Hydrophilic substrate and method for producing hydrophilic substrate

Abstract

To provide hydrophilic substrates provided with a hydrophilic polymer layer having controlled surface uniformity and irregularities, and methods for preparing the hydrophilic substrates.SOLUTION: The present invention discloses hydrophilic substrates including a substrate having a surface containing a group represented by -N(R1)2 and / or -N(R2)3+, where R1 and R2 are the same or different and represent, respectively, a hydrogen atom or a substituted or unsubstituted hydrocarbon group optionally containing a hetero atom, and a hydrophilic polymer layer provided on the surface of the substrate.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a hydrophilic substrate having a hydrophilic polymer layer formed on a surface of a substrate that has been subjected to a hydrophilization treatment, and a method for producing the same. [Background technology]

[0002] A technology has been proposed to coat the surface of a substrate with a special polymer in order to create devices for capturing specific cells in blood and body fluids (blood cells, cancer cells present in blood and body fluids, etc.).

[0003] However, for some special polymers, it is difficult to produce a smooth surface by coating, and the unevenness of the surface affects the ability to capture specific cells, so there is a demand for a substrate formed with a surface with controlled unevenness that is excellent in the ability to capture specific cells such as cancer cells (see Patent Document 1, etc.). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Special Publication No. 2005-523981 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to solve the above problems and to provide a hydrophilic substrate having a hydrophilic polymer layer formed thereon, the surface of which has controlled uniformity and unevenness, and a method for producing the same. [Means for solving the problem]

[0006] The present invention relates to -N(R 1 )2 and / or -N(R 2 )3 + (R 1 and R 2are the same or different and are a hydrogen atom, or a substituted or unsubstituted hydrocarbon group which may contain a heteroatom.

[0007] The hydrophilic substrate is the -N(R 1 )2 and / or -N(R 2 )3 + The group represented by -N(R 1 )2 and / or -N(R 2 )3 + It is preferable that the silane coupling agent is a silane coupling agent having a group represented by the formula:

[0008] The hydrophilic substrate is preferably one in which the hydrophilic polymer layer is formed using a hydrophilic polymer solution and / or a hydrophilic polymer dispersion.

[0009] In the hydrophilic substrate, the hydrophilic polymer layer is preferably formed from at least one hydrophilic polymer selected from the group consisting of polymers represented by the following formula (I). [ka] (In the formula, R 51 is a hydrogen atom or a methyl group, R 52 represents an alkyl group. p is 1 to 8, m is 1 to 5, and n is the number of repetitions.

[0010] It is preferable that the hydrophilic polymer layer of the hydrophilic substrate is formed from a copolymer of at least one hydrophilic monomer selected from the group consisting of compounds represented by the following formula (II) and other monomers. [ka] (In the formula, R 51 , R 52 , p, m are the same as above.)

[0011] In the hydrophilic substrate, the hydrophilic polymer layer preferably has a thickness of 10 to 1000 nm. In the hydrophilic substrate, fibronectin is preferably adsorbed onto the surface of the hydrophilic polymer layer.

[0012] The present invention also relates to -N(R 1 )2 and / or -N(R 2 )3 + (R 1 and R 2 and each is the same or different and is a hydrogen atom, or a substituted or unsubstituted hydrocarbon group which may contain a heteroatom.

[0013] The hydrophilic substrate preparation method includes the -N(R 1 )2 and / or -N(R 2 )3 + The group represented by -N(R 1 )2 and / or -N(R 2 )3 + It is preferable that the silane coupling agent has a group represented by the following formula:

[0014] In the method for producing a hydrophilic substrate, the hydrophilic polymer layer is preferably formed using a hydrophilic polymer solution.

[0015] In the method for producing a hydrophilic substrate, it is preferable that the hydrophilic polymer layer is formed from at least one hydrophilic polymer selected from the group consisting of polymers represented by the following formula (I). [ka] (In the formula, R 51 is a hydrogen atom or a methyl group, R 52 represents an alkyl group. p is 1 to 8, m is 1 to 5, and n is the number of repetitions.

[0016] In the method for producing a hydrophilic substrate, it is preferable that the hydrophilic polymer layer is formed from a copolymer of at least one hydrophilic monomer selected from the group consisting of compounds represented by the following formula (II) and another monomer: [ka] (In the formula, R 51 , R 52 , p, m are the same as above.)

[0017] In the method for producing a hydrophilic substrate, the thickness of the hydrophilic polymer layer is preferably 10 to 1000 nm. In the method for producing a hydrophilic substrate, it is preferable that fibronectin is adsorbed onto the surface of the hydrophilic polymer layer. Effect of the Invention

[0018] According to the present invention, -N(R 1 )2 and / or -N(R 2 )3 + (R 1 and R 2 are the same or different and are substituted or unsubstituted hydrocarbon groups which may contain a hydrogen atom or a heteroatom. Since the hydrophilic substrate has a hydrophilic polymer layer formed on the surface of the substrate having a group represented by the formula (I), it is possible to provide a hydrophilic substrate having a hydrophilic polymer layer with controlled surface uniformity and unevenness. Therefore, it is expected to improve the capturing performance of specific cells such as cancer cells and suppress the variation in the capturing performance. [Brief description of the drawings]

[0019] [Figure 1] 1 is a photograph of one example of the hydrophilic substrates prepared in Examples 4 and 5 and Comparative Example 1. FIG. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The hydrophilic substrate of the present invention is -N(R 1 )2 and / or -N(R 2 )3 + (R1 and R 2 are the same or different and are hydrogen atoms or substituted or unsubstituted hydrocarbon groups which may contain heteroatoms. 1 )2 and / or -N(R 2 )3 + By forming a hydrophilic silane compound layer on the surface of a substrate having a group represented by the formula (I) introduced therein, the uniformity and unevenness of the surface can be controlled, and a hydrophilic substrate can be provided in which a hydrophilic silane compound layer having a small surface roughness and high smoothness is coated at predetermined locations. Therefore, it is expected that the capturing performance of specific cells such as cancer cells can be improved and the variation in the capturing performance can be suppressed.

[0021] The number of tumor cells (cancer cells, etc.) that appear in body fluids, such as circulating tumor cells in the blood (several to several hundred cells / mL of blood), is very small, and it is considered important to capture as many tumor cells as possible present in the collected body fluid in order to subject them to testing. 1 )2 and / or -N(R 2 )3 + By coating the surface of a substrate having a group represented by the formula (R) introduced thereon with a hydrophilic silane compound, the uniformity and unevenness of the surface are controlled, and a hydrophilic silane compound layer having small surface roughness and high smoothness is formed. The uniformity and unevenness of the hydrophilic silane compound layer affect the ability to capture specific cells such as cancer cells, and it is expected that excellent ability to capture specific cells can be achieved by controlling the uniformity and unevenness of the surface and increasing the smoothness. It is also expected that a capture performance with little variation can be achieved. Therefore, -N(R 1 )2 groups and / or -N(R 2 )3 + By measuring the number of tumor cells captured in the hydrophilic silane compound layer on the surface of the substrate with the groups introduced therein, the number of tumor cells in the body fluid can be determined, which is expected to enable confirmation of the effectiveness of cancer treatment, etc. In addition, by culturing the captured tumor cells and confirming the effectiveness of anticancer drugs, etc. using the cultured cells, the effectiveness of anticancer drugs, etc. can be confirmed outside the body before administration of the anticancer drugs, etc., and this is also useful for selecting anticancer drugs, etc.

[0022] "-N(R 1 )2 and / or -N(R 2 )3 + With respect to "a substrate surface having a group represented by -N(R 1 ) R in the group represented by 2 1 , -N(R 2 )3 + R in the group represented by 2 are the same or different and each is (1) a hydrogen atom, or (2) a substituted or unsubstituted hydrocarbon group which may contain a heteroatom.

[0023] R 1 ~R 2 The substituted or unsubstituted hydrocarbon group, which may contain a heteroatom, may be any of linear, branched, or cyclic groups. The heteroatom is not particularly limited, and examples thereof include oxygen, nitrogen, and the like. The substituent is not particularly limited, and examples thereof include known groups such as a hydroxyl group and a halogen group (-Cl, -Br, and the like). The number of these heteroatoms and substituents may be one or more.

[0024] The substituted or unsubstituted hydrocarbon group which may contain a heteroatom preferably has 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms, and further preferably 1 to 8 carbon atoms.

[0025] The substituted or unsubstituted hydrocarbon group which may contain a heteroatom includes a monovalent hydrocarbon group and a divalent hydrocarbon group.

[0026] Examples of the substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom include a substituted or unsubstituted linear alkyl group, branched alkyl group, cyclic alkyl group, aryl group, aralkyl group, alkoxy group, and the like which may contain a heteroatom.

[0027] Examples of substituted or unsubstituted straight-chain alkyl groups and branched alkyl groups which may contain heteroatoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, 2-ethylhexyl, octyl, nonyl, decyl, and groups containing these heteroatoms. Examples of substituted or unsubstituted cyclic alkyl groups which may contain heteroatoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, 1-ethylcyclopentyl, 1-ethylcyclohexyl, and groups containing these heteroatoms. Examples of the substituted or unsubstituted cyclic ether group that may contain a heteroatom include an oxirane group, an oxetane group, an oxolane group, an oxane group, an oxopane group, an oxocane group, an oxete group, an oxole group, a dioxolane group, a dioxane group, a dioxepane group, a dioxecane group, and the like, and groups containing these heteroatoms. Examples of the substituted or unsubstituted aryl group that may contain a heteroatom include a phenyl group, a tolyl group, a xylyl group, a biphenyl group, a naphthyl group, an anthryl group, a phenanthryl group, and groups containing these heteroatoms. Examples of the substituted or unsubstituted aralkyl group that may contain a heteroatom include a benzyl group, a phenethyl group, and groups containing these heteroatoms. Examples of the substituted or unsubstituted alkoxy group which may contain a heteroatom include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, an isobutoxy group, a t-butoxy group, an n-pentyloxy group, an n-hexyloxy group, and groups containing these heteroatoms.

[0028] Examples of the substituted or unsubstituted divalent hydrocarbon group which may contain a heteroatom include a substituted or unsubstituted alkylene group, alkenylene group, cycloalkylene group, cycloalkylalkylene group, arylene group, aralkylene group, oxyalkylene group, and the like which may contain a heteroatom.

[0029] Specific examples of substituted or unsubstituted alkylene groups that may contain heteroatoms include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, octylene, nonylene, decylene, 1,2-propylene, and groups containing these heteroatoms. Examples of substituted or unsubstituted alkenylene groups that may contain heteroatoms include vinylene, 1-propenylene, 2-propenylene, and groups containing these heteroatoms. Examples of substituted or unsubstituted cycloalkylene groups that may contain heteroatoms include cyclohexylene and groups containing this heteroatom. Examples of substituted or unsubstituted cycloalkylalkylene groups that may contain heteroatoms include cyclohexylmethylene and groups containing this heteroatom. Examples of substituted or unsubstituted arylene groups that may contain heteroatoms include phenylene, tolylene, xylylene, and groups containing these heteroatoms. Examples of the substituted or unsubstituted aralkylene group which may contain a heteroatom include a benzylidene group and a group containing this heteroatom, etc. Examples of the substituted or unsubstituted oxyalkylene group which may contain a heteroatom include an oxyethylene group, an oxypropylene group, an oxybutylene group, an oxytetramethylene group, and groups containing these heteroatoms, etc.

[0030] "-N(R 1 )2 and / or -N(R 2 )3 + With regard to "a substrate surface having a group represented by the formula (I)", examples of the substrate include glass such as soda lime glass and borosilicate glass, acrylic resins (polyacrylic resins) such as polymethyl acrylate, polymethyl methacrylate, polyacrylic acid, and polymethacrylic acid, cycloolefin resins (polycycloolefins), carbonate resins (polycarbonate), styrene resins (polystyrene), polyester resins such as polyethylene terephthalate (PET), and polydimethylsiloxane. Among these, for coating with a hydrophilic polymer, it is preferable that the constituent material has high hydrophilicity, and polyacrylic resins and soda lime glass are preferred.

[0031] "-N(R1 )2 and / or -N(R 2 )3 + The "substrate surface having a group represented by -N(R 1 )2 and / or -N(R 2 )3 + The compound can be prepared by any method capable of introducing a group represented by the formula: 1 )2 and / or -N(R 2 )3 + Examples of the treatment include treatment of the substrate surface with a silane coupling agent having a group represented by the formula (silane coupling agent treatment), treatment of the substrate surface with NH3 gas (NH3 gas treatment), etc. Among these, the silane coupling agent treatment is preferred from the viewpoint of uniformity of the hydrophilic polymer layer and control of the unevenness.

[0032] -N(R) that can be used for silane coupling agent treatment 1 )2 and / or -N(R 2 )3 + The silane coupling agent having a group represented by the formula (I) is not particularly limited, and examples thereof include, for example, -N(R 1 )2 and / or -N(R 2 )3 + and -Si(R 3 and a compound (R 1 and R 2 R are the same or different and each is a hydrogen atom or a substituted or unsubstituted hydrocarbon group which may contain a heteroatom. 3 are the same or different and are substituted or unsubstituted hydrocarbon groups which may contain heteroatoms.) etc. can be used.

[0033] -Si(R 3 R in the group represented by 3 3 are the same or different and are substituted or unsubstituted hydrocarbon groups which may contain heteroatoms. Examples of the substituted or unsubstituted hydrocarbon groups which may contain heteroatoms include the above-mentioned R 1 and R 2Examples of the substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom include the same groups as those of the substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. Among them, a linear alkyl group, a branched alkyl group, a cyclic alkyl group, and an alkoxy group are preferred. Specific examples of the linear alkyl group, the branched alkyl group, the cyclic alkyl group, and the alkoxy group are the same as those of the linear alkyl group, the branched alkyl group, the cyclic alkyl group, and the alkoxy group described above. 1 and R 2 The same groups as those shown in R (e.g., methyl group, ethyl group, methoxy group, ethoxy group, etc.) can also be mentioned. 3 At least one of these is preferably an alkoxy group, more preferably two, and even more preferably three.

[0034] -N(R 1 )2 and / or -N(R 2 )3 + and -Si(R 3 As the compound having a group represented by formula (1-3), for example, compounds represented by the following formulas (1-1) and (1-2) can be suitably used.

[0035] [ka] (In the formula, R 11 ~R 12 R is the same or different and is a hydrogen atom or a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. 16 ~R 18 R may be the same or different and is a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. 19 is a substituted or unsubstituted divalent hydrocarbon group which may contain a heteroatom.

[0036] [ka] (In the formula, R 11 ~R 13 R is the same or different and is a hydrogen atom or a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. 16 ~R 18 R may be the same or different and is a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom.19 is a substituted or unsubstituted divalent hydrocarbon group which may contain a heteroatom. X is a halogen.

[0037] R in formulas (1-1) and (1-2) 11 , R 12 , R 13 Examples of the "substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom" include the above-mentioned R 1 ~R 2 The substituted or unsubstituted monovalent hydrocarbon groups which may contain a heteroatom are also preferred. 11 , R 12 , R 13 is preferably a hydrogen atom, a linear alkyl group or a branched alkyl group which may contain a heteroatom, and is preferably a hydrogen atom, a linear alkyl group, a branched alkyl group, -C p H 2p -OC q H 2q+1 A group represented by the formula (p and q are integers) is more preferred.

[0038] R in formulas (1-1) and (1-2) 16 , R 17 , R 18 Examples of the "substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom" include the above-mentioned R 1 ~R 2 The substituted or unsubstituted monovalent hydrocarbon groups which may contain a heteroatom are also preferred. 16 , R 17 , R 18 is preferably a substituted or unsubstituted alkoxy group which may contain a hetero atom, more preferably an alkoxy group, and further preferably a methoxy group or an ethoxy group.

[0039] R in formulas (1-1) and (1-2) 19 Examples of the "substituted or unsubstituted divalent hydrocarbon group which may contain a heteroatom" include the above-mentioned R 1 ~R 2 The heteroatom-containing substituted or unsubstituted divalent hydrocarbon groups are also exemplified. 1In addition to the specific examples of the substituted or unsubstituted divalent hydrocarbon group which may contain a heteroatom, -CO-N(R 111 )-(R 112 )-, a group represented by (R 111 R represents a hydrogen atom or an alkyl group. 112 -C p H 2p - (p is an integer of 1 to 8). 19 is a substituted or unsubstituted alkylene group which may contain a heteroatom, -CO-N(R 111 )-(R 112 )- is preferred, and a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a -CO-N(R 111 )-(R 112 )- is more preferred.

[0040] Examples of the halogen represented by X in the formula (1-2) include chlorine (chlorine ion) and bromine (bromine ion).

[0041] -NR 1 2 and / or -NR 1 3 + and -Si(R 2 As the compound having a group represented by formula (1-3), a compound represented by the following formula (1-3) can also be suitably used.

[0042] [ka] (In the formula, R 21 ~R 23 R is the same or different and is a hydrogen atom or a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. 24 ~R 26 R may be the same or different and is a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. 27 ~R 30 is a substituted or unsubstituted divalent hydrocarbon group which may contain a heteroatom. X is a halogen. n represents the number of repetitions.

[0043] R in formula (1-3)21 , R 22 , R 23 Examples of the "substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom" include the above-mentioned R 1 ~R 2 The substituted or unsubstituted monovalent hydrocarbon groups which may contain a heteroatom are also preferred. 21 , R 22 , R 23 is preferably a hydrogen atom, a linear alkyl group or a branched alkyl group which may contain a heteroatom, and more preferably a hydrogen atom.

[0044] R in formula (1-3) 24 , R 25 , R 26 Examples of the "substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom" include the above-mentioned R 1 ~R 2 The substituted or unsubstituted monovalent hydrocarbon groups which may contain a heteroatom are also preferred. 24 , R 25 , R 26 is preferably a substituted or unsubstituted alkoxy group which may contain a hetero atom, more preferably an alkoxy group, and further preferably a methoxy group or an ethoxy group.

[0045] R in formula (1-3) 27 , R 28 , R 29 , R 30 Examples of the "substituted or unsubstituted divalent hydrocarbon group which may contain a heteroatom" include the above-mentioned R 1 ~R 2 The following groups are also exemplified: 27 , R 28 , R 29 , R 30 is preferably a substituted or unsubstituted alkylene group which may contain a heteroatom, and more preferably a methylene group, an ethylene group, a trimethylene group, or a tetramethylene group.

[0046] Examples of the halogen represented by X in the formula (1-3) include chlorine (chlorine ion) and bromine (bromine ion).

[0047] The degree of polymerization of the constitutional unit represented by formula (1-3) is not particularly limited, and may be appropriately selected in consideration of the processability (coatability) of the compound, adhesion to the hydrophilic polymer layer, and the like.

[0048] The number average molecular weight (Mn) of the compound (polymer) represented by the formula (1-3) is preferably 500 to 6,000, more preferably 1,000 to 4,000, and even more preferably 1,000 to 3,000.

[0049] -N(R 1Specific examples of silane coupling agents having a group represented by the formula (2) include 3-aminopropyltrimethoxysilane, 3-aminopropyltriethoxysilane, 3-aminopropyltriisopropoxysilane, 3-aminopropylmethyldimethoxysilane, 3-aminopropylmethyldiethoxysilane, 3-(2-aminoethyl)aminopropyltrimethoxysilane, 3-(2-aminoethyl)aminopropylmethyldimethoxysilane, 3-(2-aminoethyl)aminopropyltriethoxysilane, 3-(2-aminoethyl)aminopropylmethyldiethoxysilane, 3-(2-aminoethyl)aminopropyltriisopropoxysilane, 3-(2-(2 amino group-containing silane coupling agents such as (N-aminoethyl)aminoethyl)aminopropyltrimethoxysilane, 3-(6-aminohexyl)aminopropyltrimethoxysilane, 3-(N-ethylamino)-2-methylpropyltrimethoxysilane, N-phenyl-3-aminopropyltrimethoxysilane, N-benzyl-3-aminopropyltrimethoxysilane, N-vinylbenzyl-3-aminopropyltriethoxysilane, N-cyclohexylaminomethyltriethoxysilane, N-cyclohexylaminomethyldiethoxymethylsilane, N-phenylaminomethyltrimethoxysilane, and (2-aminoethyl)aminomethyltrimethoxysilane;3-Ureidopropyltrimethoxysilane (1-[3-(trimethoxysilyl)propyl]urea), 3-Ureidopropyltriethoxysilane, 3-Ureidopropyltriisopropoxysilane, 3-Ureidopropylmethyldimethoxysilane, 3-Ureidopropylmethyldiethoxysilane, Ureidomethyltrimethoxysilane, Ureidomethyltriethoxysilane, Ureidomethyltriisopropoxysilane, Ureidomethylmethyldimethoxysilane, Ureidomethylmethyldiethoxysilane, 3-[(2-Ureidoethyl)amino]propyltrimethoxysilane, 1,3-Bis[3-(trimethoxysilyl)propyl]urea , 1,3-bis[3-(triethoxysilyl)propyl]urea, 1-[3-(triethoxysilyl)propyl]-3-phenylurea, 1,3-bis[3-(tripropylsilyl)propyl]urea, 1-[3-(triethoxysilyl)propyl]-3,3-dioctylurea, 1-[3-(triethoxysilyl)propyl]-3,3-dihexadecylurea, 1-[3-(triethoxysilyl)propyl]-3-propylurea, 3-(3-dodecylureido)propyltriethoxysilane, N-(1-phenylethyl)-N'-[3-(triethoxysilyl)propyl]urea, and other silane coupling agents having a urea group;

[0050] -N(R 1 )3 +Specific examples of the silane coupling agent having a group represented by the formula (I) include N-trimethoxysilylpropyl-N,N,N-trimethylammonium chloride, N-trimethoxysilylpropyl-N,N,N-tri-n-butylammonium chloride, octadecyldimethyl(3-trimethoxysilylpropyl)ammonium chloride, N-(trimethoxysilylethyl)benzyl-N,N,N-trimethylammonium chloride, and N-(trimethoxysilylethyl)benzyl-N,N,N-trimethylammonium chloride. CHLORID), N,N-didecyl-N-methyl-N-(3-trimethoxysilyl-propyl)ammonium chloride, BIS(METHOXYETHYL)-3-TRIMETHOXYSILYLPROPYLAMMONIUM CHLORIDE, trimethoxysilylpropyl modified (polyethyleneimine), and dimethoxymethylsilylpropyl modified (polyethyleneimine).

[0051] Among these, 3-aminopropyltriethoxysilane, bis(methoxyethyl)-3-trimethoxysilylpropyl ammonium chloride (BIS(METHOXYETHYL)-3-TRIMETHOXYSILYLPROPYLAMMONIUM CHLORIDE), trimethoxysilylpropyl modified (polyethyleneimine) (TRIMETHOXYSILYLPROPYL MODIFIED(POLYETHYLENIMINE)), and N-trimethoxysilylpropyl-N,N,N-trimethylammonium chloride (N-TRIMETHOXYSILYLPROPYL-N,N,N-TRI-METHYLAMMONIUM CHLORIDE) are preferred. 1 )2 and / or -N(R 1 )3 + -N(R 1 )2 and / or -N(R 1 )3 + The silane coupling agent having a group represented by the following formula (I) may be used alone or in combination of two or more.

[0052] Silane coupling agent treatment (-N(R 1 )2 and / or -N(R 1 )3 + The method of treating the substrate surface with a silane coupling agent having a group represented by the formula (I) is not particularly limited, and any method capable of coating (treating) the substrate surface with a silane coupling agent can be used. Specifically, a substrate whose surface is coated (treated) with a silane coupling agent can be produced by known techniques such as coating (applying), spraying (spraying) or immersing the substrate surface with a silane coupling agent solution or dispersion in which the silane coupling agent is dissolved or dispersed in various solvents. Known methods can be used for the coating method, spraying method and immersion method.

[0053] The solvent is not particularly limited as long as it can dissolve and disperse the silane coupling agent, and may be appropriately selected depending on the silane coupling agent used. For example, water, organic solvents, and mixed solvents thereof can be mentioned, and examples of the organic solvent include alcohols such as methanol, ethanol, n-propanol, i-propanol, and methoxypropanol; ketones such as acetone and methyl ethyl ketone; tetrahydrofuran, acetonitrile, ethyl acetate, and toluene.

[0054] The concentration of the silane coupling agent solution / dispersion may be appropriately set depending on the silane coupling agent, the type of solvent, the treatment method (coating method, spraying method, immersion method), and the like.

[0055] The treatment conditions such as the treatment temperature and treatment time of the silane coupling agent treatment may be appropriately set depending on the type of silane coupling agent, solvent, treatment method, etc., but it is preferable to treat (maintain) the silane coupling agent solution / dispersion on the substrate surface (coating, spraying, immersion, etc.) under conditions of humidity of 50% or more. This tends to strengthen the chemical bond between the substrate surface and the silane coupling agent. The humidity is more preferably 60% or more, and even more preferably 80% or more. There is no particular upper limit, but for example, 100% or less is preferable.

[0056] When the treatment (holding) is performed under conditions of a humidity of 50% or more, the treatment time and treatment temperature may be appropriately set from the viewpoint of strengthening the chemical bond between the substrate surface and the silane coupling agent, from the viewpoint of economy, etc. For example, the treatment time (holding time) is preferably 1 to 60 hours, more preferably 1 to 20 hours. The treatment temperature (holding temperature) is preferably 20 to 65°C, more preferably 25 to 50°C.

[0057] The substrate surface coated (treated) with a silane coupling agent may be prepared by the above-mentioned method or may be a commercially available product. Examples of commercially available products treated with a silane coupling agent include MAS-coated slide glass, MAS-GP type-coated slide glass, Frontier-coated slide glass, and APS-coated slide glass (manufactured by Matsunami Glass Industry Co., Ltd.).

[0058] -N(R 1 )2 and / or -N(R 2 )3 + From the viewpoint of adhesion of the hydrophilic polymer layer to the substrate surface, at least a portion (part or all) of the substrate surface having a group represented by the following formula (I) preferably has a water contact angle of 50 to 120 degrees, more preferably 70 to 100 degrees.

[0059] The hydrophilic substrate may be prepared by the above-mentioned method or the like. 1 )2 and / or -N(R 2 )3 + The hydrophilic polymer layer is formed on the surface of a substrate having a group represented by the following formula (I): The hydrophilic polymer constituting the hydrophilic polymer layer can be appropriately selected from those having hydrophilicity.

[0060] Examples of hydrophilic polymers include homopolymers and copolymers of one or more hydrophilic monomers, and copolymers of one or more hydrophilic monomers with one or more other monomers.

[0061] As the hydrophilic monomer constituting the homopolymer or copolymer, various monomers having a hydrophilic group can be used, for example, known hydrophilic groups such as an amide group, a sulfate group, a sulfonic acid group, a carboxyl group, a hydroxyl group, an amino group, an amide group, and an oxyethylene group.

[0062] Specific examples of hydrophilic monomers include (meth)acrylic acid, (meth)acrylic acid esters, (alkoxyalkyl (meth)acrylates such as methoxyethyl (meth)acrylate, hydroxyalkyl (meth)acrylates such as hydroxyethyl (meth)acrylate), (meth)acrylamide, (meth)acrylamide derivatives having a cyclic group ((meth)acryloylmorpholine, etc.), etc. Among these, (meth)acrylic acid, (meth)acrylic acid esters, and alkoxyalkyl (meth)acrylates are preferred, alkoxyalkyl (meth)acrylates are more preferred, and 2-methoxyethyl acrylate is particularly preferred.

[0063] The other monomers in the copolymer may be appropriately selected within a range that does not impair the action and effect of the hydrophilic polymer, and examples thereof include aromatic monomers such as styrene, vinyl acetate, and N-isopropylacrylamide that can impart temperature responsiveness.

[0064] Specific examples of the homopolymer and copolymer include homopolymers composed of one hydrophilic monomer such as polyacrylic acid, polyacrylic acid esters, polymethacrylic acid, polymethacrylic acid esters, polyacrylamide, and polymethacrylamide; copolymers composed of two or more of the hydrophilic monomers exemplified above; and copolymers composed of one or more of the hydrophilic monomers exemplified above and one or more of the other monomers exemplified above. The hydrophilic polymer may be used alone or in combination of two or more.

[0065] Among them, the hydrophilic polymer is preferably at least one selected from the group consisting of polymers represented by the following formula (I). [ka] (In the formula, R 51 is a hydrogen atom or a methyl group, R 52 represents an alkyl group. p is 1 to 8, m is 1 to 5, and n is the number of repetitions.

[0066] As the polymer represented by the formula (I), for example, a polymer represented by the following formula (I-1) can be suitably used. [ka] (In the formula, R 51 is a hydrogen atom or a methyl group, R 52 represents an alkyl group. p is 1 to 8, m is 1 to 5, and n is the number of repetitions.

[0067] R 52 The number of carbon atoms in the alkyl group of R is preferably 1 to 10, and more preferably 1 to 5. 52 is particularly preferably a methyl group or an ethyl group. p is preferably an integer of 1 to 5, and more preferably an integer of 1 to 3. m is preferably an integer of 1 to 3. n (the number of repeating units) is preferably an integer of 15 to 1,500, and more preferably an integer of 40 to 1,200.

[0068] Furthermore, as the hydrophilic polymer, a copolymer of at least one hydrophilic monomer selected from the group consisting of compounds represented by the following formula (II) and other monomers can also be suitably used.

[0069] [ka] (In the formula, R 51 , R 52 , p, m are the same as above.)

[0070] As the compound represented by the formula (II), for example, a compound represented by the following formula (II-1) can be suitably used. [ka] (In the formula, R 51 , R 52 , m is the same as above.)

[0071] Among the above-mentioned hydrophilic polymers, the hydrophilic polymer represented by the above formula (I) is particularly suitable from the viewpoints of the uniformity and unevenness of the hydrophilic polymer layer.

[0072] From the viewpoint of selective adsorptivity and adhesiveness to cancer cells, the number average molecular weight (Mn) of the hydrophilic polymer is preferably 8,000 to 150,000, more preferably 10,000 to 60,000, and even more preferably 12,000 to 50,000. In this specification, Mn can be determined in terms of standard polystyrene based on measurements obtained by gel permeation chromatography (GPC) (GPC-8000 series manufactured by Tosoh Corporation, detector: differential refractometer, column: TSKGEL SUPERMALTPORE HZ-M manufactured by Tosoh Corporation).

[0073] The thickness of the hydrophilic polymer layer (layer formed of a hydrophilic polymer) is preferably 10 to 1000 nm, more preferably 30 to 700 nm, and even more preferably 50 to 400 nm. By adjusting the thickness within the above range, good low adsorption to proteins and cells and selective capture of cancer cells can be obtained.

[0074] At least a portion (part or all) of the surface of the hydrophilic polymer layer (the surface of the hydrophilic polymer layer in the hydrophilic substrate) preferably has a water contact angle of 20 degrees or more and 70 degrees or less, more preferably 30 degrees or more and 60 degrees or less.

[0075] The surface of the hydrophilic polymer layer (the surface of the hydrophilic polymer layer in the hydrophilic substrate) preferably has a surface roughness Ra of 0.30 μm or less, more preferably 0.20 μm or less, and even more preferably 0.18 μm or less. There is no particular lower limit, and the smaller the better. In this specification, the surface roughness Ra is the center line surface roughness Ra specified in JIS B0601-2001.

[0076] The hydrophilic polymer layer is formed by dissolving or dispersing a hydrophilic polymer in various solvents, and then dispersing the hydrophilic polymer in the -N(R 1 )2 and / or -N(R 2 )3 +A substrate having a polymer layer formed by a hydrophilic polymer can be manufactured by coating the hydrophilic polymer solution or dispersion on all or a part of the substrate surface by known techniques such as (1) a method of injecting the hydrophilic polymer solution or dispersion into the surface of a substrate (such as a recess of the substrate) having a group represented by the formula: and holding and drying for a predetermined time, or (2) a method of applying (spraying) the hydrophilic polymer solution or dispersion onto the substrate surface. Then, by adding other parts as necessary to the substrate having the hydrophilic polymer layer formed thereon, a device capable of capturing, culturing, inspecting, etc. specific cells can be manufactured.

[0077] As the solvent, injection method, coating (spraying) method, and the like, conventionally known materials and methods can be used. The holding and drying times of (1) and (2) may be appropriately set depending on the size of the substrate, the type of liquid introduced, etc. The holding time is preferably 5 minutes to 10 hours, more preferably 10 minutes to 5 hours, and even more preferably 15 minutes to 2 hours. Drying is preferably performed at room temperature (about 23°C) to 80°C, and more preferably room temperature to 50°C. Drying may also be performed under reduced pressure. Furthermore, after a certain period of holding, excess hydrophilic polymer solution / dispersion may be appropriately discharged and dried.

[0078] The solvent is not particularly limited as long as it can dissolve the hydrophilic polymer, and may be appropriately selected depending on the hydrophilic polymer used. For example, the above-mentioned solvents that can be used to dissolve and disperse the silane coupling agent can be used.

[0079] The hydrophilic polymer layer may have fibronectin adsorbed on the surface of the hydrophilic polymer layer. By further adsorbing fibronectin on the surface of the hydrophilic polymer layer, the ability to capture specific cells such as cancer cells can be improved.

[0080] The method for adsorbing fibronectin to the hydrophilic polymer layer is not particularly limited, and known methods can be applied. For example, the hydrophilic polymer layer can be brought into contact with a fibronectin buffer solution (phosphate buffered saline, PBS, etc.) by a known method, left at a predetermined temperature for a predetermined time, and washed as necessary, to allow the layer to adsorb fibronectin. The temperature and time can be appropriately set, and the adsorption can be performed, for example, at 10 to 60°C for about 0.1 to 24 hours.

[0081] In order to adsorb fibronectin onto the hydrophilic polymer layer, it is preferable to use a solution, dispersion, etc. in which the fibronectin concentration is adjusted to preferably 0.5 to 500 μg / ml, more preferably 1 to 250 μg / ml. By adjusting the concentration within the above range, excellent capture properties for specific cells such as cancer cells can be obtained.

[0082] The method for producing a hydrophilic substrate of the present invention comprises the steps of: 1 )2 and / or -N(R 2 )3 + (R 1 and R 2 are the same or different and each is a hydrogen atom or a substituted or unsubstituted hydrocarbon group which may contain a heteroatom.) is a method for forming a hydrophilic polymer layer on the surface of a substrate having a group represented by the formula: -N(R 1 )2 and / or -N(R 2 )3 + By subjecting the surface to a treatment for introducing a group represented by the following formula (I) and then forming a hydrophilic polymer layer on the surface to which the group has been introduced, the uniformity and unevenness of the surface can be controlled, and a hydrophilic polymer layer having small surface roughness and high smoothness can be formed.

[0083] In the method for preparing a hydrophilic substrate, for example, a sample (blood, body fluid, etc.) is 1 )2 and / or -N(R 2 )3 +By contacting the hydrophilic substrate having a hydrophilic polymer layer formed on the surface of the substrate having a group represented by the formula (I) introduced thereinto, it is expected that the capturing performance of specific cells can be improved and the variation in the capturing performance can be suppressed. Then, by measuring the number of captured specific cells, the number of specific cells in the collected blood or body fluid can be determined, and it is expected that the effect of cancer treatment can be confirmed. EXAMPLES

[0084] The present invention will be specifically described below based on examples, but the present invention is not limited to these examples.

[0085] (Preparation of hydrophilic polymers) Poly(2-methoxyethyl acrylate) (PMEA) was prepared by thermally polymerizing 2-methoxyethyl acrylate (25 wt% toluene) at 60°C for 7 hours using a 12.5 mg / ml toluene solution of AIBN (azobisisobutyronitrile).

[0086] Example 1 A 1N NaOH aqueous solution was added to a chambered slide glass (bottom surface: made of soda-lime glass) and left for 1 hour. After that, the chamber surface was washed with water and naturally dried. Next, a 0.5% concentration 3-aminopropyltriethoxysilane (Tokyo Chemical Industry A0439) solution (a mixed solution of methanol / water = 50 / 50) was added to the chambered slide glass, left at 80% humidity and 40 ° C for 5 hours, and dried under reduced pressure at 60 ° C. Then, the slide glass was washed with water, dried, and the prepared 0.25% methanol solution of PMEA was poured into the chambered slide glass. Then, it was immediately dried in a vacuum in an oven at 40 ° C for 5 minutes to prepare a hydrophilic substrate.

[0087] Example 2 A hydrophilic substrate was prepared in the same manner as in Example 1, except that the silane coupling agent was changed from 3-aminopropyltriethoxysilane to BIS(METHOXYETHYL)-3-TRIMETHOXYSILYLPROPYLAMMONIUM CHLORIDE (SIB1500 manufactured by Gelest, formula shown below). [ka]

[0088] Example 3 A hydrophilic substrate was prepared in the same manner as in Example 1, except that the silane coupling agent was changed from 3-aminopropyltriethoxysilane to TRIMETHOXYSILYLPROPYL MODIFIED (POLYETHYLENIMINE) (SSP-060 manufactured by Gelest, the following formula, Mn 1500 to 1800). [ka]

[0089] Example 4 Instead of a chambered slide glass, NH3 + A 0.25% methanol solution of PMEA was poured into a commercially available product (Matsunami Glass Industry Co., Ltd. chamber slide, MAS-coated type) with a group introduced therein, and the resulting solution was immediately vacuum-dried in an oven at 40°C for 5 minutes to prepare a hydrophilic substrate.

[0090] Example 5 In Example 4, fibronectin was further adsorbed after vacuum drying in an oven at 40° C. for 5 minutes. Specifically, a 200 μg / ml fibronectin solution in PBS (phosphate buffered saline) was prepared, injected, and left at 40° C. for 1 hour, and then washed with PBS solution to prepare a hydrophilic substrate.

[0091] Comparative Example 1 The prepared 0.25% methanol solution of PMEA was poured into an untreated slide chamber, and then immediately vacuum-dried in an oven at 40°C for 5 minutes to prepare a hydrophilic substrate.

[0092] [Water contact angle (-N(R 1 )2 groups or -N(R 2 )3 + (substrate surface having a group) -N(R 1 )2 or -N(R 2 )3 +2 μl of distilled water was dropped onto the surface of the base material into which a group represented by the following formula had been introduced, and the contact angle after 30 seconds was measured by the θ / 2 method (room temperature). In Comparative Example 1, the contact angle was measured on an untreated slide glass.

[0093] [Film thickness of hydrophilic polymer layer (coating layer)] The film thickness of the hydrophilic polymer layer of the hydrophilic substrate was measured (photographed) by using a TEM to measure (photograph) a cross section of the hydrophilic polymer layer at an accelerating voltage of 15 kV and a magnification of 1000 times.

[0094] [Surface roughness Ra (hydrophilic polymer layer)] Using a laser microscope, the surface roughness was measured non-contact at four points (first peak) on one hydrophilic substrate (hydrophilic polymer layer), and the average of the Ra values ​​at the four points was taken as the surface roughness Ra (average of center line surface roughness Ra defined in JIS B0601-2001).

[0095] [Table 1]

[0096] Of the coated substrates produced in Examples 1 to 5 and Comparative Example 1, photographs of Examples 4, 5 and Comparative Example 1 are shown in FIG.

[0097] In Comparative Example 1, a thin white cloud was observed overall and at the same time, white spots were observed. When poly(2-methoxyethyl acrylate) was produced several times in the same manner as in Comparative Example 1, the white cloud sometimes appeared in a ring shape or sometimes in a spot, but the white cloud was always observed.

[0098] In contrast, -N(R 1 )2 groups or -N(R 2 )3 +In Examples 4 and 5, which used a substrate having a group, a coating film was formed that was not cloudy (Example 4) or was very thin (Example 5), and the uniformity and unevenness of the surface were controlled. The cloudy parts reflect the aggregation state and surface unevenness of poly(2-methoxyethyl acrylate), and it is easy to imagine that these parts show a different ability to capture specific cells than other smooth parts, which causes variation in the capture performance. For this reason, it was expected that a surface with a controlled uniformity and unevenness without cloudiness (Ra 0.30 or less) would show a capture performance with less variation.

Claims

1. -N(R １ ) ２ and / or -N(R ２ ) ３ ＋ (R １ and R ２ are the same or different and each is a hydrogen atom, or a substituted or unsubstituted hydrocarbon group which may contain a heteroatom. the surface of the hydrophilic polymer layer has a surface roughness Ra of 0.30 μm or less; The hydrophilic polymer layer is formed of at least one hydrophilic polymer selected from the group consisting of polymers represented by the following formula (I): 【Chemistry 1】 (In the formula, R ５１ is a hydrogen atom or a methyl group, R ５２ represents an alkyl group, p is 1 to 8, m is 1 to 5, and n is the number of repetitions. The groups represented by -N(R 1 ) 2 and / or -N(R 2 ) 3 + are introduced by treating the surface of the substrate with a silane coupling agent having groups represented by -N(R 1 ) 2 and / or -N(R 2 ) 3 + ; The silane coupling agent is at least one selected from the group consisting of a compound represented by the following formula (1-1), a compound represented by the following formula (1-2), and a compound represented by the following formula (1-3): A hydrophilic base material. 【Chemistry 2】 (In the formula, R 11 and R 12 are the same or different and are a hydrogen atom or a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 16 to R 18 are the same or different and are a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 19 is a substituted or unsubstituted divalent hydrocarbon group which may contain a heteroatom.) 【Chemistry 3】 (In the formula, R 11 to R 13 are the same or different and are a hydrogen atom or a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 16 to R 18 are the same or different and are a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 19 is a substituted or unsubstituted divalent hydrocarbon group which may contain a heteroatom. X is a halogen.) 【Chemistry 4】 (In the formula, R 21 to R 23 are the same or different and are a hydrogen atom or a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 24 to R 26 are the same or different and are substituted or unsubstituted monovalent hydrocarbon groups which may contain a heteroatom. R 27 to R 30 are substituted or unsubstituted divalent hydrocarbon groups which may contain a heteroatom. X is a halogen. n represents the number of repetitions.)

2. -N(R １ ) ２ and / or -N(R ２ ) ３ ＋ (R １ and R ２ are the same or different and each is a hydrogen atom, or a substituted or unsubstituted hydrocarbon group which may contain a heteroatom. the surface of the hydrophilic polymer layer has a surface roughness Ra of 0.30 μm or less; The hydrophilic polymer layer is formed of a copolymer of at least one hydrophilic monomer selected from the group consisting of compounds represented by the following formula (II) and another monomer, 【Chemistry 5】 (In the formula, R ５１ is a hydrogen atom or a methyl group, R ５２ represents an alkyl group; p represents 1 to 8, and m represents 1 to 5. The groups represented by -N(R 1 ) 2 and / or -N(R 2 ) 3 + are introduced by treating the surface of the substrate with a silane coupling agent having groups represented by -N(R 1 ) 2 and / or -N(R 2 ) 3 + ; The silane coupling agent is at least one selected from the group consisting of a compound represented by the following formula (1-1), a compound represented by the following formula (1-2), and a compound represented by the following formula (1-3): A hydrophilic base material. 【Chemistry 6】 (In the formula, R 11 and R 12 are the same or different and are a hydrogen atom or a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 16 to R 18 are the same or different and are a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 19 is a substituted or unsubstituted divalent hydrocarbon group which may contain a heteroatom.) 【Chemistry 7】 (In the formula, R 11 to R 13 are the same or different and are a hydrogen atom or a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 16 to R 18 are the same or different and are a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 19 is a substituted or unsubstituted divalent hydrocarbon group which may contain a heteroatom. X is a halogen.) 【Chemistry 8】 (In the formula, R 21 to R 23 are the same or different and are a hydrogen atom or a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 24 to R 26 are the same or different and are substituted or unsubstituted monovalent hydrocarbon groups which may contain a heteroatom. R 27 to R 30 are substituted or unsubstituted divalent hydrocarbon groups which may contain a heteroatom. X is a halogen. n represents the number of repetitions.)

3. 3. The hydrophilic substrate according to claim 1, wherein the hydrophilic polymer layer is formed using a hydrophilic polymer solution and / or a hydrophilic polymer dispersion.

4. 4. The hydrophilic substrate according to claim 1, wherein the hydrophilic polymer layer has a thickness of 10 to 1000 nm.

5. 5. The hydrophilic substrate according to claim 1, wherein fibronectin is adsorbed onto the surface of the hydrophilic polymer layer.

6. -N(R １ ) ２ and / or -N(R ２ ) ３ ＋ (R １ and R ２ and each is the same or different and is a hydrogen atom, or a substituted or unsubstituted hydrocarbon group which may contain a heteroatom. the surface of the hydrophilic polymer layer has a surface roughness Ra of 0.30 μm or less; The hydrophilic polymer layer is formed of at least one hydrophilic polymer selected from the group consisting of polymers represented by the following formula (I): 【Chemistry 9】 (In the formula, R ５１ is a hydrogen atom or a methyl group, R ５２ represents an alkyl group, p is 1 to 8, m is 1 to 5, and n is the number of repetitions. The groups represented by -N(R 1 ) 2 and / or -N(R 2 ) 3 + are introduced by treating the surface of the substrate with a silane coupling agent having groups represented by -N(R 1 ) 2 and / or -N(R 2 ) 3 + ; The silane coupling agent is at least one selected from the group consisting of a compound represented by the following formula (1-1), a compound represented by the following formula (1-2), and a compound represented by the following formula (1-3): 【Chemistry 10】 (In the formula, R 11 and R 12 are the same or different and are a hydrogen atom or a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 16 to R 18 are the same or different and are a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 19 is a substituted or unsubstituted divalent hydrocarbon group which may contain a heteroatom.) 【Chemistry 11】 (In the formula, R 11 to R 13 are the same or different and are a hydrogen atom or a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 16 to R 18 are the same or different and are a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 19 is a substituted or unsubstituted divalent hydrocarbon group which may contain a heteroatom. X is a halogen.) 【Chemistry 12】 (In the formula, R 21 to R 23 are the same or different and are a hydrogen atom or a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 24 to R 26 are the same or different and are substituted or unsubstituted monovalent hydrocarbon groups which may contain a heteroatom. R 27 to R 30 are substituted or unsubstituted divalent hydrocarbon groups which may contain a heteroatom. X is a halogen. n represents the number of repetitions.)

7. -N(R １ ) ２ and / or -N(R ２ ) ３ ＋ (R １ and R ２ and each is the same or different and is a hydrogen atom, or a substituted or unsubstituted hydrocarbon group which may contain a heteroatom. the surface of the hydrophilic polymer layer has a surface roughness Ra of 0.30 μm or less; The hydrophilic polymer layer is formed of a copolymer of at least one hydrophilic monomer selected from the group consisting of compounds represented by the following formula (II) and another monomer, 【Chemistry 13】 (In the formula, R ５１ is a hydrogen atom or a methyl group, R ５２ represents an alkyl group; p represents 1 to 8, and m represents 1 to 5. The groups represented by -N(R 1 ) 2 and / or -N(R 2 ) 3 + are introduced by treating the surface of the substrate with a silane coupling agent having groups represented by -N(R 1 ) 2 and / or -N(R 2 ) 3 + ; The silane coupling agent is at least one selected from the group consisting of a compound represented by the following formula (1-1), a compound represented by the following formula (1-2), and a compound represented by the following formula (1-3): 【Chemistry 14】 (In the formula, R 11 and R 12 are the same or different and are a hydrogen atom or a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 16 to R 18 are the same or different and are a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 19 is a substituted or unsubstituted divalent hydrocarbon group which may contain a heteroatom.) 【Chemistry 15】 (In the formula, R 11 to R 13 are the same or different and are a hydrogen atom or a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 16 to R 18 are the same or different and are a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 19 is a substituted or unsubstituted divalent hydrocarbon group which may contain a heteroatom. X is a halogen.) 【Chemistry 16】 (In the formula, R 21 to R 23 are the same or different and are a hydrogen atom or a substituted or unsubstituted monovalent hydrocarbon group which may contain a heteroatom. R 24 to R 26 are the same or different and are substituted or unsubstituted monovalent hydrocarbon groups which may contain a heteroatom. R 27 to R 30 are substituted or unsubstituted divalent hydrocarbon groups which may contain a heteroatom. X is a halogen. n represents the number of repetitions.)

8. 8. The method for producing a hydrophilic substrate according to claim 6, wherein the hydrophilic polymer layer is formed using a hydrophilic polymer solution.

9. 9. The method for producing a hydrophilic substrate according to claim 6, wherein the thickness of the hydrophilic polymer layer is 10 to 1000 nm.

10. The method for producing a hydrophilic substrate according to any one of claims 6 to 9, wherein fibronectin is adsorbed onto the surface of the hydrophilic polymer layer.

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