JP4325259B2 - Stent manufacturing method - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for manufacturing a stent (intraluminal graft) used in recent surgery, particularly coronary artery surgery. In detail, it is related with the manufacturing method of the stent which covered the stent main body with the polymer film which has a softness | flexibility.
[0002]
[Prior art]
Conventional treatment of ischemic heart disease is percutaneous transluminal coronary angioplasty (PTCA), that is, a balloon catheter is carried through a lumen in a blood vessel to, for example, a stenotic site, and then the balloon is expanded with a liquid such as physiological saline. Treatment methods were common. However, with this method, there is a high probability that coronary occlusion in the acute phase and re-stenosis (so-called restenosis) at the site where PTCA is performed occur. In order to solve these problems, an intraluminal graft called a stent has been developed and recently put into practical use and has become widespread. Recent data show that nearly 75% of balloon catheter surgery has already been replaced by stent surgery.
[0003]
The stent body is an intraluminal graft that is carried through the inside of a lumen such as a blood vessel and supported by an action from the inside by expanding its diameter at the treatment site of the lumen. Although it is mainly used in the above-mentioned coronary artery surgery, it is mainly described here, but the stent is a ureter, ureter, fallopian tube, aortic aneurysm, peripheral artery, renal artery, carotid artery, It can also be used for other luminal parts of the human body such as cerebral blood vessels. In particular, in order to understand the present invention, it is expected that the field of use of stents will expand further, that stents will be used in many surgeries in the future, and that the importance of ultrafine stents will increase with the use in the field of brain surgery. The
[0004]
Restenosis can be drastically prevented by the spread of surgery using stents. However, since the metallic stent body is a foreign substance in the body, thrombosis develops within a few weeks after insertion of the stent body. In other words, since the metal stent itself has thrombogenicity, when exposed to blood, it contacts with plasma proteins such as albumin and fibrinogen and aggregation occurs due to adhesion of platelets. It is also pointed out that the placement of a metal stent body promotes intimal thickening, which is one cause of restenosis. Japanese Patent Laid-Open No. 11-299901 describes a stent 20 in which the outer peripheral surface of a metal stent body is covered with a flexible polymer film 19 in which fine holes are fused, as shown in FIGS. FIG. 4 shows a state where the diameter of the stent 20 is expanded.
[0005]
[Patent Document 1]
JP-A-11-299901 [0006]
[Problems to be solved by the invention]
In living tissue, inner surfaces such as blood vessels, that is, portions that come into contact with blood are covered with a cell layer called endothelial cells. Since the surface of these endothelial cells is covered with sugar and the endothelial cells themselves secrete substances that suppress platelet activation such as prostaglandins, thrombus and the like are unlikely to occur in living tissues. The stent disclosed in JP-A-11-299901 promotes moderate cell endothelialization and reduces thrombogenicity by coating the outer peripheral surface of a metal stent body with a polymer film.
[0007]
It is an object of the present invention to provide a method for producing a stent in which thrombus generation is further reduced and the flexibility is excellent.
[0008]
[Means for Solving the Problems]
The stent manufacturing method of the present invention includes a tubular stent body capable of expanding diameter, and a flexible polymer film having a plurality of micropores attached to both the inner peripheral surface and the outer peripheral surface of the stent main body. A method of manufacturing a stent in which a plurality of stent bodies are arranged in the longitudinal direction and integrated by the polymer film, wherein the mandrill is immersed in a polymer solution and the polymer is coated in a cylindrical shape On top of this, a plurality of stent bodies are stacked with a space between each stent body, and further coated on both sides by being immersed in a polymer solution to form a coating, and then laser-processed to form a fine polymer film. After the holes are formed, the polymer films at both ends are cut off, and the stent is extracted .
[0009]
In the stent manufactured according to the present invention , not only the outer peripheral surface of the stent body but also the inner peripheral surface is covered with a flexible polymer film, and thrombus generation can be sufficiently suppressed. The stent manufactured by the present invention includes a plurality of stent main bodies and flexes flexibly between the stent main bodies, and thus has excellent flexibility.
[0010]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, embodiments will be described with reference to the drawings. 1 and 2 are explanatory views of the stent body, and FIGS. 5 and 6 are explanatory views of the stent. 5 and 6 are schematic diagrams, and particularly the thickness is shown to be significantly thicker than actual.
[0011]
As illustrated in FIGS. 5 and 6, in the stent 1 according to this embodiment, a plurality of stent bodies 10 are coaxially arranged, both inner and outer peripheral surfaces are covered with a polymer film 2, and the polymer film 2. Are integrated.
[0012]
The stent main body constituting the stent of the present invention is a tube having a length of about 2 to 40 mm and a diameter of about 10 to 100% of the length. The stent body is preferably in a mesh shape so that the diameter of the stent can be expanded flexibly, and in particular, it is preferably an oblique lattice shape as shown in FIG. 1 and the extending direction of the lattice is a spiral direction.
[0013]
The stent body is preferably made of a biocompatible metal. Examples of the biocompatible metal include stainless steel, titanium, tantalum, aluminum, tungsten, nickel / titanium alloy, and the like.
[0014]
In the present invention, a plurality of stent main bodies, preferably 2 to 10, and particularly preferably 2 to 5, are arranged in the longitudinal direction. Preferably, an interval of about 0.1 to 100% of the diameter of the stent body is formed between the stent bodies.
[0015]
It is preferable that the stent main bodies are independent from each other and are connected to each other only by the covering polymer film. However, one place in the circumferential direction of the end portion of the stent body may be preferably connected by a linear material made of the same material as the stent. Even if one place of the circumferential direction is connected, the flexibility of a stent is not inhibited so much. By connecting the stent main bodies with this linear body, the tensile strength in the longitudinal direction of the stent can be increased. However, by omitting this linear body, the flexibility of the stent becomes remarkably high.
[0016]
The plurality of stent bodies are preferably arranged in a line coaxially with high accuracy, and a flexible polymer film is applied to both the inner and outer peripheral surfaces to form a continuous cylinder. This polymer film also exists in a cylindrical shape between the joints of the stent body, and the polymer film 2 continuously exists from one end to the other end on both the inner and outer peripheral surfaces of the stent 1.
[0017]
As the material used as the flexible polymer film, a high-flexibility polymer elastomer is suitable, for example, polystyrene, polyolefin, polyester, polyamide, silicone, urethane, fluorine resin, natural rubber, etc. Various elastomers and their copolymers or their polymer alloys can be used. Among them, segmented polyurethane is most suitable because it is highly flexible and strong.
[0018]
A segmented polyurethane polymer has a flexible polyether portion as a soft segment and a portion rich in aromatic rings and urea bonds as a hard segment, and the soft segment and hard segment phase separate to form a fine structure. It is what. This segmented polyurethane polymer film is excellent in antithrombotic properties. Moreover, it is excellent in properties such as strength and elongation, and can be sufficiently expanded without breaking even when the stent is expanded in diameter.
[0019]
This segmented polyurethane polymer film preferably has a thickness of 10 to 100 μm, in particular 20 to 50 μm.
[0020]
The polymer film is provided with a plurality of fine holes. The fine holes may be randomly arranged, but preferably the fine holes are perforated at substantially uniform intervals. The fact that the micropores are perforated at a substantially uniform interval does not mean that the intervals are the same, but that the micropores are arranged at a substantially constant interval by a controlled method. Accordingly, the substantially uniform interval includes diagonal, circular, and elliptical arrangements that appear to be randomly arranged at first glance. The micropore may have any size and shape as long as the endothelial cells can enter and exit. Preferably, it is a circle having a diameter of 5 to 500 μm, most preferably 20 to 100 μm. Needless to say, other shapes such as an ellipse, a square, and a rectangle are also included. These are the states before expansion, and when the stent body is expanded and placed in the lumen, the circle is deformed into an oval shape, and the diameter changes accordingly.
[0021]
If the arrangement density of the micropores is too high, the strength of the polymer film is lowered and the intimal tissue penetrates too much. If the density is too low, the endothelial cells do not sufficiently grow inside the stent. Therefore, the micropores are arranged on a plurality of straight lines at intervals of 50 to 500 μm, preferably 100 to 300 μm. The plurality of straight lines include, for example, 10 to 50 straight lines arranged at a predetermined constant angular interval in the axial direction of the stent.
[0022]
The micropores, after the polymer film is applied to the inner and outer peripheral surfaces of the stent body, Ru provided more perforated laser over.
[0023]
In the present invention, a base polymer film such as a segmented polyurethane polymer film may be coated with a biodegradable polymer. Examples of such biodegradable polymers include gelatin, polylactic acid, polyglycolic acid, caprolactone, lactic acid-glycolic acid copolymer, polygioxanone, and chitin.
[0024]
The biodegradable polymer may contain a therapeutic agent such as an antiplatelet agent, an antithrombotic agent, a growth promoter, a growth inhibitor, or an immunosuppressant. This therapeutic agent is released into the body along with the degradation of the biodegradable polymer, and is effective in suppressing the formation of thrombus or promoting the proliferation of endothelial cells and obtaining early endothelialization.
[0025]
The therapeutic agents include heparin, low molecular weight heparin, hirudin, argatroban, formacholine, bapiprost, prostamorin, prostakyrin congener, dextran, lofepro-algchloromethyl ketone, dipyridamole, glycoprotein platelet membrane receptor antibody, combination Reversible hirudin, thrombin inhibitor, vascular peptin, vascular tensin converting enzyme inhibitor, steroid, fibroblast growth factor antagonist, fish oil, omega-3 fatty acid, histamine, antagonist, HMG-CoA reductase inhibitor, ceramine, Examples include serotonin blocking antibodies, thioprotein inhibitors, trimazole pyridimine, interferon, vascular endothelial growth factor (VEGF), rapamycin, FK506, and the like.
[0026]
The biodegradable polymer coating layer can be formed by immersing the stent in a biodegradable polymer solution. The polymerization may be promoted by ultraviolet rays after being dipped in the polymer solution and pulled up. When a polymer film is formed by a centrifugal molding method described later, the biodegradable polymer layer may also be formed by a centrifugal molding method. When the therapeutic agent is blended in the biodegradable polymer solution, a coating containing the therapeutic agent is formed. By adjusting the biodegradable polymer type, molecular weight, coating thickness, and the like, it is possible to set the time and period during which the therapeutic agent is released into the body.
[0027]
The stent of the present invention may be coated on the outer surface with a lubricious polymer in order to smooth movement in small blood vessels in the human body. Examples of such a lubricious polymer include polyethylene glycol, polyacrylamide, and polyvinyl pyrrolidone.
[0028]
Method for producing a stent of the present invention is to coat the mandrel into the polymer solution by dipping it into a cylindrical polymer such as polyurethane, this on the overlapped strongly metallic stent body was a bit extension, it was further immersed in a polymer solution coating of double-sided coated by causing, then, after laser processing, disconnect film at both ends, in which to leave disconnect the stent.
[0029]
Further, a cylindrical cover strip with one end sealed may be manufactured, and this may be attached to the outer peripheral surface and inner peripheral surface of the stent body. In order to attach the cover strip to the outer peripheral surface of the stent body, a gas is sent into the cover strip, the stent is inserted into the cover strip with the cover strip fully opened, and the air blowing is stopped. Thus, the cover strip may be contracted to adhere to the outer peripheral surface of the stent. In order to attach the cover strip to the inner peripheral surface of the stent body, the cover strip is inserted into the stent main body, and then gas is supplied into the cover strip to expand the diameter so that the cover strip adheres to the inner peripheral surface of the stent body. That's fine. Excess cover strips that protrude from the stent body are preferably excised.
[0032]
【Example】
Example 1
As the stent body, a mesh-shaped stent body 10 having a diameter of 4 mm, a length of 13 mm, and a thickness of 0.2 mm shown in FIG. 1 was employed.
[0033]
FIG. 2 is a side view of the metallic stent body 10 ′ after expansion. The metal stent body 10 ′ has a diameter of 8 mm, a length of 13 mm, and a thickness of 0.2 mm.
[0034]
A stent was manufactured by attaching segmented polyurethane polymer film 2 to the inner and outer peripheral surfaces of three metal stent bodies 10. Specifically, a mandrill is dipped in a polyurethane solution to coat polyurethane in a cylindrical shape, and three metal stent bodies slightly expanded on this are strongly stacked with a space of 2 mm between each stent body, and further a polyurethane solution. Both surfaces were coated by immersing the film into a film, and further laser processing was performed to form fine holes in the polymer film. Then, the films on both ends were cut off, immersed in methanol, and the stent was extracted from the mandrill. As a result, a cylindrical molded body (stent body) having a polymer film thickness of 30 μm on the inner peripheral surface and a polymer film thickness of 50 μm on the outer peripheral surface was obtained.
[0035]
The polyurethane solution was prepared by mixing a segmented polyurethane (Kontoron) under the trade name Capdiomat with a mixed solution of tetrahydrofuran and dioxane.
Cardiovascular Inc. The product is 10% by weight.
[0036]
Holes with a diameter of 100 μm were formed almost uniformly at intervals of 200 μm on the stent body by an excimer laser. After making a row of holes in the long axis direction, the cylindrical polymer film was rotated by 15 ° in the circumferential direction to make 24 rows of holes on the entire circumference.
[0037]
Comparative Example 1
A stent was manufactured in the same manner as in Example 1 except that only one stent body having a length of 40 mm was used.
[0038]
When these stents of Example 1 and Comparative Example 1 were arranged horizontally, one end thereof was fixed, and a vertical downward load of 5 g was applied to the other end, the displacement in Example 1 was 5 mm. The displacement in Example 1 remained at 0 mm.
[0039]
The stent of Example 1 was transplanted into the carotid artery and observed one month later. As a result, it was confirmed that intimal thickening was thin and thrombus formation was suppressed.
[0040]
【The invention's effect】
The metal stent manufactured according to the present invention and provided with polymer film covers on both the inner and outer peripheral surfaces can be flexibly bent and can prevent adverse effects on human tissues such as antithrombotic action due to metal.
[Brief description of the drawings]
FIG. 1 is a perspective view of a stent body.
FIG. 2 is a perspective view of the expanded stent body.
FIG. 3 is a perspective view of a conventional stent.
4 is a perspective view of the stent of FIG. 3 having an enlarged diameter. FIG.
FIG. 5 is a schematic perspective view of a stent according to an embodiment.
6A is a cross-sectional view taken along line VI-VI in FIG. 5, and FIG. 6B is an enlarged view of a portion B in FIG.
[Explanation of symbols]
DESCRIPTION OF SYMBOLS 1 Stent 2 Polymer film 10 Stent main body 19 Polymer film 20 Stent

Claims (10)

A stent having an expandable tubular stent body and a flexible polymer film having a plurality of micropores attached to both the inner peripheral surface and the outer peripheral surface of the stent main body. A method of manufacturing a stent that is aligned in their longitudinal direction and integrated by the polymer film comprising :
A mandrill is immersed in a polymer solution to coat the polymer in a cylindrical shape, and a plurality of stent bodies are stacked on top of each other with a space between each stent body, and further immersed in the polymer solution to form a film. , was then drilled pores in the polymer film was coated by laser processing, disconnect the polymer film at both ends, the manufacturing method of the stent, characterized in that withdrawing the stent. The stent manufacturing method according to claim 1, wherein the stent bodies are independent of each other. The stent manufacturing method according to claim 1 or 2, wherein the stent body is made of a mesh-like metal member. The method for manufacturing a stent according to any one of claims 1 to 3, wherein the micropores are arranged at substantially uniform intervals. The method for producing a stent according to any one of claims 1 to 4, wherein the micropores are provided at intervals of 50 to 500 µm and have a diameter of 5 to 500 µm. The method for manufacturing a stent according to any one of claims 1 to 5, wherein the flexible polymer film is a segmented polyurethane polymer film. The method for manufacturing a stent according to claim 6, wherein the segmented polyurethane polymer film has a thickness of 10 to 100 m. The method for manufacturing a stent according to any one of claims 1 to 7, wherein the polymer film is coated with a biodegradable polymer. The method for producing a stent according to claim 8, wherein the biodegradable polymer contains a drug. The method for producing a stent according to claim 9, wherein the drug is selected from FK506, heparin, hirudin, and argatroban.

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