding the driving liquid, and FIG. 5 (b) shows the configuration of the pump section for feeding the reagent. Here, reference numeral 24 denotes a drive fluid container, which corresponds to the drive fluid tank 10 in FIG. The driving fluid may be either an oil system such as mineral oil or an aqueous system. Reference numeral 25 denotes a sealing liquid storage unit that stores a sealing liquid for sealing a reagent stored in advance. This sealing liquid is for preventing the reagent from reacting due to leakage into the fine channel. The sealing liquid may be filled in a fine flow path or may be filled in a reservoir provided for the sealing liquid.

[0054] Although not shown in Figs. 6 (a) and (b), the first liquid chamber 48 is connected to the port 72 connected to the driving liquid tank 10, and the second liquid chamber 49 is connected to the pump connecting portion. Port 73 is provided. The first fluid chamber plays the role of a “reservoir”, and receives supply of drive fluid from the drive fluid tank 10 at port 72. The second liquid chamber forms a flow path for the micropump unit, and the end of the flow path 73 and connects to the “pump connection” 12 of the chip.

Note that the micropump itself can also be incorporated on the chip. In particular, this form can be adopted when the flow path on the chip is relatively simple and the microreactor is used for the purpose or application premised on repeated use, for example, a chemical synthesis reaction.

'Water repellent valve

Fig. 7 schematically shows the structure of a water repellent valve (also called a hydrophobic valve). As shown in Fig. 7, the water-repellent valve is composed of a portion with a narrowed passage diameter, that is, a "restricted passage", so that fluid that reaches this portion from one end passes to the other end. Is regulated. In other words, by narrowing the flow path halfway, the passage of fluid is blocked until the liquid feeding pressure in the forward direction (usually the direction in which the fluid is pushed out by the pump, that is, the downstream direction) reaches a predetermined pressure. It functions so as to allow passage of fluid by applying the above liquid feeding pressure. This throttle channel is formed, for example, so that the length and breadth are about 200 m × 30 m with respect to the channel of 200 m × 200 m connected in series on both sides. By providing the water repellent valve in this way, it is possible to prevent the fluid from moving freely by capillary force when the pump is stopped.

[0056] Further, after the fluid stops at the water repellent valve, the pump drive voltage is not stopped, and the drive voltage is continuously applied to the pump at a pressure that does not allow the fluid to move for a predetermined time. After the time elapses, the fluid is pushed out from the end of the narrow throttle channel to the downstream downstream channel by increasing the drive voltage so that the liquid feed pressure is higher than the allowable pressure of the water repellent nozzle. . Therefore, the stopping and passage of the fluid can be controlled by the pump pressure from the micropump. For example, the movement of the fluid is temporarily stopped at a predetermined position of the flow path, and the force at the desired timing is also detected. It is also possible to resume liquid feeding to the previous flow path.

If the water repellency of the water repellent valve and the flow path connected to the water repellent valve is poor, the stoppage of the fluid is deteriorated, and the fluid flows little by little. The effectiveness of the water repellent valve is improved by increasing the water repellency. In addition, in the fine flow path, the viscous behavior is more dominant than the inertial force in the behavior of the fluid, and if the flow path is water repellent, the fluid is less likely to stick to the flow path wall, so the viscous resistance is reduced. The fluid flows smoothly and stabilizes. For this reason, the flow rate of the fluid can be easily decelerated and stopped. 'Quantitative liquid feeding mechanism

It is desirable to install a check valve in order to prevent the fluid from flowing backward and accurately deliver the specified liquid. A check valve is provided at an appropriate position in the flow path between the reagent storage unit, the reaction unit, and the detection unit. In addition to the above, it is preferable to provide a check valve at an appropriate position for preventing contamination as well as cross contamination as described above.

[0058] As a check valve used in the flow path of the microreactor of the present invention, a microsphere is used as a valve body, and an opening formed in the substrate is opened and closed by the movement of the microsphere to allow and block the passage of fluid. Check valve (the valve element closes the flow path opening due to the backflow pressure). Alternatively, a flexible substrate that is laminated on a substrate and whose end portion extends to the upper side of the opening may be a check valve that opens and closes the opening by moving the upper side of the opening up and down by hydraulic pressure. Good.

[0059] As a suitable mechanism using the water-repellent valve and the check valve, there can be mentioned a quantitative liquid feeding mechanism shown in FIG. In this mechanism, the flow path (fluid filling flow path 15A) between the check valve 16 and the water repellent valve 13a is filled with a predetermined amount of fluid, for example, a reagent. A branch flow path 15B is provided that branches from the fluid filling flow path 15A and communicates with the micropump 11 that feeds the driving liquid.

[0060] In order to quantitatively send the fluid, the flow of the fluid is blocked until the fluid flow pressure in the forward direction and the fluid feed pressure in the forward direction reach a prescribed pressure, and a fluid delivery pressure higher than the prescribed pressure is applied. Thus, the liquid feeding control unit 13 that allows passage of the fluid and can control the passage of the fluid by the pumping pressure of the pump, and the backflow prevention unit that prevents the backflow of the fluid in the flow path are included. In FIG. 8, the fluid (reagent liquid) 60 is first supplied from the check valve 16 side to the reagent filling flow path 15A at a liquid feed pressure that prevents the fluid (reagent liquid) 60 from passing through the water repellent valve 13a first. Fill 60. Next, with the liquid feed pressure that allows the fluid 60 to pass through the water repellent valve 13a, the micropump 11 feeds the driving liquid 70 in the direction toward the branch flow path 15B toward the reagent filling flow path 15A. By doing so, the fluid 60 filled in the fluid filling channel 15A is pushed out from the liquid feeding control unit 15A first, and thereby the fluid 60 is quantitatively fed. In addition, by providing a large volume reservoir 7 in the fluid-filling flow path 15A, the quantitative variation is reduced. O This quantitative liquid feeding mechanism is also used for reagent quantitative mixing and specimen quantitative liquid feeding. do it Yes.

[0061] The micro-analysis system of the present invention comprises:

A pump connection part having a channel opening for communicating with a micropump separate from the chip, a fine channel through which fluid flows, and a mixing channel through which two or more fluids merge and mix are provided at least A microfluidic chip,

The system itself,

The system body is at least

A base body,

A micropump unit including a chip connection portion disposed in the base body and having a channel opening for communicating with the chip; and the micropump;

A control device for controlling at least the function of the micropump unit;

With

It is characterized in that the measurement is automatically performed by mounting the microreactor on the apparatus main body in which these components are integrated.

Hereinafter, an embodiment of the present invention will be described with reference to FIGS. 1 and 2, which are conceptual diagrams showing a configuration in an embodiment of the micro-analysis system of the present invention. As shown in the figure, together with the microreactor chip, as a device for housing this chip, a heating / cooling unit (Peltier element, heater) for reaction, a micropump for liquid feeding, a driving liquid tank, and a micropump having a chip connection part Detection data that includes the unit, a control device (not shown) related to the control of liquid feeding, temperature, and reaction (not shown) and an optical detection system (LED, photodiode, etc.), and is also responsible for data collection (measurement) and processing There is a system unit with a processing unit (CPU).

[0063] It is desirable that the components other than the chip are configured as a system device main body in which these are integrated, and the chip is attached to and detached from the device main body. In general, a plurality of micropumps having substantially the same shape are incorporated in the apparatus main body. A micropump unit including the plurality of micropumps and a chip connecting part having a channel opening for communicating with the chip is arranged in the base body of the system body of the present invention. As shown in the figure, the chip is attached to the main body and the surfaces are overlapped The pump connection part of the chip is connected to the port of the chip connection part in the micro pump unit of the main body of the device.

[0064] The device of the electric control system that controls the micropump sets a target value of flow rate and timing of liquid feeding, and supplies a drive voltage corresponding to the target value to the micropump. The control device responsible for such control is also incorporated into the main body of the system of the present invention as described later, and operates when the pump connection part of the microreactor chip is connected to the chip connection part of the micro pump cup of the main body. You can make it control!

[0065] The detection processing apparatus, which is a unit responsible for optical detection, data collection and processing, is not particularly limited as a means for optical measurement when a technique such as visible spectroscopy or fluorescence photometry is applied. It is desirable that LEDs, photomultipliers, photodiodes, CCD cameras, etc. be installed as appropriate in the system unit body.

[0066] A control device that controls at least the function of the micropump unit and the function of the detection processing device is incorporated in the main body of the system of the present invention. The control device may further control the system as a whole, including temperature management and measurement data recording and processing. In this case, the control device incorporates various conditions set in advance for the order, volume, and timing of the liquid delivery into the software installed in the microanalysis system as the contents of the program along with the micropump and temperature control. . A series of analysis steps of sample pretreatment, reaction, and detection is performed in a state where a chip is mounted on a system apparatus body in which the micro pump, the detection processing apparatus, and the control apparatus are integrated. The analysis may be started after the sample is injected into the mounted chip, or after the chip into which the sample is injected is mounted in the apparatus main body. Predetermined reactions and optical measurements based on the feeding, pretreatment and mixing of specimens and reagents are automatically performed as a series of continuous processes, and the measurement data is stored in a file together with the necessary conditions and recorded items. The stored form is desirable.

'Analytical Embodiment

The microreactor of the present invention has at least a sample receiving part, a reagent storage part, a waste liquid storage part, a microphone port pump connection part, and a fine flow path, and communicates each part through the fine flow path. The sample liquid is passed through the flow path constituting the reaction unit provided downstream of the sample receiving unit, and then the detection unit. The microreactor is characterized in that the reaction product is measured by flowing it into the flow path, and the waste liquid generated as a result of the measurement is transferred to the waste liquid storage part and confined.

[0067] Further, in addition to each storage section, flow path, and pump connection section, each element such as a liquid feed control section, a backflow prevention section, a reagent quantification section, and a mixing section has a microfabrication technique at a functionally appropriate position. It is installed by.

[0068] In the microreactor chip used in the microanalysis system of the present invention, a target substance in a specimen can be analyzed by performing the following processing:

After mounting the chip in the base body in a state where the pump connection part of the chip and the chip connection part of the micropump unit are liquid-tightly sealed, the sample in the sample container (or the sample) A target substance contained in a processing solution processed in the flow path),

The reagent stored in the reagent storage unit,

Liquid is sent to the flow path that constitutes the reaction part and merged,

After reacting these, the obtained reaction product substance or its treatment substance is sent to the flow path constituting the detection section, and the detection is performed by the detection treatment apparatus.

[0069] Typically, as shown in FIG. 2, each reagent 31 accommodated in a plurality of reagent accommodating portions 18 located in the most upstream part is mixed in a flow channel downstream from the reagent accommodating portion 18, The mixed reagent is sent to the downstream analysis channel. In the analysis channel, the sample and the mixed reagent are merged and mixed from the Y-shaped channel or the like, the reaction is started by temperature rise or the like, and the reaction is detected in the detection unit provided downstream of the channel.

[0070] The specimen pretreatment section and the detection section communicate with each other through a through hole, and are a hollow chamber provided at the bottom of the microreactor, and are a sealed waste liquid reservoir that contains waste liquid generated as a result of specimen measurement. It is comprised so that it may have a waste liquid storage part, It is characterized by the above-mentioned. The waste liquid reservoir is completely sealed in the microreactor and is a disposable chip, so it is discarded in the hazard box after use. For this reason, after injecting clinical specimens into the microreactor, inspectors who are involved in the examination need to be consistently in contact with the specimen even during the examination and after the examination, ensuring infectious safety.

Although the embodiments of the present invention have been described above, the present invention is limited to these embodiments. In various embodiments, arbitrary modifications and changes can be made in accordance with the spirit of the present invention, and they are included in the present invention.

Claims

The scope of the claims

[1] A chip-type microreactor that reacts by flowing a fluid in a microchannel, and at least a chip substrate on which the microchannel is formed;

A coated thin plate having an adhesive layer on the bonding surface;

A microreactor comprising: a surface of a chip substrate on a fine flow path side and a bonding surface of a coated thin plate that are bonded to each other.

[2] The microreactor according to claim 1, wherein the coated thin plate is a sheet-like body or a film-like body.

[3] The microreactor according to [1] or [2], wherein the adhesive layer of the coated thin plate is an adhesive layer in which a pressure-sensitive adhesive material is applied to a bonding surface.

[4] The microreactor according to claim 3, wherein the pressure-sensitive adhesive material is a silicone-based adhesive material.

[5] The microreactor according to claim 4, which is an adhesive material comprising the silicone-based adhesive material polydiorganosiloxane polyurea copolymer and a silicone tackifying resin.

[6] The silicone tackifier resin is a silicone resin having a molecular weight of about 100 to about 50,000 and a silanol (Si-OH) content of about 1.5% by mass or less. The microreactor according to claim 5, wherein:

7. The microreactor according to any one of claims 1 to 6, wherein the chip substrate is made of a resin material selected from polystyrene, polyolefin, polypropylene, and polycarbonate.

[8] Each of the fine channels is individually connected to a micropump separate from the chip substrate, and each fluid is sent to each channel force mixing channel by driving the micropump. The microreactor according to any one of claims 1 to 7, wherein the microreactor is a flow path.

[9] A branched microchannel,

A liquid feed control unit that blocks passage of fluid at a lower pressure than a preset pressure, and allows passage of fluid at a pressure higher than a preset pressure; A backflow prevention unit for preventing backflow of fluid in the flow path;

Consisting of

The microreactor according to any one of claims 1 to 8, further comprising a quantitative liquid feeding mechanism that controls the liquid feeding and the liquid feeding amount in the branched flow path.

[10] It has a sample receiving part, a reagent storage part, a waste liquid storage part, a micropump connection part, and a fine channel that communicates each part,

Furthermore, the sample in the sample receiving unit and the reagent storing unit are passed through a fine channel by the action of a separate micro pump connected to the micro pump connecting unit provided downstream from the sample receiving unit and the reagent storing unit. 10. The reaction part according to claim 1, further comprising a reaction part into which a reagent in the part flows and a detection part for measuring a reaction product obtained by the reaction in the reaction part. Microreactor.

[11] The microreactor according to any one of claims 1 to 10, and

The device body;

With

The device itself is

At least the base body,

A micropump unit including a chip connection part disposed in the base body and having a channel opening for communicating with the microreactor; and a micropump;

A detection device for optically detecting the reaction product;

By mounting the microreactor on the device body in which these components are integrated

A micro-analysis system characterized by performing measurements.

[12] The micropump

A second flow path provided in the flow path and having a flow rate resistance change ratio with respect to a change in differential pressure smaller than that of the first flow path; A pressurization chamber provided in the flow path and connected to the first flow path and the second flow path; an actuator for changing the internal pressure of the pressurization chamber;

A driving device for driving the actuator;

12. The micro analysis system according to claim 11, wherein the micro analysis system comprises: