JP2007248218A - Microchip - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel microvalve capable of functioning even as a changeover valve or a check valve when the microvalve is mounted on a microchip and capable of easily performing the fine adjustment of a flow rate. <P>SOLUTION: In the microchip composed of an upper substrate and a lower substrate and having at least one microchannel arranged between both substrates, at least one microvalve is inserted in the microchannel at a proper place, the microvalve is composed of two sheet members different in thickness, at least one recess and the air flow channel communicating with the recess are arranged to the thick sheet member, the thin sheet member is bonded to the thick sheet member so as to shield the groove and recess of the thick sheet member, the ratio (T<SB>1</SB>:T<SB>2</SB>) of the thickness (T<SB>1</SB>) of the thin sheet member and the bottom part thickness (T<SB>2</SB>) of the recess is within a range of 1:2-1:10 and the depth (D) of the recess is within a range of 1.3-5 times of the bottom part thickness (T<SB>2</SB>) of the recess. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a microchip with a microfluidic control mechanism widely used for chemical / biochemical analysis such as gene analysis. More specifically, the present invention relates to a microchannel for controlling a flow of a fluid in a microchannel or a reaction vessel formed in a microchip substrate.

  Recently, micro-channels, reaction vessels, ports, and other microstructures have been created in the substrate, as is known by the names such as Micro Total Analysis Systems (μTAS) or Lab-on-Chip (Lab-on-Chip). Microdevices configured to perform various operations such as chemical reaction, synthesis, purification, extraction, generation and / or analysis of substances within the microstructure have been proposed and partially put into practical use. Structures manufactured for this purpose and having a microstructure such as microchannels, ports and reaction vessels in the substrate are collectively referred to as “microchips” or “microfluidic devices”. Microchips can be used in a wide range of applications such as chemical industry and environmental measurement as well as chemical, biochemical, pharmaceutical, medical, and veterinary fields such as gene analysis, clinical diagnosis, and drug screening. Compared with the same type of equipment of the common size, the microchip is (1) significantly less sample and reagent usage, (2) shorter analysis time, (3) higher sensitivity, (4) carried on-site, It can be analyzed in the field and (5) can be disposable.

  In the conventional microchip 100, for example, as shown in FIGS. 6A and 6B, at least one microchannel 104 is formed on the upper substrate 102, and an input / output port 106 is provided at least at one end of the microchannel 104. , 106 are formed, and a lower substrate 108 is bonded to the lower surface side of the substrate 102. The presence of the lower substrate 108 seals the ports 106 and 106 and the bottom of the microchannel 104. The main uses of the input / output ports 106 and 106 are (a) injection of reagents and specimen samples (dispensing), (b) extraction of waste liquids and products, and (c) supply of gas pressure (mainly for liquid feeding (D) Release to the atmosphere (dispersion of internal pressure generated during liquid delivery, release of gas generated by reaction) and (e) Sealing (preventing liquid evaporation and deliberately reducing internal pressure) For the purpose of generating).

  In such a microchip, a microvalve may be provided in the middle of the microchannel for the purpose of controlling the flow of a continuous fluid (for example, liquid or gas) and the transfer of microdroplets. Such a microvalve is described in Patent Document 1 and Patent Document 2, for example.

  The microvalve described in FIG. 1 of Patent Document 1 has a thick first conduit and a diameter smaller than that of the first conduit, and one end communicates with the first conduit. A plurality of connected thin tubes and a second conduit formed so as to be larger in diameter than the thin tube and connected to the other end of the thin tube, and the inner wall of the thin tube is made hydrophobic. It consists of being formed. According to the microvalve, when the liquid is introduced into the first conduit, the first pressure is determined according to the pressure difference between the pressure on the first conduit side and the pressure on the second conduit side with the liquid as a boundary. The position of the liquid in the conduit can be arbitrarily controlled. However, in the microvalve disclosed in Patent Document 1, it is very difficult to form a plurality of capillaries, and there is a risk that the capillaries will be damaged if the pressure difference is too large. In addition, it is very difficult to make only the thin tube portion specifically hydrophobic. Furthermore, the microvalve of the microvalve of Patent Document 1 cannot function as a check valve, and a pressure difference cannot be generated unless a pump is used. Therefore, fine adjustment of the flow rate is very difficult.

  The microvalve described in FIG. 3 of Patent Document 2 is composed of two polydimethylsiloxane (PDMS) micro-channel chips and one membrane, and the membrane that moves in the valve region operates by attaching and detaching to the valve seat. A valve mechanism for opening and closing the fluid passage; Further, in this microvalve, a driving fluid passage having a pressure chamber in which the pressure of the driving fluid acts in the valve region is formed by bonding to the membrane, and the membrane is obtained by supplying and discharging the pressure of the driving fluid to and from the pressure chamber. Is configured to be opened and closed as a one-way valve by detaching it from the valve seat. However, the microvalve described in Patent Document 2 has only insufficient displacement between the membrane and the valve seat when the valve is opened because the membrane that is attached to and detached from the toilet seat is only displaced in one direction toward the pressure chamber. The fluidity of the fluid is low, causing pulsating flow. Even if the valve can be opened and closed, it is difficult to finely adjust the flow rate. Furthermore, since the pressure of the driving fluid is supplied from the vacuum pump via the glass pipe, the entire apparatus becomes complicated and expensive.

  The microvalves as shown in Patent Documents 1 and 2 are only considered for use as a flow system from an access tube to a chip. The use of the access tube means that an external pressure is used. As a result, the apparatus becomes large and the structure becomes complicated. Furthermore, when a process for processing a silicon wafer by anisotropic reactive ion etching is required in the manufacturing process as in the invention described in Patent Document 1, due to processing time, reaction chamber capacity limit, throughput problems, etc. This method is unsuitable for mass production and is unsuitable for disposable chips because of the increased cost and processing time of the reaction gas used. Moreover, the microvalves as shown in Patent Documents 1 and 2 cannot be used for the purpose of switching a plurality of liquid reagents in random order and supplying them to the microchannel.

JP 2000-27813 A Japanese Patent No. 3418727

  Accordingly, an object of the present invention is to provide a novel microvalve that can function as a switching valve and a check valve when mounted on a microchip, and can easily perform fine adjustment of the flow rate. is there.

According to a first aspect of the present invention, there is provided a microchip that includes an upper substrate and a lower substrate, and has one or more microchannels disposed between the substrates.
One or more microvalves are inserted in place in the microchannel,
The microvalve is composed of two sheet members having different thicknesses, and the thick sheet member is provided with one or more recesses and an air flow path communicating with the recesses, and is thin. The sheet member is bonded to the surface of the thick sheet member so as to shield the groove and the recess of the thick sheet member,
The ratio (T ₁ : T ₂ ) of the thickness (T ₁ ) of the thin sheet member to the bottom thickness (T ₂ ) of the recess is in the range of 1: 2 to 1:10;
The depth (D) of the recess is within a range of 1.3 to 5 times the bottom thickness (T ₂ ) of the recess.

  According to the present invention, when pressurized air is sent to the recess through the air flow path, the thin sheet member is greatly bulged like a balloon, and then the thick sheet member is also deformed to be slightly bulged. Due to the deformation stress difference generated in this way, the tip portion of the recess is bent toward the thick sheet member side. By utilizing this bending phenomenon, the valve can be opened and closed. The microvalve inserted into the microchannel of the microchip can be bent to open and close the microchannel.

  The invention of claim 2 as means for solving the above-mentioned problems is characterized in that the thick sheet member and the thin sheet member are both made of silicone rubber made of polydimethylsiloxane (PDMS). It is a microchip.

  According to the present invention, the thick sheet member and the thin sheet member can be permanently bonded to each other at locations other than the air flow path and the recess. As a result, when pressurized air is fed into the recess, only the thin sheet member of the recess can selectively expand like a balloon.

  The invention of claim 3 as means for solving the above-mentioned problems is the microchip according to claim 1, characterized in that the microvalve further has an adapter having a through hole communicating with the air flow path.

  According to this invention, pressurized air can be easily fed into the air flow path through the through hole of the adapter.

  Since the microvalve of the present invention can control the opening and closing operation by air pressure, it is not only easy to operate, but the valve structure is subtly changed by adjusting the air pressure, and the valve opening and closing amount is controlled to finely adjust the flow rate can do. The microvalve of the present invention can also function as a switching valve and a check valve. Furthermore, since it can be manufactured separately from the microchip, it is easy to manufacture, and as a result, low cost can be realized. After use, it can be reused by removing it from the microchip and mounting it on another new microchip.

  1 is a schematic plan view of an example of the microvalve of the present invention, FIG. 2 is a cross-sectional view taken along line II-II in FIG. 1, and FIG. 3 shows a driving state of the microvalve shown in FIG. 4 is a schematic sectional view, FIG. 4 is a partial schematic sectional view of an example of a microchip on which the microvalve shown in FIG. 1 is mounted, and FIG. 5 is a partial schematic sectional view showing a driving state of the microvalve in the microchip. is there.

  1 and 2, the microvalve 1 of the present invention has a two-sheet structure in which a thick first sheet member 3 and a thin second sheet member 5 are bonded together. The first sheet member 3 having a large thickness is formed with a recess 7 having a predetermined volume and an air flow path 9 communicating with the recess 7. Further, an adapter 11 for sending pressurized air into the recess 7 through the air flow path 9 is fixed on the upper surface of the second sheet member 5 having a small thickness. A through hole 13 communicating with the air flow path 9 is disposed in the adapter 11. A tube (not shown) from a pressure pump (not shown) can be connected to the through hole 13.

  As shown in FIG. 3, when pressurized air is sent from the through hole 13 of the adapter 11 to the concave portion 7 through the air flow path 9, the thin second sheet member 5 bulges greatly like a balloon, The thick first sheet member 3 is also deformed to slightly bulge. Due to the deformation stress difference thus generated, the tip portion of the recess 7 is bent toward the thick first sheet member 3 side. By utilizing this bending phenomenon, the microvalve 1 can be opened and closed. The magnitude of the bending changes according to the applied pressure. The applied pressure is about 40 kPa to 300 kPa. When the applied pressure is less than 40 kPa, bending hardly occurs. If the pressure exceeds 300 kPa, the bending angle saturates at around 180 °, and there is a risk that the microvalve itself may be damaged.

  In the microvalve 1 of the present invention, the first sheet member 3 and the second sheet member 5 are made of a flexible and stretchable material. Such a material is preferably a silicone rubber such as polydimethylsiloxane (PDMS). In particular, PDMS is particularly preferable because the sheets are permanently bonded to each other by surface modification and do not cause peeling.

What is important in the microvalve 1 of the present invention is the ratio of the thickness of the first sheet member 3 and the thickness of the second sheet member 5 in the recess 7. Generally, the thickness ratio of _{T 2} of the thickness _{T 1} of the second sheet member 5 in the recess 7 and the first sheet member _{3, T 1: T 2 = 1} : 2~1: 10 in the range of It is preferable that When T ₁ : T ₂ is less than 1: 2, for example, 1: 1, the expansion ratio and deformation stress of the first sheet member 3 and the second sheet member 5 become equal, and the recess 7 is a perfect circle. It just expands like a balloon and doesn't bend. On the other hand, when T ₁ : T ₂ is greater than 1:10, for example, 1:11, even if the second sheet member 5 expands, the first sheet member 3 hardly expands or contracts, so the deformation stress is the first. However, there is a risk that the second sheet member 5 may burst without being generated in the first sheet member 3.

In addition, the depth D from the bottom of the recess 7 to the lower surface of the second sheet member 5 (hereinafter referred to as “depth D of the recess 7”) is greater than the thickness T _{2 of} the first sheet member 3. is necessary. The depth D of the recess 7 is preferably about 1.3 to 5 times larger than the thickness T ₂ of the first sheet member 3. The depth D of the concave portion 7 is less than 1.3 times greater than the thickness T ₂ of the first sheet member 3, it is difficult to precisely control the degree of flexion. On the other hand, the depth D of the concave portion 7 is in the 5-fold greater than the thickness T ₂ of the first sheet member 3, the volume of the recess 7 becomes too large, the bending response is reduced.

  The width and height of the air flow path 9 can be selected as appropriate. For example, the air channel 9 may have a width of about 10 μm to 500 μm and a height of about 10 μm to 300 μm.

  As a method of forming the air flow path 9 and the concave portion 7 in the first sheet member 3, any conventional method known to those skilled in the art can be used. For example, a PDMS prepolymer can be poured into a silicone mold produced by photolithography and polymerized, or a mechanical engraving method can be used.

  When using the adapter 11, it is preferable that this member is also comprised from PDMS. This is because when the adapter 11 is made of PDMS, the adapter 11 can be permanently bonded to the upper surface of the second sheet member 5 made of PDMS. However, the adapter 11 can be made of other materials (for example, thermoplastic synthetic resin). When the adapter 11 is made of a material other than PDMS, an adhesive (for example, epoxy resin) or the like can be used as necessary to fix the adapter 11 to the upper surface of the second sheet member 5. .

  FIG. 4A is a partial schematic cross-sectional view of an example of a microchip 20 on which the microvalve 1 of the present invention is mounted. The microchip 20 has an upper surface substrate 22 and a lower surface substrate 24 as well as known and commonly used microchips, and a microchannel (flow path) 26 between the substrates. The microvalve 1 is inserted vertically from one substrate side (upper surface substrate 22 side in FIG. 4A) so as to close the microchannel (flow path) 26. A suitable adhesive or sealant 28 can be used to seal the top of the insertion hole formed in the top substrate 22. In FIG. 4A, a step is provided on the lower substrate 24 side, but this step may not be provided.

  FIG. 4B is a partial schematic cross-sectional view showing the operating state of the microvalve 1. When pressurized air is sent from the through hole 13 of the adapter 11 to the recess 7 through the air flow path 9, the thin second sheet member 5 bulges like a balloon, and then the thick first sheet member 3 also Deforms to slightly bulge. Bending occurs due to the deformation stress difference between the second sheet member 5 and the first sheet member 3 caused by the swelling. By utilizing this bending, the microvalve 1 can be opened and closed. Therefore, as shown in FIG. 4A, when pressurized air is not sent, the microvalve 1 maintains the microchannel 26 in a closed state, and when pressurized air is fed as shown in FIG. 4B, the microvalve 1 Opens the microchannel 26. If the supply of pressurized air is stopped and the pressure is returned to atmospheric pressure, the microvalve 1 is restored to the state shown in FIG. 4A again. In this way, the microvalve 1 can be bent and the microchannel 26 can be opened and closed by feeding and stopping the pressurized air.

  In FIG. 4A, the microvalve 1 is inserted vertically into the microchannel 26 from the upper substrate 22 side, but can also be inserted vertically into the microchannel 26 from the lower substrate 24 side. Alternatively, the microvalve 1 can be inserted horizontally into the microchannel 26.

  FIG. 5 is a schematic plan view of another embodiment of the microvalve of the present invention. The recess is not rectangular but circular, and a plurality of circular recesses 7-1 and 7-2 are connected by the air flow path 9. Such a microvalve 1A can cause different bends, such as a finger joint, by combining the deformation stress differences around the plurality of circular recesses 7-1 and 7-2. As a result, a plurality of microchannels can be opened and closed with a single microvalve.

(1) Fabrication of microvalve According to a conventional optical lithography method, the air channel protrusion having a width of about 20 μm, a height of about 20 μm and a length of about 300 μm, a lateral width of about 200 μm, a vertical width of about 100 μm, and a height of about 70 μm. A 4 inch-size mold having a concave projection was prepared. The surface of this mold was treated with a reactive ion etching system in the presence of fluorocarbon (CHF ₃ ) to form a CHF ₃ release film on the surface. SYLGARD 184 SILICONE ELASTOMER, manufactured by Dow Corning, USA, is molded as a PDMS prepolymer mixture on the master's release film forming surface in a thick mold, and stretched to a thickness of about 0.5 mm with N ₂ spray. , Warmed (65 ° C., 4 hours). After 4 hours, the first sheet member made of PDMS having a thickness of about 120 μm was peeled from the mold. The bottom surface thickness of the recess was about 50 μm. A second sheet member made of PDMS having a thickness of about 20 μm was prepared. A through hole was previously drilled at an appropriate position of the second sheet member. After surface modification of both sheets in accordance with a conventional method, the through hole of the second sheet member is aligned with the end of the air flow path of the first sheet member, and then the second sheet is formed on the upper surface of the first sheet member. The sheet member was permanently bonded. Thereafter, the adapter prepared in advance was permanently bonded to both members in which the through hole of the adapter and the through hole of the second sheet member were aligned.
(2) Production of microvalve-mounted microchip A microchip having a width of about 200 μm and a height of about 400 μm and an open port with an inner diameter of about 2 mm at both ends of the channel was produced according to a conventional method. A through hole was drilled from the outer surface side of the upper substrate, and the microvalve produced in (1) was inserted through this through hole. An epoxy resin adhesive was applied to the external interface between the microvalve and the through hole, the through hole was sealed, and a microvalve-mounted microchip as shown in FIG. 4A was produced.
(2) Liquid feeding confirmation test A tube for applying air pressure was connected to the adapter of the microvalve of the microchip manufactured in (2). When purified water colored in red was forcibly injected from one port, it was blocked at the microvalve. When pressurized air is sent from a tube connected to the adapter of the microvalve, the microvalve gradually begins to bend, and a gap is created between the bottom of the microvalve and the bottom of the microchannel with an applied pressure of about 100 kPa. The colored liquid has been pushed out to the other port. When the pressure applied to the microvalve was returned to atmospheric pressure, the colored liquid was not pushed out to the other port.

  The microchip using the microvalve of the present invention can be used in various fields such as medicine, veterinary medicine, dentistry, pharmacy, life science, food, agriculture, and fisheries. In particular, as an optimal microchip for fluorescent antibody method, in situ hybridization, etc., immunological disease test, cell culture, virus fixation, pathological test, cytology, biopsy histology, blood test, bacterial test, protein analysis, DNA analysis, It can be used in a wide range of areas such as RNA analysis.

It is an outline top view of an example of a microvalve of the present invention. It is sectional drawing along the II-II line in FIG. It is a schematic sectional drawing which shows the drive state of the microvalve shown by FIG. It is a partial outline sectional view of an example of microchip 20 which mounts microvalve 1 of the present invention. FIG. 4B is a partial schematic cross-sectional view showing an operating state of the microvalve 1 shown in FIG. 4A. It is a general | schematic top view of another embodiment of the microvalve of this invention. It is a general | schematic top view of an example of the conventional microchip. It is a schematic sectional drawing in alignment with the BB line in FIG. 6A.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Micro valve of this invention 3 1st sheet | seat member 5 2nd sheet | seat member 7 Recessed part 9 Air flow path 11 Adapter 13 Through-hole 20 Microchip 22 Upper surface substrate 24 Lower surface substrate 26 Microchannel 100 Conventional microchip 102 Upper surface substrate 104 Micro channel 106 Port 108 Bottom substrate

Claims (3)

In a microchip comprising an upper substrate and a lower substrate and having one or more microchannels disposed between the substrates,
One or more microvalves are inserted in place in the microchannel,
The microvalve is composed of two sheet members having different thicknesses, and the thick sheet member is provided with one or more recesses and an air flow path communicating with the recesses, and is thin. The sheet member is bonded to the surface of the thick sheet member so as to shield the groove and the recess of the thick sheet member,
The ratio (T ₁ : T ₂ ) of the thickness (T ₁ ) of the thin sheet member to the bottom thickness (T ₂ ) of the recess is in the range of 1: 2 to 1:10;
The depth (D) of the recess is in the range of 1.3 to 5 times the bottom thickness (T ₂ ) of the recess. 2. The microchip according to claim 1, wherein both the thick sheet member and the thin sheet member are made of silicone rubber made of polydimethylsiloxane (PDMS). The microchip according to claim 1, wherein the microvalve further includes an adapter having a through hole communicating with the air flow path.

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