Thrombus capture device and method for manufacturing same

Abstract

The purpose of the present invention is to provide a means capable of improving the thrombus-capturing capability of a thrombus capture device (in particular, a thrombus capture device provided with a metal substrate) by imparting excellent thrombus adhesiveness. The above problem is solved by a thrombus capture device including a metal substrate and a functional layer bonded to the metal substrate, the functional layer including a polymer containing a structural unit A and a structural unit B covalently bonded to the structural unit A, the structural unit A being derived from a binding monomer having a phosphoric or phosphonic acid group and an ethylenically unsaturated group, the structural unit B being derived from a cationic monomer having an ethylenically unsaturated group, wherein the polymer has, on a side chain thereof, a cationic functional group derived from the cationic monomer.

Description

Thrombosis capture device and method for manufacturing the same

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

[0002] Thrombosis and embolism are diseases in which blood clots block blood vessels, causing organ damage. Specifically, myocardial infarction, cerebral infarction, deep vein thrombosis, pulmonary embolism, and economy class syndrome are known. One treatment method for thrombosis and embolism is thrombectomy, which involves using a metal mesh stent-type retrieval device (thrombus retriever) attached to the tip of a catheter to entangle and retrieve the blood clot. For example, the expandable thrombectomy device described in Japanese Patent Publication No. 2016-104212 (corresponding to International Publication No. 2011 / 082319) comprises an expandable retrieval scaffold having a plurality of interconnected pillars that form a cell, having a cell size determined and configured to allow penetration or protrusion of the blood clot within the cell. According to this document, the retrieval scaffold can promote the engagement of the blood clot.

[0003] However, according to the inventors' research, the expandable thrombectomy devices (thrombus capture devices) described in the above-mentioned literature had the problem that they sometimes did not have sufficient thrombus capture capabilities.

[0004] Therefore, the present invention aims to provide a means to improve thrombus capture performance by imparting excellent thrombus adhesion to thrombus capture devices (particularly thrombus capture devices equipped with a metal substrate).

[0005] The inventors of the present invention conducted diligent research to solve the above problems. As a result, they discovered that the above problems can be solved by coating the surface of a metal substrate with a polymer containing a constituent unit that has bonding properties to the surface of a metal substrate and a constituent unit that exhibits thrombus adhesion, and thus completed the present invention.

[0006] In other words, the above objective can be achieved by the present invention having the following configuration, and the present invention encompasses the following aspects and forms.

[0007] One aspect of the present invention is: 1. A metal substrate; and a functional layer including a polymer containing a structural unit A derived from a binding monomer having a phosphate group or a phosphonic acid group and an ethylenically unsaturated group, which is bonded to the metal substrate, and a structural unit B derived from a cationic monomer having an ethylenically unsaturated group, which is covalently bonded to the structural unit A; The polymer has a cationic functional group derived from the cationic monomer in its side chain, and is a thrombus capture device. 2. In the thrombus capture device according to 1. above, the cationic functional group is preferably one or more selected from the group consisting of an amino group and a functional group represented by the following formula (1);

[0008]

[0009] In the above formula (1), R ２３ , R ２４ and R ２５ each independently represent a monovalent hydrocarbon group. 3. In the thrombus capture device according to 1. or 2. above, the cationic monomer is preferably one or more selected from the group consisting of monomers represented by the following formulas (i) and (ii);

[0010]

[0011] In the above formula (i), R １１ represents a hydrogen atom or a methyl group, R １２ represents a linear or branched alkylene group having 1 to 6 carbon atoms, R １３ and R １４ each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, Y １１ represents an oxygen atom or -NH-, and m11 represents 0 or 1;

[0012]

[0013] In the above formula (ii), A － represents an anion, R ２１ represents a hydrogen atom or a methyl group, R ２２ represents a linear or branched alkylene group having 1 to 6 carbon atoms, R ２３ , R２４ and R ２５ Each of these independently represents a linear or branched alkyl group having 1 to 4 carbon atoms, Y ２１ represents an oxygen atom or -NH-, and m21 represents 0 or 1. 4. In the thrombus capture device described in any of 1. to 3. above, the binding monomer is preferably one or more selected from the group consisting of monomers represented by the following formulas (I) and (II);

[0014]

[0015] In the above formula (I), R １ represents a hydrogen atom or a methyl group, p represents an integer from 1 to 20, m1 represents 0 or 1, m2 represents 0 or 1, and n1 represents 1 or 2;

[0016]

[0017] In the above formula (II), R ２represents a hydrogen atom or a methyl group, q represents an integer from 1 to 20, m3 represents 0 or 1, and m4 represents 0 or 1. 5. In the thrombus capture device described in any of 1 to 4 above, the binding monomer is preferably one or more selected from the group consisting of 2-(meth)acryloyloxyethyl acid phosphate, bis[2-(meth)acryloyloxy)ethyl phosphate, 11-phosphonowndecyl (meth)acrylate, vinylphosphonic acid, and allylphosphonic acid. 6. The above 1 to 5. In a thrombus capture device according to any of the above, the cationic monomer is (meth)acrylamide, N-methyl(meth)acrylamide, N-ethyl(meth)acrylamide, N-propyl(meth)acrylamide, N,N-dimethyl(meth)acrylamide, N,N-diethyl(meth)acrylamide, N,N-dipropyl(meth)acrylamide, aminoethyl(meth)acrylate, aminoisopropyl(meth)acrylate, amino-n-butyl(meth)acrylate, N-methylaminoethyl(meth)acrylate, N-ethylaminoisobutyl(meth)acrylate, N-isopropylaminoethyl(meth)acrylate, N - n-butylaminoethyl (meth)acrylate, N-tert-butylaminoethyl (meth)acrylate, N,N-dimethylaminoethyl (meth)acrylate, N,N-dimethylaminopropyl (meth)acrylate, N,N-dimethylaminobutyl (meth)acrylate, N-methyl-N-ethylaminoethyl (meth)acrylate, N-methyl-N-butylaminoethyl (meth)acrylate, N,N-diethylaminoethyl (meth)acrylate, N,N-diethylaminopropyl (meth)acrylate, N,N-dipropylaminoethyl (meth)acrylate, N,N-dipropylaminopropyl (meth)acrylate, N,N-dibutylaminopropyl (meth)acrylate, aminoethyl (meth)acrylamide, aminoisopropyl (meth)acrylamide, amino-n-butyl (meth)acrylamide, N-methylaminoethyl (meth)acrylamide, N-ethylaminoisobutyl (meth)acrylamide, N-isopropylaminoethyl (meth)acrylamide, N-n-butylaminoethyl (meth)acrylamide, N-tert-butylaminoethyl (meth)acrylamide, N,N-dimethylaminoethyl (meth)acrylamide, N,N-dimethylaminopropyl (meth)acrylamide, N,N-dimethylaminobutyl (meth)acrylamide, N-methyl-N-ethylaminoethyl (meth)acrylamide, N-methyl-N-butylaminoethyl (meth)acrylamide, N,N-diethylaminoethyl (meth)acrylamide, N,N-diethylaminopropyl (meth)acrylamide, N,N-dipropylaminoethyl (meth)acrylamide, N,N-dipropylaminopropyl (meth)acrylamide and N,1. Preferably, the thrombus capture device is one or more selected from the group consisting of N-dibutylaminopropyl(meth)acrylamide, and its alkyl halide derivatives and alkyl sulfate derivatives. 7. In the thrombus capture device according to any one of 1 to 6 above, the metal material constituting the metal substrate 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. 8. The thrombus capture device according to any one of 1 to 7 above preferably has an expandable expander made of the metal substrate. 9. In the thrombus capture device according to 8 above, the expander preferably has a mesh-like frame structure made of the metal substrate. 10. In the thrombus capture device according to any one of 1 to 9 above, the polymer preferably includes a cationic polymer chain made of the constituent unit B, and the ends of the cationic polymer chains are preferably covalently bonded to the constituent unit A bonded to the metal substrate. 11. In the thrombus capture device described in item 10 above, it is preferable that the ratio of the number of constituent units B to the number of constituent units A in the polymer is 30 or more.

[0018] Furthermore, another aspect of the present invention is a method for manufacturing a thrombus capture device according to claim 10 or 11, comprising: 12. Irradiating at least a portion of the surface of the metal substrate with plasma; contacting the metal substrate with the binding monomer after the plasma irradiation; and contacting the metal substrate with the cationic monomer after contact with the binding monomer to form the cationic polymer chain on the surface of the metal substrate via the constituent unit A derived from the binding monomer.

[0019] Figure 1 is a diagram illustrating one embodiment of polymer fixation in the present invention. Figure 2 is a schematic partial cross-sectional view showing the structure of a typical embodiment of the thrombus capture device according to the present invention. Figure 3 is a schematic partial cross-sectional view showing a configuration example with a different structure as an application example of the embodiment in Figure 2. Figure 4 is a schematic diagram showing the overall structure of a typical embodiment of a thrombus capture system to which the thrombus capture device of the present invention is applied. Figure 5 is a schematic diagram illustrating the method of using the thrombus capture system shown in Figure 4. Figure 6(a) is an SEM image used to evaluate the thrombus adhesion of the NiTi substrate (NiTi (untreated with plasma)) of Comparative Example 1 before plasma treatment. Figure 6(b) is an SEM image used to evaluate the thrombus adhesion of the NiTi substrate (NiTi-PHA-DMAEMA) in which DMAEMA was polymerized via PHA in Example 1. Figure 7(a) is a confocal fluorescence microscope image of the NiTi substrate (NiTi (untreated with plasma)) of Comparative Example 1 before plasma treatment. Figure 7(b) is a confocal fluorescence microscope image of the NiTi substrate (NiTi-PHA-DMAEMA) polymerized via PHA in Example 1. Figure 8(a) is an SEM image used to evaluate the thrombus formation properties of the NiTi substrate (NiTi (untreated with plasma)) before plasma treatment in Comparative Example 1. Figure 8(b) is an SEM image used to evaluate the thrombus formation properties of the NiTi substrate (NiTi-PHA-DMAEMA) polymerized via PHA in Example 1.

[0020] According to one embodiment of the present invention, a thrombus capture device comprising a metal substrate and a functional layer is provided. The functional layer comprises a polymer containing a constituent unit A derived from a bonding monomer having a phosphate group or a phosphonic acid group and an ethylenically unsaturated group, bonded to the metal substrate, and a constituent unit B derived from a cationic monomer having an ethylenically unsaturated group, covalently bonded to constituent unit A. The polymer has a cationic functional group derived from the cationic monomer in its side chain. According to the present invention, excellent thrombus adhesion can be imparted to a thrombus capture device comprising a metal substrate.

[0021] To our surprise, the inventors have discovered that a thrombus capture device having such a configuration possesses excellent thrombus adhesion properties (i.e., the thrombus adheres more easily to the thrombus capture device, thereby improving the thrombus capture performance of the thrombus capture device). The mechanism by which the above effects are exerted by the configuration of the present invention is presumed to be as follows.

[0022] The thrombus capture device according to the present invention comprises a metal substrate and a functional layer containing a polymer bonded to the metal substrate. The polymer contains constituent unit A and constituent unit B. Constituent unit A is derived from a binding monomer having a phosphate group or phosphonic acid group and an ethylenically unsaturated group. Constituent unit B is derived from a cationic monomer having an ethylenically unsaturated group. The phosphate group or phosphonic acid group contained in the binding monomer is chemically bonded to the surface of the metal substrate by covalent bonds (particularly hydroxyl groups (-OH) generated by plasma treatment). This firmly fixes the polymer to the surface of the metal substrate. The ethylenically unsaturated group contained in the binding monomer and the ethylenically unsaturated group contained in the cationic monomer polymerize, forming a polymer containing constituent units A and B. The polymer has cationic functional groups derived from the cationic monomer in its side chains. This forms ionic bonds between the anionic functional groups (phosphate groups) of the DNA strands present on the surface of the thrombus and the cationic functional groups of the polymer's side chains, causing the thrombus to adhere to the surface of the thrombus capture device. As a result, the thrombus capture device according to the present invention exhibits excellent thrombus adhesion. Furthermore, since the polymer is bonded to the metal substrate via covalent bonds, the thrombus adhesion can be maintained for a long period of time. Therefore, the thrombus capture device according to the present invention also has excellent durability. It should be noted that the above mechanism is speculative and does not limit the technical scope of the present invention in any way.

[0023] Embodiments of the present invention will be described below. However, the present invention is not limited to the embodiments described below, and can be modified in various ways within the scope of the claims. Furthermore, the embodiments described herein can be combined in any way to form other embodiments. The dimensional ratios in the drawings are exaggerated for illustrative purposes and may differ from actual ratios. Also, when describing embodiments of the present invention with reference to the drawings, the same elements are denoted by the same reference numerals in the description of the drawings, and redundant explanations are omitted.

[0024] Figure 1 is a diagram illustrating one embodiment of polymer immobilization in the present invention. As shown in Figure 1, in the thrombus capture device according to the present invention, constituent unit A derived from 2-methacryloyloxyethyl acid phosphate (PHA; binding monomer) is covalently bonded to the surface of a NiTi substrate (metal substrate). The ends of cationic polymer chains consisting of constituent unit B derived from 2-(dimethylamino)ethyl methacrylate (DMAEMA; cationic monomer) are covalently bonded to the above constituent unit A. In this way, a polymer having an amino group (cationic functional group) in its side chain is immobilized on the NiTi substrate via covalent bonds. That is, the thrombus capture device shown in Figure 1 has a structure in which a DMAEMA polymer chain (cationic polymer chain) consisting of constituent unit B derived from DMAEMA is bonded to the NiTi substrate via constituent unit A derived from PHA (a DMAEMA polymer chain consisting of constituent unit B is grafted onto constituent unit A). The amino groups of the side chains of the DMAEMA polymer chain (cationic polymer chain) form ionic bonds with the anionic functional groups (phosphate groups) of the DNA chain present on the surface of the thrombus, thereby exhibiting thrombus adhesion.

[0025] As shown in Figure 1, the polymer in the present invention preferably includes a DMAEMA polymer chain (cationic polymer chain), and the ends of the cationic polymer chain are covalently bonded to a constituent unit A bonded to a metal substrate. However, the polymer in the present invention is not limited to the form in which a cationic polymer chain consisting of constituent unit B is grafted onto constituent unit A as shown in Figure 1 (hereinafter also referred to as "form (1)"), but may also be a block copolymer containing constituent unit A and constituent unit B (hereinafter also referred to as "form (2)") or a random copolymer containing constituent unit A and constituent unit B (hereinafter also referred to as "form (3)"). When the polymer is a block copolymer or a random copolymer (form (2) or form (3)), the polymer is fixed to the metal substrate by covalent bonding of constituent unit A contained in the block copolymer or random copolymer to the surface of the metal substrate. Furthermore, the cationic functional groups of the side chains of the block copolymer or random copolymer form ionic bonds with the anionic functional groups (phosphate groups) of the DNA chain present on the surface of the thrombus, thereby exhibiting thrombus adhesion.

[0026] In this specification, a thrombus capture device having the above configuration is also simply referred to as "the thrombus capture device according to the present invention" or "thrombus capture device." In this specification, "constituent unit A derived from a binding monomer having a phosphate group or a phosphonic acid group and an ethylenically unsaturated group" is also simply referred to as "constituent unit A according to the present invention" or "constituent unit A." In this specification, "constituent unit B derived from a cationic monomer" is also simply referred to as "constituent unit B according to the present invention" or "constituent unit B." In this specification, a polymer containing constituent unit A and constituent unit B is also simply referred to as "the polymer according to the present invention" or "polymer."

[0027] In this specification, when a constituent unit is defined as "derived from" a monomer, it means that the constituent unit is produced by a condensation reaction of the reactive groups of the corresponding monomer, and / or by the cleavage of one of the bonds of an ethylenically unsaturated group (polymerizable unsaturated double bond).

[0028] In this specification, the term "(meth)acrylic" includes both acrylic and methacrylic. Therefore, for example, the term "(meth)acryloyl" includes both acryloyl and methacryloyl. Therefore, for example, the term "(meth)acryloyl group" includes both acryloyl and methacryloyl groups. Similarly, the term "(meth)acrylate" includes both acrylate and methacrylate. Therefore, for example, the term "alkoxyalkyl (meth)acrylate" includes both alkoxyalkyl acrylate and alkoxyalkyl methacrylate.

[0029] In this specification, the range "X to Y" includes X and Y, meaning "X or greater and Y or less." Furthermore, "A and / or B" includes A, B individually, and any combination thereof. Unless otherwise specified, operations and measurements of physical properties are performed under room temperature (20-25°C) / relative humidity of 40-50% RH.

[0030] [Thrombosis Capture Device] The configuration of a thrombus capture device according to one embodiment of the present invention will be described below with reference to the attached drawings.

[0031] Figure 2 is a schematic partial cross-sectional view showing the structure of a typical embodiment of the thrombus capture device according to the present invention. Figure 3 is a schematic partial cross-sectional view showing a different configuration example as an application example of this embodiment.

[0032] As shown in Figures 2 and 3, a thrombus capture device 100 according to one embodiment of the present invention comprises a metal substrate (also simply referred to as "substrate") 10 and a functional layer 11 having thrombus-adhering properties formed on at least a portion of the substrate 10. Here, in this embodiment, the thrombus capture device 100 is formed by directly laminating the substrate 10 and the functional layer 11 in this order. That is, the substrate 10 and the functional layer 11 are laminated adjacent to each other in this order.

[0033] In this embodiment, the polymer constituting the functional layer (particularly the phosphate group or phosphonic acid group of constituent unit A derived from a bonding monomer) and the surface of the metal substrate (particularly the hydroxyl group (-OH) generated by plasma treatment) are chemically bonded together by covalent bonds, thereby enabling the thrombus adhesion properties of the functional layer to be maintained on the metal substrate for a long period of time.

[0034] Furthermore, the reason why this specification states that "the functional layer is formed on at least a part of the metal substrate" is that, in examples of applications for thrombus capture devices such as thrombus retrievers, thrombus capturers, and thrombus filters, it is not necessarily required to impart thrombus adhesion to all surfaces (the entire surface) of these thrombus capture devices. It is sufficient for the functional layer to be formed only on the surface portion (which may be a part or the entire surface) where thrombus adhesion is required. For this reason, it is preferable that the functional layer be formed on at least a portion of the substrate 10 that can come into contact with a thrombus generated in a blood vessel. For example, if the thrombus capture device is a thrombus retriever, a thrombus capturer, or a thrombus filter, it is preferable that the functional layer be formed on the entire surface of the substrate.

[0035] 《Metal Substrate (Metal Substrate Layer)》 The substrate 10 constituting the thrombus capture device according to one embodiment of the present invention is a metal substrate. As the metal substrate, the optimal substrate can be appropriately selected according to the characteristics required for the thrombus capture device such as a thrombus retriever, thrombus capturer, or thrombus filter (for example, mechanical strength, etc.). As an example, a substrate having the characteristics required for the substrate such as mechanical strength, elasticity, and toughness is preferred.

[0036] The base material 10 only needs to have at least its surface made of a metal material. For example, as shown in Figure 2, the entire base material may be made of a metal material. Alternatively, as shown in Figure 3, the base material may have a structure in which a base material core portion 10a made of a material such as plastic (polymer material) or ceramic material is formed on the surface of a base material surface layer 10b made of a metal material. Alternatively, the base material core portion 10a and the base material surface layer 10b may be composited (through an appropriate reaction treatment) to form the base material 10. Therefore, the base material core portion 10a may be a multilayer structure formed by stacking different materials in multiple layers, or a structure (composite) in which members made of different materials are joined together for each part of the thrombus capture device. Furthermore, another middle layer (not shown) may be formed between the base material core portion 10a and the base material surface layer 10b. Furthermore, the substrate surface layer 10b may also be a multilayer structure formed by laminating different materials in multiple layers, or a composite structure in which members made of different materials are joined together for each part of the thrombus capture device, as long as its surface is composed of (formed) a metallic material.

[0037] The metal materials constituting (forming) the base material 10 and the base material surface layer 10b are not particularly limited, and metal materials commonly used in thrombus capture devices such as thrombus retrievers, thrombus capturers, and thrombus filters can be used. Specifically, examples include gold, platinum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin, stainless steel (e.g., SUS304, SUS314, SUS316, SUS316L, SUS420J2, SUS630, SUS631), nickel-titanium alloys, nickel-cobalt alloys, cobalt-chromium alloys, zinc-tungsten alloys, etc. These may be used individually or in combination of two or more. The above metal materials can be appropriately selected depending on the application of the thrombus capture device. As for the metal material that constitutes (forms) the base material of a thrombus retriever, thrombus capturer, thrombus filter, etc., which are examples of applications, it is more preferable that the metal material is selected from the group consisting of stainless steel and nickel-titanium alloys, and even more preferable from the viewpoint of versatility that it is selected from the group consisting of nickel-titanium alloys. That is, in the thrombus capture device according to one embodiment of the present invention, the metal material is 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, one or more. In a more preferred embodiment, the metal material is selected from the group consisting of stainless steel and nickel-titanium alloys. In an even more preferred embodiment, the metal material is selected from the group consisting of nickel-titanium alloys, one or more.

[0038] The material that can be used for the base core portion 10a described above is not particularly limited, and any material that can adequately express the function of the base core portion 10a as optimal for the application of the thrombus capture device should be appropriately selected. Examples include polyamide resins such as nylon 6, nylon 11, nylon 12, and nylon 66 (all 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 (silicon resins), polyether resins such as polyetheretherketone (PEEK), polyimide resins, and various other polymer materials, as well as inorganic materials such as various ceramic materials. However, the material is not limited to these examples.

[0039] Alternatively, the base material core portion 10a may be composed of a metal material other than the metal material that forms (constitutes) the base material surface layer 10b. Examples of such metal materials are not particularly limited and include those similar to those described above. These may be used individually or in combination of two or more types.

[0040] Preferably, the base material 10 contains or is composed of a metal material, or the base material surface layer 10b contains or is composed of a metal material. More preferably, the base material 10 is composed of a metal material, or the base material surface layer 10b is composed of a metal material. Furthermore, it is preferable that the thrombus capture device has self-expanding properties that maintain an expanded state when no external force is applied. For this reason, it is preferable that the entire base material 10 is composed of a metal material such as a nickel-titanium alloy that has superelasticity.

[0041] The shape of the base material 10 is not particularly limited and can be sheet-like, film-like, tubular, bifurcated or having multiple branched tubes (e.g., Y-shaped), linear (wire), mesh-like, fibrous (thread), etc., and can be appropriately selected depending on the manner of use. When the thrombus capture device is an intravascular implantable device such as a thrombus retriever, thrombus capturer, or thrombus filter, it is preferable that it is an expandable and retractable expander made of the above-mentioned metal base material. That is, the thrombus capture device according to one embodiment of the present invention has an expandable and retractable expander made of the above-mentioned metal base material. With such a configuration, after being transported to a specific site in the blood vessel, the expander can be expanded to exhibit the function of capturing thrombi in the blood. Furthermore, it is preferable that the expander has a mesh-like frame structure made of the metal base material. Having a mesh-like frame structure makes it possible to efficiently capture thrombi in the blood.

[0042] Figure 4 is a schematic diagram illustrating the overall structure of a typical embodiment of a thrombus capture system to which the thrombus capture device of the present invention is applied. Figure 5 is a schematic diagram illustrating the method of using the thrombus capture system shown in Figure 4. Figure 5 shows the state in which the thrombus 310 has been captured by the thrombus retriever 210.

[0043] As shown in Figure 4, the thrombus capture system 200 according to one embodiment of the present invention includes a thrombus retriever 210, a thrombus filter 220, a microcatheter 211, and a delivery catheter 221. Thus, the thrombus capture system 200 shown in Figure 4 is a combination of two thrombus capture devices (thrombus retriever 210 and thrombus filter 220). Both the thrombus retriever 210 and the thrombus filter 220 have expandable and retractable bodies with a mesh-like frame structure made of a metal substrate, and a functional layer having thrombus adhesion properties is formed on each metal substrate. The thrombus retriever 210 and the thrombus filter 220 are then housed inside the microcatheter 211 and the delivery catheter 221, respectively, in a contracted state, and are transported to a specific site in the blood vessel 300 where the thrombus 310 is located, as shown in Figure 5. First, the delivery catheter 221 is transported to a specific site within the blood vessel 300, and then the delivery catheter 221 is moved proximal to expand the thrombus filter 220. The thrombus filter 220 expands to the diameter of the blood vessel 300, preventing the thrombus 310 from moving. Next, the microcatheter 211 is transported so as to penetrate the thrombus 310. Then, while maintaining the position of the thrombus retriever 210 within the blood vessel, the microcatheter 211 is moved proximal to expand the thrombus retriever 210. As the thrombus retriever 210 expands inside the thrombus 310, the thrombus 310 becomes embedded in the thrombus retriever 210. As a result, the thrombus 310 is captured by the thrombus retriever 210. Subsequently, by moving the thrombus retriever 210, along with the microcatheter 211, towards the proximal end of the thrombus filter 220, the thrombus 310 captured by the thrombus retriever 210 is housed inside the thrombus filter 220. At this time, the thrombus 310 adheres to the thrombus retriever 210 via the functional layer formed on the metal substrate of the thrombus retriever 210. As a result, the amount of thrombus left behind in the blood vessel 300 is reduced compared to cases without a functional layer. Furthermore, even if there are thrombus fragments separated from the thrombus 310, these thrombus fragments adhere to the thrombus filter 220 via the functional layer formed on the metal substrate of the thrombus filter 220.Therefore, the amount of thrombus fragments left behind in the blood vessel 300 is reduced compared to when there is no functional layer. Then, the thrombus capture system 200 is removed from the blood vessel 300.

[0044] 《Functional Layer》 The functional layer according to the present invention is a phosphate group (-OP(=O)(OH) ２ , -OP(=O)(OH)O-) or phosphonic acid group (-P(=O)(OH) ２ The present invention includes a polymer comprising a constituent unit A derived from a binding monomer having an ethylenically unsaturated group, and a constituent unit B derived from a cationic monomer. The polymer has cationic functional groups derived from the cationic monomer in its side chains. The functional layer containing such a polymer forms an ionic bond between the anionic functional group (phosphate group) of the DNA strand present on the surface of the thrombus and the cationic functional group of the side chain of the polymer contained in the functional layer. As a result, excellent thrombus adhesion is exhibited in the thrombus capture device. As described above, the polymer in the present invention is not limited to the form in which a graft chain consisting of constituent unit B is bonded to constituent unit A as shown in Figure 1 (form (1)), but may also be a block copolymer containing constituent unit A and constituent unit B (form (2)) or a random copolymer containing constituent unit A and constituent unit B (form (3)). Furthermore, the functional layer may be a single layer or a laminated form of two or more layers. Preferably, the functional layer is a single layer.

[0045] The phosphate 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, forming phosphate ester bonds or phosphonic acid ester bonds. As a result, the functional layer is firmly fixed to the metal substrate.

[0046] The ethylenically unsaturated groups in bonding monomers are groups that can polymerize with cationic monomers, as described later. Examples of ethylenically unsaturated groups include the acryloyl group (CH₂). ２ =CH-C(=O)-), methacryloyl group (CH ２ = C(CH ３ )-C(=O)-), vinyl group (CH ２ =CH-), allyl group (CH ２= CH - CH ２ -) are some examples. In particular, it is preferable that the binding monomer has at least one of an acryloyl group and a methacryloyl group.

[0047] Specific examples of bonding monomers include the monomers represented by the following formulas (I) and (II).

[0048]

[0049] In the above formula (I), R １ represents a hydrogen atom or a methyl group, p represents an integer from 1 to 20, m1 represents 0 or 1, m2 represents 0 or 1, and n1 represents 1 or 2.

[0050]

[0051] In the above formula (II), R ２ represents a hydrogen atom or a methyl group, q represents an integer from 1 to 20, m3 represents 0 or 1, and m4 represents 0 or 1.

[0052] In the above formula (I), R １ is a hydrogen atom or a methyl group, preferably R １ It is a methyl group.

[0053] In the above formula (I), p is an integer from 1 to 20. From the viewpoint of providing high thrombus adhesion, p is preferably an integer from 1 to 10, more preferably an integer from 1 to 6, even more preferably an integer from 2 to 4, and particularly preferably 2.

[0054] In the above formula (I), m1 is 0 or 1, preferably m1 is 1.

[0055] In the above formula (I), m2 is 0 or 1, preferably m2 is 1.

[0056] In the above formula (I), n1 is 1 or 2, preferably n1 is 1.

[0057] In the above formula (II), R ２ is a hydrogen atom or a methyl group, preferably R ２ This is a methyl group.

[0058] In the above formula (II), q is an integer from 1 to 20. From the viewpoint of providing high thrombus adhesion, q is preferably an integer from 1 to 10, more preferably an integer from 1 to 6, even more preferably an integer from 2 to 4, and particularly preferably 2.

[0059] In the above formula (II), m3 is 0 or 1, preferably m3 is 1.

[0060] In the above formula (II), m4 is 0 or 1, preferably m4 is 1.

[0061] Specific examples of the binding monomer represented by formula (I) or formula (II) above include, but are not limited to, 2-(meth)acryloyloxyethyl acid phosphate, bis[2-(meth)acryloyloxy)ethyl phosphate, 11-phosphonundecyl (meth)acrylate, vinylphosphonic acid, and allylphosphonic acid. That is, in the thrombus capture 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-phosphonundecyl (meth)acrylate, vinylphosphonic acid, and allylphosphonic acid. Of these, from the viewpoint of further improving thrombus adhesion, the binding monomer is more preferably 2-acryloyloxyethyl acid phosphate and / or 2-methacryloyloxyethyl acid phosphate. Furthermore, "acid phosphate" is also called "acidic phosphate ester," and phosphoric acid (P(=O)(OH) ３ Among the esters (phosphate esters) of ) and alcohol (R-OH), P(=O)(OH) ２ (OR)(monophosphate ester) and / or P(=O)(OH)(OR) ２ This refers to (phosphate diesters) (that is, "acid phosphate" refers to a partial ester of phosphoric acid and alcohol).

[0062] These binding monomers may be used individually or in combination of two or more.

[0063] The cationic monomer has an ethylenically unsaturated group that can covalently bond to a constituent unit A derived from a bonding monomer, and a cationic functional group in the portion that forms the side chain of the polymer. The presence of this cationic functional group in the side chain of the polymer allows an ionic bond to be formed between the anionic functional group (phosphate group) of the DNA strand present on the surface of the thrombus and the cationic functional group, enabling the thrombus to adhere to the surface of the thrombus capture device. In this specification, "cationic functional group" refers to a functional group that carries a positive charge in the environment in which the thrombus capture device is used (e.g., in blood).

[0064] As described above, the cationic functional group is not particularly limited as long as it is a functional group that carries a positive charge in the environment in which the thrombus capture device is used (e.g., in blood). However, from the viewpoint of further improving thrombus adhesion, it is preferable that it be one or more selected from the group consisting of an amino group and a functional group represented by the following formula (1).

[0065]

[0066] In the above formula (1), R ２３ , R ２４ and R ２５ Each of these independently represents a monovalent hydrocarbon group.

[0067] Specifically, the amino group is -NH ２ , - NHR １３ , -NR １４ R １５ Here, R １３ , R １４ and R １５ Each of these independently represents a monovalent hydrocarbon group. From the perspective of further improving thrombus adhesion, each of the amino groups independently represents -NHR １３ or -NR １４ R １５ Preferably, -NR １４ R １５ It is more preferable that R １３ , R １４ and R １５Each of these groups is preferably a linear or branched alkyl group having 1 to 4 carbon atoms, more preferably a linear or branched alkyl group having 1 to 3 carbon atoms, even more preferably a methyl group or an ethyl group, and particularly preferably a methyl group.

[0068] In the above formula (1), R ２３ , R ２４ and R ２５ Each of these independently represents a monovalent hydrocarbon group. From the perspective of being able to impart high thrombus adhesion, R ２３ , R ２４ and R ２５ Each of these groups is preferably a linear or branched alkyl group having 1 to 4 carbon atoms, more preferably a linear or branched alkyl group having 1 to 3 carbon atoms, even more preferably a methyl group or an ethyl group, and particularly preferably a methyl group.

[0069] Specific examples of cationic monomers include those represented by formulas (i) and (ii) below. Homopolymers derived from these monomers can exhibit excellent thrombus adhesion properties.

[0070]

[0071] In the above formula (i), R １１ R represents a hydrogen atom or a methyl group. １２ R represents a linear or branched alkylene group with 1 to 6 carbon atoms. １３ and R １４ Each of these independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, Y １１ represents an oxygen atom or -NH-, and m11 represents 0 or 1.

[0072]

[0073] In the above equation (ii), A － R represents an anion. ２１ R represents a hydrogen atom or a methyl group. ２２ R represents a linear or branched alkylene group with 1 to 6 carbon atoms. ２３ , R ２４ and R２５ Each of these independently represents a linear or branched alkyl group having 1 to 4 carbon atoms, Y ２１ represents an oxygen atom or -NH-, and m21 represents 0 or 1.

[0074] In the above formula (i), R １１ R is a hydrogen atom or a methyl group, and from the viewpoint of obtaining excellent thrombus adhesion, it is preferably R １１ It is a methyl group.

[0075] In the above formula (i), R １２ R is a linear or branched alkylene group having 1 to 6 carbon atoms, specifically including methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, and hexamethylene groups. Of these, R is selected from the viewpoint of obtaining excellent thrombus adhesion. １２ The group 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, even more preferably an ethylene group or a trimethylene group, and particularly preferably an ethylene group.

[0076] In the above formula (i), R １３ and R １４ Each of these is independently a linear or branched alkyl group having 1 to 4 carbon atoms, specifically including methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, etc. Of these, R is selected from the viewpoint of obtaining excellent thrombus adhesion. １３ and R １４ Each of these is preferably an independent 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.

[0077] In the above formula (i), Y １１ is an oxygen atom or -NH-, and from the viewpoint of obtaining excellent thrombus adhesion, Y １１ It is an oxygen atom.

[0078] In the above formula (i), m11 is 0 or 1, preferably m11 is 1.

[0079] In the above formula (ii), A － is an anion, specifically, a halogen ion, an ion of a compound containing a halogen, a hydroxide ion, a carboxylate ion (for example, acetate ion, etc.), a nitrate ion, a nitrite ion, a hydrogen carbonate ion, a dihydrogen phosphate ion, a hydrogen sulfate ion, an alkylsulfonate ion, a hydrogen sulfide ion, a hydrogen oxalate ion, a cyanate ion, a thiocyanate ion, etc. Examples of the ion of the compound containing a halogen include hexafluoroantimonate (SbF ６ － ), tetrafluoroborate (BF ４ － ), hexafluorophosphate (PF ６ － ), hexafluoroarsenate (AsF ６ － ), hexachloroantimonate (SbCl ６ － ), trifluoromethanesulfonate ion (CF ３ SO ３ － ), fluorosulfonate ion (FSO ３ － ), PF ３ (C ２ F ５ ), etc. Among these, A ３ － is preferably one or more selected from a halogen ion, a hydrogen sulfate ion, and an alkylsulfonate ion. － ２１

[0080] In the above formula (ii), R ２１ is a hydrogen atom or a methyl group, and from the viewpoint of obtaining excellent thrombus adhesiveness, preferably, R ２１ is a methyl group.

[0081] In the above formula (ii), R ２２R is a linear or branched alkylene group having 1 to 6 carbon atoms, specifically including methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, and hexamethylene groups. Of these, R is selected from the viewpoint of obtaining excellent thrombus adhesion. ２２ The group 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, even more preferably an ethylene group or a trimethylene group, and particularly preferably an ethylene group.

[0082] In the above formula (ii), R ２３ , R ２４ and R ２５ Each of these is independently a linear or branched alkyl group having 1 to 4 carbon atoms, specifically including methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, etc. Of these, R is selected from the viewpoint of obtaining excellent thrombus adhesion. ２３ , R ２４ and R ２５ Each of these is preferably an independent 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.

[0083] In the above equation (ii), Y ２１ is an oxygen atom or -NH-, and from the viewpoint of obtaining excellent thrombus adhesion, Y ２１ It is an oxygen atom.

[0084] In the above formula (ii), m21 is 0 or 1, preferably m21 is 1.

[0085] Specific examples of monomers represented by formula (i) or (ii) above include cationic monomers such as (meth)acrylamide, N-methyl(meth)acrylamide, N-ethyl(meth)acrylamide, N-propyl(meth)acrylamide, N,N-dimethyl(meth)acrylamide, N,N-diethylacrylamide, N,N-dipropyl(meth)acrylamide, aminoethyl(meth)acrylate, aminoisopropyl(meth)acrylate, amino-n-butyl(meth)acrylate, and N-methylaminoethyl(meth)acrylate. N-ethylaminoisobutyl (meth)acrylate, N-isopropylaminoethyl (meth)acrylate, N-n-butylaminoethyl (meth)acrylate, N-tert-butylaminoethyl (meth)acrylate, N,N-dimethylaminoethyl (meth)acrylate (also called "2-(dimethylamino)ethyl (meth)acrylate"), N,N-dimethylaminopropyl (meth)acrylate, N,N-dimethylaminobutyl (meth)acrylate, N-methyl-N-ethylaminoethyl (meth)acrylate, N -Methyl-N-butylaminoethyl (meth)acrylate, N,N-diethylaminoethyl (meth)acrylate, N,N-diethylaminopropyl (meth)acrylate, N,N-dipropylaminoethyl (meth)acrylate, N,N-dipropylaminopropyl (meth)acrylate, N,N-dibutylaminopropyl (meth)acrylate, aminoethyl (meth)acrylamide, aminoisopropyl (meth)acrylamide, amino-n-butyl (meth)acrylamide, N-methylaminoethyl (meth)acrylamide, N- Ethylaminoisobutyl(meth)acrylamide, N-isopropylaminoethyl(meth)acrylamide, N-n-butylaminoethyl(meth)acrylamide, N-tert-butylaminoethyl(meth)acrylamide, N,N-dimethylaminoethyl(meth)acrylamide, N,N-dimethylaminopropyl(meth)acrylamide, N,N-dimethylaminobutyl(meth)acrylamide, N-methyl-N-ethylaminoethyl(meth)acrylamide, N-methyl-N-butylaminoethyl(meth)acrylamide, N,Examples include, but are not limited to, N-diethylaminoethyl (meth)acrylamide, N,N-diethylaminopropyl (meth)acrylamide, N,N-dipropylaminoethyl (meth)acrylamide, N,N-dipropylaminopropyl (meth)acrylamide, and N,N-dibutylaminopropyl (meth)acrylamide, as well as their halogenated alkyl derivatives and sulfated alkyl derivatives. Of these, N,N-dimethylaminoethyl acrylate, N,N-dimethylaminoethyl methacrylate (DMAEMA), and N,N-dimethylaminopropyl (meth)acrylamide are preferred, and N,N-dimethylaminoethyl acrylate and N,N-dimethylaminoethyl methacrylate (DMAEMA) are more preferred.

[0086] These cationic monomers may be used individually or in combination of two or more. That is, a cationic polymer chain consisting of constituent units B derived from cationic monomers may be a homopolymer composed of a single cationic monomer, or a copolymer composed of two or more of the above cationic monomers. When two or more are used, the form of constituent unit B may be a block copolymer or a random copolymer.

[0087] In the case where the polymer according to the present invention is in the above-described form (1) (i.e., a form in which a graft chain consisting of constituent units B is bonded to a constituent unit A), the ratio of the number of constituent units B to the number of constituent units A is not particularly limited, but in order to exhibit sufficient thrombus adhesion, the ratio is preferably 30 or more, more preferably 30 to 200, and even more preferably 30 to 150. That is, in the thrombus capture device according to one embodiment of the present invention, the ratio of the number of constituent units B to the number of constituent units A in the polymer is 30 or more. By controlling the number of moles of cationic monomer that are subjected to (contacted with) the substrate after the bonding monomer has been reacted, and the reaction time of the cationic monomer with the substrate, a polymer in which a predetermined number of constituent units B are linked to one constituent unit A can be obtained. In this specification, the "ratio of the number of constituent units B to the number of constituent units A" can be determined by elemental analysis using SEM-EDX.

[0088] The ends of the polymer according to the present invention are not particularly limited and can be appropriately defined depending on the type of monomer used. In one embodiment, the ends of the polymer according to the present invention (* in Figure 1) are hydrogen atoms. Furthermore, when the polymer according to the present invention is prepared by radical polymerization, the ends of the polymer (* in Figure 1) can be encapsulated by structural units (functional groups) derived from the polymerization initiator. In the latter form (encapsulated by functional groups derived from the polymerization initiator), the ends of the polymer can be carboxyl groups.

[0089] The weight-average molecular weight of the polymer according to the present invention is several thousand to several million, preferably 10,000 to 5 million. In this specification, "weight-average molecular weight" refers to the 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 based on the type and number of constituent units.

[0090] The thickness of the functional layer (dry film thickness) is, for example, 0.1 to 10 μm, preferably 0.5 to 5 μm, and more preferably about 1 to 3 μm.

[0091] [Method for Manufacturing a Thrombus Capture Device] Another aspect of the present invention also provides a method for manufacturing the thrombus capture device described above. That is, one embodiment of the present invention is a method for manufacturing a thrombus capture device (hereinafter also simply referred to as "the method for manufacturing a thrombus capture device according to the present invention"), comprising: irradiating at least a portion of the surface of the metal substrate with plasma; contacting the metal substrate after the plasma irradiation with the binding monomer; and contacting the metal substrate after contact with the binding monomer with the cationic monomer to form the cationic polymer chain on the surface of the metal substrate via the constituent unit A derived from the binding monomer.

[0092] The following describes preferred embodiments of each step in the method for manufacturing a thrombus capture device according to the present invention. However, the method for manufacturing a thrombus capture device according to the present invention is not limited to the embodiments described below.

[0093] 《Plasma Irradiation Process (Plasma Treatment Process)》 In this process, plasma is irradiated onto at least a portion of the surface of the metal substrate (plasma treatment is performed). This can generate hydroxyl groups (-OH) on the surface of the metal substrate. Then, by bringing a binding monomer into contact with the surface of the metal substrate, the phosphate groups or phosphonic acid groups contained in the binding monomer react (condensation reaction) with the hydroxyl groups (-OH) formed on the substrate surface, and a phosphate ester bond or phosphonic acid ester bond can be formed. As a result, the polymer according to the present invention is firmly fixed on the metal substrate, making it possible to manufacture a thrombus capture device that can maintain thrombus adhesion over a long period of time.

[0094] From the viewpoint of enabling uniform plasma treatment of the surface of a substrate having any structure, the plasma irradiation process is preferably carried out by ionized gas plasma treatment.

[0095] 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 ionized gas plasma irradiation, it is preferable to smooth the surface of the metal substrate or remove any oils, 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 used as appropriate. Among these, 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, pouring a cleaning solvent over it, etc.).

[0096] The pressure conditions for plasma treatment are not particularly limited and can be performed under reduced pressure or atmospheric pressure. However, it is preferable to perform the treatment under atmospheric pressure because it allows for irradiation of the plasma gas from any angle, eliminates the need for a vacuum device, enables a space-saving and low-cost system configuration, and is economically superior. Furthermore, by irradiating the workpiece with plasma gas while rotating the plasma irradiation nozzle around the workpiece, it is possible to uniformly plasma treat the entire circumference of the workpiece without unevenness.

[0097] The ionizing gas that can be used for 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, and hydrogen. The plasma treatment conditions (irradiation time, LF output, overcurrent, gas flow rate, electrode gap, plasma irradiation distance) are not particularly limited and can be appropriately selected depending on the bonding properties (ease of immobilization) between the bonding monomer and the metal substrate, the type and area of ​​the metal substrate used, etc.

[0098] As an example, the irradiation time in 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 bonding monomer can be bonded (fixed) to the surface of the metal substrate.

[0099] As an example, the LF output in plasma processing is preferably 100 to 300 W, more preferably 150 to 250 W, and even more preferably 200 W.

[0100] As an example, the gas flow rate in plasma processing is preferably 5 to 20 sccm, more preferably 10 to 20 sccm, and even more preferably 15 sccm.

[0101] The temperature of the workpiece (metal substrate) in plasma processing is not particularly limited and may be at room temperature, or heated or cooled. From an economic standpoint, it is preferable to perform the process at a temperature that does not require heating or cooling equipment (for example, 5 to 35°C).

[0102] There are no particular limitations on the plasma irradiation device (system) that can be used for plasma processing. For example, a plasma irradiation device (system) can be described as having a plasma generation tube that introduces and excites gas molecules to generate plasma, and an electrode that excites the gas molecules in the plasma generation tube, with the plasma emitted from one end of the plasma generation tube. However, there are no limitations to such configurations (systems). Examples include devices employing high-frequency induction, capacitively coupled electrode, corona discharge electrode-plasma jet, parallel plate type, remote plasma type, atmospheric pressure plasma type, low-pressure plasma type, and ICP-type high-density plasma type. In addition, commercially available ionized gas plasma irradiation devices (systems) suitable for irradiation of thrombus retrievers, thrombus capture devices, thrombus filters, etc., especially plasma irradiation devices (systems) at atmospheric pressure, can be used. Specifically, plasma irradiation devices such as DURADYNE (product name or trademark name) manufactured by TRI-STAR TECHNOLOGIES, PLASMABEAM and Pico Full PC manufactured by DIENER ELECTRONIC can be used, but are not limited to these.

[0103] <Contacting with Bonding Monomer> In this step, the bonding monomer is brought into contact with the substrate after plasma irradiation. As a result, the phosphate group or phosphonic acid group contained in the bonding monomer reacts (condensation reaction) with the hydroxyl group (-OH) formed on the surface of the substrate, and a phosphate ester bond or phosphonic acid ester bond may be formed.

[0104] In this process, the specific method for contacting the substrate with the binding monomer after plasma irradiation may be either to contact the binding monomer directly with the substrate, or to prepare a binding monomer solution by dissolving the binding monomer in a solvent, and then to contact the substrate with the binding monomer solution. From the viewpoint of forming a more uniform functional layer, it is preferable to adopt the latter method of contacting the substrate with a binding monomer solution.

[0105] 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 any are 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 may be used individually or in combination of two or more (in the form of a mixed solvent).

[0106] 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.

[0107] Next, the binding monomer solution prepared as described above is brought into contact with the substrate after plasma irradiation. Here, as a specific method of "contact," conventionally known methods such as coating the binding monomer solution onto the surface of the substrate or immersing the substrate in the binding monomer solution can be appropriately employed. Of these, the immersion method, which is easy to operate, is preferred.

[0108] Alternatively, contact by immersion may be carried out while stirring the binding monomer solution. This further promotes contact between the binding monomer solution and the material to be treated. The stirring can be performed using known devices such as stirring with a stirring bar, an orbital shaker, a rotary shaker, or a paint shaker. Furthermore, the stirring conditions are not particularly limited. From the viewpoint of more efficient contact with the material to be treated, the stirring speed is, for example, 200 to 600 rpm, preferably 300 to 400 rpm. From a similar 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 immersion may be around room temperature (for example, 20 to 40°C), but it may also be heated (for example, 40 to 60°C).

[0109] Furthermore, when forming a functional layer on only a portion of the substrate, the binding monomer can be bonded to a desired surface area of ​​the substrate by immersing only a portion of the substrate in a binding monomer solution.

[0110] If it is difficult to immerse only a portion of a metal substrate in a binding monomer solution, the binding monomer can be bonded to a desired surface portion of the substrate by first protecting (coating, etc.) the surface portion of the substrate that does not require the formation of a functional layer with a suitable removable member or material, then immersing the substrate in the binding monomer solution, and finally removing the protective member (material) from the surface portion of the substrate that does not require the formation of a functional layer. However, the present invention is not limited in any way to these formation methods, and binding monomers can be bonded using conventionally known methods as appropriate. For example, if it is difficult to immerse only a portion of a metal substrate in a binding monomer solution, other coating methods may be applied instead of the immersion method (for example, a method of applying a binding monomer solution to a predetermined surface portion of a thrombus capture device using a coating device such as a spray device, bar coater, die coater, reverse coater, comma coater, gravure coater, spray coater, or doctor knife). Furthermore, in cases where the structure of a thrombus capture device requires both the outer and inner surfaces of the cylindrical instrument to have a functional layer, the dipping method is preferred because it allows binding monomers to be bonded to both the outer and inner surfaces at once.

[0111] In this process, if necessary, the substrate may be washed after contact with the binding monomer. The washing method is not particularly limited and can be carried out by washing with a suitable solvent (e.g., ultrasonic washing, immersion in a washing solvent, pouring a washing solvent over it, etc.). The washing time is not particularly limited, but is preferably 1 to 60 minutes. If necessary, the above washing process may be repeated multiple times (e.g., 2 to 5 times).

[0112] <Cationic Monomer Contact Process> In this process, the cationic monomer is brought into contact with the substrate after it has been contacted with the binding monomer. As a result, the cationic monomer binds to the ethylenically unsaturated groups contained in the constituent unit A derived from the binding monomer that is bound to the substrate, and the remaining cationic monomer undergoes graft polymerization with the cationic monomer that is bound to the ethylenically unsaturated groups, thereby forming a cationic polymer chain on the substrate surface via the constituent unit A derived from the binding monomer. In other words, a functional layer is formed on the substrate surface.

[0113] In this process, the specific method for contacting the substrate with the cationic monomer after contact with the binding monomer is either to directly contact the substrate with the binding monomer, or to prepare a cationic monomer solution by dissolving the cationic monomer in a solvent, and then to contact the substrate with the binding monomer. From the viewpoint of forming a more uniform functional layer, it is preferable to adopt the latter method of contacting the substrate with the binding monomer using a cationic monomer solution.

[0114] The solvent (polymerization solvent) used to prepare the cationic monomer solution is not particularly limited as long as it can dissolve the cationic 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, deionized water, distilled water, etc.); alcohols such as ethanol, isopropanol, n-propanol, n-butanol, isobutanol, sec-butanol, t-butanol, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, etc.; and organic solvents such as chloroform, tetrahydrofuran, acetone, dioxane, benzene, etc. Furthermore, the concentration of cationic monomer in the cationic monomer solution is not particularly limited, but setting the concentration relatively high can increase the weight-average molecular weight of the resulting polymer. As an example, the concentration (total concentration) of cationic monomer in the cationic monomer solution is preferably 10% by mass or more, and more preferably 15% by mass or more. Furthermore, there is no particular upper limit to the concentration (total concentration) of the above-mentioned cationic monomer, but it is, for example, below the saturation concentration, for example, 70% by mass or less, and preferably 50% by mass or less.

[0115] In this process, by contacting the substrate with the cationic monomer after contacting it with the bonding monomer, the cationic monomer bonds to the ethylenically unsaturated group contained in the constituent unit A derived from the bonding monomer bonded to the substrate, and the remaining cationic monomer undergoes graft polymerization to the cationic monomer bonded to the ethylenically unsaturated group. The specific method of polymerization is not particularly limited, and conventionally known polymerization methods such as radical polymerization and polymerization using macroinitiators can be applied. Furthermore, methods for the polymerization reaction include (a) dissolving the cationic monomer and a suitable polymerization initiator in a polymerization solvent and heating the resulting polymerization reaction solution to carry out the polymerization reaction; and (b) dissolving the cationic monomer in a polymerization solvent, mixing the resulting solution with a separately prepared polymerization initiator solution to prepare a polymerization reaction solution, and carrying out the polymerization reaction. From the viewpoint of ease of operation, method (a) is preferred.

[0116] Furthermore, the polymerization reaction solution may be degassed before the polymerization reaction takes place. Degassing can be performed, for example, by bubbling it with an inert gas such as nitrogen or argon for about 5 minutes to 1 hour.

[0117] Furthermore, there are no particular restrictions on the polymerization initiator used at this time, and known ones can be used. Preferably, radical polymerization initiators are used in terms of their excellent polymerization stability, and specifically, persulfates such as potassium persulfate (KPS), sodium persulfate, and ammonium persulfate; 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, di(s-butyl) peroxydicarbonate, etc. Examples of oxides include 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 described above may be used individually or in combination of two or more.

[0118] Furthermore, for example, the radical polymerization initiator may be combined with a reducing agent such as sodium sulfite, sodium bisulfite, or ascorbic acid and used as a redox initiator. The amount of polymerization initiator added is preferably 0.01 to 5% by mass, and more preferably 0.05 to 3% by mass, based on 100% by mass of the total cationic monomers. Alternatively, the amount of polymerization initiator added is preferably 0.01 to 5 moles, and more preferably 0.05 to 3 moles, based on 100 moles of the total cationic monomers. With such amounts of polymerization initiator added, the polymerization reaction can proceed efficiently.

[0119] Furthermore, when using method (b), the solvent used to pre-dissolve the polymerization initiator (solvent of the polymerization initiator solution) is not particularly limited as long as it can dissolve the polymerization initiator, but examples of solvents similar to the polymerization solvent described above are available. The solvent of the polymerization initiator solution may be the same as or different from the polymerization solvent described above, but considering the ease of controlling polymerization, it is preferable that it be the same solvent as the polymerization solvent described above.

[0120] By heating the polymerization reaction solution prepared as described above, the ethylenically unsaturated group contained in the constituent unit A derived from the bonding monomer bonded to the substrate and the cationic monomer can be polymerized. Here, as a polymerization method, known polymerization methods such as anionic polymerization and cationic polymerization can be used in addition to the radical polymerization described above, but radical polymerization is preferred considering the simplicity of the operation.

[0121] The polymerization conditions are not particularly limited as long as they allow polymerization between the ethylenically unsaturated group contained in the constituent unit A derived from the bonding monomer bonded to the substrate and the cationic monomer. For example, the polymerization temperature is preferably 30 to 150°C, more preferably 35 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.

[0122] Furthermore, during polymerization, chain transfer agents, polymerization rate regulators, surfactants, and other additives may be used as needed.

[0123] The environment in which the polymerization reaction is carried out is not particularly limited and can be carried out in an atmospheric environment, an inert gas atmosphere such as nitrogen gas or argon gas, etc., but it is preferable to carry it out in a nitrogen gas atmosphere. In addition, the reaction solution may be stirred during the polymerization reaction.

[0124] In this process, if necessary, the substrate may be washed after contact with the cationic monomer. The washing method is not particularly limited and can be carried out by washing with a suitable solvent (e.g., ultrasonic washing, immersion in a washing solvent, pouring a washing solvent over it, etc.). The washing time is not particularly limited, but is preferably 1 to 60 minutes. If necessary, the washing process may be repeated multiple times (e.g., 2 to 5 times).

[0125] By the above method, a thrombus capture device with excellent functionality (e.g., thrombus adhesion) can be manufactured.

[0126] [Applications of the Thrombosis Capture Device] The thrombus capture device according to the present invention has excellent thrombus adhesion. Therefore, it is suitable as a medical device used for the treatment of thrombosis and embolism (e.g., thrombus retrieval therapy) and for the prevention of embolism (e.g., inferior vena cava filter placement). Examples of the thrombus capture device according to the present invention include intravascular implantation devices. In particular, the thrombus capture device is preferably an intravascular implantation device, and specifically, examples include thrombus retrievers, thrombus capturers, thrombus filters, etc. That is, the thrombus capture device according to one embodiment of the present invention is a thrombus retriever, a thrombus capturer, or a thrombus filter.

[0127] 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 units "parts" or "%" may be used, but unless otherwise specified, they represent "parts by mass" or "mass%". Also, unless otherwise specified, each operation was carried out at room temperature (25°C).

[0128] <Preparation of NiTi-PHA-DMAEMA> (1) Preparation of NiTi substrate Nickel titanium (NiTi) (manufactured by Saes Material Co., Ltd., thickness: 0.5 mm) was cut to 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. The washed NiTi was placed in distilled water and washed with water in an ultrasonic cleaner for 3 minutes. This operation was repeated 3 times to remove the polishing solution adhering to the surface of the NiTi. The NiTi after washing was dried at room temperature to obtain a NiTi substrate (NiTi (untreated with plasma)). This NiTi substrate was used as Comparative Example 1.

[0129] (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 both sides were irradiated with plasma (argon ionized gas plasma irradiation) 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. This resulted in a NiTi substrate with a plasma-treated surface (NiTi (after plasma treatment)).

[0130] (3) 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 added to a glass vial containing 2-methacryloyloxyethyl acid phosphate (PHA) and the reagent was dissolved. The NiTi substrate was added to this solution and the reaction was carried out overnight at room temperature. After that, the NiTi substrate was removed and left to stand in ethanol for 1 hour to remove unreacted PHA, and then dried at room temperature. This yielded a NiTi substrate with PHA bound to it (NiTi-PHA).

[0131] (4) In a polymerized glass bottle of 2-(dimethylamino)ethyl methacrylate (DMAEMA), 1.57 g (9.99 mmol) of 2-(dimethylamino)ethyl methacrylate (DMAEMA, manufactured by Tokyo Chemical Industry Co., Ltd.), 4.7 mg (0.015 mmol) 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 added and stirred at room temperature until all reagents were dissolved. The reagent solution in the glass bottle was transferred to a round-bottom flask, and NiTi substrate with PHA bonded to it (NiTi-PHA) was added to the reagent solution. Nitrogen gas was introduced for 10 minutes to replace the gas in the system with nitrogen gas. The round-bottom flask was covered with a rubber stopper. This round-bottom flask was placed in a 37°C water bath and the reaction was carried out for 4 hours. After that, the NiTi substrate was removed and washed by immersion in ethanol to remove unreacted material. This resulted in obtaining a NiTi substrate (NiTi-PHA-DMAEMA) in which DMAEMA was polymerized via PHA.

[0132] <Evaluation of thrombus adhesion> Using the NiTi substrate (NiTi-PHA-DMAEMA) and NiTi substrate (NiTi (untreated with plasma)) prepared above, in which DMAEMA was polymerized via PHA, as samples, the thrombus adhesion was evaluated according to the following: 3.2 (w / v)% sodium citrate (anticoagulant) aqueous solution was added to fresh pig blood to obtain anticoagulated fresh pig blood (1). At this time, the mixing ratio (volume ratio) of fresh pig blood and sodium citrate aqueous solution was 9:1. 1M calcium chloride solution was added to the anticoagulated fresh pig blood (1) using a stirring rod to obtain anticoagulated fresh pig blood (2). At this time, the final concentration of calcium chloride in the anticoagulated fresh pig blood (2) was 20 mM. The samples were left to stand at room temperature for 30 minutes to form thrombi. Small thrombi separated from these thrombi were placed in physiological saline, and the above samples were immersed in this solution at room temperature for 3 minutes. Subsequently, each sample was washed with physiological saline and fixed with a 1 (w / v)% glutaraldehyde / phosphate buffer (PBS) solution. After standing at room temperature for 4 hours, it was washed with distilled water. Each sample was dried at room temperature, platinum deposition was performed, and then it was observed and photographed (50x and 1000x) using a scanning electron microscope (SEM). The results are shown in Figure 6. In Figure 6, (a) is an SEM image used to evaluate the thrombus adhesion of the NiTi substrate (NiTi (untreated with plasma)) of Comparative Example 1 before plasma treatment, and (b) is an SEM image used to evaluate the thrombus adhesion of the NiTi substrate (NiTi-PHA-DMAEMA) in which DMAEMA was polymerized via PHA of Example 1. In each SEM image, the black areas represent attached thrombi.

[0133] Furthermore, each sample was stained with the nuclear dye Sytox Green, and then observed and photographed (10x magnification, 3 fields) using a confocal fluorescence microscope. The obtained confocal fluorescence microscope images are shown in Figure 7. In Figure 7, (a) is a confocal fluorescence microscope image of the NiTi substrate (NiTi (untreated with plasma)) of Comparative Example 1 before plasma treatment, and (b) is a confocal fluorescence microscope image of the NiTi substrate (NiTi-PHA-DMAEMA) in which DMAEMA was polymerized via PHA of Example 1. The fluorescence intensity of thrombotic deposits (fluorescence) was measured from the obtained confocal fluorescence microscope images, and the arithmetic mean of the fluorescence intensities of the 3 fields was calculated. The results are shown in Table 1 below. The fluorescence intensity values ​​in Table 1 are relative values ​​with the fluorescence intensity of Comparative Example 1 set to 100.

[0134]

[0135] <Evaluation of thrombus formation> Using the NiTi substrate (NiTi-PHA-DMAEMA) and NiTi substrate (NiTi (untreated with plasma)) prepared above, in which DMAEMA was polymerized via PHA, as samples, the thrombus formation was evaluated according to the following. 3.2 (w / v)% sodium citrate (anticoagulant) aqueous solution was added to fresh porcine blood to obtain anticoagulated fresh porcine blood (1). At this time, the mixing ratio (volume ratio) of fresh porcine blood and sodium citrate aqueous solution was 9:1. 1M calcium chloride solution and heparin were simultaneously added to the anticoagulated fresh porcine blood (1) using a stirring rod, and the activated clotting time (ACT) was adjusted to 400 seconds, which is commonly used in clinical blood, to obtain fresh porcine blood (2). After immersing each sample in fresh porcine blood (2) at room temperature for 1 hour, it was washed with PBS and fixed with 1 (w / v)% glutaraldehyde / PBS solution. After standing overnight at 4°C, the samples were washed with distilled water. Each sample was dried at room temperature, platinum deposition was performed, and then observed and photographed using SEM (50x and 1000x). The results are shown in Figure 8. In Figure 8, (a) is an SEM image used to evaluate the thrombus formation properties of the NiTi substrate (NiTi (untreated with plasma)) of Comparative Example 1 before plasma treatment, and (b) is an SEM image used to evaluate the thrombus formation properties of the NiTi substrate (NiTi-PHA-DMAEMA) in which DMAEMA was polymerized via PHA of Example 1.

[0136] As shown in Figures 6 and 7 and Table 1, the adhesion of thrombi to the NiTi substrate surface was significantly improved in the sample of Example 1 compared to the sample of Comparative Example 1. This indicates that the present invention can provide excellent thrombus adhesion to a thrombus capture device equipped with a metal substrate.

[0137] Furthermore, as shown in Figure 8, the sample from Example 1, like the sample from Comparative Example 1, does not have any thrombus attached. This also indicates that the thrombus capture device according to the present invention does not induce thrombus formation.

[0138] This application is based on Japanese Patent Application No. 2024-221889, filed on 18 December 2024, the disclosures of which are referenced and incorporated in whole.

[0139] 10...Metal substrate, 10a...Substrate core, 10b...Substrate surface layer, 11...Functional layer, 100...Thrombosis capture device, 200...Thrombosis capture system, 210...Thrombosis retriever, 211...Microcatheter, 220...Thrombosis filter, 221...Delivery catheter, 300...Blood vessel, 310...Thrombosis.

Claims

1. A thrombus capture device comprising: a metal substrate; and a functional layer comprising a polymer containing a constituent unit A derived from a bondable monomer having a phosphate group or a phosphonic acid group and an ethylenically unsaturated group, bonded to the metal substrate, and a constituent unit B derived from a cationic monomer having an ethylenically unsaturated group, covalently bonded to constituent unit A, wherein the polymer has a cationic functional group derived from the cationic monomer in its side chain.

2. The thrombus capture device according to claim 1, wherein the cationic functional group is one or more selected from the group consisting of an amino group and a functional group represented by the following formula (1); In the above formula (1), R ２３ , R ２４ and R ２５ Each of these independently represents a monovalent hydrocarbon group.

3. The cationic monomer is one or more selected from the group consisting of monomers represented by the following formulas (i) and (ii), the thrombus capture device according to claim 1; In the above formula (i), R １１ represents a hydrogen atom or a methyl group, and R １２ represents a linear or branched alkylene group having 1 to 6 carbon atoms, and R １３ and R １４ each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and Y １１ represents an oxygen atom or -NH-, and m11 represents 0 or 1; In the above formula (ii), A － represents an anion, and R ２１ represents a hydrogen atom or a methyl group, and R ２２ represents a linear or branched alkylene group having 1 to 6 carbon atoms, and R ２３ , R ２４ and R ２５ each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms, and Y ２１ represents an oxygen atom or -NH-, and m21 represents 0 or 1.

4. The thrombus capture device according to claim 1, wherein the binding monomer is one or more selected from the group consisting of 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 from 1 to 20, m1 represents 0 or 1, m2 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 from 1 to 20, m3 represents 0 or 1, and m4 represents 0 or 1.

5. The thrombus capture 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-phosphonundecyl(meth)acrylate, vinylphosphonic acid, and allylphosphonic acid.

6. The cationic monomers are (meth)acrylamide, N-methyl(meth)acrylamide, N-ethyl(meth)acrylamide, N-propyl(meth)acrylamide, N,N-dimethyl(meth)acrylamide, N,N-diethyl(meth)acrylamide, N,N-dipropyl(meth)acrylamide, aminoethyl(meth)acrylate, aminoisopropyl(meth)acrylate, amino-n-butyl(meth)acrylate, N-methylaminoethyl(meth)acrylate, N-ethylaminoisobutyl(meth)acrylate, N-isopropyl(meth)acrylate Pyraminoethyl (meth)acrylate, N-n-butylaminoethyl (meth)acrylate, N-tert-butylaminoethyl (meth)acrylate, N,N-dimethylaminoethyl (meth)acrylate, N,N-dimethylaminopropyl (meth)acrylate, N,N-dimethylaminobutyl (meth)acrylate, N-methyl-N-ethylaminoethyl (meth)acrylate, N-methyl-N-butylaminoethyl (meth)acrylate, N,N-diethylaminoethyl (meth)acrylate, N,N-diethylaminopropyl (meth)acrylate Acrylate, N,N-dipropylaminoethyl (meth)acrylate, N,N-dipropylaminopropyl (meth)acrylate, N,N-dibutylaminopropyl (meth)acrylate, aminoethyl (meth)acrylamide, aminoisopropyl (meth)acrylamide, amino-n-butyl (meth)acrylamide, N-methylaminoethyl (meth)acrylamide, N-ethylaminoisobutyl (meth)acrylamide, N-isopropylaminoethyl (meth)acrylamide, N-n-butylaminoethyl (meth)acrylamide , N-tertiary butylaminoethyl (meth)acrylamide, N,N-dimethylaminoethyl (meth)acrylamide, N,N-dimethylaminopropyl (meth)acrylamide, N,N-dimethylaminobutyl (meth)acrylamide, N-methyl-N-ethylaminoethyl (meth)acrylamide, N-methyl-N-butylaminoethyl (meth)acrylamide, N,N-diethylaminoethyl (meth)acrylamide, N,N-diethylaminopropyl (meth)acrylamide, N,N-dipropylaminoethyl (meth)acrylamide, N,The thrombus capture device according to claim 1, comprising one or more selected from the group consisting of N-dipropylaminopropyl(meth)acrylamide and N,N-dibutylaminopropyl(meth)acrylamide, and their halogenated alkyl derivatives and sulfated alkyl derivatives.

7. The thrombus capture device according to claim 1, wherein the metal material constituting the metal substrate 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 thrombus capture device according to claim 1, wherein the thrombus capture device has an expandable body made of the metal substrate.

9. The thrombus capture device according to claim 8, wherein the expandable body has a mesh-like frame structure made of the metal substrate.

10. The thrombus capture device according to claim 1, wherein the polymer comprises a cationic polymer chain consisting of the constituent unit B, and the ends of the cationic polymer chains are covalently bonded to the constituent unit A bonded to the metal substrate.

11. The thrombus capture device according to claim 10, wherein the ratio of the number of constituent units B to the number of constituent units A in the polymer is 30 or more.

12. A method for manufacturing a thrombus capture device according to claim 10, comprising: irradiating at least a portion of the surface of the metal substrate with plasma; contacting the metal substrate with the binding monomer after the plasma irradiation; and contacting the metal substrate with the cationic monomer after contact with the binding monomer to form the cationic polymer chain on the surface of the metal substrate via the constituent unit A derived from the binding monomer.

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