JPH10151190A - Stent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To maintain anti-thrombogenic performance, and improve tissue re- forming performance by covalently bonding an anti-thrombogenic agent on a base material treated by an oxidizing agent through a coupling agent having amino groups not less than the specific number and a cross-linking agent having aldehyde groups or epoxy groups not less than the specific number. SOLUTION: In a stent 1, an anti-thrmobogenic agent 2 is covalently bonded to a surface, but X-ray untransmissive metal plating 3 is also performed at least on a part. Treatment to impart anti-thrombogenic performance and X-ray image forming performance exists as surface treatment of the stent 1. It is desirable that anti-thrombogenic treatment is performed after X-ray image forming treatment is performed when both are performed. In the anti thrombogenic treatment, first of all, a surface of the stent 1 is treated by an oxidizing agent. Next, an anti-thrombogenic agent is covalently bonded through a coupling agent having two or more amino groups and a cross-linking agent having two or more aldehyde groups or epoxy groups.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a stent used for dilating a stenosed blood vessel.

[0002]

2. Description of the Related Art PTCA (Percutaneous Transformer) which pushes a stenotic blood vessel (coronary artery) from the lumen side to secure blood flow.
luminal Coronary Angioplasty: Percutaneous coronary angioplasty)
Is now widespread as a treatment for obstructive coronary artery disease-angina, myocardial infarction.

In order to prevent restenosis after vasodilation, an expandable intraluminal graft ("stent") is disclosed in Japanese Patent Publication No. 4-6377.
Was developed.

[0004] A stent is a cylindrical medical device used for maintaining the shape of a living body lumen such as a blood vessel or a bile duct.
It is inserted into the body lumen in a thin and small folded state, expanded at the target site (stenosis site), and adheres to the inner wall of the lumen,
The lumen shape is maintained by fixing.

[0005] There are two types of expansion means, one means for expanding the balloon from the inside of the stent and expanding it in the radial direction by an external force, and the other means for removing the force holding the thin and small folded stent. This is a means of radially expanding the stent with its own restoring force.

[0006] A stent that expands in the radial direction by an external force due to expansion of the balloon is called a balloon-expandable stent, and has no expansion function itself. The balloon-expandable stent is made of a metal material that does not easily return to its original shape after expansion, and is made of stainless steel, tantalum, or the like, which has low reactivity in a living body from the viewpoint of safety for the living body.

[0007] A stent that expands with its own restoring force is called a self-expanding stent, and has a contraction and expansion function itself. For example, the stent is contracted and stored in a tube having an outer diameter smaller than the inner diameter of the target portion, and after the distal end of the tube reaches the target portion, the stent is pushed out of the tube. Such a self-expandable stent is manufactured using stainless steel, a superelastic metal and a shape memory metal (both nickel-titanium alloy) because a restoring force to the original shape is required. Among self-expanding stents, stents using superelastic alloys (shape memory alloys)
It is disclosed in Japanese Patent Publication No. 5-43392.

Thus, most of the current stents are made of metal. However, metals are selected for their physical properties / functions and safety / compatibility with living tissues.For blood, a material that is easily recognized by foreign substances, that is, it easily forms a thrombus, activates platelets, and activates blood vessels It is a material that causes smooth muscle migration and proliferation. For this reason, there is always a risk of stenosis or occlusion of blood vessels due to migration and proliferation of thrombus and vascular smooth muscle after stent placement, which often takes a complex network structure, so that the stent inner surface is almost It is necessary to administer an antithrombotic agent such as heparin or warfarin to the patient for about two weeks after the operation, which is said to be covered. This administration may cause bleeding complications from the arterial puncture site and peripheral blood vessels. Prevents restenosis due to migration and proliferation of vascular smooth muscle due to platelet activity for a short period of time after stent placement, and is necessary if the administration period of the antithrombotic agent is reduced, the dosage is reduced, or if administration is unnecessary. In addition, the length of hospital stay and bleeding complications can be reduced.

On the other hand, attempts have been made to impart antithrombotic properties to medical materials or medical devices. Tokiko Sho 49-
No. 48336 discloses a method for imparting antithrombotic properties to the plastic surface by ionically bonding heparin cross-linked with glutaraldehyde to the cationic surfactant adsorbed on the plastic surface. Japanese Patent Publication No. 28504/1985 discloses that a complex compound of heparin and a quaternary amine is coated on the surface of a base material such as plastic, glass or metal, treated with glutaraldehyde, and a Schiff base is formed. Discloses a method of imparting antithrombotic properties to a substrate and a method of imparting antithrombotic properties to the substrate surface by coating a complex compound of heparin and a quaternary amine (benzalkonium chloride) on the surface of the substrate. .

However, in these methods, the substrate and the compound of heparin or heparin and the quaternary amine and / or glutaraldehyde are not covalently bonded, and the IPN
(Interpenetrating stitches) Bonding is weaker than covalent bonding because they are bonded by structure or intermolecular force. JP-A-8-52
No. 221 discloses a method of imparting antithrombotic properties to a stent by applying a parylene resin coating by vacuum deposition to the stent. Japanese Patent Publication No. 6-38851 discloses a method of covalently bonding heparin or a compound thereof to various plastic materials. In this method, since the heparin compound is covalently bonded to the substrate, the heparin compound is not lost from the substrate surface.
However, since metal materials are more inactive than various plastic materials, it is unclear whether heparin compounds can be bonded to metal materials in the same manner. Further, it is not known at all whether or not it is used for a stent that expands in a blood vessel to suppress the migration and proliferation of vascular smooth muscle.

[0011] Stainless steel, which is widely used as a material for stents at present, has high X-ray permeability, and the stent has a net-like structure, and the width of the stainless steel material constituting the mesh is as small as about 0.2 mm. After the operation, it is extremely difficult to confirm the position and condition. Contrast markers are provided on the catheter to clarify the position of the stent during the operation, but there is a risk that the stent may deviate from a predetermined position on the catheter, which is not perfect. Furthermore, since the shape of the stent cannot be confirmed,
It is difficult to find an elastic recoil (the expanded stent returns to its original state) due to incomplete expansion or the restoring force of the material metal.

A stent with a radiopaque marker for solving such a problem is disclosed in JP-A-8-126704. There is a danger of stenosis and occlusion of blood vessels after placement of such a radiopaque treated metal-plated stent.

[0013]

DISCLOSURE OF THE INVENTION The present invention provides a stent for solving the above-mentioned problems, which has a sustained antithrombotic property and excellent tissue remodeling properties. It is another object of the present invention to provide a stent capable of confirming its position and state under X-ray contrast and a method of manufacturing the same.

[0014]

This and other objects are achieved by the present invention which is defined below as (1) to (6). (1) An antithrombotic agent is covalently bonded to a substrate treated with an oxidizing agent via a coupling agent having two or more amino groups and a crosslinking agent having two or more aldehyde groups or epoxy groups. A stent. (2) The stent according to (1), wherein the oxidizing agent is ozone. (3) The stent according to (1) or (2), wherein the antithrombotic agent is aminated heparin. (4) The stent according to (1), wherein the metal substrate is stainless steel. (5) The stent according to (1), wherein the coupling agent is at least one selected from the group consisting of polyethylene imine, polyethylene glycol diamine, ethylene diamine, and tetramethylene diamine. (6) The stent according to the above (1), wherein the crosslinking agent is glutaraldehyde or ethylene glycol diglycidyl ether. (7) The stent according to the above (1), wherein at least a part of the outer surface of the metal base is plated with a radiopaque metal. (8) A stent having a surface in contact with blood having antithrombotic properties and a surface not in contact with blood having radiopaque properties.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION The base material of the stent of the present invention is not particularly limited, and a base material such as resin and metal can be used. Examples include stainless steel, tantalum, superelastic nickel-titanium (Ni-Ti) alloy, and thermoplastic polymer, and are preferably biocompatible materials.

The shape of the stent of the present invention is not particularly limited. However, it is preferable that the stent has a shape that can be expanded and contracted in a radial direction from a contracted state to an expanded state and is flexible in a longitudinal direction. One unit of a coiled, net-shaped or bellows-shaped cylindrical body or a shape in which a plurality of these one units are continuous in the axial direction is exemplified. FIG. 1 shows an example of the shape of the stent. (A) is a development view of a shape in a contracted state (b)
Is a development view of the shape in the expanded state.

FIG. 2 is a perspective view showing one example of the stent of the present invention. An antithrombotic agent 2 is covalently bonded to the surface of the stent 1 of the present invention, and at least a part thereof is coated with a radiopaque metal plating 3. In the example of FIG. 2, an anti-thrombotic agent 2 is covalently bonded to a surface in contact with blood, and an X-ray opaque metal plating 3 is applied to a surface not in contact with blood, as shown in a partial cross-sectional view in FIG. An example is shown. That is, the outer surface of the stent is provided with a radiopaque metal plating 3, and the antithrombotic agent 2 is covalently bonded to the back and side surfaces of the metal plating 3 surface. The surface treatment of the stent includes a treatment for imparting antithrombotic properties and X-ray contrast properties. Each of these surface treatments may be performed alone, or both may be performed. When both are performed, it is preferable to perform the antithrombotic treatment after performing the X-ray contrast treatment.

The X-ray opacity treatment is performed by plating an X-ray opaque metal such as Au, Ag, platinum, iridium, and tantalum. Conventionally, such an X-ray opaque treated metal-plated surface has a lot of noble metals, and its surface is considered to be difficult to further treat because its surface is inactive. Therefore, no antithrombotic treatment or the like has been attempted at all. . In the present invention, a stent having both X-ray opacity and antithrombotic properties can be obtained in a simple process by plating a part of the base material of the stent with metal and treating the other with antithrombotic treatment. The plating is preferably on the outer surface of the stent (the surface not in contact with blood). The plating may be part of the outer surface. From the viewpoint of X-ray opacity, it is preferable to plate the entire outer surface of the stent because the visibility is better. As the radiopaque metal, gold having excellent stability is preferable. Since the degree of contrast varies depending on the type of metal to be plated, it is preferable to apply a plating having a thickness that does not hinder angiography after the stent is placed. When gold is used, plating with a thickness of 10 to 40 μm is preferable.

When plating only the outer surface of a cylindrical stent or the like, a mask or the like is provided on the inner side so as to prevent plating. Preferably, the ends of the metal pipe before forming into a stent shape are sealed by closing both ends with stoppers or the like, so that the plating solution does not enter inside, only the outer surface is plated, and then punched into a stent shape, or laser Process. The following antithrombotic treatment is performed regardless of whether or not the radiopaque treatment is performed on the stent substrate.

1) The surface of the stent is treated with an oxidizing agent. Examples of the oxidizing agent treatment include a treatment with a halogen gas, a chromic acid-related compound, and the like, and an ozone treatment is preferable.
Ozonation is a very powerful oxidizing agent and is suitable for activating chemically inert metal surfaces such as stainless steel.

The substrate surface is chemically activated by the oxidizing action of ozone. On the other hand, since the surface is roughened, irregularities are formed and can also serve as anchors of the coupling agent, so that they are physically activated. Further, impurities that hinder the bond with the coupling material due to ozone are oxidized and decomposed and disappear, so that a stronger bond is formed.

In the ozone treatment, ozone generated by oxidizing oxygen with an ozone generator is brought into contact with a stent substrate.
The ozone concentration, the flow rate of oxygen (ozone), the reaction temperature, the reaction time, and the like are selected according to the material of the stent to be used. When the surface to be treated is a metal compound, the treatment is preferably performed under conditions stronger than that of the organic resin. The ozone concentration is preferably in the range of 20 to 100 mg / l. That is, if it is less than 20 mg / l, sufficient activation cannot be obtained, and if it is more than 100 mg / l, a heterogeneous reaction may occur. Also, the flow rate of oxygen (ozone) is preferably in the range of 50 to 1000 ml / min. If it is less than 50 ml / min, the reaction unevenness occurs depending on the location of the base material, and if it is more than 1000 ml / min, ozone not participating in the reaction increases and is wasteful. Also,
The reaction temperature is preferably raised within the range of 0 to 70 ° C. in consideration of the properties of the material when oxidation is impossible at room temperature. The reaction time is 30 to
Preferably, it is 120 minutes. If the time is less than 30 minutes, it is difficult to control the reaction. If the time is longer than 120 minutes, the process takes a long time and the efficiency is lowered.

2) Next, an antithrombotic agent is covalently bonded via a coupling agent having two or more amino groups and a crosslinking agent having two or more aldehyde groups or epoxy groups. The activated substrate surface is reacted with an antithrombotic agent, preferably a coupling agent having two or more amino groups necessary for temporarily ion-binding a heparin molecule. Examples of the coupling agent include polyethylene imine, polyethylene glycol diamine, ethylene diamine, and tetramethylene diamine. A heparin molecule is brought into contact with the base material having the amino group on the surface to form an ionic bond. This ionic bond is temporarily immobilized for later covalent bonding of the substrate and heparin.

The heparin molecule to be bound may be used as it is, but it is preferable that some of the N-sulfate groups present in the heparin molecule are desulfated and primary aminated in order to fix more firmly. . However, since the activity of heparin decreases in proportion to the degree of desulfation, the amount of primary amino groups in the heparin molecule is more preferably set to 5 to 25%. When heparin is used as an antithrombotic agent, it has sufficient antithrombotic properties for about two weeks immediately after the stent is placed in the body. On the other hand, the restoration rate of tissues in the body after a long period of time is high.

As an antithrombotic agent, instead of heparin or aminated heparin, a compound that inhibits antithrombotic activity or migration of vascular smooth muscle, for example, a calcium antagonist, an angiotensin converting enzyme inhibitor, a platelet membrane glycoprotein receptor antagonist (II
b IIIa antagonist) and the like, and a compound capable of ion-bonding to an amino group may be used.

A) The coupling agent can be applied by applying or dipping a solution on the surface of the substrate. pH
Is preferably 4 to 12. If the pH is less than 4 or greater than 12, ions may flow out depending on the type of metal as the base material, and the activated surface may be lost. The reaction temperature is preferably from 0 to less than 80C. If the temperature is lower than 0 ° C., the reactivity is lowered. If the temperature is higher than 80 ° C., the coupling agent may be undesirably denatured.
The reaction time is preferably from 10 minutes to 24 hours. If the reaction time is less than 10 minutes, the reaction does not sufficiently proceed, and if it is longer than 24 hours, the coupling agent may be denatured depending on the pH value or the reaction temperature, which is not preferable.

Next, the ionic bond of an antithrombotic agent, preferably heparin, can be carried out by coating or dipping a heparin solution on a substrate provided with a coupling agent.
In this case, the pH is preferably 2 to 5. If the pH is less than 2, the stability of heparin decreases, and if it is more than 5, the positive charge on the surface of the base material decreases and the amount of bound heparin decreases, which is not preferable. The reaction temperature is preferably from 0 to 80C.
If the reaction temperature is lower than 0 ° C., the ionic bonding rate of heparin is remarkably reduced, and if it is higher than 80 ° C., the stability of heparin is undesirably lowered. The reaction time is preferably from 10 minutes to 24 hours. If the reaction time is less than 10 minutes, ionic bonding is insufficient, and if the reaction time is longer than 24 hours, the activity of heparin decreases, which is not preferable. Heparin concentration is 0.05%
It is preferable that the concentration is not less than the saturation concentration.

Next, covalent bonding with a cross-linking agent can be performed by applying or dipping a cross-linking agent solution on the surface of the substrate. The crosslinker concentration is preferably from 0.1 to 0.5%. When the concentration of the crosslinking agent is less than 0.1%, the crosslinking is not sufficiently performed, and when the concentration is more than 0.5%, the activity of heparin is adversely affected. The pH is preferably 2-5. If the pH is less than 2, the stability of heparin is lowered, and if it is higher than 5, the heparin is quickly separated from the substrate surface before the cross-linking reaction of the ion-bonded heparin is performed. The reaction temperature is 0 to 60.
C is preferred. If the reaction temperature is lower than 0 ° C., the reaction does not proceed sufficiently, and if it is higher than 60 ° C., the activity of heparin is deactivated, which is not preferable. The reaction time is preferably 30 minutes to 24 hours. If the reaction time is less than 30 minutes, the crosslinking reaction does not proceed sufficiently, and if it is longer than 24 hours, the activity of heparin is deactivated, which is not preferable.

B) Subsequently, a compound having at least two or more aldehyde groups or epoxy groups is reacted as a crosslinking agent between the coupling agent and the heparin molecule in order to covalently bind the antithrombotic agent, preferably heparin. . Examples of the cross-linking agent include glutaraldehyde and ethylene glycol diglycidyl ether. When a dialdehyde derivative is used, the formed bond is unstable, so that further stabilization by a reduction reaction is required.
A solution of a reducing agent is applied or dipped to stabilize an unstable bond (Schiff base) formed when a dialdehyde derivative is used as a coupling agent. Preferably, a reducing agent is mixed into the solution during the crosslinking reaction. Thus, heparin can be immobilized in a series of reaction systems, and can be reduced without breaking an unstable covalent bond. The reducing agent may be added in an amount equal to or more than the chemical equivalent of the bond to be reduced or more. When a reducing agent is mixed, a small amount of a high-concentration reducing agent is preferably added so as not to change the temperature and concentration of the crosslinking agent during the reaction. The reaction time should not exceed 2 hours in order to avoid inactivation of heparin.

[0030]

【Example】

(Example 1) A 1 mm thick stainless steel plate (material: SUS316L) was cut and processed into 8 x 8 mm to obtain a sample. These samples were subjected to ozone treatment under the conditions of an ozone concentration of 88 mg / l and an oxygen flow rate of 800 ml / min with reaction times of 0, 30, 60, 120 and 180 minutes. X-ray spectroscopy (Electron Spectro
The oxygen element fraction present on the surface was measured by scopy for Chemical Analysis (hereinafter abbreviated as ESCA). Table 1 shows the results.

[0031]

Since the oxygen element fraction substantially followed the parallel line when the reaction time was 60 minutes or more, it is considered that the oxide on the sample surface reached saturation in the reaction time of 60 minutes. Therefore, the reaction for more than 60 minutes is useless. If the reaction time is less than 60 minutes, the reaction is insufficient because of the tendency to increase.
From the above, it was confirmed that the substrate surface was activated by the ozone treatment, and at the same time, the optimal conditions for SUS316L could be determined. Similarly, optimum conditions can be determined for other metal substrates.

Example 2 In order to impart polyethyleneimine (hereinafter abbreviated as PEI) as a coupling agent to the sample of Example 1, the sample was immersed in a 0.5% aqueous solution of PEI for 5 hours. In addition, a rubbing test using a polyethylene terephthalate film was performed on each sample in order to confirm that the sample was bonded to the surface instead of adhering. Each sample was analyzed by ESCA. The element to be measured was nitrogen derived from PEI. Table 2 shows the results.

[0034]

In the sample not subjected to the ozone treatment (reaction time: 0 minutes), PEI peeling was clearly observed. It was also confirmed that PEI was most frequently fixed at a reaction time of 60 minutes. As described above, the surface of the base material was effectively activated by the ozone treatment, and the SUS31 obtained in Example 1 was used.
It was confirmed that the optimal conditions for 6 L were effective for PEI.

(Example 3) Ozone reaction time 6 of Example 2
In order to make heparin ion-bond to the 0-minute sample, heparin in which a part of the N-sulfate group is desulfated and converted to a primary amine (the synthesis of aminated heparin is disclosed in
-38851) was adjusted to pH 4.0.
0.05% concentration dissolved in 0 mM succinate buffer
Was immersed in the solution at 45 ° C. for 2 hours. The sample up to this point (state in which heparin is ion-bonded) is referred to as sample A. Further, the following series of reactions was carried out in order to covalently bond all the samples except the sample A. It was immersed in 2 ml of 0.1, 0.2, 0.3 and 0.5% glutaraldehyde aqueous solution at 55 ° C. for 2 hours as a crosslinking agent. After immersion, in order to reduce the binding site, 0.2 ml of a 20-fold aqueous solution of sodium cyanoborohydride of each glutaraldehyde solution was added, and the mixture was stirred well and left at 55 ° C. for 2 hours. To remove excess cross-linking agent and reducing agent, 55
C. in water for 1 hour. These samples are referred to as B1, B2, B3 and B5, respectively. Samples obtained by performing a crosslinking reaction and a reduction reaction at 4 ° C. were C1 and C
2, C3 and C5.

These samples were subjected to circulating flow washing with physiological saline at 37 ° C. at 410 ml / min for 3 days, and the activity of heparin remaining on the surface was measured using a commercially available measurement kit (test team heparin s kit). , First chemical agent). Table 3 shows the results.

[0038]

[0039]

The activity of heparin immobilization in the cross-linking reaction was confirmed because the activity of sample A, which had not been cross-linked, was clearly reduced after washing. Example 3
In the cross-linking reaction at a temperature of 4 ° C. and a concentration of 0.2 or 0.3% were optimal.

(Embodiment 4) Ethylene oxide gas sterilization (hereinafter abbreviated as EOG sterilization) was performed on the C3 sample and the target sample (untreated stainless steel (material: SUS316L)) which were the optimum conditions in Example 3. Thereafter, a platelet expansion ability test was performed. Sterilization condition is temperature 5
At 0 ° C., 65% humidity, EOG pressure of 0.7 kgf / cm ² , reaction time of 3 hours and gas replacement frequency of 3 times, the samples were each left for 7 days after sterilization. Table 5 shows the results. From this, the reactivity of the sample surface to platelets is required.

The method and significance of the platelet dilatation test are as follows. Platelet-rich plasma (hereinafter abbreviated as PRP) whose platelet count has been adjusted in advance is brought into contact with the sample surface for a certain period of time, and by knowing the number and morphology of the attached platelets, the antithrombotic level of the surface can be evaluated.

Human venous blood (3.8% sodium citrate supplemented) is centrifuged to separate PRP, and a part thereof is further centrifuged to separate platelet poor plasma (hereinafter abbreviated as PPP). Platelet count 10 × 10 ⁴ using PRP and PPP
Prepare pcs / μl of adjusted PRP. 200 μl of the adjusted PRP was dropped on an 8 × 8 mm sample surface, and a polystyrene Petri dish was placed so as to have a liquid thickness of 2 mm.
Leave for 30 minutes. After washing, the cells are fixed with a 1% aqueous solution of glutaraldehyde, and observed and photographed with an electron microscope.
From the photograph, the number of platelets adhering to a certain area was counted for each morphology shown below. Table 4 shows the results.

[0044] Type I: Spheroidized from a discoid form, which is a normal form of platelets, and slightly pseudopod. Type II: More than a few pseudopodia have been extended and the endoplasmic reticulum has begun to spread. Type III: Fully expanded and crushed endoplasmic reticulum. It was confirmed that heparin coating reduced the reactivity of the stainless steel substrate surface against platelets, and as a result, exhibited antithrombotic properties.

Example 5 and Comparative Examples 1 and 2 Nine stainless steel pipes (material: SUS316L, length 20 mm, outer diameter: 1.4 mm, wall thickness: 0.1 mm) were balloon-processed by laser processing. An expandable stent configuration was used. Perform heparin-coated against three of these in terms of C3 samples of Example 3 (HC samples, H e
parin C oated sample), heparin is a known technique to three as the target - benzalkonium (heparin - dimethyl stearyl benzyl chloride)
Carried out of the application (HB sample, H eparin- B en
zalkonium sample), the remaining three were directly used as (NH samples, N on H eparin
sample). 37 for each stent
After circulating and washing at a flow rate of 410 ml / min for 14 days in a physiological saline solution at 14 ° C., the value of heparin activity was measured in the same manner as in Example 3. Table 5 shows the results.

[0046] As is clear from the results, it was confirmed that the activity can be maintained for a long time by immobilizing heparin on the substrate surface by the method according to the present invention.

(Example 6 and Comparative Examples 3 and 4) Example 5
And three kinds of samples were prepared in the same manner as in Comparative Examples 1 and 2.
EOG sterilization was performed on the obtained nine stents under the same conditions as in Example 4, and the resulting stents were allowed to stand for 7 days to degas. These stents are weighed 2.5-3.0 kg.
Was inserted into 9 abdominal aorta (blood vessel diameter 3 mm) of a white rabbit (Kitayama Labes) using a balloon catheter through a femoral artery via a catheter, dilatated, and then placed. The balloon diameter used when expanded was 3 mm. Anticoagulant therapy with heparin administration was performed only during surgery. Two weeks after the operation, he died due to heparin administration and an excessive administration of an anesthetic, and the stent was removed. In the HC sample group, the thrombus was hardly adhered to three cases, whereas in the HB sample group and the NH sample group, two out of three cases each had a large amount of thrombus and the remaining 1 Moderate thrombus adhesion was also observed in the case. In addition, the blood vessel in which the stent was placed was embedded in paraffin, and a pathological specimen of soft tissue was prepared.
When the vascular endothelial cells were observed, the HC sample group and H
In the B sample group, no new tissue of smooth muscle was observed, but N
The H sample showed signs of neoplasia in one case. Table 6 shows the results.

[0048] ：: None of the three cases showed any signs of thrombus or new tissue. Δ: Out of 3 cases, 1 case showed signs of thrombus or new tissue. ×: Signs of thrombus or new tissue were observed in all three cases.

Example 7 Two stainless steel pipes (material: SUS316L, length 20 mm, outer diameter:
(1.4 mm, wall thickness: 0.1 mm), only one outer surface was gold-plated with a thickness of 30 μm by electroplating.
These pipes were formed into a stent form that could be balloon-expanded by laser processing, and these stents were heparin-coated under the conditions of the C3 sample of Example 3.
When these stents were expanded with a balloon and the visibility was checked using an X-ray contrast apparatus, almost no contrast was obtained with the unplated stent, but not only with the gold-plated stent, but also with the appearance. Even the laser cut design was clearly imaged.

In the above, the stainless steel stent has been mainly described in the embodiments. Naturally, the X-ray contrast processing of the present invention is performed or performed on a balloon-expandable stent having a gold plating on the entire surface or an expandable stent as necessary. Instead, the stent of the present invention can be formed by coating with various synthetic resins (for the synthetic resins that can be used, see Japanese Patent Publication No. 6-38851) and then performing the antithrombotic treatment of the present invention. In addition to the stent, the antithrombotic treatment and / or the X-ray contrast treatment of the present invention can be applied to metal medical materials and medical instruments that come into contact with blood.

[0051]

As described in detail above, the antithrombotic stent having the antithrombotic agent of the present invention fixed on its surface has a stronger effect on heparin molecules than the well-known technique of heparin-benzalkonium application. It can be immobilized and maintain its activity even under the severe conditions of being exposed to the bloodstream. From this, it is possible to avoid the risk of stent occlusion due to thrombus adhesion and reduce therapies such as administration of antithrombotic agents.

By fixing the antithrombotic agent on the surface,
Restenosis due to vascular hypertrophy caused by migration and proliferation of vascular smooth muscle can be reduced. Also, by plating a radiopaque metal before fixing the antithrombotic agent to the stent, X
An antithrombotic property and an X-ray contrast property can be simultaneously imparted to a metal-based stent having almost no line contrast property by a simple process.

[Brief description of the drawings]

FIGS. 1A and 1B are developed views showing one example of a stent of the present invention.

FIG. 2 is a perspective view showing an example of the stent of the present invention.

FIG. 3 is a cross-sectional view of a portion of the stent shown in FIG.

[Explanation of symbols]

 Reference Signs List 1 stent 2 antithrombotic agent 3 radiopaque metal plating

Claims (7)

[Claims] 1. An antithrombotic agent is covalently bonded to a substrate treated with an oxidizing agent via a coupling agent having two or more amino groups and a crosslinking agent having two or more aldehyde groups or epoxy groups. A stent characterized by being made. 2. The stent according to claim 1, wherein the oxidizing agent is ozone. 3. The stent according to claim 1, wherein the antithrombotic agent is aminated heparin. 4. The stent according to claim 1, wherein said metal substrate is stainless steel. 5. The stent according to claim 1, wherein the coupling agent is at least one selected from the group consisting of polyethylene imine, polyethylene glycol diamine, ethylene diamine, and tetramethylene diamine. 6. The stent according to claim 1, wherein the crosslinking agent is glutaraldehyde or ethylene glycol diglycidyl ether. 7. The stent according to claim 1, wherein at least a part of the metal base is plated with a radiopaque metal.