JP2004261567A - Stent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a stent which further surely prevents a thrombus from occurring and which eliminates the problem of the deviation of a stent body from a coating layer. <P>SOLUTION: The stent comprises a radially enlargeable tubular stent body and a flexible polymer layer coating this stent body. The polymer layer is brought into close contact with the entire outer surface of the stent body to coat the stent body. Since the flexible polymer layer is brought into contact with not only the outer peripheral surface of the stent body but also the entire outer surface to coat the stent body, problems, such as occurrence of a metal allergy, a cell stimulation by a metal, a rust do not exist. Further, since the inner peripheral surface of the stent is a smooth surface coated with the polymer layer, the occurrence of the thrombus can be suppressed sufficiently. There is no problem of the positional deviation of the stent body from the polymer layer at a stent enlarging time. The positional relationship between the stent body and the polymer layer is maintained before and after the enlargement of the stent. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

【００６２】
比較例２
スピロンベンゾフェノン系の光反応性ゼラチン５％、ヘパリン２．５％及び銀粉末０．１％を含む混合水溶液を調製した。比較例１で作成したステントを水平に静置し、ステント内壁に１ｃｍ^２あたりに混合水溶液を２０μＬ相当量を滴下して、ＰＴＦＥ製丸棒にて均質に引き延ばした後に光照射を行って固定した。この操作を２回繰り返した。このようにして内壁がコーティングされたステントを空気中でバルーンカテーテルにて拡張した後に、Ｘ線顕微鏡にて観察した。撮影されたＸ線透過像が図１３である。
【００６３】
以上より、拡張前にステントストラットが存在した部分は薬剤が塗布されておらず、拡張によってステントストラットとポリマーフィルムとの間で滑り現象が生じ、薬剤が塗布されていない部分が表面に露出したことがわかる。ここで、比較例１において穿孔された微細孔は、ステント本体の拡張時にステントストラットは矢印Ｘのように、ポリマー層上をすべるように移動し、微細孔の位置はＸ線不透過性のステントストラットの裏側へ移動した結果、図１３のＸ線透過像には観察されなかった。つまり、微細孔は閉塞されたことになる。従って、厳密に設計された孔の直径と配置間隔がステント本体の拡張によって変化することは、図８に示されるように、孔密度も変化し、内膜肥厚の問題を惹起する可能性があることが示唆された。
【００６４】
【発明の効果】
本発明のステントであれば、ステント本体の全外表面にポリマー層が密着してこれを被覆しているので、ステントに優れた生体適合性を与えることができ、金属によるアレルギーや血栓作用のような人体組織に与える悪影響を防ぐことができる。しかも、ステント拡張時のステント本体とポリマー層との位置ずれの問題もない。
【図面の簡単な説明】
【図１】本発明のステントのポリマー層による被覆状態を示す模式的断面図である。
【図２】ステント本体の斜視図である。
【図３】拡径させたステント本体の斜視図である。
【図４】ステントの斜視図である。
【図５】拡径させたステントの斜視図である。
【図６】特開平１１−２９９９０１号公報のステントのポリマーフィルムによる被覆状態を示す模式的な断面図である。
【図７】ポリマー層の微細孔のパターンと、微細孔の直径及び配置間隔と孔密度との関係を示す説明図である。
【図８】ポリマー層の孔密度と血管内へステント留置した際に形成される血管内膜の肥厚厚みとの関係を示すグラフである。
【図９】実施例１のステントのＸ線透過像である。
【図１０】比較例１のステントのＸ線透過像である。
【図１１】移植１ヶ月後のステントの顕微鏡写真である。
【図１２】ステントが移植された生体組織の断面の顕微鏡写真である。
【図１３】比較例２のステント内壁をコーティングした後に拡張させたもののＸ線透過像である。
【符号の説明】
１０ ステント本体
１１ ステントストラット
１２ ポリマー層
１９ ポリマーフィルム
２０ ステント[0001]
TECHNICAL FIELD OF THE INVENTION
BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a stent (endoluminal graft) used in recent years for endovascular therapy or surgical operation, particularly for dilatation of a stenotic coronary artery, stenotic carotid artery, bile duct, esophagus, and aneurysm occlusion. In particular, the present invention relates to a stent in which a plurality of expandable tubular stent bodies are arranged at intervals in their longitudinal direction, covered with a polymer film and integrated.
[0002]
[Prior art]
Conventionally, the treatment of ischemic heart disease is percutaneous transluminal coronary angioplasty (PTCA), in which a balloon catheter is carried through a lumen in a blood vessel, for example, to a stenosis, and then the balloon is inflated with a liquid such as saline. The method of treatment was common. However, according to this method, the probability of occurrence of coronary occlusion in the acute phase and re-stenosis of the PTCA site (so-called restenosis) was high. In order to solve these problems, an intraluminal graft called a stent has been developed, and has recently been rapidly put into practical use and spread. Recent data shows that nearly 75% of balloon catheter surgery has already been replaced by stent-based surgery.
[0003]
The stent body is an endoluminal graft that is carried through the lumen of a blood vessel or the like and is supported at its treatment site in the lumen by expanding its diameter to act from the inside. Currently, it is mainly used for the above-mentioned coronary artery surgery, so coronary artery surgery will be mainly described here. It can also be used in other luminal parts of the human body such as arteries, carotid arteries, cerebral blood vessels, and the like. In particular, stents are increasingly used in many fields, such as stenosis dilatation, aneurysm occlusion, and cancer therapy. It is expected that the importance will increase.
[0004]
With the spread of surgery using a stent, restenosis can be dramatically prevented. However, since the metallic stent body is a foreign substance in the body, thrombosis develops within a few weeks after the stent body is inserted. That is, since the metal stent itself has a thrombotic property, when exposed to blood, it comes into contact with plasma proteins such as albumin and fibrinogen, and aggregation occurs due to platelet adhesion. It has also been pointed out that the indwelling of the metallic stent body promotes thickening of the vascular endothelium, which is also one of the causes of restenosis. Therefore, Japanese Patent Application Laid-Open No. H11-299901 describes that the outer peripheral surface of a metallic stent body is covered with a flexible polymer film having micropores.
[0005]
FIG. 2 is a perspective view showing a metal stent main body 10 on a mesh used for such a stent, and FIG. 3 is a perspective view showing a state 10 ′ in which the diameter of the stent main body 10 in FIG. 2 is expanded. . FIG. 4 is a perspective view showing a stent 20 in which the outer peripheral surface of such a stent body 10 is covered with a flexible polymer film 19 having micropores, and FIG. 5 shows a state where the stent 20 is expanded. It is a perspective view.
[0006]
In a living tissue, an inner surface such as a blood vessel, that is, a portion that comes into contact with blood is covered with a cell layer called an endothelial cell. Since the surface of the endothelial cells is covered with sugar and the endothelial cells themselves secrete substances that suppress platelet activation, such as prostaglandins, thrombus and the like hardly occur in living tissues. In the stent disclosed in Japanese Patent Application Laid-Open No. H11-299901, by covering the outer peripheral surface of the metal stent body with the polymer film, it is possible to promote appropriate endothelialization of cells and reduce thromboticity.
[0007]
In JP-A-11-299901, the polymer film covering the outer peripheral surface of the stent body is formed as follows. That is, first, a mandrill for a cover strip is impregnated with a polymer solution, dried and perforated, and then the mandrill is pulled out to form a thin cover strip (bag-shaped cover film). The gas is fed into the bag-shaped cover film, and the stent body is inserted into the bag-shaped cover film with the cover film sufficiently opened, and then the gas is stopped and the cover film is contracted. By doing so, an outer film of a polymer film is formed on the outer peripheral surface of the stent body.
[0008]
[Patent Document 1]
JP-A-11-299901
[0009]
[Problems to be solved by the invention]
In the case of the stent disclosed in Japanese Patent Application Laid-Open No. H11-299901, the outer peripheral surface of a metallic stent body is coated with a flexible polymer film having micropores, thereby promoting endothelialization of cells on the outer peripheral surface to promote thrombus. Although the occurrence rate can be reduced, the stent disclosed in Japanese Patent Application Laid-Open No. H11-299901 does not cover the inner peripheral surface of the stent body with the polymer film and leaves the metallic stent body exposed. On the inner peripheral surface of the above, there are problems of thrombus generation, metal allergy, metal irritation, and rust generation. In particular, since the stent struts constituting the mesh-shaped stent main body protrude from the inner peripheral surface of the stent as ridges, blood flow is disturbed and thrombus is easily generated. The thrombus that has formed detaches and flies downstream (flows to the periphery along the bloodstream), infarcts small blood vessels on the downstream side, and platelet-derived growth factors released from platelets in the thrombus Stimulates vascular cells to cause intimal thickening, so the problem of thrombus formation in this area is significant.
[0010]
Moreover, simply inserting the stent body into the bag-shaped cover film and simply shrinking the bag-shaped cover film to form the outer film of the polymer film on the outer peripheral surface of the stent body has the following problems. That is, as shown in FIGS. 2 and 3, the stent body 10 used in Japanese Patent Application Laid-Open No. 11-299901 has an oblique lattice mesh shape. When the outer coating of the polymer film was formed, as shown in FIG. 6, the outer coating was fixed on the outer peripheral surface of the mesh-shaped stent main body at the contact portion with each of the stent struts 11 constituting the mesh-shaped stent main body. Therefore, the integrity of the polymer film 19 and the stent body is low.
[0011]
Therefore, at the time of expanding the diameter of the stent body, the contact portion between the stent strut 11 and the polymer film 19 slides. That is, the position of the polymer film 19 covering the outer peripheral surface of the stent body is shifted when the stent is expanded.
[0012]
In JP-A-11-299901, micropores are arranged in a polymer film 19 at substantially uniform intervals. Since the micropores are pierced for the purpose of suppressing endothelial cells on the inner wall of the stent and causing thrombus and suppressing intimal thickening, it is considered that the micropores are pierced avoiding the position directly above the stent skeleton. If the position of the polymer film with respect to the stent body shifts during the expansion of the stent, the micropores may be closed by the stent struts, and if so, the layout design of the micropores is completely meaningless. It will be.
[0013]
JP-A-11-299901 also describes that a biodegradable polymer or a drug is coated on the polymer film. When such a functional agent is coated on the inner peripheral surface of the stent body, Although the functional layer coating layer is not formed on the inner peripheral surface of the polymer film where the struts of the mesh-shaped stent body are present, the position of the polymer film is shifted with respect to the stent body when the stent is expanded. As a result, the surface not coated with the functional agent becomes exposed, and this coating also becomes meaningless.
[0014]
In the paragraph [0040] of JP-A-11-299901, when the stent body is covered with the cover strip, a heated gas is sent to ensure the close contact with the outer peripheral portion of the stent body 10 by thermal fusion. Although there is a statement that this operation may be performed, the adhesion of the contact point between the polymer film 19 and the stent strut 11 constituting the mesh-shaped stent main body is increased by this operation, but the stent strut 11 is planarized by the polymer film 19. It cannot be coated. Generally, the stent main body is formed by laser processing of a metal tube. Therefore, the sharp edge of the cut stent strut portion is rounded by chemical polishing and sonic processing, and the surface of the stent main body itself is often mirror-finished. Just as it is difficult to bond a resin material to a smooth surface metal material, bonding the stent body to the polymer film is not easy. In order to cover the stent strut 11 in a planar shape with the polymer film 19 and to further enhance the adhesion by the polymer film 19, it is necessary to melt the cover strip even momentarily and press it against the stent body. To do this, it is necessary to deliver a considerable amount of high-temperature gas, while the cover strip is a thin film with fine pores.By supplying a high-temperature gas that melts the polymer film, The film cannot maintain its shape, leading to defects such as rupture, breakage, pinholes and cracks.
[0015]
The present invention solves the drawbacks of the stent disclosed in Japanese Patent Application Laid-Open No. H11-299901, and further reliably prevents thrombus generation by coating the stent body with a polymer layer with good adhesion. An object of the present invention is to provide a stent in which the problem of displacement from the coating layer has been solved.
[0016]
[Means for Solving the Problems]
A stent according to the present invention comprises a stent having an expandable tubular stent body and a flexible polymer layer covering the stent body, wherein the polymer layer is in close contact with and covers the entire outer surface of the stent body. It is characterized by having.
[0017]
Such a stent of the present invention has a problem of metal allergy, metal irritation of cells, and rust generation at all because not only the outer peripheral surface of the stent body but also the entire outer surface thereof is covered with a flexible polymer layer in close contact. In addition, since the inner peripheral surface of the stent is a smooth surface covered with the polymer layer and has no protruding ridge of the stent base material, the generation of thrombus can be sufficiently suppressed without disturbing the blood flow. Further, there is no problem of displacement between the stent body and the polymer layer at the time of stent expansion, and the positional relationship between the stent body and the polymer layer is maintained before and after expansion.
[0018]
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, embodiments will be described with reference to the drawings.
[0019]
The stent main body constituting the stent of the present invention is preferably a tube having a length of about 2 to 40 mm and a diameter of about 1/10 to 1/2 of the length. Further, the thickness of the stent body (wall thickness of the tubular portion) is preferably 11 to 2000 μm, more preferably 51 to 500 μm, and particularly preferably 101 to 300 μm. The stent body is preferably in the form of a mesh so as to be able to expand its diameter in a flexible manner. In particular, it is preferably in the form of an oblique lattice as shown in FIG. 2 and the lattice extends in the spiral direction.
[0020]
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, cobalt-chromium-nickel-iron alloy, and the like. The metal stent body is preferably subjected to a heat treatment in order to make the shape memory. By this heat treatment, self-expandability can be imparted to the stent body.
[0021]
As the material used for the flexible polymer layer, a high-polymer elastomer having high flexibility is preferable, and examples thereof include polystyrene, polyolefin, polyester, polyamide, silicone, urethane, fluorine resin, and natural rubber. Various elastomers and their copolymers or their polymer alloys can be used. Among them, a segmented polyurethane, a polyolefin-based polymer, and a silicone-based polymer are preferable. In particular, a segmented polyurethane having high flexibility and high strength is most suitable.
[0022]
The segmented polyurethane polymer has a flexible polyether portion as a soft segment and a portion rich in an aromatic ring and a urethane bond as a hard segment, and the soft segment and the hard segment undergo phase separation to form a microstructure. Is what it is. This segmented polyurethane polymer has excellent antithrombotic properties. Further, the stent has excellent properties such as strength and elongation, and can be sufficiently expanded without breaking even when the stent is expanded in diameter.
[0023]
The coating thickness of the polymer layer such as the segmented polyurethane polymer (FIG. 1 d described later) is preferably 1 μm to 100 μm, particularly preferably 5 μm to 50 μm.
[0024]
The polymer layer is preferably provided with a plurality of micropores. The fine holes may be arranged at random, but preferably, the fine holes are formed at substantially uniform intervals. The fact that the micro holes are formed at substantially uniform intervals does not mean that the intervals are the same, but that the micro holes are arranged at substantially constant intervals in a controlled manner. Therefore, the substantially uniform intervals include oblique, circular, and elliptical arrangements that appear to be arranged randomly at first glance. The micropore may have any size and shape as long as the endothelial cells can enter and exit. Preferably, it is circular with a diameter of 5 to 500 μm, most preferably 10 to 100 μm. It goes without saying that other shapes such as ellipses, squares and rectangles are also included. These are the states before expansion, and when the stent body is expanded and placed in the lumen, the circular shape changes to an oblong shape, and the diameter changes accordingly. Micropores are arranged on a plurality of straight lines at intervals of 51 to 10000 μm, preferably 101 to 8000 μm, more preferably 201 to 5000 μm. The plurality of straight lines are, for example, 10 to 50 straight lines arranged at a predetermined fixed angular interval in the axial direction of the stent.
[0025]
However, the most preferable diameters and arrangement intervals of the micropores are dependent on each other, and the relation is easy to understand when considered as the pore density on the polymer layer. That is, for example, when substantially circular holes are arranged at substantially constant intervals as in the three patterns shown in FIG. 7, the density per unit area naturally depends on the diameter and arrangement interval of the fine holes.
[0026]
FIG. 8 shows the relationship between the pore density and the thickness of the vascular intima formed when the stent is placed in the blood vessel.
[0027]
From FIG. 8, it can be seen that there is a relationship between the preferable diameter of the fine holes and the arrangement interval in the hole density. However, no matter how good the density is, if the pore diameter is too small, endothelial cells will not grow sufficiently inside the stent, and if the pore diameter is too large, the strength of the polymer layer will decrease and the intimal tissue It goes without saying that the intrusion proceeds too much, which is not desirable.
[0028]
The polymer layer may be coated with a biodegradable polymer (bioabsorbable polymer). Examples of such biodegradable polymers include gelatin, polylactic acid, polyglycolic acid, caprolactone, lactic acid-glycolic acid copolymer, polygioxanone, chitin, and the like.
[0029]
The biodegradable polymer may contain a therapeutic agent such as an antiplatelet agent, an antithrombotic agent, a growth promoter, a growth inhibitor, an immunosuppressant, and the like. This therapeutic agent is released into the body as the biodegradable polymer degrades, and suppresses the formation of thrombus, suppresses the growth of smooth muscle cells to prevent stenosis, and reduces the growth of cancerous cells. It is effective for suppressing endothelialization and promoting endothelial cell proliferation to obtain endothelialization at an early stage.
[0030]
Therapeutic agents include heparin, low molecular weight heparin, hirudin, argatroban, formacholine, bapiprost, prostamoline, a prostachyline homolog, dextran, lofepro-argochloromethylketone, depyridamole, a platelet membrane receptor antibody for glycoprotein, Recombinant 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, Drugs such as serotonin blocking antibodies, thioproteinase inhibitors, trimazole pyridimine, interferons, vascular endothelial growth factor (VEGF), rapamycin, FK506 and the like.
[0031]
Further, the polymer layer on the outer peripheral surface side of the stent may be coated on its outer surface with a lubricating substance in order to smoothly move in small blood vessels in the human body. Such lubricating substances include low-molecular-weight hydrophilic substances such as glycerin, biocompatible substances such as hyaluronic acid and gelatin, and synthetic hydrophilic polymers such as polyethylene glycol, polyacrylamide, polydimethylacrylamide, and polyvinylpyrrolidone. No.
[0032]
The stent of the present invention in which the entire outer surface of the stent body is closely covered with a polymer layer can be manufactured by, for example, the following method (1) or (2). The method is not limited to the following methods (1) and (2).
[0033]
(1) A mold having a cylindrical inner hole is rotated around its axis, and a polymer solution is supplied into the mold to form an outer polymer layer. Then, the stent body is placed in the mold. After the supply, the mold is rotated around its axis and a polymer solution is supplied into the mold to form the inner polymer layer, and then the mold is removed from the mold.
[0034]
In this method, first, a preferably cylindrical mold having a cylindrical inner peripheral surface is used, and the mold is rotated around its axis and the polymer solution for the outer polymer layer is poured therein. Feed and centrifuge the outer polymer layer.
[0035]
The polymer solution may be a polymer solution or a polymerizable solution of a monomer or the like. As the polymer solution, for example, a segmented polyurethane polymer solution composed of an organic solvent such as dioxane and tetrahydrofuran can be used. As a polymerizable solution of a monomer or the like, for example, a de-acetone type, a dealcohol type, or a deoxime type condensation-curable silicone rubber can be used.
[0036]
Either the supply of the polymer solution or the rotation of the mold may be performed first, but it is preferable to supply the polymer solution into the rotating mold. In addition, it is preferable that the injection position of the polymer solution is moved along the axial direction of the mold, and the polymer solution is uniformly supplied to a wide area in the mold.
[0037]
After a film of the outer layer polymer solution is formed on the inner peripheral surface of the mold, the stent body is supplied to the inside of the mold, and then a polymer solution for forming the inner polymer layer is supplied into the mold, Centrifuge. Thereafter, after performing a curing treatment such as drying, ultraviolet irradiation, and heat treatment, the stent body is released from the mold, and the stent body is subjected to a perforation treatment.
[0038]
In addition, it is preferable to supply the stent main body into the mold after forming a film of the polymer solution for the outer layer along the inner peripheral surface of the mold, and performing a curing treatment such as drying and ultraviolet irradiation. When supplying the stent body into the mold, the stent body may be supplied as it is into the mold, or may be immersed in a resin material liquid and pre-wetted before being supplied into the mold.
[0039]
When forming the coating layer of the biodegradable polymer on the outer polymer layer, the biodegradable polymer solution is supplied into a mold to form a first layer, and then a polymer solution such as the segmented polyurethane polymer is formed. May be supplied into a mold to centrifugally mold the second layer. Similarly, when forming a biodegradable polymer coating layer on the inner polymer layer, the first layer is centrifugally molded with a polymer solution such as the above-mentioned segmented polyurethane polymer, and then the biodegradable polymer polymer solution is molded. To form the second layer.
[0040]
When forming a coating layer of a biodegradable polymer, a stent body is prepared as described above using a polymer solution for forming a polymer layer such as a segmented polyurethane polymer. The coating layer may be formed by dipping in a polymer solution for use. In this case, after dipping in the biodegradable polymer solution and pulling it up, polymerization can be promoted by ultraviolet rays or the like to form a coating layer.
[0041]
When a therapeutic agent is blended in the biodegradable polymer solution, a coating containing the therapeutic agent is formed. By adjusting the type, molecular weight, coating thickness and the like of the biodegradable polymer, the time and period during which the therapeutic agent is released into the body can be set.
[0042]
As described above, micro holes are formed in the stent body removed from the mold by laser or the like. Either the formation of a coating layer of a biodegradable polymer or a lubricating polymer and the perforation of micropores by laser processing can be performed first, but here the method of perforating micropores by laser processing is described later. Described.
[0043]
(2) After immersing the mandrel in the polymer solution, the mandrel is pulled up vertically to form an inner polymer layer, and then the stent body is mounted so as to be externally fitted to the mandrill having the inner polymer layer. After immersing the mandrill with the stent body in the polymer solution, it is pulled up to form an outer polymer layer, and then the mandrill is pulled out.
[0044]
That is, the mandrill is slowly immersed in a polymer solution so that air bubbles are not entrained, then lifted vertically upward, and if necessary, subjected to a curing treatment such as drying or ultraviolet irradiation to form an inner polymer layer. When the polymer solution is a polymer solution, drying is preferable as a curing treatment, and when the polymer solution is a polymerizable solution of a monomer, ultraviolet irradiation or heat curing is preferable as the curing treatment.
[0045]
Next, the stent body is mounted so as to be externally fitted to the mandrill having the inner polymer layer, and the mandrill equipped with the stent body is slowly immersed in the polymer solution, and then pulled up vertically to raise the outer polymer layer. To form After curing the outer polymer layer, the stent body is manufactured by pulling out the mandrel. In the manufactured stent body, since the inner polymer layer and the outer polymer layer usually protrude longer than both ends of the stent body, the extra protruding polymer layer is cut off.
[0046]
When forming a biodegradable polymer layer, a mandrill is immersed in a biodegradable polymer solution prior to formation of the inner polymer layer or after formation of the outer polymer layer, and a coating treatment is performed in the same manner as described above. Just do it. If a therapeutic agent is blended in the biodegradable polymer solution, a coating containing the therapeutic agent can be formed, and the type, molecular weight, coating thickness, etc. of the biodegradable polymer can be adjusted. By doing so, it is possible to set the timing and the period when the therapeutic agent is released into the body. Also, a lubricating polymer layer can be formed in a similar manner.
[0047]
The micropores of the polymer layer can be provided by laser processing or the like so as to penetrate the inner polymer layer and the outer polymer layer before or after the above-described mandrel is drawn.
[0048]
When the mandrel is pulled out from the formed stent body, the polymer film formed on the surface of the stent is slightly swelled, and is preferably immersed in an organic solvent which swells at a volume expansion rate of 10% or less. It becomes possible to pull it out. Although it depends on the material of the polymer film, for example, when a segmented polyurethane resin is used for the polymer film, the mandrill is treated with a lower alcohol, preferably methanol or ethanol, particularly preferably methanol for preferably 1 to 30 hours, particularly preferably 5 to 30 hours. It is preferable to soak for up to 20 hours. Thereby, the mandrel can be easily pulled out. Although the reason is not necessarily clear, the polymer film slightly swells to weaken the adhesion with the mandrill, and the low-grade liquid which has an affinity for both the metal and the polymer layer and has a low surface tension. This is presumed to be because alcohol enters the interface between the metal mandrill and the inner polymer layer to reduce the adhesive force between the mandrel surface and the polymer layer and at the same time to improve the slidability.
[0049]
In the stent of the present invention thus manufactured, for example, as shown in a cross section in FIG. 1, the entire outer surface of a stent strut 11 constituting a mesh-shaped stent body is covered with a polymer layer 12 in close contact therewith. Thus, the inner peripheral surface A of the stent is a smooth surface made of the polymer layer 12. With such a stent, since there is no exposed surface of the metal stent body, the problems of metal allergy, metal irritation, and rust generation are solved. Further, the occurrence of thrombus is also prevented, and in particular, since the inner peripheral surface is a smooth surface without unevenness, the occurrence of thrombus in the uneven portion is eliminated. Moreover, there is no problem of displacement between the polymer layer and the stent body before and after the expansion of the stent.
[0050]
Note that the above-mentioned coating thickness of the polymer layer indicates a thickness portion of the polymer layer 12 directly covering the stent strut 11 shown in FIG.
[0051]
【Example】
Example 1
As the stent main body, a mesh-shaped stent main body 10 having a diameter of 4 mm, a length of 20 mm, and a thickness of 0.2 mm shown in FIG. 2 was employed.
[0052]
FIG. 3 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 20 mm, and a thickness of 0.2 mm.
[0053]
A stent having the entire outer surface of the metal stent body 10 covered with a segmented polyurethane polymer layer was manufactured. Specifically, a SUS316 mandrill is dipped in a polyurethane solution to coat the polyurethane layer on the inner surface of the cylindrical shape of the mandrel, and a slightly expanded metal stent body is strongly overlapped thereon, and further dipped in the polyurethane solution to form a film. After coating on both sides, and further laser processing, the films at both ends were cut off, immersed in ethanol, and the stent body was extracted from the mandrill.
[0054]
The polyurethane solution is a 10% by weight solution of Capdiomat ™ SPU: Segmented Polyurethane (Kontoron Cardiovascular Inc.) in a mixed solution of tetrahydrofuran and dioxane.
[0055]
Holes having a diameter of 100 μm were formed substantially uniformly at intervals of 200 μm in the formed polyurethane polymer layer using an excimer laser. After drilling one row of holes in the long axis direction, the stent body was rotated by 15 ° in the circumferential direction, and 24 rows of holes were drilled on the entire circumference.
[0056]
FIG. 9 shows an X-ray transmission image of the stent obtained in this way taken with an X-ray microscope system (Model 1072, manufactured by Skyscan), and the coating thickness d was 25 μm. FIG. 9 corresponds to an enlarged view of the IX portion of the stent shown in FIG.
[0057]
As shown in FIG. 1, this stent has a polyurethane polymer layer 12 covering the entire outer surface of a lattice strut 11 of the stent body with good adhesion. It can be seen that the layer follows this, preserving the positional relationship between the polymer layer and the stent. In addition, it can be seen that the protruding ridge structure of the stent strut that obstructs blood flow is smoothed by lamination with the polymer film.
[0058]
Comparative Example 1
By the method described in JP-A-11-299901, a coating of a polyurethane polymer film was provided only on the outer peripheral surface of the stent body, and micropores were formed as in Example 1. FIG. 10 shows an X-ray transmission image of the obtained stent taken in the same manner as in Example 1. As shown in FIG. 6, in this stent, it can be seen that the polymer film is fitted on the outer peripheral surface of the stent body by point (line) contact and fixed only at the contact portion. It is suggested that this contact slide when the stent is expanded.
[0059]
These stents were implanted in the rabbit carotid artery and observed one month later. The results are shown in Table 1 and FIGS. 11 (a), (b) and FIG.
[0060]
FIG. 11A shows Comparative Example 1, and FIG. 11B shows Example 1. The outside of the polymer layer is the old intima, and the inside is the neointima. As is clear from FIG. 11, the intimal thickening of Example 1 (FIG. (B)) is smaller than that of Comparative Example 1 (FIG. (A)). As shown in FIG. 12, in Comparative Example 1, since the stent strut protrudes to the blood flow surface, thrombus formation occurs around the strut, platelet-derived growth factor and the like are released, and intimal hyperplasia tends to occur. On the other hand, in Example 1, since the blood flow surface was a smooth polymer layer surface, thrombus formation was suppressed.
[0061]
[Table 1]

[0062]
Comparative Example 2
A mixed aqueous solution containing 5% of a spirone benzophenone-based photoreactive gelatin, 2.5% of heparin and 0.1% of silver powder was prepared. The stent prepared in Comparative Example 1 was allowed to stand horizontally, and 1 cm was placed on the inner wall of the stent. ² Around 20 μL of the mixed aqueous solution was dropped, and the mixture was uniformly stretched with a PTFE round bar and then irradiated with light to be fixed. This operation was repeated twice. The stent having the inner wall coated in this way was expanded with a balloon catheter in air, and then observed with an X-ray microscope. FIG. 13 shows a photographed X-ray transmission image.
[0063]
From the above, the drug was not applied to the part where the stent strut was present before expansion, and a slip phenomenon occurred between the stent strut and the polymer film due to expansion, and the part where the drug was not applied was exposed on the surface. I understand. Here, the micropores drilled in Comparative Example 1 are such that the stent struts move on the polymer layer as shown by arrow X when the stent body is expanded, and the position of the micropores is determined by the X-ray impermeable stent. As a result of moving to the back side of the strut, it was not observed in the X-ray transmission image of FIG. That is, the micropore is closed. Thus, varying the strictly designed hole diameter and spacing with the expansion of the stent body can also change the hole density and cause intimal thickening problems, as shown in FIG. It has been suggested.
[0064]
【The invention's effect】
According to the stent of the present invention, since the polymer layer is in close contact with and covers the entire outer surface of the stent body, it is possible to provide the stent with excellent biocompatibility, such as metal allergy and thrombotic action. Adverse effects on the human body tissue can be prevented. In addition, there is no problem of displacement between the stent body and the polymer layer when the stent is expanded.
[Brief description of the drawings]
FIG. 1 is a schematic cross-sectional view showing a state where a stent of the present invention is covered with a polymer layer.
FIG. 2 is a perspective view of a stent body.
FIG. 3 is a perspective view of an expanded stent body.
FIG. 4 is a perspective view of a stent.
FIG. 5 is a perspective view of an expanded stent.
FIG. 6 is a schematic cross-sectional view showing a state in which a stent of Japanese Patent Application Laid-Open No. H11-299901 is covered with a polymer film.
FIG. 7 is an explanatory diagram showing a pattern of micropores in a polymer layer, and the relationship between the diameter and arrangement interval of the micropores and the pore density.
FIG. 8 is a graph showing the relationship between the pore density of a polymer layer and the thickness of the intimal lining formed when a stent is placed in a blood vessel.
FIG. 9 is an X-ray transmission image of the stent of Example 1.
FIG. 10 is an X-ray transmission image of the stent of Comparative Example 1.
FIG. 11 is a micrograph of a stent one month after implantation.
FIG. 12 is a micrograph of a cross section of a living tissue in which a stent is implanted.
FIG. 13 is an X-ray transmission image of a stent which is expanded after coating the inner wall of the stent of Comparative Example 2.
[Explanation of symbols]
10 Stent body
11 Stent strut
12 polymer layer
19 Polymer film
20 stents

Claims (14)

A stent having an expandable tubular stent body and a flexible polymer layer covering the stent body,
The stent wherein the polymer layer is in intimate contact with and covers the entire outer surface of the stent body. 2. The stent according to claim 1, wherein the main stent body is made of a mesh-shaped metal member. 3. The stent according to claim 2, wherein the mesh-like metal member is made of a cobalt-chromium-nickel-iron alloy. 3. The stent according to claim 2, wherein the mesh-like metal member is made of a nickel-titanium alloy. The stent according to any one of claims 1 to 4, wherein a plurality of micropores are formed in the polymer layer. 6. The stent of claim 5, wherein said micropores are arranged at substantially uniform intervals. The stent according to claim 5, wherein the micropores are provided at intervals of 51 to 10000 μm and have a diameter of 5 to 500 μm. The stent according to any one of claims 1 to 7, wherein the polymer layer is made of segmented polyurethane. The stent according to any one of claims 1 to 7, wherein the polymer layer is made of a polyolefin-based polymer. The stent according to any one of claims 1 to 7, wherein the polymer layer is made of a silicone-based polymer film. The stent according to any one of claims 1 to 10, wherein a coating thickness of the polymer layer is 10 to 100 µm. The stent according to any one of claims 1 to 11, wherein the polymer layer is further coated with a biodegradable polymer. 13. The stent of claim 12, wherein the bioerodible polymer contains a drug. The drug is heparin, low molecular weight heparin, hirudin, argatroban, formacholine, bapiprost, prostamoline, a prostakyrin homolog, dextran, lofepro-argochloromethyl ketone, depyridamole, a glycoprotein protein platelet membrane receptor antibody, recombinant 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, serotonin inhibition Characterized by being selected from the group consisting of an antibody, a thioproteinase inhibitor, trimazole pyridimine, interferon, vascular endothelial growth factor (VEGF), rapamycin, and FK506. The stent of claim 12,.

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