Medical instrument and production method for same

Abstract

The purpose of the present invention is to provide a means capable of imparting excellent functionality (for example, antithrombotic property) in a medical instrument (in particular, a medical instrument provided with a metal base material). This problem is solved by a medical instrument comprising a metal base material and a functional layer bonded to the base material, the functional layer having a polymer comprising a functional polymer chain composed of a constituent unit A derived from a bonding monomer having a phosphoric acid group or a phosphonic acid group and an ethylenically unsaturated group and a constituent unit B derived from a functional monomer, an end of the functional polymer chain being bonded to the constituent unit A.

Description

Medical device and its manufacturing method

[0001] The present invention relates to a medical device and a method for manufacturing the same.

[0002] In recent years, medical materials using various metallic materials have been investigated, and their use in stent grafts, covered stents, stents, guidewires, cardiac pacemakers, and other devices is anticipated. In these applications, metallic materials, which are foreign to the living body, are used in contact with biological tissues and bodily fluids such as blood. Therefore, medical materials must be biocompatible. The biocompatibility required of medical materials varies depending on their purpose and method of use. However, medical materials that come into contact with blood must have the following properties (antithrombotic properties): inhibition of the blood coagulation system, inhibition of platelet adhesion and activation, and inhibition of complement activation.

[0003] Conventionally, the method of imparting antithrombotic properties to medical devices has mainly been to coat the substrate constituting the medical device with an antithrombotic material. For example, International Publication No. 2020 / 166605 (corresponding to U.S. Patent Application Publication No. 2022 / 0135806) discloses a copolymer-containing varnish containing a copolymer of a phosphate-containing compound having a phosphate group and a (meth)acryloyl group and a compound having a cationic monovalent organic group and a (meth)acryloyl group. According to this document, synthesizing the copolymer using a phosphate-containing compound with a purity of 70% by mass or more suppresses gelation of the copolymer in the copolymer-containing varnish. Furthermore, this document also describes that a biocompatible coating film can be formed by applying a copolymer-containing varnish to the surface of a substrate and drying the coating.

[0004] However, according to the investigations of the present inventors, it has been found that the copolymers described in the above documents tend to aggregate, and it may be difficult to obtain a copolymer-containing varnish having sufficient handleability. Medical devices manufactured using copolymer-containing varnishes in which the copolymer aggregates and has poor handleability may have insufficient functionality (e.g., antithrombogenicity), and therefore a new method for imparting functionality (e.g., antithrombogenicity) to medical devices has been desired.

[0005] Therefore, an object of the present invention is to provide a means for imparting excellent functionality (for example, antithrombogenicity) to medical devices (particularly medical devices having a metal substrate).

[0006] The present inventors have conducted extensive research to solve the above-mentioned problems, and as a result have found that the above-mentioned problems can be solved by fixing functional polymer chains to the surface of a metal substrate via a predetermined structural unit, thereby completing the present invention.

[0007] That is, the above object can be achieved by the present invention having the following configuration, and the present invention includes the following aspects and configurations.

[0008] One aspect of the present invention is a medical device comprising: 1. a metal substrate; and a functional layer bonded to the substrate, the functional layer comprising a polymer including a functional polymer chain composed of a structural unit A derived from a binding monomer having a phosphate group or a phosphonate group and an ethylenically unsaturated group, and a structural unit B derived from a functional monomer, wherein an end of the functional polymer chain is bonded to the structural unit A.

[0009] 2. In the medical device described in 1 above, it is preferable that the ratio of the number of structural units B to the number of structural units A in the polymer is 30 or more.

[0010] 3. In the medical device according to 1. or 2. above, the binding monomer is preferably one or more selected from monomers represented by the following formulas (I) and (II):

[0011]

[0012] In the above formula (I), R １ represents a hydrogen atom or a methyl group, p represents an integer of 0 to 20, m1 represents 0 or 1, and n1 represents 1 or 2;

[0013]

[0014] In the above formula (II), R ２ represents a hydrogen atom or a methyl group; q represents an integer of 0 to 20; and m2 represents 0 or 1.

[0015] 4. In the medical device according to any one of 1. to 3. above, the binding monomer is preferably one or more selected from 2-(meth)acryloyloxyethyl acid phosphate, bis[2-((meth)acryloyloxy)ethyl]phosphate, 11-phosphonoundecyl(meth)acrylate, vinylphosphonic acid, and allylphosphonic acid.

[0016] 5. In the medical device according to any one of 1. to 4. above, the functional monomer is preferably one or more selected from the monomers represented by the following formulas (III) to (V):

[0017]

[0018] In the above formula (III), R ３ represents a hydrogen atom or a methyl group, R ４ represents a linear or branched alkylene group having 1 to 6 carbon atoms; R ５ and R ６ each independently represents a linear or branched alkyl group having 1 to 4 carbon atoms; R ７ represents a linear or branched alkylene group having 1 to 4 carbon atoms, and X is —COO － or -SO ３ － represents Y １ represents an oxygen atom or —NH—;

[0019]

[0020] In the above formula (IV), R ８ represents a hydrogen atom or a methyl group, Z represents a group of the formula: -O-(R ９ O) ｍ -R １０ a group represented by the formula: —O—(CH ２ CHOH ｎ -CH ２ OH or a tetrahydrofurfuryloxy group, in which R ９ each independently represents a linear or branched alkylene group having 1 to 4 carbon atoms; R １０represents a linear or branched alkyl group having 1 to 4 carbon atoms, m represents an integer of 1 to 5, and n represents an integer of 1 to 5;

[0021]

[0022] In the above formula (V), R ９ represents a hydrogen atom or a methyl group, R １０ and R １１ each independently represents a linear or branched alkylene group having 1 to 6 carbon atoms; R １２ ~R １４ each independently represents a linear or branched alkyl group having 1 to 4 carbon atoms; Y ２ represents an oxygen atom or —NH—.

[0023] 6. In the medical device described in any one of 1. to 5. above, the functional monomer is selected from the group consisting of N-(meth)acryloyloxymethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxypropyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxymethyl-N,N-diethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxyethyl-N,N-diethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxypropyl-N,N-diethylammonium-α-N-methylcarboxybetaine, methoxymethyl acrylate, and 2-methoxyethyl acrylate.

[0046] Preferably, the acrylate is one or more selected from the group consisting of methyl acrylate, 3-methoxypropyl acrylate, ethoxymethyl acrylate, ethoxyethyl acrylate, 2-(2-ethoxyethoxy)ethyl acrylate, ethoxypropyl acrylate, ethoxybutyl acrylate, propoxymethyl acrylate, butoxyethyl acrylate, methoxybutyl acrylate, tetrahydrofurfuryl acrylate, methoxymethyl methacrylate, methoxyethyl methacrylate, ethoxymethyl methacrylate, ethoxyethyl methacrylate, 2-(2-ethoxyethoxy)ethyl methacrylate, propoxymethyl methacrylate, butoxyethyl methacrylate, tetrahydrofurfuryl methacrylate, glycerol (meth)acrylate, and 2-methacryloyloxyethyl phosphorylcholine.

[0024] 7. In the medical device according to any one of 1. to 6. above, the metal is preferably one or more selected from the group consisting of gold, platinum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin, stainless steel, nickel-titanium alloy, nickel-cobalt alloy, cobalt-chromium alloy, and zinc-tungsten alloy.

[0025] 8. In the medical device according to any one of 1. to 7. above, the medical device is preferably a stent graft, a covered stent, a stent, a guidewire or a cardiac pacemaker.

[0026] Another aspect of the present invention is a method for producing the medical device according to any one of 1. to 8. above, comprising: 9. irradiating at least a portion of the surface of the substrate with plasma; bringing the binding monomer into contact with the substrate after the plasma irradiation; and bringing the functional monomer into contact with the substrate after the contact with the binding monomer, thereby forming the functional polymer chain on the surface of the substrate via the constituent unit A derived from the binding monomer.

[0027] FIG. 1 is a diagram illustrating the immobilization of an antithrombotic material in accordance with the present invention. FIG. 2 is a partial cross-sectional view schematically illustrating the structure of a representative embodiment of a medical device according to the present invention. FIG. 3 is a partial cross-sectional view schematically illustrating an example of a different structure as an application of the embodiment of FIG. 2. FIG. 4 is an SEM image of a NiTi substrate before plasma treatment (NiTi (untreated plasma)) observed with a scanning electron microscope. FIG. 5 is an SEM image of a NiTi substrate in which CBA has been polymerized via PHA (NiTi-PHA-CBA) observed with a scanning electron microscope. FIG. 6 is an SEM image of a NiTi substrate in which MEA has been polymerized via PHA (NiTi-PHA-MEA) observed with a scanning electron microscope. FIG. 7 is an SEM image of a NiTi substrate in which MC3A has been polymerized via PHA (NiTi-PHA-MC3A) observed with a scanning electron microscope. FIG. 8 is an SEM image of a NiTi substrate in which MPC is polymerized via PHA (NiTi-PHA-MPC), observed with a scanning electron microscope.

[0028] According to one aspect of the present invention, there is provided a medical device comprising a metal substrate and a functional layer. The functional layer comprises a functional polymer chain composed of a constituent unit A derived from a binding monomer having a phosphate group or a phosphonate group and an ethylenically unsaturated group, and a constituent unit B derived from a functional monomer, bound to the substrate, and the functional polymer chain is bound at the end to the constituent unit A. This aspect can impart excellent functionality (e.g., antithrombogenicity) to a medical device comprising a metal substrate.

[0029] In the following, a detailed description will be given taking as an example a medical device having an antithrombogenic layer as a functional layer (in this case, the structural unit B is derived from an antithrombogenic monomer), but the present invention can be applied to medical devices having any functional layer, such as an antithrombogenic layer, an antibacterial layer, an anti-inflammatory layer, or a biodegradable layer.

[0030] The present inventors have surprisingly found that a medical device having such a configuration has excellent antithrombotic properties (i.e., it can effectively inhibit the adhesion of proteins, cells, etc. that can form thrombi).The mechanism by which the configuration of the present invention exhibits the above-mentioned effects is presumed to be as follows.

[0031] FIG. 1 is a diagram illustrating the immobilization of an antithrombogenic material according to the present invention. As shown in FIG. 1 , the medical device according to the present invention comprises a metal substrate (e.g., a NiTi substrate) having a plurality of structural units B derived from an antithrombogenic monomer (e.g., N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA)) immobilized on its surface via a structural unit A derived from a binding monomer (e.g., 2-methacryloyloxyethyl acid phosphate (PHA)) having a phosphate or phosphonate group and an ethylenically unsaturated group. According to the present invention, by using a binding monomer having a phosphate or phosphonate group, ethylenically unsaturated groups can be constructed on the metal substrate surface via covalent bonds. Furthermore, an antithrombogenic layer can be formed on the metal substrate surface by polymerizing the antithrombogenic monomer with the ethylenically unsaturated groups. Because the antithrombogenic layer is bound to the metal substrate via covalent bonds, it can maintain its antithrombogenicity for a longer period of time than conventional methods for immobilizing antithrombogenic materials using coatings. Therefore, a medical device with excellent durability can be provided. Furthermore, in conventional methods for immobilizing an antithrombogenic material by coating, a copolymer is synthesized in advance and then applied to the surface of a substrate. However, according to the present invention, there is no need to synthesize the copolymer in advance, and therefore, problems such as reduced handleability due to aggregation do not occur in principle. Therefore, it is possible to form a uniform antithrombogenic layer on the surface of a metal substrate, and a medical device with excellent antithrombogenicity can be provided. Another advantage is that the functional layer can be formed using a variety of functional monomers, not just antithrombogenic monomers.

[0032] The above mechanism is merely speculation and does not limit the technical scope of the present invention.

[0033] Herein, a medical device having the above configuration is also referred to simply as "a medical device according to the present invention" or "a medical device." Herein, "structural unit A derived from a binding monomer having a phosphate group or a phosphonate group, and an ethylenically unsaturated group" is also referred to simply as "structural unit A according to the present invention" or "structural unit A." Herein, "structural unit B derived from a functional monomer" is also referred to simply as "structural unit B according to the present invention" or "structural unit B." Herein, a polymer (polymer) comprising structural unit A and structural unit B is also referred to simply as "a polymer according to the present invention" or "polymer."

[0034] In this specification, when a certain structural unit is defined as being "derived from" a certain monomer, it means that the structural unit is a structural unit that is generated by a condensation reaction of reactive groups possessed by the corresponding monomer and / or is generated by cleavage of one bond of an ethylenically unsaturated group (polymerizable unsaturated double bond).

[0035] As used herein, the term "(meth)acrylic" encompasses both acrylic and methacrylic. Thus, for example, the term "(meth)acrylic acid" encompasses both acrylic acid and methacrylic acid. Similarly, the term "(meth)acryloyl" encompasses both acryloyl and methacryloyl. Thus, for example, the term "(meth)acryloyl group" encompasses both acryloyl and methacryloyl groups. Similarly, the term "(meth)acrylate" encompasses both acrylate and methacrylate. Thus, for example, the term "alkoxyalkyl(meth)acrylate" encompasses both alkoxyalkylacrylate and alkoxyalkylmethacrylate.

[0036] In this specification, the range "X to Y" includes both X and Y and means "X or more and Y or less." Furthermore, "A and / or B" means that A and B are included, as well as any combination thereof. Furthermore, unless otherwise specified, measurements of operations and physical properties are performed under conditions of room temperature (20 to 25°C) and a relative humidity of 40 to 50% RH.

[0037] Hereinafter, embodiments of the present invention will be described. Note that the present invention is not limited to the following embodiments, and various modifications can be made within the scope of the claims. Furthermore, the embodiments described in this specification can be arbitrarily combined to form other embodiments. The dimensional proportions in the drawings are exaggerated for the convenience of explanation and may differ from the actual proportions. Furthermore, when embodiments of the present invention are described with reference to the drawings, the same elements are given the same reference numerals in the description of the drawings, and duplicate explanations will be omitted.

[0038] [Medical Device] Hereinafter, the configuration of a medical device according to one embodiment of the present invention will be described with reference to the accompanying drawings.

[0039] Fig. 2 is a partial cross-sectional view schematically showing the structure of a representative embodiment of a medical device according to the present invention, and Fig. 3 is a partial cross-sectional view schematically showing an example of a different structure as an application example of this embodiment.

[0040] 2 and 3, a medical device 100 according to one embodiment of the present invention includes a metal substrate 10 and an antithrombogenic layer 11 formed on at least a portion of the metal substrate 10. Here, the medical device 100 of this embodiment is formed by directly laminating the metal substrate (also simply referred to as "substrate") 10 and the antithrombogenic layer 11 in this order. That is, the substrate 10 and the antithrombogenic layer 11 are laminated adjacently in this order.

[0041] In this embodiment, the polymer constituting the antithrombogenic layer (particularly the phosphate group or phosphonate group of the structural unit A derived from the binding monomer) and the surface of the metal substrate (particularly the hydroxyl group (—OH) generated by the plasma treatment) are chemically bonded by a covalent bond, thereby enabling the antithrombogenicity to be maintained for a long period of time.

[0042] Furthermore, in this specification, the phrase "an antithrombogenic layer is formed on at least a portion of the metal substrate" is used because, in stent grafts, covered stents, stents, guidewires, cardiac pacemakers, and the like, which are examples of uses of medical devices, it is not necessary to impart antithrombogenicity to the entire surface (entire surface) of these medical devices, and it is sufficient that the antithrombogenic layer is formed only on the surface portion (which may be a portion or the entire surface) that is required to have antithrombogenicity. For this reason, it is preferable that the antithrombogenic layer is formed on at least the portion of the substrate 10 that comes into contact with blood. For example, when the medical device is a stent graft, covered stent, stent, or cardiac pacemaker, it is preferable that the antithrombogenic layer is formed on the entire surface of the substrate.

[0043] <<Metallic Substrate (Metallic Substrate Layer)>> The substrate 10 constituting the medical device according to one embodiment of the present invention is a metallic substrate. As the metallic substrate, an optimum substrate can be appropriately selected depending on the properties (e.g., mechanical strength, etc.) required for medical devices such as stent grafts, covered stents, stents, guidewires, cardiac pacemakers, etc. As an example, a substrate having the properties required for a substrate, such as mechanical strength, elasticity, and toughness, is preferred.

[0044] The substrate 10 may be formed of at least its surface using a metal material. For example, as shown in FIG. 2, the entire substrate may be formed of a metal material. Alternatively, as shown in FIG. 3, the substrate may have a structure in which a substrate surface layer 10b made of a metal material is formed on the surface of a substrate core portion 10a made of a material such as plastic (polymer material) or ceramic material. Alternatively, the substrate core portion 10a and the substrate surface layer 10b may be combined (by suitable reaction treatment) to form the substrate 10. Therefore, the substrate core portion 10a may be a multilayer structure formed by laminating different materials in multiple layers, or a structure (composite) in which components made of different materials are joined together for each portion of the medical device. Furthermore, a separate middle layer (not shown) may be formed between the substrate core portion 10a and the substrate surface layer 10b. Furthermore, with regard to the substrate surface layer 10b, as long as its surface is constructed (formed) of a metal material, it may be a multilayer structure formed by laminating different materials in multiple layers, or a structure (composite) in which components formed of different materials for each part of the medical device are joined together.

[0045] The metallic material constituting (forming) the substrate 10 and the substrate surface layer 10b is not particularly limited, and metallic materials commonly used in medical devices such as stent grafts, covered stents, stents, guidewires, and cardiac pacemakers can be used. Specific examples include gold, platinum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin, stainless steel (e.g., SUS304, SUS314, SUS316, SUS316L, SUS420J2, SUS630, and SUS631), nickel-titanium alloys, nickel-cobalt alloys, cobalt-chromium alloys, and zinc-tungsten alloys. These may be used alone or in combination of two or more. The metallic material can be selected appropriately depending on the intended use of the medical device. The metal material constituting (forming) the substrate of a stent graft, covered stent, stent, guidewire, cardiac pacemaker, or the like, which are examples of uses, is preferably one or more selected from the group consisting of stainless steel and nickel-titanium alloys, and from the viewpoint of versatility, it is even more preferably one or more selected from the group consisting of nickel-titanium alloys. That is, in a medical device according to one embodiment of the present invention, the metal is one or more selected from the group consisting of gold, platinum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin, stainless steel, nickel-titanium alloy, nickel-cobalt alloy, cobalt-chromium alloy, and zinc-tungsten alloy. In a more preferred embodiment, the metal is one or more selected from the group consisting of stainless steel and nickel-titanium alloys. In an even more preferred embodiment, the metal is one or more selected from the group consisting of nickel-titanium alloys.

[0046] There are no particular restrictions on the materials that can be used for the above-mentioned substrate core portion 10a, and it is sufficient to select an appropriate material that can fully exhibit the optimal function as the substrate core portion 10a depending on the application of the medical device. Examples of the resin include polyamide resins such as nylon 6, nylon 11, nylon 12, and nylon 66 (all of which are registered trademarks); polyethylenes such as linear low-density polyethylene (LLDPE), low-density polyethylene (LDPE), high-density polyethylene (HDPE), and modified polyethylene; polyolefin resins such as polypropylene; polyester resins such as polyethylene terephthalate; styrene resins such as polystyrene; cyclic polyolefin resins, modified polyolefin resins, epoxy resins, urethane resins, diallyl phthalate resins (allyl resins), polycarbonate resins, fluororesins such as polytetrafluoroethylene (PTFE) and ePTFE (expanded polytetrafluoroethylene); polyurethane resins; amino resins (urea resins, melamine resins, benzoguanamine resins), acrylic resins, polyacetal resins, vinyl acetate resins, phenolic resins, vinyl chloride resins, silicone resins, polyether resins such as polyether ether ketone (PEEK), and various polymer materials such as polyimide resins; and inorganic materials such as various ceramic materials, but the resin is not limited to these.

[0047] Alternatively, the substrate core portion 10a may be made of a metal material other than the metal material forming (constituting) the substrate surface layer 10b. Examples of such metal materials are not particularly limited, and include the same as those described above. These may be used alone or in combination of two or more.

[0048] Preferably, the substrate 10 contains or is made of a metal material, or the substrate surface layer 10b contains or is made of a metal material. More preferably, the substrate 10 is made of a metal material, or the substrate surface layer 10b is made of a metal material.

[0049] The shape of the substrate 10 is not particularly limited, and may be appropriately selected depending on the usage mode, such as a sheet, a film, a tube, a shape having multiple branched tubes such as a bifurcated shape (e.g., a Y-shape), a linear (wire), a mesh, a fiber (thread), or the like.

[0050] <<Functional Layer>> The functional layer according to the present invention is a layer containing a phosphate group (-OP(=O)(OH) ２ , -OP(=O)(OH)O-) or a phosphonic acid group (-P(=O)(OH) ２ ), and a polymer including a functional polymer chain including a structural unit A derived from a binding monomer having an ethylenically unsaturated group and a structural unit B derived from a functional monomer. The polymer is a polymer in which the end of the functional polymer chain is bonded to the structural unit A. The functional layer may be in the form of a single layer or a laminate of two or more layers. Preferably, the functional layer is in the form of a single layer. The functional layer can be appropriately selected depending on the application of the medical device, and examples thereof include, but are not limited to, an antithrombogenic layer, an antibacterial layer, an anti-inflammatory layer, and a biodegradable layer. When the medical device is used in an application in which it comes into contact with blood, the functional layer is preferably an antithrombogenic layer. In this specification, "antithrombogenic" refers to the property of reducing blood coagulation on a surface that comes into contact with blood.

[0051] The phosphoric acid or phosphonic acid groups in the bonding monomer react (condensation reaction) with hydroxyl groups (-OH) generated on the surface of the metal substrate by plasma treatment to form phosphate or phosphonate ester bonds, thereby firmly immobilizing the functional layer on the metal substrate.

[0052] The ethylenically unsaturated group in the binding monomer is a group capable of polymerizing with the functional monomer described below. Examples of the ethylenically unsaturated group include an acryloyl group (CH ２ ═CH—C(═O)—), methacryloyl group (CH ２ =C(CH ３ )-C(=O)-), vinyl group (CH ２ ═CH—), allyl group (CH ２ =CH-CH ２Among these, it is preferable that the binding monomer has at least one of an acryloyl group and a methacryloyl group.

[0053] Specific examples of the binding monomer include monomers represented by the following formulas (I) and (II).

[0054]

[0055] In the above formula (I), R １ represents a hydrogen atom or a methyl group; p represents an integer of 0 to 20; m1 represents 0 or 1; and n1 represents 1 or 2.

[0056]

[0057] In the above formula (II), R ２ represents a hydrogen atom or a methyl group; q represents an integer of 0 to 20; and m2 represents 0 or 1.

[0058] In the above formula (I), R １ is a hydrogen atom or a methyl group, and preferably, R １ is a methyl group.

[0059] In the above formula (I), p is an integer of 0 to 20. From the viewpoint of being able to impart high functionality (for example, antithrombotic properties), p is preferably an integer of 1 to 20, more preferably an integer of 1 to 10, even more preferably 1 to 5, and particularly preferably 2.

[0060] In the above formula (I), m1 is 0 or 1, and preferably m1 is 1.

[0061] In the above formula (I), n1 is 1 or 2, and preferably n1 is 1.

[0062] In the above formula (II), R ２ is a hydrogen atom or a methyl group, and preferably, R ２ is a methyl group.

[0063] In the above formula (II), q is an integer of 0 to 20. From the viewpoint of further improving functionality (for example, antithrombotic properties), q is preferably an integer of 1 to 20, more preferably an integer of 1 to 10, even more preferably 1 to 5, and particularly preferably 2.

[0064] In the above formula (II), m2 is 0 or 1, and preferably m2 is 1.

[0065] Specific examples of the binding monomer represented by formula (I) or (II) above include, but are not limited to, 2-(meth)acryloyloxyethyl acid phosphate, bis[2-((meth)acryloyloxy)ethyl]phosphate, 11-phosphonoundecyl(meth)acrylate, vinylphosphonic acid, and allylphosphonic acid. That is, in a medical device according to one embodiment of the present invention, the binding monomer is one or more selected from 2-(meth)acryloyloxyethyl acid phosphate, bis[2-((meth)acryloyloxy)ethyl]phosphate, 11-phosphonoundecyl(meth)acrylate, vinylphosphonic acid, and allylphosphonic acid. Of these, from the viewpoint of further improving functionality (e.g., antithrombogenicity), it is more preferable that the binding monomer be 2-acryloyloxyethyl acid phosphate and / or 2-methacryloyloxyethyl acid phosphate. "Acid phosphate" is also called "acidic phosphate ester" and is a compound of phosphoric acid (P(=O)(OH) ３ ) and alcohol (R—OH) esters (phosphate esters), P(═O)(OH) ２ (OR) (phosphate monoester) and / or P(═O)(OH)(OR) ２ (phosphate diester) (i.e., "acid phosphate" refers to a partial ester of phosphoric acid and an alcohol).

[0066] These binding monomers may be used alone or in combination of two or more.

[0067] The functional monomer is not particularly limited as long as the homopolymer thereof has the desired function of the medical device (e.g., antithrombogenicity, antibacterial property, anti-inflammatory property, biodegradability, etc.) When antithrombogenicity is to be imparted to the medical device, the homopolymer may be a compound that exhibits the property of reducing blood coagulation on the surface that comes into contact with blood.

[0068] Specific examples of functional monomers include the monomers represented by the following formulae (III) to (V): Homopolymers derived from these monomers can exhibit excellent antithrombotic properties.

[0069]

[0070] In the above formula (III), R ３ represents a hydrogen atom or a methyl group, R ４ represents a linear or branched alkylene group having 1 to 6 carbon atoms; R ５ and R ６ each independently represents a linear or branched alkyl group having 1 to 4 carbon atoms; R ７ represents a linear or branched alkylene group having 1 to 4 carbon atoms, and X is —COO － or -SO ３ － represents Y １ represents an oxygen atom or —NH—.

[0071]

[0072] In the above formula (IV), R ８ represents a hydrogen atom or a methyl group, Z represents a group of the formula: -O-(R ９ O) ｍ -R １０ a group represented by the formula: —O—(CH ２ CHOH ｎ -CH ２ OH or a tetrahydrofurfuryloxy group, in which R ９ each independently represents a linear or branched alkylene group having 1 to 4 carbon atoms; R １０ represents a linear or branched alkyl group having 1 to 4 carbon atoms; m represents an integer of 1 to 5; and n represents an integer of 1 to 5.

[0073]

[0074] In the above formula (V), R ９ represents a hydrogen atom or a methyl group, R １０ and R １１ each independently represents a linear or branched alkylene group having 1 to 6 carbon atoms; R １２ ~R １４ each independently represents a linear or branched alkyl group having 1 to 4 carbon atoms; Y ２ represents an oxygen atom or —NH—.

[0075] In the above formula (III), R ３ is a hydrogen atom or a methyl group, and from the viewpoint of obtaining excellent antithrombotic properties, R ３ is a methyl group.

[0076] In the above formula (III), R ４ is a linear or branched alkylene group having 1 to 6 carbon atoms, and specific examples thereof include a methylene group, an ethylene group, a trimethylene group, a propylene group, a tetramethylene group, a pentamethylene group, and a hexamethylene group. Of these, from the viewpoint of obtaining excellent antithrombotic properties, R ４ is preferably a linear or branched alkylene group having 1 to 4 carbon atoms, more preferably a methylene group, an ethylene group, or a trimethylene group, and particularly preferably an ethylene group or a trimethylene group.

[0077] In the above formula (III), R ５ and R ６ are each independently a linear or branched alkyl group having 1 to 4 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. Of these, from the viewpoint of obtaining excellent antithrombotic properties, R ５ and R ６ are each independently preferably a linear or branched alkyl group having 1 to 3 carbon atoms, more preferably an alkyl group having 1 or 2 carbon atoms (methyl group, ethyl group), and particularly preferably a methyl group.

[0078] In the above formula (III), R ７ is a linear or branched alkylene group having 1 to 4 carbon atoms, and specific examples thereof include a methylene group, an ethylene group, a trimethylene group, a propylene group, and a tetramethylene group. Of these, from the viewpoint of obtaining excellent antithrombotic properties, R ７ is preferably a methylene group, an ethylene group, or a trimethylene group, and more preferably a methylene group.

[0079] In the above formula (III), X is —COO － (carboxybetaine type zwitterionic monomers), or -SO ３ － (sulfobetaine type zwitterionic monomer). From the viewpoint of obtaining excellent antithrombotic properties, X is preferably —COO － is.

[0080] In the above formula (III), Y １ is an oxygen atom or —NH—, and from the viewpoint of obtaining excellent antithrombotic properties, preferably, Y １ is an oxygen atom.

[0081] In the above formula (IV), R ８ is a hydrogen atom or a methyl group, and from the viewpoint of obtaining excellent antithrombotic properties, R ８ is a hydrogen atom.

[0082] In the above formula (IV), Z is a group represented by the formula: -O-(R ９ O) ｍ -R １０ In the case where R ９ are each independently a linear or branched alkylene group having 1 to 4 carbon atoms, and specific examples thereof include a methylene group, an ethylene group, a trimethylene group, a propylene group, and a tetramethylene group. Of these, from the viewpoint of obtaining excellent antithrombotic properties, R ９ are each independently more preferably a methylene group, an ethylene group, or a trimethylene group, particularly preferably an ethylene group or a trimethylene group, and most preferably an ethylene group. ９ When there are a plurality of -O- (m is 2 or more), each -R ９The O- can be the same or different.

[0083] In the above formula (IV), Z is a group represented by the formula: -O-(R ９ O) ｍ -R １０ In the case where R １０ is a linear or branched alkyl group having 1 to 4 carbon atoms, and specific examples thereof include linear or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl groups. Of these, from the viewpoint of obtaining excellent antithrombotic properties, R １０ is preferably a linear or branched alkyl group having 1 to 3 carbon atoms, more preferably an alkyl group having 1 or 2 carbon atoms (methyl group, ethyl group), and particularly preferably a methyl group.

[0084] In the above formula (IV), Z is a group represented by the formula: -O-(R ９ O) ｍ -R １０ In the case where m is a group represented by (-R ９ O—) groups and is an integer of 1 to 5. From the viewpoint of improving antithrombotic properties, m is preferably an integer of 1 to 3, more preferably 1 or 2, and particularly preferably 1.

[0085] In the above formula (IV), Z is a group represented by the formula: —O—(CH ２ CHOH ｎ -CH ２ When n is a group represented by (-CH ２ represents the number of CHOH— groups and is an integer of 1 to 5. From the viewpoint of improving antithrombotic properties, m is preferably an integer of 1 to 3, more preferably 1 or 2, and particularly preferably 1.

[0086] In the above formula (IV), Z is —O—(R ９ O) ｍ -R １０ a group represented by —O—(CH ２ CHOH ｎ -CH ２ From the viewpoint of obtaining excellent antithrombotic properties, Z is a group represented by —O—(R９ O) ｍ -R １０ It is preferable that the group is represented by the following formula:

[0087] In the above formula (V), R ９ is a hydrogen atom or a methyl group, and from the viewpoint of obtaining excellent antithrombotic properties, R ９ is a methyl group.

[0088] In the above formula (V), represents R １０ and R １１ are each independently a linear or branched alkylene group having 1 to 6 carbon atoms. １０ and R １１ may be the same or different. Specific examples of the linear or branched alkylene group having 1 to 6 carbon atoms include a methylene group, an ethylene group, a trimethylene group, a propylene group, a tetramethylene group, a pentamethylene group, and a hexamethylene group. Among these, from the viewpoint of obtaining excellent antithrombotic properties, R １０ and R １１ are each independently preferably a linear or branched alkylene group having 1 to 3 carbon atoms, more preferably a methylene group or an ethylene group, and particularly preferably an ethylene group.

[0089] In the above formula (V), R １２ ~R １４ are each independently a linear or branched alkyl group having 1 to 4 carbon atoms. １２ ~R １４ may be the same or different. Specific examples of alkyl groups having 1 to 4 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl groups. Among these, from the viewpoint of obtaining excellent antithrombotic properties, R １２ ~R １４ are each independently preferably a linear or branched alkyl group having 1 to 3 carbon atoms, more preferably an alkyl group having 1 or 2 carbon atoms (methyl group, ethyl group), and particularly preferably a methyl group.

[0090] In the above formula (V), Y ２ is an oxygen atom or —NH—, and from the viewpoint of obtaining excellent antithrombotic properties, preferably, Y ２ is an oxygen atom.

[0091] The monomer represented by the formula (IV) above has cell adhesive properties to vascular endothelial cells in addition to antithrombotic properties. Therefore, by using one or more monomers selected from the monomers represented by the formula (IV) above as antithrombotic monomers, a functional layer having both antithrombotic properties and vascular endothelial cell adhesive properties can be formed on the surface of a metal substrate. This makes it easier for the surface of a metal substrate exposed to the blood to be covered with endothelial cells in medical devices such as stents, stent grafts, and covered stents, thereby further reducing the risk of thrombus formation.

[0092] Among the zwitterionic monomers represented by the above formula (III), zwitterionic monomers having a carboxybetaine skeleton (carboxybetaine-type zwitterionic monomers; X=-COO － Examples of the alkyl acrylate copolymer include N-(meth)acryloyloxymethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxypropyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxymethyl-N,N-diethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxyethyl-N,N-diethylammonium-α-N-methylcarboxybetaine, and N-(meth)acryloyloxypropyl-N,N-diethylammonium-α-N-methylcarboxybetaine. Of these, from the viewpoint of obtaining excellent antithrombotic properties, N-(meth)acryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine is preferred, and N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA) is more preferred.

[0093] Among the zwitterionic monomers represented by the above formula (III), a zwitterionic monomer having a sulfobetaine skeleton (sulfobetaine-type zwitterionic monomer; X=-SO ３ － Examples of the 2-((meth)acryloyloxy)ethyl dimethyl-(3-sulfopropyl)ammonium hydroxide include [2-((meth)acryloyloxy)ethyl]dimethyl-(3-sulfobutyl)ammonium hydroxide, [2-((meth)acryloyloxy)ethyl]diethyl-(3-sulfopropyl)ammonium hydroxide, and [2-((meth)acryloyloxy)ethyl]diethyl-(3-sulfobutyl)ammonium hydroxide. Of these, [2-((meth)acryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide is preferred.

[0094] Specific examples of the monomer represented by formula (IV) above include, but are not limited to, methoxymethyl acrylate, 2-methoxyethyl acrylate (MEA), 3-methoxypropyl acrylate (MC3A), ethoxymethyl acrylate, ethoxyethyl acrylate (EEA), 2-(2-ethoxyethoxy)ethyl acrylate (EEEA), ethoxypropyl acrylate, ethoxybutyl acrylate, propoxymethyl acrylate, butoxyethyl acrylate, methoxybutyl acrylate, tetrahydrofurfuryl acrylate (THFA), methoxymethyl methacrylate, methoxyethyl methacrylate, ethoxymethyl methacrylate, ethoxyethyl methacrylate, 2-(2-ethoxyethoxy)ethyl methacrylate, propoxymethyl methacrylate, butoxyethyl methacrylate, tetrahydrofurfuryl methacrylate, and glycerol (meth)acrylate. Of these, 2-methoxyethyl acrylate (MEA), 3-methoxypropyl acrylate (MC3A), and tetrahydrofurfuryl acrylate (THFA) are preferred, and 2-methoxyethyl acrylate (MEA) and 3-methoxypropyl acrylate (MC3A) are more preferred.

[0095] A specific example of the monomer represented by formula (V) is 2-(meth)acryloyloxyethyl phosphorylcholine, of which 2-methacryloyloxyethyl phosphorylcholine (MPC) is more preferred.

[0096] That is, in the medical device according to one embodiment of the present invention, the functional monomer is selected from the group consisting of N-(meth)acryloyloxymethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxypropyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxymethyl-N,N-diethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxyethyl-N,N-diethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxypropyl-N,N-diethylammonium-α-N-methylcarboxybetaine, methoxymethyl acrylate, 2-methoxyethyl and 2-(2-ethoxyethoxy)ethyl acrylate, ethoxypropyl acrylate, ethoxymethyl acrylate, ethoxyethyl acrylate, 2-(2-ethoxyethoxy)ethyl acrylate, ethoxypropyl acrylate, ethoxybutyl acrylate, propoxymethyl acrylate, butoxyethyl acrylate, methoxybutyl acrylate, tetrahydrofurfuryl acrylate, methoxymethyl methacrylate, methoxyethyl methacrylate, ethoxymethyl methacrylate, ethoxyethyl methacrylate, 2-(2-ethoxyethoxy)ethyl methacrylate, propoxymethyl methacrylate, butoxyethyl methacrylate, tetrahydrofurfuryl methacrylate, glycerol (meth)acrylate, and 2-methacryloyloxyethyl phosphorylcholine.According to a more preferred embodiment, the functional monomer is one or more selected from the group consisting of methoxymethyl acrylate, 2-methoxyethyl acrylate (MEA), 3-methoxypropyl acrylate (MC3A), ethoxymethyl acrylate, ethoxyethyl acrylate (EEA), 2-(2-ethoxyethoxy)ethyl acrylate (EEEA), ethoxypropyl acrylate, ethoxybutyl acrylate, propoxymethyl acrylate, butoxyethyl acrylate, methoxybutyl acrylate, tetrahydrofurfuryl acrylate (THFA), methoxymethyl methacrylate, methoxyethyl methacrylate, ethoxymethyl methacrylate, ethoxyethyl methacrylate, 2-(2-ethoxyethoxy)ethyl methacrylate, propoxymethyl methacrylate, butoxyethyl methacrylate, tetrahydrofurfuryl methacrylate, and glycerol (meth)acrylate.

[0097] These functional monomers may be used alone or in combination of two or more. That is, the functional polymer chain consisting of the structural unit B derived from the functional monomer may be a homopolymer type consisting of one functional monomer alone, or a copolymer type consisting of two or more of the functional monomers. When two or more types are used, the structural unit B may be in the form of a block copolymer or a random copolymer.

[0098] In the polymer according to the present invention, the ratio of the number of structural units B to the number of structural units A is not particularly limited, but in order to exhibit sufficient functionality (e.g., antithrombotic properties), this ratio is preferably 30 or more, more preferably 30 to 200, and even more preferably 30 to 150. That is, in the medical device according to one embodiment of the present invention, the ratio of the number of structural units B to the number of structural units A in the polymer is 30 or more. By controlling the number of moles of the functional monomer that is reacted with (contacted with) the base material after the reaction of the binding monomer, and the reaction time of the functional monomer with the base material, it is possible to obtain a polymer in which a predetermined number of structural units B are linked to one structural unit A.

[0099] The terminals of the polymer according to the present invention are not particularly limited and can be appropriately determined depending on the type of monomer used. In one embodiment, the terminals of the polymer according to the present invention (marked * in FIG. 1 ) are hydrogen atoms. Furthermore, when the polymer according to the present invention is prepared by radical polymerization, the terminals of the polymer (marked * in FIG. 1 ) can be capped with a structural unit (functional group) derived from the polymerization initiator. In the latter form (a form capped with a functional group derived from the polymerization initiator), the terminals of the polymer can be carboxyl groups.

[0100] The weight-average molecular weight of the polymer according to the present invention is several thousand to several million, preferably 10,000 to 5,000,000. In this specification, the "weight-average molecular weight" is a value measured by gel permeation chromatography (GPC) using polystyrene as the standard substance and tetrahydrofuran (THF) as the mobile phase. The molecular weight of the copolymer can also be calculated from the type and number of constituent units.

[0101] The thickness (dry film thickness) of the functional layer is, for example, about 0.1 to 10 μm, preferably about 0.5 to 5 μm, and more preferably about 1 to 3 μm.

[0102] [Method for producing a medical device] Another aspect of the present invention also provides a method for producing the medical device. That is, one embodiment of the present invention is a method for producing the medical device (also simply referred to in this specification as the "method for producing a medical device according to the present invention"), comprising: irradiating at least a portion of the surface of the substrate (metal substrate) with plasma; contacting the substrate after the plasma irradiation with the binding monomer; and contacting the substrate after the contact with the binding monomer with the functional monomer, thereby forming the functional polymer chain on the surface of the substrate via the structural unit A derived from the binding monomer.

[0103] Hereinafter, preferred embodiments of each step performed in the method for producing a medical device according to the present invention will be described, but the method for producing a medical device according to the present invention is not limited to the following embodiments.

[0104] <<Plasma Irradiation Step (Plasma Treatment Step)>> In this step, at least a portion of the surface of a substrate (metal substrate) is irradiated with plasma (plasma treatment is performed). This can generate hydroxyl groups (—OH) on the surface of the metal substrate. Then, by contacting such a metal substrate surface with a binding monomer, the phosphate group or phosphonic acid group contained in the binding monomer can react (condensation reaction) with the hydroxyl group (—OH) formed on the substrate surface to form a phosphate ester bond or a phosphonate ester bond. As a result, the polymer according to the present invention is firmly fixed on the metal substrate, making it possible to produce a medical device that can maintain functionality (e.g., antithrombogenicity) for a long period of time.

[0105] Since the desired plasma treatment can be performed even on a thin and narrow inner surface of a small-diameter artificial blood vessel or the like, the plasma irradiation step is preferably performed by ionized gas plasma treatment.

[0106] Before irradiating the surface of a metal substrate with ionized gas plasma, it is preferable to polish and / or clean the surface of the metal substrate by an appropriate method. That is, before generating hydroxyl groups (—OH) on the surface of the metal substrate by irradiating it with ionized gas plasma, it is preferable to smooth the surface of the metal substrate and remove oils, grease, dirt, etc. adhering to the surface of the metal substrate. The polishing method is not particularly limited, and known polishing methods (e.g., chemical polishing, electrolytic polishing, mechanical polishing) can be appropriately adopted. Among them, chemical polishing is preferred because it is suitable for polishing fine details. The cleaning method is also not particularly limited, and can be performed by cleaning with an appropriate solvent (e.g., ultrasonic cleaning, immersion in a cleaning solvent, or flushing with a cleaning solvent).

[0107] The pressure conditions for the plasma treatment are not particularly limited, and either reduced pressure or atmospheric pressure is possible. Atmospheric pressure is preferred because it allows plasma gas to be irradiated from any angle, the device can be made smaller because a vacuum device is not required, a space-saving, low-cost system configuration can be achieved, and it is also economically advantageous. Furthermore, by irradiating the plasma gas while rotating the plasma irradiation nozzle around the object to be treated, such as an artificial blood vessel, the entire circumference of the object can be uniformly plasma-treated without unevenness.

[0108] The ionized gas that can be used in the plasma treatment is one or more gases selected from the group consisting of helium, neon, argon, krypton, air, oxygen, carbon dioxide, carbon monoxide, water vapor, nitrogen, hydrogen, etc. The plasma treatment conditions (irradiation time, LF output, applied current, gas flow rate, inter-electrode gap, plasma irradiation distance) are not particularly limited and can be appropriately selected depending on the binding strength (ease of immobilization) between the binding monomer and the metal substrate, the type and area of ​​the metal substrate used, etc.

[0109] For example, the irradiation time in the plasma treatment is preferably more than 10 seconds, more preferably 30 seconds to 10 minutes, and particularly preferably 1 to 5 minutes. Under these conditions, a sufficient amount of the binding monomer can be bound (fixed) to the surface of the metal substrate.

[0110] As an example, the LF output in the plasma treatment is preferably 100 to 300W, more preferably 150 to 250W, and even more preferably 200W.

[0111] As an example, the gas flow rate in the plasma treatment is preferably 5 to 20 sccm, more preferably 10 to 20 sccm, and even more preferably 15 sccm.

[0112] The temperature of the workpiece (metal substrate) in the plasma treatment is not particularly limited, and may be room temperature or may be heated or cooled. From an economical viewpoint, it is preferable to perform the treatment at a temperature (e.g., 5 to 35°C) at which a heating or cooling device is not required.

[0113] Plasma irradiation devices (systems) that can be used for plasma treatment are not particularly limited, and examples include plasma irradiation devices (systems) that have a plasma generating tube that introduces gas molecules and excites them to generate plasma, and an electrode that excites the gas molecules in the plasma generating tube, and that emit plasma from one end of the plasma generating tube. However, the present invention is not limited to such configurations (systems). Examples include devices that employ a high-frequency induction system, a capacitively coupled electrode system, a corona discharge electrode-plasma jet system, a parallel plate system, a remote plasma system, an atmospheric pressure plasma system, a low-pressure plasma system, an ICP high-density plasma system, and the like. Additionally, commercially available ionized gas plasma irradiation devices (systems), particularly atmospheric pressure plasma irradiation devices (systems), that are suitable for irradiation of stent grafts, covered stents, stents, guidewires, cardiac pacemakers, and the like, can be used. Specifically, plasma irradiation equipment such as DURADYNE (product name or trademark) manufactured by TRI-STAR TECHNOLOGIES, and plasma irradiation equipment such as PLASMABEAM and Pico Full PC manufactured by DIENER ELECTRONIC can be used, but the present invention is not limited to these.

[0114] In this step, the substrate after the plasma irradiation is brought into contact with the binding monomer, which causes a reaction (condensation reaction) between the phosphate group or phosphonate group contained in the binding monomer and the hydroxyl group (—OH) formed on the surface of the substrate, thereby forming a phosphate ester bond or a phosphonate ester bond.

[0115] In this step, the specific method for contacting the binding monomer with the substrate after plasma irradiation may be either a method of contacting the binding monomer directly with the substrate, or a method of preparing a binding monomer solution by dissolving the binding monomer in a solvent and then contacting the binding monomer solution with the substrate. From the viewpoint of forming a more uniform functional layer, it is preferable to adopt the latter method of contacting the binding monomer solution with the substrate.

[0116] The solvent used to prepare the binding monomer solution is not particularly limited and is appropriately selected depending on the type of binding monomer (and other components, if used). From the viewpoint of high solubility, water (reverse osmosis water (RO water), pure water, ion-exchanged water, distilled water, etc.); alcoholic solvents such as methanol, ethanol, isopropyl alcohol, and butanol; and organic solvents such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran (THF), dimethyl sulfoxide, N,N-dimethylformamide (DMF), acetone, dioxane, and benzene are preferably used. These solvents may be used alone or in combination of two or more (in the form of a mixed solvent).

[0117] The concentration of the binding monomer in the binding monomer solution is not particularly limited. For example, it is preferably 0.0001 to 10% by mass, more preferably 0.0001 to 1% by mass, and particularly preferably 0.0003 to 1% by mass. If the concentration of the binding monomer is within the above range, the resulting functional layer can exhibit sufficient functionality.

[0118] Next, the binding monomer solution prepared as described above is brought into contact with the substrate after plasma irradiation. Here, as a specific method for "contacting," a conventionally known method such as a method of applying the binding monomer solution to the surface of the substrate or a method of immersing the substrate in the binding monomer solution can be appropriately adopted. Among these, the immersion method is preferably used because it is easy to operate.

[0119] When forming a functional layer on a narrow inner surface of a stent graft, a covered stent, a stent, a guidewire, a cardiac pacemaker, or the like, the metal substrate may be immersed in the binding monomer solution and degassed by reducing the pressure in the system. By reducing the pressure and degassing, the solution can be rapidly penetrated into the narrow inner surface, facilitating the binding of the binding monomer to the substrate surface.

[0120] Alternatively, the contact by the immersion method may be performed while stirring the binding monomer solution. This further promotes contact between the binding monomer solution and the object to be treated. The stirring can be performed using a known device such as a stirrer, an orbital shaker, a rotary shaker, or a paint shaker. The stirring conditions are not particularly limited. From the viewpoint of more efficient contact with the object to be treated, the stirring speed is, for example, 200 to 600 rpm, preferably 300 to 400 rpm. From the same viewpoint, the stirring time is, for example, 0.5 to 24 hours, preferably 1 to 12 hours. The temperature of the binding monomer solution during contact by the immersion method may be around room temperature (e.g., 20 to 40°C), but it may also be heated (e.g., 40 to 60°C).

[0121] Furthermore, when forming a functional layer only on a portion of a substrate, the binding monomer can be bound to the desired surface portion of the substrate by immersing only a portion of the substrate in a binding monomer solution.

[0122] If it is difficult to immerse only a portion of the metal substrate in the binding monomer solution, the surface portion of the substrate that does not require the formation of a functional layer can be protected (coated, etc.) with a suitable detachable (removable) member or material, and then the substrate can be immersed in the binding monomer solution. The protective member (material) from the surface portion of the substrate that does not require the formation of a functional layer can then be removed, thereby allowing the binding monomer to be bonded to the desired surface portion of the substrate. However, the present invention is not limited to these formation methods, and any conventionally known method can be used as appropriate to bond the binding monomer. For example, if it is difficult to immerse only a portion of the metal substrate in the binding monomer solution, other coating methods (e.g., applying the binding monomer solution to a predetermined surface portion of a medical device using an application device such as a sprayer, bar coater, die coater, reverse coater, comma coater, gravure coater, spray coater, or doctor knife) may be used instead of the immersion method. In addition, when the structure of a medical device requires that both the outer and inner surfaces of a cylindrical device have a functional layer, the immersion method (dipping method) is preferably used because it allows the binding monomer to be bonded to both the outer and inner surfaces at the same time.

[0123] In this step, if necessary, the substrate may be washed after contact with the binding monomer. The method of washing is not particularly limited, and can be performed by washing with an appropriate solvent (e.g., ultrasonic washing, immersion in a washing solvent, pouring off a washing solvent, etc.). The washing time is not particularly limited, but is preferably 1 to 60 minutes. If necessary, the above washing treatment may be repeated multiple times (e.g., 2 to 5 times).

[0124] <<Functional Monomer Contacting Step>> In this step, the functional monomer (antithrombotic monomer) is contacted with the substrate after contacting with the binding monomer. As a result, the functional monomer bonds to the ethylenically unsaturated group contained in the constituent unit A derived from the binding monomer bound to the substrate, and the remaining functional monomers are graft polymerized to the functional monomer bound to the ethylenically unsaturated group, thereby forming a functional polymer chain on the surface of the substrate via the constituent unit A derived from the binding monomer. That is, a functional layer is formed on the surface of the substrate.

[0125] In this step, a specific method for contacting the functional monomer with the substrate after contacting the binding monomer may be either a method of contacting the functional monomer as is with the substrate after contacting the binding monomer, or a method of preparing a functional monomer solution by dissolving the functional monomer in a solvent and then contacting the functional monomer solution with the substrate after contacting the binding monomer.From the viewpoint of forming a more uniform functional layer, it is preferable to adopt the latter method of contacting the functional monomer solution with the substrate after contacting the binding monomer.

[0126] The solvent (polymerization solvent) used in preparing the functional monomer solution is not particularly limited as long as it can dissolve the functional monomer and a suitable polymerization initiator. Examples include, but are not limited to, one or more solvents selected from water (reverse osmosis water (RO water), pure water, ion-exchanged water, distilled water, etc.); alcohols such as ethanol, isopropanol, n-propanol, n-butanol, isobutanol, sec-butanol, t-butanol, ethylene glycol, diethylene glycol, propylene glycol, and dipropylene glycol; and organic solvents such as chloroform, tetrahydrofuran, acetone, dioxane, and benzene. The concentration of the functional monomer contained in the functional monomer solution is not particularly limited, but by setting the concentration relatively high, the weight-average molecular weight of the resulting polymer can be increased. As an example, the concentration (total concentration) of the functional monomer in the functional monomer solution is preferably 10% by mass or more, and more preferably 15% by mass or more. The upper limit of the concentration (total concentration) of the functional monomers is not particularly limited, but is, for example, equal to or lower than the saturated concentration, for example, equal to or lower than 70% by mass, and preferably equal to or lower than 50% by mass.

[0127] In this step, by contacting the functional monomer with the substrate after contacting the binding monomer, the functional monomer bonds to the ethylenically unsaturated group contained in the structural unit A derived from the binding monomer bound to the substrate, and the remaining functional monomer undergoes graft polymerization to the functional monomer bound to the ethylenically unsaturated group. The specific polymerization method is not particularly limited, and conventionally known polymerization methods such as radical polymerization and polymerization using a macroinitiator can be applied. Examples of polymerization methods include (i) a method in which a functional monomer and a suitable polymerization initiator are dissolved in a polymerization solvent and the resulting polymerization reaction solution is heated to carry out the polymerization reaction; and (ii) a method in which a functional monomer is dissolved in a polymerization solvent and the resulting solution is mixed with a separately prepared polymerization initiator solution to prepare a polymerization reaction solution and carry out the polymerization reaction. From the viewpoint of ease of operation, method (i) is preferred.

[0128] The polymerization reaction solution may be degassed before the polymerization reaction, for example, by bubbling with an inert gas such as nitrogen gas or argon gas for about 5 minutes to 1 hour.

[0129] The polymerization initiator used here is not particularly limited, and known initiators can be used. Preferably, radical polymerization initiators are used in terms of excellent polymerization stability, and specific examples thereof include persulfates such as potassium persulfate (KPS), sodium persulfate, and ammonium persulfate; peroxides such as hydrogen peroxide, t-butyl peroxide, methyl ethyl ketone peroxide, 3-hydroxy-1,1-dimethylbutyl peroxyneodecanoate, α-cumyl peroxyneodecanoate, 1,1,3,3-tetrabutyl peroxyneodecanoate, t-butyl peroxyneodecanoate, t-butyl peroxyneoheptanoate, t-butyl peroxypivalate, t-amyl peroxyneodecanoate, t-amyl peroxypivalate, di(2-ethylhexyl)peroxydicarbonate, and di(s-butyl)peroxydicarbonate. oxides; azo compounds such as azobisisobutyronitrile (AIBN), 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile), 2,2'-azobis(2,4-dimethylvaleronitrile), 2,2'-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride, 2,2'-azobis[2-(2-imidazolin-2-yl)propane]disulfate dihydrate, 2,2'-azobis(2-methylpropionamidine)dihydrochloride, 2,2'-azobis[N-(2-carboxyethyl)-2-methylpropionamidine)]hydrate, 2,2'-azobis[N-(2-carboxyethyl)-2-methylpropionamidine)]tetrahydrate, and azobiscyanovaleric acid. The polymerization initiators may be used alone or in combination of two or more.

[0130] Furthermore, for example, the radical polymerization initiator may be combined with a reducing agent such as sodium sulfite, sodium hydrogen sulfite, or ascorbic acid to be used as a redox initiator. The amount of the polymerization initiator blended (added) is preferably 0.01 to 5 mass %, and more preferably 0.05 to 3 mass %, relative to 100 mass % of the total functional monomers. Alternatively, the amount of the polymerization initiator blended (added) is preferably 0.01 to 5 mol, and more preferably 0.05 to 3 mol, relative to 100 mol of the total functional monomers. Such an amount of the polymerization initiator blended (added) allows the polymerization reaction to proceed efficiently.

[0131] Furthermore, when the method (ii) is used, the solvent in which the polymerization initiator is dissolved in advance (the solvent for the polymerization initiator solution) is not particularly limited as long as it can dissolve the polymerization initiator, and examples thereof include the same solvents as the polymerization solvent. The solvent for the polymerization initiator solution may be the same as or different from the polymerization solvent, but is preferably the same solvent as the polymerization solvent in consideration of ease of control of polymerization, etc.

[0132] By heating the polymerization reaction solution prepared as described above, the ethylenically unsaturated group contained in the structural unit A derived from the binding monomer bonded to the base material can be polymerized with the functional monomer. Here, as the polymerization method, for example, in addition to the above-mentioned radical polymerization, known polymerization methods such as anionic polymerization and cationic polymerization can be used, but in consideration of ease of operation, it is preferable to use radical polymerization.

[0133] The polymerization conditions are not particularly limited as long as they allow the ethylenically unsaturated group contained in the structural unit A derived from the binding monomer bonded to the base material to polymerize with the functional monomer. For example, the polymerization temperature is preferably 30 to 150°C, more preferably 40 to 100°C. The polymerization time is preferably 30 minutes to 30 hours, more preferably 1 to 10 hours. Under such conditions, the polymerization reaction can proceed efficiently.

[0134] During the polymerization, a chain transfer agent, a polymerization rate adjuster, a surfactant, and other additives may be used as needed.

[0135] The environment in which the polymerization reaction is carried out is not particularly limited, and the reaction can be carried out in the air or in an inert gas atmosphere such as nitrogen gas or argon gas, but is preferably carried out in a nitrogen gas atmosphere. The reaction solution may be stirred during the polymerization reaction.

[0136] In this step, if necessary, the substrate may be washed after contact with the functional monomer. The method of washing is not particularly limited, and can be performed by washing with an appropriate solvent (e.g., ultrasonic washing, immersion in a washing solvent, pouring the washing solvent, etc.). The washing time is not particularly limited, but is preferably 1 to 60 minutes. If necessary, the above washing treatment may be repeated multiple times (e.g., 2 to 5 times).

[0137] By the above method, a medical device having excellent functionality (for example, antithrombogenicity) can be produced.

[0138] [Uses of Medical Devices] The medical device according to the present invention has excellent functionality (e.g., antithrombogenicity). Examples of medical devices according to the present invention include implantable artificial organs and treatment instruments, extracorporeal circulation artificial organs, catheters, guidewires, and the like. Among these, the medical device is preferably an intravascular device, and specific examples include a stent graft, a covered stent, a stent, a guidewire, and a cardiac pacemaker. That is, the medical device according to one embodiment of the present invention is a stent graft, a covered stent, a stent, a guidewire, or a cardiac pacemaker. Other examples of medical devices include the following: Specific examples include implantable medical devices such as artificial tracheas, artificial joints, and artificial pericardiums; artificial organ systems such as artificial heart systems, artificial lung systems, artificial heart-lung systems, artificial kidney systems, artificial liver systems, and immunoregulatory systems; catheters inserted or placed in blood vessels such as indwelling needles, IVH catheters, drug solution administration catheters, thermodilution catheters, angiography catheters, vasodilator catheters, dilators, or introducers; guide wires and stylets for these catheters; and catheters inserted or placed in biological tissues other than blood vessels, such as gastric catheters, nutritional catheters, enteral feeding (ED) tubes, urethral catheters, urinary catheters, balloon catheters, and various suction catheters and drainage catheters, including endotracheal suction catheters.

[0139] The effects of the present invention will be explained using the following examples and comparative examples. However, the technical scope of the present invention is not limited to the following examples. In the following examples, the terms "parts" and "%" may be used, but unless otherwise specified, they represent "parts by mass" or "% by mass." Furthermore, unless otherwise specified, each operation was performed at room temperature (25°C).

[0140] Example 1 Preparation of NiTi-PHA-CBA (1) Preparation of NiTi Substrate Nickel titanium (NiTi) (manufactured by SAES Material Corporation, thickness: 0.5 mm) was cut into a size of 1.0 cm x 2.0 cm. The cut NiTi and 300 mL of MicroClean BS polishing solution (manufactured by RD Chemical Company) were placed in a 500 mL beaker and washed in an ultrasonic cleaner for 3 minutes. This operation was repeated 10 times. After washing, the NiTi was placed in distilled water and washed in an ultrasonic cleaner for 3 minutes. This operation was repeated three times to remove the polishing solution adhering to the surface of the NiTi. After washing, the NiTi was dried at room temperature to obtain a NiTi substrate (NiTi (untreated plasma)).

[0141] (2) Plasma treatment of NiTi substrate The NiTi substrate was placed in a plasma irradiation device (Pico Full PC, manufactured by DIENER ELECTRONIC, low-pressure type) and plasma irradiation (argon ionized gas plasma irradiation) was performed on both sides for 3 minutes under the following conditions: pressure: 0.3 mbar, power: 50%, introduced gas: 100% Ar gas, LF output: 200 W, gas flow rate: 15 sccm. After plasma irradiation, the NiTi substrate was taken out into the atmosphere and left to stand for 10 to 30 minutes. This resulted in a NiTi substrate with a plasma-treated surface (NiTi (after plasma treatment)).

[0142] (3) Bonding of 2-methacryloyloxyethyl acid phosphate (PHA) 16.6 μL (0.1 mmol) of 2-methacryloyloxyethyl acid phosphate (PHA) (Light Ester P-1M, manufactured by Kyoeisha Chemical Co., Ltd.) and 10 mL of ethanol were placed in a glass bottle to dissolve the reagent. The NiTi substrate was placed in this solution and allowed to react overnight at room temperature. The NiTi substrate was then removed and allowed to stand in ethanol for 1 hour to remove unreacted PHA, after which it was dried at room temperature. This yielded a NiTi substrate bonded with PHA (NiTi-PHA).

[0143] (4) Polymerization of N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA) 1.97 g (9.15 mmol) of N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA, monomer concentration 20% by mass, manufactured by Osaka Organic Chemical Industry Co., Ltd.), 1.9 mg of 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), and 10 mL of ethanol were placed in a glass bottle and stirred at room temperature until all reagents were dissolved. The reagent solution in the glass bottle was transferred to a recovery flask, and the PHA-bonded NiTi substrate (NiTi-PHA) was placed in this reagent solution. Nitrogen gas was introduced for 10 minutes to replace the gas in the system with nitrogen gas. The recovery flask was covered with a rubber stopper. The recovery flask was placed in a 37°C water bath and the reaction was carried out for 4 hours. The NiTi substrate was then removed and washed by immersing it in ethanol to remove any unreacted material, thereby obtaining a NiTi substrate in which CBA had been polymerized via PHA (NiTi-PHA-CBA).

[0144] Example 2 Preparation of NiTi-PHA-MEA (4) Polymerization of 2-methoxyethyl acrylate (MEA) A NiTi substrate in which MEA was polymerized via PHA (NiTi-PHA-MEA) was obtained in the same manner as in Example 1, except that in the above "(4) Polymerization of N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA)" above, "2.5 g (19.21 mmol) of 2-methoxyethyl acrylate (MEA, 1.73 mol / L, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.)" was used instead of "1.97 g (monomer concentration 20 mass%) of N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA, manufactured by Osaka Organic Chemical Industry Ltd.)."

[0145] Example 3 Preparation of NiTi-PHA-MC3A (4) Polymerization of 3-methoxypropyl acrylate (MC3A) A NiTi base material in which MC3A was polymerized via PHA (NiTi-PHA-MC3A) was obtained in the same manner as in Example 1, except that in the above "(4) Polymerization of N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA)" 1.97 g (monomer concentration 20 mass%) of N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA) manufactured by Osaka Organic Chemical Industry Ltd., 2.48 g (17.20 mmol) of 3-methoxypropyl acrylate (MC3A, 1.73 mol / L, manufactured by Tokyo Chemical Industry Co., Ltd.) was used.

[0146] Example 4 Preparation of NiTi-PHA-MPC (4) Polymerization of 2-(methacryloyloxy)ethyl 2-(trimethylammonio)ethyl phosphate (also known as 2-methacryloyloxyethyl phosphorylcholine, MPC) A NiTi base material in which MPC was polymerized via PHA (NiTi-PHA-MPC) was obtained in the same manner as in Example 1, except that in the above "(4) Polymerization of N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA)" "1.97 g (monomer concentration 20 mass%) of N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA, manufactured by Osaka Organic Chemical Industry Ltd.)" was replaced with "1.477 g (5.00 mmol) of 2-(methacryloyloxy)ethyl 2-(trimethylammonio)ethylphosphate (MPC, 0.5 mol / L, manufactured by Tokyo Chemical Industry Co., Ltd.)."

[0147] <Platelet Adhesion Test> Using the samples prepared above and NiTi (untreated with plasma), a platelet adhesion test was performed as follows to evaluate antithrombotic properties. A 3.2 (w / v)% aqueous solution of sodium citrate (anticoagulant) was added to fresh porcine blood to obtain anticoagulated fresh porcine blood (1). The volume ratio of the fresh porcine blood to the aqueous sodium citrate solution was 9:1. A 1M calcium chloride solution and heparin were simultaneously added to the anticoagulated fresh porcine blood (1) using a stirring rod to obtain anticoagulated fresh porcine blood (2). 820 μL of the 1M calcium chloride solution and 1000 U of heparin were mixed in 50 mL of anticoagulated fresh porcine blood (2). The final concentration of heparin in the anticoagulated fresh porcine blood (2) was 2 U / mL. 100 μL of anticoagulated fresh porcine blood (2) was centrifuged (1500 × g) at 22°C for 10 minutes to obtain platelet-rich plasma (PRP). This PRP was filled into cylindrical containers with the above samples attached to their bottoms and allowed to stand overnight at room temperature. Each sample was then washed with a 3.2 wt% sodium citrate / phosphate buffer solution (PBS) (= 1 / 9 (volume ratio)) and fixed with a 1 (w / v)% glutaraldehyde solution in PBS. After standing at room temperature for 4 hours, the samples were washed with distilled water. Each sample was dried at room temperature, platinum-coated, and then observed and photographed (1000x magnification, 5 fields of view) using a scanning electron microscope (SEM). The number of adhered (adhered) platelets was counted for each photograph, and the total number of adhered platelets for the 5 fields of view was calculated. The results are shown in Table 1 below. SEM photographs of each example are also shown in Figures 4 to 8. FIG. 4 is an SEM image of the NiTi substrate before plasma treatment (NiTi (unplasma treated)) in Comparative Example 1. FIG. 5 is an SEM image of the NiTi substrate in which CBA has been polymerized via PHA in Example 1 (NiTi-PHA-CBA). FIG. 6 is an SEM image of the NiTi substrate in which MEA has been polymerized via PHA in Example 2 (NiTi-PHA-MEA). FIG. 7 is an SEM image of the NiTi substrate in which MC3A has been polymerized via PHA in Example 3 (NiTi-PHA-MC3A). FIG. 8 is an SEM image of the NiTi substrate in which MPC has been polymerized via PHA in Example 4 (NiTi-PHA-MPC).

[0148]

[0149] 4 to 8, the adhesion (sticking) of platelets to the surface of the NiTi substrate was significantly reduced in the samples of Examples 1 to 4 according to the present invention. This demonstrates that the present invention can impart excellent functionality (antithrombogenicity) to medical devices equipped with metal substrates.

[0150] This application is based on Japanese Patent Application No. 2023-098416, filed on June 15, 2023, the disclosure of which is hereby incorporated by reference in its entirety.

[0151] 10...metal substrate, 10a...substrate core portion, 10b...substrate surface layer, 11...antithrombogenic layer, 100...medical device.

Claims

1. A medical device comprising: a metal substrate; and a functional layer bound to the substrate, the functional layer comprising a functional polymer chain composed of a structural unit A derived from a binding monomer having a phosphate group or a phosphonic acid group and an ethylenically unsaturated group, and a structural unit B derived from a functional monomer, the functional polymer chain being bound to the structural unit A at an end thereof.

2. The medical device according to claim 1, wherein the ratio of the number of said structural units B to the number of said structural units A in said polymer is 30 or more.

3. The medical device according to claim 1, wherein the binding monomer is one or more monomers selected from the monomers represented by the following formulas (I) and (II): In the above formula (I), R １ represents a hydrogen atom or a methyl group, p represents an integer of 0 to 20, m1 represents 0 or 1, and n1 represents 1 or 2; In the above formula (II), R ２ represents a hydrogen atom or a methyl group; q represents an integer of 0 to 20; and m2 represents 0 or 1.

4. The medical device according to claim 1, wherein the binding monomer is one or more selected from the group consisting of 2-(meth)acryloyloxyethyl acid phosphate, bis[2-((meth)acryloyloxy)ethyl]phosphate, 11-phosphonoundecyl (meth)acrylate, vinylphosphonic acid and allylphosphonic acid.

5. The medical device according to claim 1, wherein the functional monomer is one or more monomers selected from the monomers represented by the following formulas (III) to (V): In the above formula (III), R ３ represents a hydrogen atom or a methyl group; R ４ represents a linear or branched alkylene group having 1 to 6 carbon atoms; R ５ and R ６ each independently represents a linear or branched alkyl group having 1 to 4 carbon atoms; R ７ represents a linear or branched alkylene group having 1 to 4 carbon atoms; X is -COO － or -SO ３ － represents Y １ represents an oxygen atom or -NH-; In the above formula (IV), R ８ represents a hydrogen atom or a methyl group, Z represents a group of the formula: -O-(R ９ O) ｍ -R １０ a group represented by the formula: -O-(CH ２ CHOH) ｎ -CH ２ OH or a tetrahydrofurfuryloxy group, in which R ９ each independently represents a linear or branched alkylene group having 1 to 4 carbon atoms; R １０ represents a linear or branched alkyl group having 1 to 4 carbon atoms, m represents an integer of 1 to 5, and n represents an integer of 1 to 5; In the above formula (V), R ９ represents a hydrogen atom or a methyl group; R １０ and R １１ each independently represents a linear or branched alkylene group having 1 to 6 carbon atoms; R １２ ~R １４ each independently represents a linear or branched alkyl group having 1 to 4 carbon atoms; ２ represents an oxygen atom or --NH--.

6. The functional monomer is N-(meth)acryloyloxymethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxypropyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxymethyl-N,N-diethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxyethyl-N,N-diethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxypropyl-N,N-diethylammonium-α-N-methylcarboxybetaine, methoxymethyl acrylate, 2-methoxyethyl acrylate, 3-methoxypropyl The medical device according to claim 1, which is one or more selected from the group consisting of acrylate, ethoxymethyl acrylate, ethoxyethyl acrylate, 2-(2-ethoxyethoxy)ethyl acrylate, ethoxypropyl acrylate, ethoxybutyl acrylate, propoxymethyl acrylate, butoxyethyl acrylate, methoxybutyl acrylate, tetrahydrofurfuryl acrylate, methoxymethyl methacrylate, methoxyethyl methacrylate, ethoxymethyl methacrylate, ethoxyethyl methacrylate, 2-(2-ethoxyethoxy)ethyl methacrylate, propoxymethyl methacrylate, butoxyethyl methacrylate, tetrahydrofurfuryl methacrylate, glycerol (meth)acrylate and 2-methacryloyloxyethyl phosphorylcholine.

7. The medical device according to claim 1, wherein the metal is one or more selected from the group consisting of gold, platinum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin, stainless steel, nickel-titanium alloy, nickel-cobalt alloy, cobalt-chromium alloy, and zinc-tungsten alloy.

8. The medical device according to claim 1, wherein the medical device is a stent graft, a covered stent, a stent, a guidewire or a cardiac pacemaker.

9. A method for producing a medical device according to claim 1, comprising: irradiating at least a portion of the surface of the substrate with plasma; contacting the substrate after the plasma irradiation with the binding monomer; and contacting the substrate after the contact with the binding monomer with the functional monomer, thereby forming the functional polymer chain on the surface of the substrate via the constituent unit A derived from the binding monomer.