Microchannel Chip and Its Manufacturing Method

Abstract

An object of the present invention is to provide a microchannel chip and a manufacturing method thereof. Even after high-temperature and high-pressure sterilization treatment, the channels of the microchannel chip will not deform, and strong bonding between the substrates can be maintained. The microchannel chip of the present invention includes a channel substrate having microchannels formed on at least one surface, a cover substrate, and a bonding layer for bonding them. The channel substrate, the cover substrate, and the bonding layer are made of a cyclic olefin polymer, and the glass transition temperature Tg of the cyclic olefin polymer constituting the channel substrate s1 , the glass transition temperature Tg of the cyclic olefin polymer constituting the cover substrate s2 , and the glass transition temperature Tg2 of the cyclic olefin polymer constituting the bonding layer satisfy the relationship: Tg s1 > Tg2, and Tg s2 > Tg2, and the thickness of the bonding layer is within a specified range.

Description

Technical Field

[0001] The present invention relates to a microchannel chip and a method for manufacturing the same. Background Art

[0002] In recent years, a chip (microchannel chip) having microchannels and reaction vessels in the micron order formed by microfabrication technology has been used in various fields such as analysis and inspection of biological substances such as DNA, RNA, and proteins, drug research and pharmaceutical development, organic synthesis, and water quality analysis.

[0003] In addition, as a microchannel chip, a resin microchannel chip that can be manufactured at low cost has attracted attention.

[0004] Moreover, a resin microchannel chip is manufactured by interposing a bonding layer between a resin substrate having microchannels formed on at least one surface and a resin cover substrate as a cover material and bonding them by heating (see, for example, Patent Documents 1 to 4).

[0005] Prior Art Documents

[0006] Patent Documents

[0007] Patent Document 1: Japanese Patent No. 5948248;

[0008] Patent Document 2: Japanese Unexamined Patent Application Publication No. 2008-304352;

[0009] Patent Document 3: Japanese Patent No. 5948248;

[0010] Patent Document 4: International Publication No. 2014 / 178439. Summary of the Invention

[0011] Problems to be Solved by the Invention

[0012] In the case of performing a high-temperature and high-pressure sterilization treatment such as steam sterilization on a microchannel chip, when the bonding layer is thick, a problem of channel deformation occurs during the sterilization treatment. In addition, in a microchannel chip made of a cyclic olefin polymer that is transparent and has low autofluorescence as a substrate material, conventionally, in order to enhance the bondability between the substrates, an adhesive material other than the cyclic olefin polymer is used. In such a microchannel chip, a problem of noise during optical signal detection due to the autofluorescence of the adhesive material occurs. A microchannel chip in which all components are made of a cyclic olefin polymer and can maintain strong bondability between the substrates without using an autofluorescent material such as an adhesive material has not been known so far.

[0013] Accordingly, an object of the present invention is to provide a microchannel chip and a method for manufacturing the same. Even when the microchannel chip is subjected to high-temperature and high-pressure sterilization treatment, the channels will not deform, and even when a cyclic olefin polymer is used as the material for the entire microchannel chip, strong bonding between the substrates can be maintained.

[0014] Solution to the problem

[0015] The inventors of the present invention conducted in-depth research to solve the above problems and found that by forming the bonding layer into a thin film, deformation of the channels caused by high-temperature and high-pressure sterilization treatment can be suppressed, and by using cyclic olefin polymers having a relationship of a specified glass transition temperature as the materials for the substrate and the bonding layer, respectively, strong bonding between the substrates can be maintained, thus completing the present invention.

[0016] Thus, according to the present invention, a microchannel chip and a method for manufacturing the same as described below can be provided.

[0017] [1] A microchannel chip, comprising a channel substrate having microchannels formed on at least one surface, a cover substrate, and a bonding layer for bonding them,

[0018] The channel substrate, the cover substrate, and the bonding layer are made of a cyclic olefin polymer,

[0019] The glass transition temperature Tg of the cyclic olefin polymer constituting the channel substrate s1 , the glass transition temperature Tg of the cyclic olefin polymer constituting the cover substrate s2 , and the glass transition temperature Tg of the cyclic olefin polymer constituting the bonding layer 2 are related as follows:

[0020] Tg s1 >Tg 2 , and

[0021] Tg s2 >Tg 2 ,

[0022] The thickness of the bonding layer is less than 50 μm.

[0023] [2] The microchannel chip according to the above [1], wherein Tg s1 and Tg s2 are 125° C. or higher, and

[0024] Tg s1 ≥Tg 2 +10° C.,

[0025] Tg s2 ≥Tg 2 +10° C.

[0026] [3]A manufacturing method of a microchannel chip, which is the manufacturing method of the microchannel chip described in the above [1] or [2],

[0027] including the step of bonding a channel substrate and a cover substrate via a bonding layer by thermal fusion bonding.

[0028] [4]According to the manufacturing method described in the above [3], wherein: it includes:

[0029] a process of forming a bonding layer on at least one of the channel-forming substrate and the cover substrate,

[0030] a process of forming a channel on the channel-forming substrate with the bonding layer formed thereon or the channel-forming substrate without the bonding layer formed thereon, and forming a channel substrate with the bonding layer formed thereon or a channel substrate without the bonding layer formed thereon,

[0031] a process of bonding at least one combination of a channel substrate with the bonding layer formed thereon and a cover substrate without the bonding layer formed thereon, a channel substrate without the bonding layer formed thereon and a cover substrate with the bonding layer formed thereon, and a channel substrate with the bonding layer formed thereon and a cover substrate with the bonding layer formed thereon via the bonding layer by thermal fusion bonding.

[0032] [5]According to the manufacturing method described in the above [3], wherein, it includes:

[0033] a process of forming a channel substrate having channels formed on at least one surface,

[0034] a process of forming a bonding layer on at least one surface of at least one of the channel substrate and the cover substrate except for the part corresponding to the channel,

[0035] a process of bonding at least one combination of a channel substrate with the bonding layer formed thereon and a cover substrate without the bonding layer formed thereon, a channel substrate without the bonding layer formed thereon and a cover substrate with the bonding layer formed thereon, and a channel substrate with the bonding layer formed thereon and a cover substrate with the bonding layer formed thereon via the bonding layer by thermal fusion bonding.

[0036] Advantages of the Invention

[0037] According to the present invention, it is possible to provide a microchannel chip and a manufacturing method thereof. Even when the above microchannel chip is subjected to high-temperature and high-pressure sterilization treatment, the channels are not deformed, and strong bondability between the substrates can be maintained. Brief Description of the Drawings

[0038] Figure 1 It is a schematic diagram of the manufacturing method of the microchannel chip of the present invention in which channels are formed after the bonding layer is formed.

[0039] Figure 2It is a schematic diagram of a manufacturing method of a microchannel chip according to the present invention in which a bonding layer is formed after a channel substrate having channels is formed.

[0040] Figure 3 (a) of is a top view showing an example of a channel substrate of a microchannel chip, Figure 3 and (b) of is a top view showing an example of a cover substrate of a microchannel chip. Detailed Description of the Invention

[0041] Hereinafter, embodiments of the present invention will be described in detail.

[0042] (Microchannel Chip)

[0043] The microchannel chip of the present invention includes a channel substrate s1 having microchannels formed on at least one surface, a cover substrate s2, and a bonding layer for bonding them. In addition, in the microchannel chip of the present invention,

[0044] the channel substrate s1, the cover substrate s2, and the bonding layer are made of a cyclic olefin polymer,

[0045] the glass transition temperature Tg of the cyclic olefin polymer constituting the channel substrate s1 , the glass transition temperature Tg of the cyclic olefin polymer constituting the cover substrate s2 , the glass transition temperature Tg of the cyclic olefin polymer constituting the bonding layer 2 are related as follows:

[0046] Tg s1 > Tg 2 , and

[0047] Tg s2 > Tg 2 ,

[0048] the thickness of the bonding layer is less than 50 μm.

[0049] <Channel Substrate>

[0050] As the channel substrate, a substrate made of a cyclic olefin polymer having microchannels formed on at least one surface can be used. Moreover, the channel substrate bonds to the cover substrate with the surface on which the microchannels are formed as the bonding surface.

[0051] Here, the width, depth, and shape of the microchannels can be appropriately changed according to the use of the microchannel chip, and are usually below the millimeter level, and can also be at the nanometer level, preferably at the micrometer level. Specifically, the width of the microchannels is not particularly limited and can be, for example, 10 μm or more and 800 μm or less.

[0052] Moreover, the formation of microchannels on a substrate made of a cyclic olefin polymer can be carried out using, for example, microfabrication techniques such as photolithography and hot embossing, cutting, injection molding, etc. In addition, the formation of channels can be carried out on a channel-forming substrate without a bonding layer formed thereon, or on a channel-forming substrate after a bonding layer is formed. The formation of channels on a channel-forming substrate without a bonding layer formed thereon can be carried out using, for example, microfabrication techniques such as photolithography and hot embossing, cutting, injection molding, etc. The formation of channels on a channel-forming substrate after a bonding layer is formed can be carried out by applying, for example, microfabrication techniques such as photolithography and hot embossing, cutting, etc. to the surface of the channel-forming substrate where the bonding layer is formed.

[0053] <Cover substrate>

[0054] As the cover substrate, any substrate made of a cyclic olefin polymer that can cover the microchannels formed on the channel substrate can be used. Specifically, as the cover substrate, a substrate having a smooth surface that can cover the channel substrate and optionally having a through hole that serves as an injection port for injecting a sample or the like into the microchannels of the channel substrate when forming a microchannel chip together with the channel substrate can be used. Moreover, the cover substrate is bonded to the channel substrate with the smooth surface side as the bonding surface. In addition, as the cover substrate, a substrate having microchannels formed on the surface opposite to the smooth surface side bonded to the channel substrate can also be used.

[0055] In addition, the formation of through holes on a substrate made of a cyclic olefin polymer can be carried out using, for example, microfabrication techniques such as photolithography and hot embossing, cutting, injection molding, etc. In addition, the formation of through holes can be carried out on a channel-forming substrate without a bonding layer formed thereon, or on a channel-forming substrate after a bonding layer is formed. The formation of through holes on a channel-forming substrate without a bonding layer formed thereon can be carried out using, for example, microfabrication techniques such as photolithography and hot embossing, cutting, injection molding, etc. The formation of through holes on a channel-forming substrate after a bonding layer is formed can be carried out by applying, for example, microfabrication techniques such as photolithography and hot embossing, cutting, etc. to the surface of the channel-forming substrate where the bonding layer is formed.

[0056] <Bonding layer>

[0057] The bonding layer is a member formed on the channel substrate or the cover substrate for bonding the channel substrate and the cover substrate.

[0058] The thickness of the bonding layer is less than 50 μm, preferably 40 μm or less, more preferably 10 μm or less, and further preferably 5 μm or less. The thinner the bonding layer, the thinner the bonding layer becomes a film. Therefore, channel deformation during steam sterilization treatment of the microchannel chip can be suppressed. In addition, the thickness of the bonding layer may be the minimum thickness that can ensure the adhesiveness between the channel substrate and the cover substrate, and may be, for example, 0.1 μm or more, preferably 0.12 μm or more, more preferably 0.15 μm or more, and further preferably 0.2 μm or more.

[0059] The ratio of the thickness of the bonding layer to the depth of the channel may be, for example, 0.1 / 100 or more, preferably 0.12 / 100 or more, more preferably 0.15 / 100 or more, and further preferably 0.2 / 100 or more. In addition, the ratio of the thickness of the bonding layer to the depth of the channel may be, for example, 50 / 100 or less, preferably 30 / 100 or less, more preferably 20 / 100 or less, and further preferably 10 / 100 or less.

[0060] <Materials of the channel substrate, cover substrate, and bonding layer>

[0061] As the materials of the channel substrate, cover substrate, and bonding layer, cyclic olefin polymers can be used. Since cyclic olefin polymers have less reduction in bonding strength over time due to moisture absorption and less reduction in optical stability, they are suitable for microchannel chips with excellent durability. In addition, since cyclic olefin polymers are transparent and have low autofluorescence, they are suitable for detecting optical signals from the microchannels of the microchannel chip. By making all the materials of the microchannel chip cyclic olefin polymers and not using adhesive materials such as autofluorescent materials, noise during optical signal detection caused by the autofluorescence of the adhesive material can be suppressed. The cyclic olefin polymers used as the materials of the channel substrate, cover substrate, and bonding layer satisfy the relationship of the glass transition temperature described below. By satisfying such a relationship of the glass transition temperature, even if all the materials of the microchannel chip are cyclic olefin polymers, strong bonding between the substrates can be maintained. The types of cyclic olefin polymers used as the materials of the channel substrate, cover substrate, and bonding layer can be appropriately selected, for example, from the specific examples described below, cyclic olefin polymers that satisfy the relationship of the glass transition temperature. The cyclic olefin polymers used as the materials of the channel substrate, cover substrate, and bonding layer are preferably cyclic olefin polymers with a water absorption rate of 0.01% by mass or less. The types of cyclic olefin polymers used as the materials of the channel substrate and cover substrate may be the same or different.

[0062] <<Glass transition temperature of cyclic olefin polymer>>

[0063] The glass transition temperature Tg of the cyclic olefin polymer used as the material of the channel substrate s1 s1, the glass transition temperature Tg of the cyclic olefin polymer used as the material of the cover substrate s2 s2 , the glass transition temperature Tg of the cyclic olefin polymer used as the material of the bonding layer 2 satisfy the following relationship.

[0064] Tg sl > Tg 2 , and

[0065] Tg s2 > Tg 2 .

[0066] By satisfying the above relationship, if, in the manufacture of the microchannel chip, the channel substrate and the cover substrate are bonded at a temperature higher than Tg 2 and lower than Tg s1 and Tg s2 , then the channel substrate and the cover substrate can be prevented from softening, deforming, and deteriorating, and only the bonding layer can be softened, enabling bonding by hot melting.

[0067] Tg s1 is preferably 125 °C or higher, more preferably 130 °C or higher. By having Tg s1 within such a range, softening, deformation, and deterioration of the channel substrate caused by heating (e.g., autoclaving) during the manufacture and sterilization of the microchannel chip can be suppressed. In addition, Tg s1 is preferably 180 °C or lower, more preferably 160 °C or lower. Furthermore, in this case, the difference between Tg s1 and Tg 2 is preferably 10 °C or higher (i.e., Tg s1 ≥ Tg 2 + 10 °C), more preferably 15 °C or higher (i.e., Tg s1 ≥ Tg 2 + 15 °C), and further preferably 20 °C or higher (i.e., Tg s1 ≥ Tg 2 + 20 °C). The greater the difference between Tg s1 and Tg 2 , the easier it is to set the heating temperature that does not soften, deform, or deteriorate the channel substrate but only softens the bonding layer during the manufacture of the microchannel chip. In addition, the difference between Tg s1 and Tg 2 is preferably 100 °C or lower, more preferably 90 °C or lower, and further preferably 80 °C or lower. The smaller the difference between Tg s1 and Tg 2 , the better the temperature stability of the bonding layer.

[0068] Tg s2 is preferably 125 °C or higher, more preferably 130 °C or higher. By having Tg s2Within such a range, softening, deformation, and deterioration of the cover substrate caused by heating (e.g., autoclave) during the manufacture and sterilization of the microchannel chip can be suppressed. In addition, the Tg s2 is preferably 180 °C or lower, more preferably 160 °C or lower. Furthermore, in this case, the Tg s2 and the Tg 2 difference is preferably 10 °C or more (i.e., Tg s2 ≥ Tg 2 + 10 °C), more preferably 15 °C or more (i.e., Tg s2 ≥ Tg 2 + 15 °C), and further preferably 20 °C or more (i.e., Tg s2 ≥ Tg 2 + 20 °C). The larger the difference between Tg s2 and Tg 2 , the easier it is to set the heating temperature in the manufacture of the microchannel chip such that only the bonding layer softens without softening, deforming, or deteriorating the cover substrate. In addition, the difference between Tg s2 and Tg 2 is preferably 100 °C or lower, more preferably 90 °C or lower, and further preferably 80 °C or lower. The smaller the difference between Tg s2 and Tg 2 , the better the temperature stability of the bonding layer.

[0069] Tg 2 is preferably 50 °C or higher, more preferably 65 °C or higher. By having Tg 2 within such a range, the temperature stability of the bonding layer is good. In addition, Tg 2 is preferably 130 °C or lower, more preferably 110 °C or lower, and further preferably 100 °C or lower. By having Tg 2 within such a range, it is easy to set the heating temperature that only softens the bonding layer during the manufacture of the microchannel chip.

[0070] In the present invention, the glass transition temperature can be measured by differential scanning calorimetry (DSC) based on JIS-K7121.

[0071] <<Types of cyclic olefin polymers>>

[0072] The cyclic olefin polymer is, for example, a polymer or copolymer (hereinafter sometimes collectively referred to as "polymer") obtained by polymerizing the monomers described later or their hydrides. The cyclic olefin polymer can be crystalline or non-crystalline, and is preferably non-crystalline. As the monomer of the cyclic olefin polymer, norbornene-based monomers are preferably cited. The norbornene-based monomer is a monomer containing a norbornene ring. As the norbornene-based monomer, for example, bicyclo[2.2.1]hept-2-ene (common name: norbornene), 5-ethylidene-bicyclo[2.2.1]hept-2-ene (common name: ethylidene norbornene), and their derivatives (having substituents on the ring) and other bicyclic monomers; tricyclo[5.2.1.0 2,6 dec-3,8-diene (common name: dicyclopentadiene) and its derivatives and other tricyclic monomers; tetracyclo[7.4.0.0 2,7 .1 10,13 tetradeca-2,4,6,11-tetraene (common name: methano-tetrahydrofluorene), tetracyclo[6.2.1.1 3,6 .0 2,7 dodec-4-ene (common name: tetracyclododecene), 9-ethylidene tetracyclo[6.2.1.1 3,6 .0 2,7 dodec-4-ene, and their derivatives and other tetracyclic monomers, etc. These monomers can have substituents at any position. As the substituents, alkyl, alkylene, vinyl, alkoxycarbonyl, alkylidene, etc. can be exemplified, and the above-mentioned norbornene-based monomers can have two or more of the above-mentioned substituents. As the derivatives, specifically, 8-methoxycarbonyl-tetracyclo[4.4.0.1 2,5 .1 7,10 dodec-3-ene, 8-methyl-8-methoxycarbonyl-tetracyclo[4.4.0.1 2,5 .1 7,10 dodec-3-ene, 8-ethylidene-tetracyclo[4.4.0.1 2,5 .1 7,10 dodec-3-ene, etc. can be cited. These norbornene-based monomers can be used alone or in combination of two or more. In addition, the cyclic olefin polymer can be an addition polymer, a ring-opening polymer, or their hydrides, and is preferably a ring-opening polymer or a ring-opening polymer hydride. The cyclic olefin polymer used as the material of the substrate (channel substrate, cover substrate) is preferably a polymer obtained by polymerizing monomers in which the content of methano-tetrahydrofluorene (MTF) is 25 parts by weight or more relative to the total of 100 parts by weight of the monomers. The cyclic olefin polymer used as the material of the bonding layer is preferably a polymer obtained by polymerizing monomers in which the content of dicyclopentadiene (DCPD) is 30 parts by weight or more relative to the total of 100 parts by weight of the monomers.

[0073] The above-mentioned ring-opening polymer can be produced by a method using a ring-opening polymerization catalyst. As the ring-opening polymerization catalyst, for example, a catalyst formed from a halide, nitrate, or acetylacetone compound of a metal such as ruthenium or osmium, and a reducing agent, or a catalyst formed from a halide or acetylacetone compound of a metal such as titanium, zirconium, tungsten, or molybdenum, and an organoaluminum compound can be used. The ring-opening polymer can be produced, for example, by a method using a metathesis reaction catalyst (ring-opening polymerization catalyst) such as the ruthenium carbene complex catalyst described in International Publication No. 2010 / 110323, and a method using a ring-opening polymerization catalyst such as tungsten(phenylimide)tetrachloride-tetrahydrofuran complex, tungsten hexachloride, etc. described in Japanese Unexamined Patent Application Publication No. 2015-54885.

[0074] The above-mentioned addition polymer can be obtained by polymerizing a monomer using a known addition polymerization catalyst, for example, a catalyst formed from a titanium, zirconium, or vanadium compound and an organoaluminum compound. The addition polymer can be produced, for example, by addition copolymerizing a monomer of a cyclic olefin polymer and, if necessary, a monomer capable of addition copolymerization (other monomer) in the presence of the metathesis catalyst described in International Publication No. 2017 / 199980.

[0075] As other monomers capable of ring-opening copolymerization with a norbornene-based monomer, monocyclic cyclic olefin-based monomers such as cyclohexene, cycloheptene, and cyclooctene can be cited.

[0076] These other monomers capable of ring-opening copolymerization with a norbornene-based monomer can be used alone or in combination of two or more. When the norbornene-based monomer and other monomers capable of ring-opening copolymerization therewith are subjected to ring-opening copolymerization, the ratio of the structural unit derived from the norbornene-based monomer to the structural unit derived from other monomers capable of ring-opening copolymerization in the ring-opening polymer can be appropriately selected so as to be generally in the range of 70:30 to 99:1 by weight, preferably in the range of 80:20 to 99:1, and more preferably in the range of 90:10 to 99:1.

[0077] As other monomers capable of addition copolymerization with a norbornene-based monomer, for example, α-olefins having 2 to 20 carbon atoms such as ethylene, propylene, 1-butene, 1-pentene, and 1-hexene, and their derivatives; cycloolefins such as cyclobutene, cyclopentene, cyclohexene, cyclooctene, and 3a,5,6,7a-tetrahydro-4,7-methano-1H-indene, and their derivatives; non-conjugated dienes such as 1,4-hexadiene, 4-methyl-1,4-hexadiene, 5-methyl-1,4-hexadiene, and 1,7-octadiene can be cited. Among these, α-olefins are preferred, and ethylene is particularly preferred.

[0078] These other monomers capable of addition copolymerization with norbornene-based monomers can be used individually or in combination of two or more. When carrying out addition copolymerization of a norbornene-based monomer and other monomers capable of addition copolymerization therewith, the ratio of the structural unit derived from the norbornene-based monomer to the structural unit derived from other monomers capable of addition copolymerization in the addition polymer can be appropriately selected so that it is generally in the range of 30:70 to 99:1 by weight, preferably in the range of 50:50 to 97:3, and more preferably in the range of 70:30 to 95:5.

[0079] Furthermore, as a method for producing an alicyclic structure-containing ring-opening polymer hydride by hydrogenating a ring-opening polymer, for example, a method using a hydrogenation catalyst described in International Publication No. 2010 / 110323 can be cited. In addition, for example, after producing an alicyclic structure-containing polymer using the above ruthenium carbene complex catalyst as a ring-opening polymerization catalyst, the ruthenium carbene catalyst can also be directly used as a hydrogenation catalyst to hydrogenate the alicyclic structure-containing ring-opening polymer to produce an alicyclic structure-containing ring-opening polymer hydride.

[0080] The glass transition temperature (Tg) of the cyclic olefin polymer can be appropriately adjusted according to the type and blending ratio of the monomers used in the polymerization, the average molecular weight and molecular weight distribution of the polymer, and the like.

[0081] In the microchannel chip of the present invention, at least one of the channel substrate, the cover substrate, and the bonding layer can be composed of two or more layers having different Tg values.

[0082] (Method for manufacturing a microchannel chip)

[0083] The microchannel chip of the present invention can be manufactured by, for example, the manufacturing method described below (hereinafter referred to as "the manufacturing method of the present invention").

[0084] The manufacturing method of the present invention includes a step of bonding a channel substrate and a cover substrate via a bonding layer by thermocompression bonding.

[0085] In one embodiment, the manufacturing method of the present invention can be carried out in the order of forming a bonding layer on the entire surface of the substrate and then forming channels on the substrate. That is, the manufacturing method of the present invention can be carried out through the following processes.

[0086] (1) A process of forming a bonding layer on at least one of the channel-forming substrate and the cover substrate,

[0087] (2) A process of forming channels on the channel-forming substrate having a bonding layer formed thereon or the channel-forming substrate without a bonding layer formed thereon by, for example, cutting, photolithography, or hot embossing to form a channel substrate having a bonding layer formed thereon or a channel substrate without a bonding layer formed thereon,

[0088] (3) A step of joining at least one of the combinations of a channel substrate having a bonding layer formed thereon and a cover substrate not having a bonding layer formed thereon, a channel substrate not having a bonding layer formed thereon and a cover substrate having a bonding layer formed thereon, and a channel substrate having a bonding layer formed thereon and a cover substrate having a bonding layer formed thereon via the bonding layer.

[0089] An example of a schematic diagram of the manufacturing method of this embodiment is shown in Figure 1 .

[0090] In this embodiment, the formation of the bonding layer can be carried out by coating a solution film of a cyclic olefin polymer, which is a material to become the bonding layer, on the entire surface of the substrate and evaporating the solvent. As the solvent, for example, organic solvents such as cyclohexane, tetrahydrofuran, toluene, xylene, decalin, methylcyclohexane, and ethylcyclohexane can be cited, and a mixed solvent thereof can also be used. The evaporation of the solvent can be carried out, for example, by drying at a temperature lower than the glass transition temperature of the cyclic olefin polymer, which is the material to become the bonding layer (for example, heat drying, room temperature drying), heat vacuum (reduced pressure) drying, or a combination thereof.

[0091] In addition, in this embodiment, when forming a channel on a channel-forming substrate having a bonding layer formed thereon, for example, by performing processing such as cutting, photolithography, or hot embossing on the surface of the channel-forming substrate having the bonding layer formed thereon, the channel-forming portion of the channel-forming substrate together with the bonding layer is removed.

[0092] In another embodiment, the manufacturing method of the present invention can also be carried out in the order of forming a bonding layer on a portion other than the portion corresponding to the channel in the surface of the substrate (channel substrate, cover substrate) after manufacturing a substrate (channel substrate) having a channel formed thereon. That is, the manufacturing method of the present invention can also be carried out through the following steps.

[0093] (1) A step of forming a channel substrate having channels formed on at least one surface.

[0094] (2) A step of forming a bonding layer on a portion other than the portion corresponding to the channel in at least one surface of at least one of the channel substrate and the cover substrate.

[0095] (3) A step of joining at least one of the combinations of a channel substrate having a bonding layer formed thereon and a cover substrate not having a bonding layer formed thereon, a channel substrate not having a bonding layer formed thereon and a cover substrate having a bonding layer formed thereon, and a channel substrate having a bonding layer formed thereon and a cover substrate having a bonding layer formed thereon via the bonding layer.

[0096] An example of a schematic diagram of the manufacturing method of this embodiment is shown in Figure 2 .

[0097] In this embodiment, the channel substrate having channels formed on at least one surface can be formed by, for example, injection molding of a cyclic olefin polymer that is the material of the substrate, or can be formed by performing microfabrication techniques such as photolithography and hot embossing or cutting on a substrate for channel formation.

[0098] In addition, in this embodiment, the formation of the bonding layer can be carried out by screen printing a solution of a cyclic olefin polymer that is the material of the bonding layer on portions of the substrate other than the portions corresponding to the channels, or by masking the portions corresponding to the channels on the substrate and performing spray coating to perform pattern coating and evaporating the solvent.

[0099] From the viewpoint of ease of manufacture, the manufacturing method of the present invention is preferably carried out by an embodiment including the step of forming a bonding layer on the entire surface of the substrate.

[0100] Thermal fusion bonding is carried out by overlapping the channel substrate and the cover substrate via the bonding layer to form a temporarily fixed bonded body, and heating the temporarily fixed bonded body to a temperature higher than Tg 2 and lower than Tg s1 and Tg s2 . As a device for performing thermal fusion bonding, for example, an autoclave, a hot press, a roll press, etc. can be cited. The temperature for performing thermal fusion bonding is preferably Tg 2 +5°C or higher, more preferably Tg 2 +10°C or higher. In addition, the temperature for performing thermal fusion bonding is preferably Tg 2 +50°C or lower, more preferably Tg 2 +40°C or lower. Before performing thermal fusion bonding, it is preferable to extract the mixed air from the temporarily fixed bonded body and perform crimping. However, since a small amount of air bubbles will diffuse during autoclave processing, as long as there is no large amount of air mixed in, there is no problem.

[0101] In the manufacturing method of the present invention, at least one of the channel substrate, the cover substrate, and the bonding layer may also be composed of two or more layers having different Tgs.

[0102] Examples

[0103] Hereinafter, the present invention will be specifically described based on examples, but the present invention is not limited to these examples.

[0104] <Methods for Measuring and Evaluating Physical Properties>

[0105] The measurement and evaluation of various physical properties were carried out according to the following methods.

[0106] (Method for Measuring Weight-Average Molecular Weight Mw)

[0107] The weight-average molecular weight Mw was determined by gel permeation chromatography (GPC) using cyclohexane as the eluent and obtained as a standard polyisoprene conversion value. As the standard polyisoprene, standard polyisoprene manufactured by Tosoh Corporation was used. When the sample was insoluble in cyclohexane, tetrahydrofuran (THF) was used as the eluent and the measurement was carried out by GPC, and the value was obtained as a standard polystyrene conversion value. As the standard polystyrene, standard polystyrene manufactured by Tosoh Corporation was used.

[0108] (Method for measuring glass transition temperature)

[0109] The glass transition temperature (Tg) was measured using a differential scanning calorimeter (manufactured by Nano technology, product name: DSC6220SII) based on JIS-K7121 under the condition of a heating rate of 10 °C / minute.

[0110] [1-1. Manufacture of cyclic olefin polymer (COP)]

[0111] <Manufacture of COP-1>

[0112] (1-1-1) Manufacture of ring-opening polymer:

[0113] In a glass reaction vessel after nitrogen replacement inside, 200 parts by weight of dehydrated cyclohexane, 0.75 mol% of 1-hexene, 0.15 mol% of diisopropyl ether, and 0.44 mol% of triisobutylaluminum were added to the reactor at room temperature with respect to 100 parts by weight of the total of the monomers described below, and mixed. Then, while maintaining at 45 °C, 28 parts by weight of methano-tetrahydrofluorene (MTF) as a monomer, 35 parts by weight of tetracyclododecene (TCD), 37 parts by weight of dicyclopentadiene (DCPD), and 0.02 mol% of tungsten hexachloride (0.65 wt% toluene solution) were continuously added to the reactor over 2 hours for polymerization. Next, 0.2 mol% of isopropyl alcohol was added to the polymerization solution to deactivate the polymerization catalyst and terminate the polymerization reaction. In the above description, the amounts indicated by the unit "mol%" are all values with the total amount of the monomers set to 100 mol%. The weight-average molecular weight Mw of the obtained norbornene-based ring-opening polymer was 2.8×10 4 , and the molecular weight distribution (Mw / Mn) was 2.1. In addition, the conversion rate of the monomer to the polymer was 100%.

[0114] (1-1-2) Manufacture of hydrogenated norbornene-based cyclic olefin polymer (COP-1):

[0115] Next, transfer 300 parts by weight of the reaction solution containing the ring-opening polymer obtained in the above step (1-1-1) to an autoclave equipped with a stirrer, add 3 parts by weight of a nickel catalyst supported on diatomaceous earth ("T8400RL" manufactured by Nippon Kayaku Co., Ltd., nickel loading rate 57%), and carry out a hydrogenation reaction in the autoclave at a hydrogen pressure of 4.5 MPa and 160 °C for 4 hours.

[0116] After the hydrogenation reaction is completed, use RADIOLITE #500 as a filter bed, and pressurize and filter the obtained solution at a pressure of 0.25 MPa (Fundaback Filter manufactured by Ishikawajima-Harima Heavy Industries Co., Ltd.) to remove the hydrogenation catalyst, obtaining a colorless and transparent solution. Inject the obtained solution into a large amount of isopropyl alcohol to precipitate the norbornene-based cyclic olefin polymer (COP-1), which is a hydride of the ring-opening polymer. After filtering the precipitated norbornene-based cyclic olefin polymer (COP-1), dry it with a vacuum dryer (220 °C, 1 Torr) for 6 hours to obtain the norbornene-based cyclic olefin polymer (COP-1). The weight-average molecular weight of the norbornene-based cyclic olefin polymer (COP-1) is 3.5×10 4 , and the molecular weight distribution Mw / Mn is 2.3.

[0117] The glass transition temperature Tg of the obtained norbornene-based cyclic olefin polymer (COP-1) is 134 °C.

[0118] (1-1-3) Manufacture of thermoplastic norbornene-based resin:

[0119] Put the norbornene-based cyclic olefin polymer (COP-1) obtained in the above step (1-1-2) into a twin-screw extruder and form it into a strip-shaped molded body by hot melt extrusion molding. Use a wire cutter to cut the molded body into pieces to obtain pellets of the thermoplastic norbornene-based resin containing the norbornene-based cyclic olefin polymer (COP-1).

[0120] <Manufacture of COP-2>

[0121] As monomers, use 33 parts by weight of tetracyclododecene (TCD), 33 parts by weight of dicyclopentadiene (DCPD), and 34 parts by weight of norbornene (NB). Otherwise, carry out the same as the manufacture of COP-1 to obtain the norbornene-based cyclic olefin polymer (COP-2) and pellets of the thermoplastic norbornene-based resin containing COP-2. The glass transition temperature Tg of COP-2 is 70 °C.

[0122] <Manufacture of COP-3>

[0123] As monomers, 22 parts by weight of tetracyclododecene (TCD), 73 parts by weight of dicyclopentadiene (DCPD), and 5 parts by weight of norbornene (NB) were used. Other than this, it was carried out in the same manner as the production of COP-1 to obtain a norbornene-based cyclic olefin polymer (COP-3) and pellets of a thermoplastic norbornene-based resin containing COP-3. The glass transition temperature Tg of COP-3 was 104 °C.

[0124] <Production of COP-4>

[0125] As monomers, 8 parts by weight of methano-tetrahydrofluorene (MTF), 36 parts by weight of tetracyclododecene (TCD), and 56 parts by weight of dicyclopentadiene (DCPD) were used. Other than this, it was carried out in the same manner as the production of COP-1 to obtain a norbornene-based cyclic olefin polymer (COP-4) and pellets of a thermoplastic norbornene-based resin containing COP-4. The glass transition temperature Tg of COP-4 was 124 °C.

[0126] <Production of COP-5>

[0127] As monomers, 40 parts by weight of methano-tetrahydrofluorene (MTF), 56 parts by weight of tetracyclododecene (TCD), and 4 parts by weight of dicyclopentadiene (DCPD) were used. Other than this, it was carried out in the same manner as the production of COP-1 to obtain a norbornene-based cyclic olefin polymer (COP-5) and pellets of a thermoplastic norbornene-based resin containing COP-5. The glass transition temperature Tg of COP-5 was 156 °C.

[0128] [1-2. Production of cyclic olefin copolymer (COC)]

[0129] In a reaction vessel charged with 258 L of cyclohexane, bicyclo[2.2.1]hept-2-ene (hereinafter referred to as “NB”) (120 kg) was added under normal temperature and a nitrogen stream, and stirring was carried out for 5 minutes. Triisobutylaluminum was further added so that the concentration in the system became 1.0 mL / L. Next, while stirring, ethylene was passed through at normal pressure to make the inside of the system an ethylene atmosphere. The internal temperature of the autoclave was maintained at 70 °C, and pressurization was carried out with ethylene so that the internal pressure was 6 kg / cm 2 . After stirring for 10 minutes, a toluene solution containing isopropylidene(cyclopentadienyl)(indenyl)zirconium dichloride and methylaluminoxane, which had been prepared in advance, was added to the system, thereby initiating the copolymerization reaction of ethylene and NB. Regarding the catalyst concentration at this time, relative to the entire system, isopropylidene(cyclopentadienyl)(indenyl)zirconium dichloride was 0.018 mmol / L and methylaluminoxane was 8.0 mmol / L.

[0130] In the polymerization, ethylene was continuously supplied into the system, the temperature was maintained at 70 °C, and the internal pressure was maintained at 6 kg / cm gauge pressure. 2 After 60 minutes, isopropyl alcohol was added to terminate the polymerization reaction. After depressurization, the polymer solution was taken out, and then, at a ratio of 1:1, the polymer solution was brought into contact with an aqueous solution of concentrated hydrochloric acid containing 5 L of water per 1 m 3 to transfer the catalyst residue to the aqueous phase. After allowing the contact mixture to stand, the aqueous phase was separated and removed, and then washed twice with water to purify and separate the polymerization liquid phase.

[0131] Next, the purified and separated polymerization liquid was brought into contact with 3 times the amount of acetone under strong stirring. After the copolymer precipitated, the solid part (copolymer) was obtained by filtration and thoroughly washed with acetone. Further, in order to extract the unreacted monomer present in the polymer, the solid part was added to acetone at a concentration of 40 kg / m 3 and then an extraction operation was carried out at 60 °C for 2 hours. After the extraction treatment, the solid part was obtained by filtration and dried under a nitrogen flow at 130 °C and 350 mmHg for 12 hours to obtain an ethylene-NB copolymer (cyclic olefin copolymer: COC). 100 parts by weight of the obtained ethylene-NB copolymer (COC) and 0.1 part by weight of an antioxidant (Irganox (registered trademark) 1010) were kneaded with a biaxial kneader to obtain pellets of a thermoplastic norbornene-based resin containing the ethylene-NB copolymer (COC).

[0132] Through the above operations, the obtained ethylene-NB copolymer (COC) had a Tg of 137 °C and an NB unit content of 51 mol%.

[0133] [2. Fabrication of the substrate]

[0134] In Examples 1 to 10 and Comparative Examples 1 and 2, the substrate-use cyclic olefin polymer or cyclic olefin copolymer (pellets of a thermoplastic norbornene-based resin: COP-1, COP-5, or COC) shown in Table 1 was dried at Tg - 20 °C for 5 hours. Then, using an injection molding machine (FANUC ROBOSHOT (registered trademark) α100B, manufactured by Fanuc Corporation) by a conventional method, the pellets were injection molded at a resin temperature of Tg + 150 °C, a mold temperature of Tg - 10 °C, and a holding pressure of 80 MPa to obtain substrates (substrates for channel formation and cover substrates) as molded articles in the form of a flat plate of 100 mm × 100 mm × 2 mm.

[0135] [3. Formation of the bonding layer on the substrate]

[0136] (3-1. Formation of the bonding layer in Examples 1 to 8 and Comparative Examples 1 and 2)

[0137] With respect to 20 parts by weight of the pellets of the thermoplastic norbornene resin (COP-2, COP-3, COP-4 or COP-1) for the bonding layer shown in Table 1, 80 parts by weight of cyclohexane (special grade: manufactured by Wako Pure Chemical Industries, Ltd.) were respectively sealed in a glass-sealed container (Pyrex (registered trademark) culture medium bottle: manufactured by Corning Incorporated), and dissolved by shaking at room temperature to prepare a cyclohexane solution (solution for the bonding layer) with a solid content concentration of 20% by weight.

[0138] The obtained solution for the bonding layer was poured onto the above-obtained flat plate 100 mm × 100 mm × 2 mm molded product (substrate for channel formation: COP-1 or COC), and wet coating was performed using a small automatic coater (manufactured by Allgood Co., Ltd.). The coated flat plate molded product was dried at room temperature for about 10 minutes, and then heat-dried in an oven at 80 °C for 1 hour to obtain a molded product coated with the bonding layer (channel formation substrate with a bonding layer formed thereon).

[0139] (3-2. Formation of the bonding layer in Example 9)

[0140] With respect to 20 parts by weight of the pellets of the thermoplastic norbornene resin (COP-2) for the bonding layer shown in Table 1, 80 parts by weight of xylene (special grade: manufactured by Wako Pure Chemical Industries, Ltd.) were respectively sealed in a glass-sealed container (Pyrex (registered trademark) culture medium bottle: manufactured by Corning Incorporated), and dissolved by shaking at room temperature to prepare a xylene solution (solution for the bonding layer) with a solid content concentration of 20% by weight.

[0141] The obtained solution for the bonding layer was poured onto the above-obtained flat plate 100 mm × 100 mm × 2 mm molded product (substrate for channel formation: COP-1), and wet coating was performed using a small automatic coater (manufactured by Allgood Co., Ltd.). The coated flat plate molded product was dried at room temperature for about 10 minutes, and then heat-dried in an oven at 120 °C for 5 minutes to obtain a molded product coated with the bonding layer (channel formation substrate with a bonding layer formed thereon).

[0142] (3-3. Formation of the bonding layer in Example 10)

[0143] With respect to 20 parts by weight of the pellets of the thermoplastic norbornene resin (COP-3) for the bonding layer shown in Table 1, 80 parts by weight of cyclohexane (special grade: manufactured by Wako Pure Chemical Industries, Ltd.) were respectively sealed in a glass-sealed container (Pyrex (registered trademark) culture medium bottle: manufactured by Corning Incorporated), and dissolved by shaking at room temperature to prepare a cyclohexane solution (solution for the bonding layer) with a solid content concentration of 20% by weight.

[0144] The obtained bonding layer solution was poured onto the above-obtained flat plate molded product (channel-forming substrate: COP-5) of 100 mm × 100 mm × 2 mm, and wet coating was performed using a small automatic coater (manufactured by Allgood Co., Ltd.). The coated flat plate molded product was dried at room temperature for about 10 minutes, and then heat-dried in an oven at 80 °C for 5 minutes to obtain a molded product coated with the bonding layer (channel-forming substrate with a bonding layer formed thereon).

[0145] [4. Channel cutting of the substrate]

[0146] The molded product coated with the bonding layer (channel-forming substrate with a bonding layer formed thereon) was subjected to channel cutting and contour machining using an ultra-high-precision high-speed micro-machining machine AndroidII (manufactured by RikRik Sangyo Co., Ltd.) to obtain a channel substrate 10 with a bonding layer formed thereon having four channels 11 (width: 100 μm, depth: 100 μm) with a pattern as shown in (a) of Figure 3 on one side (thickness: 2.0 mm, contour: 76.0 mm × 26.0 mm).

[0147] In addition, as shown in (b) of Figure 3 , eight through-holes 21 (inlet ports) with a diameter of 2.0 mm were formed in the cover substrate obtained in the above [2. Manufacture of the substrate], and contour machining was performed to produce a cover substrate 20 (thickness: 2.0 mm, contour: 76.0 mm × 26.0 mm). In addition, the positions of the through-holes 21 were the positions corresponding to the ends 12 of the channels 11 of the channel substrate 10.

[0148] [5. Bonding of substrates to each other]

[0149] After overlapping the channel substrate with the bonding layer formed thereon and the cover substrate, it was pressed several times with a rubber roller to discharge the mixed air, and crimping was performed to produce a temporarily fixed bonded body A. In addition, since a small amount of air bubbles will diffuse during autoclave processing, there is no problem as long as there is no large amount of air mixed in. The temporarily fixed bonded body A was inserted into a closed-sealed bag (manufactured by Meiwa Pax Co., Ltd.), and degassing packaging was performed using a vacuum packaging machine (TECHNOVAC T1000; manufactured by Nippon Packaging Machinery Co., Ltd.). The degassed package was placed in an autoclave container (DANDELION DL-2010; manufactured by Haneda Iron Works Co., Ltd.), and heat-pressed in the autoclave at the temperature shown in Table 1 at 0.8 MPa for 90 minutes to perform bonding and defoaming treatment, and a microchannel chip was obtained as the bonded body.

[0150] [6. Evaluation]

[0151] [Adhesive strength]

[0152] The adhesive strength was measured in accordance with JIS K 6854-2 (180° peel). For the bonded body, as Figure 3 shown, a cut with a width of 10 mm was made on the sheet (cover substrate) side in a manner that penetrated the sheet and the adhesive layer. The 10-mm-wide portion with the cut made from the end was peeled off in a manner that enabled chuck fixation, the formed plate (channel substrate) side was fixed to the lower chuck of a universal testing machine with an oven (Autograph AGS-X10kN; manufactured by Shimadzu Corporation), the sheet side was fixed to the upper chuck, and it was held at room temperature for 5 minutes. After holding, 180° peeling was performed at a peeling width of 10 mm and a peeling speed of 100 mm / minute, the peeling strength was determined, and this was taken as the adhesive strength.

[0153] <Liquid Delivery Test>

[0154] For 5 samples, an ink solution was injected into each channel of the fabricated microchannel chip through the injection port using a pressure-controlled pulsation-free flow pump P-Pump (manufactured by Takasago Electric Industry Co., Ltd.). The outlet side was sealed with silicone rubber, the liquid delivery pressure was increased to 650 kPa, and it was held for 3 minutes. Then, visual confirmation was made as to whether or not the ink solution oozed from the channel to the joint portion.

[0155] <Observation of Bonding Cross-Section, Measurement of Bonding Layer Thickness>

[0156] Using an ion milling device IM4000PLUS (manufactured by Hitachi High-Technologies Corporation), a cross-section of the obtained bonded body (microchannel chip) was cut out in the low-temperature milling mode. The cross-section was observed with a field emission scanning electron microscope FE-SEM8220 (manufactured by Hitachi High-Technologies Corporation), and the thickness of the bonding layer was measured.

[0157] <Evaluation of Channel Cross-Section Before and After Steam Sterilization>

[0158] (Steam Sterilization)

[0159] The obtained bonded body (microchannel chip) was steam sterilized using a small autoclave under the conditions of 121 °C, 0.12 MPa, and 30 minutes.

[0160] (Channel Cross-Section Evaluation)

[0161] The cross-sectional area S1 before steam sterilization and the area S2 after steam sterilization were measured with a field emission scanning electron microscope FE-SEM8220 (manufactured by Hitachi High-Technologies Corporation).

[0162] The channel shape retention rate was set to S2 / S1 × 100 (%).

[0163] [7. Results]

[0164] The types of cyclic olefin polymers for the substrates (channel substrate and cover substrate) and the bonding layer, the glass transition temperature Tg, the thickness of the bonding layer, and the evaluation results are shown in Table 1. The symbols for evaluation have the following meanings.

[0165] <Liquid feeding test>

[0166] ○: No liquid leakage

[0167] ×: Liquid leakage

[0168] <Evaluation of the channel cross-section after steam sterilization>

[0169] Channel shape retention rate

[0170] ◎: 95% or more

[0171] ○: 90% or more and less than 95%

[0172] △: 80% or more and less than 90%

[0173] ×: Less than 80%

[0174] [Table 1]

[0175]

[0176] Industrial applicability

[0177] According to the present invention, it is possible to provide a microchannel chip and a method for manufacturing the same. Even when the microchannel chip is subjected to high-temperature and high-pressure sterilization treatment, the channels are not deformed, and strong bonding between the substrates can be maintained.

[0178] Explanation of reference numerals

[0179] 10 Channel substrate

[0180] 11 Channel

[0181] 12 Both ends

[0182] 20 Cover substrate

[0183] 21 Through hole

Claims

1. A microchannel chip, comprising a channel substrate having microchannels formed on at least one surface, a cover substrate, and a bonding layer for bonding them together. The channel substrate, the cover substrate, and the bonding layer are made of a cyclic olefin polymer. The glass transition temperature Tg of the cyclic olefin polymer constituting the channel substrate s1 、the glass transition temperature Tg of the cyclic olefin polymer constituting the cover substrate s2 、the glass transition temperature Tg of the cyclic olefin polymer constituting the bonding layer 2 are related as follows: Tg s1 > Tg 2 , and Tg s2 >Tg 2 , The thickness of the bonding layer is less than 50 μm.

2. The microchannel chip according to claim 1, wherein, Tg s1 and Tg s2 are above 125°C, and Tg s1 ≥Tg 2 +10 °C Tg s2 ≥Tg 2 +10 °C.

3. A method for manufacturing a microchannel chip, which is a method for manufacturing the microchannel chip according to claim 1 or 2, comprising a step of bonding the channel substrate and the cover substrate via the bonding layer by thermal fusion bonding.

4. The manufacturing method according to claim 3, wherein, comprising: a step of forming a bonding layer on at least one of the channel-forming substrate and the cover substrate; a step of forming channels on the channel-forming substrate having the bonding layer formed thereon or the channel-forming substrate without the bonding layer formed thereon, to form a channel substrate having the bonding layer formed thereon or a channel substrate without the bonding layer formed thereon; a step of bonding at least one combination of a channel substrate having the bonding layer formed thereon and a cover substrate without the bonding layer formed thereon, a channel substrate without the bonding layer formed thereon and a cover substrate having the bonding layer formed thereon, and a channel substrate having the bonding layer formed thereon and a cover substrate having the bonding layer formed thereon via the bonding layer.

5. The manufacturing method according to claim 3, wherein, comprising: a step of forming a channel substrate having channels formed on at least one surface; a step of forming a bonding layer on at least one surface of at least one of the channel substrate and the cover substrate, excluding the portion corresponding to the channels; a step of bonding at least one combination of a channel substrate having the bonding layer formed thereon and a cover substrate without the bonding layer formed thereon, a channel substrate without the bonding layer formed thereon and a cover substrate having the bonding layer formed thereon, and a channel substrate having the bonding layer formed thereon and a cover substrate having the bonding layer formed thereon via the bonding layer.

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