Stent for intravascular retention

Abstract

The present application provides a stent for intravascular placement that can balance the blood flow preservation of a branch vessel and the embolism of a tumor mouth. The stent for intravascular placement has a tubular strut (11) that can be expanded in diameter, and a polymer film (21) that covers the entire strut (11). A plurality of through-holes (22) are formed in the polymer film (21), the through-holes (22) communicate the inside of the cylinder of the stent for intravascular placement with the outside of the cylinder, the opening size is 0.02 mm or more but 0.2 mm or less, the opening occupancy rate is 25% or more but 41% or less, and the division surface density is 9.5 / mm or more but 30 / mm or less.

Description

Technical Field

[0001] This invention relates to intravascular stents placed in blood vessels. Background Technology

[0002] In the surgical treatment of aneurysms caused by localized fragility of the blood vessel wall, the use of endovascular stents has been investigated. In this procedure, an endovascular stent is placed at the site of the aneurysm to embolize the thrombus at the aneurysm opening. This embolization prevents blood from flowing into the aneurysm, causing thrombus formation within the aneurysm. Unlike treatments that replace the blood vessel with an artificial vessel or clamp the neck of the aneurysm, endovascular stent treatment does not require large incisions such as laparotomy or craniotomy.

[0003] Endothelial cells, which release vasoactive substances to regulate vascular tone and blood clotting, form the vascular endothelium in vessels with indwelling stents. The endothelium produces various antithrombotic substances, including thrombomodulin, heparin-like substances, prostacyclin, nitric oxide, and tissue plasminogen activator. Indwelling stents with the entire surface of the stent encapsulated in a polymer membrane also inhibit thrombus formation caused by metal stents by making the inner circumferential surface of the stent smooth.

[0004] Intravascular stents coated with polymer membranes can also inhibit intimal thickening caused by platelets in thrombi. The fine perforations formed in the polymer membrane facilitate the invasion of endothelial cells into the medial aspect of the intravascular stent. Endothelial cell invasion accelerates intimalization of the intravascular stent and further inhibits neointimal thickening. As an example, the perforations formed in the polymer membrane are arranged in a straight line with a diameter of 100 μm and spacing of 200 μm. The rows of perforations arranged in a straight line are evenly distributed circumferentially around a stent with a diameter of 8 mm at a central angle of 15° (see, for example, Patent Documents 1 and 2).

[0005] As is common with aneurysms arising at the branches of the internal carotid artery and posterior communicating artery, it is not uncommon for branch vessels to branch off from the aneurysm body. Intravascular stents with perforations formed in polymer membranes can inhibit neointimal thickening, embolize the aneurysm orifice within the aneurysm, and even embolize the branching points of the branch vessels. Patent Document 3 describes an intravascular stent with a configuration that, for the purpose of embolizing the aneurysm orifice and ensuring blood flow in the branch vessels, has an opening occupancy rate of 20% to 50% for the purpose of embolizing the aneurysm orifice and ensuring blood flow in the branch vessels (see, for example, Patent Document 3).

[0006] Existing technical documents

[0007] Patent documents

[0008] Patent Document 1: Japanese Patent Application Publication No. 2004-261567

[0009] Patent Document 2: Japanese Patent Application Publication No. 2004-313322

[0010] Patent Document 3: Japanese Patent Application Publication No. 2012-55649 Summary of the Invention

[0011] The problem that the invention aims to solve

[0012] On the one hand, the range of opening occupancy disclosed in Patent Document 3 is determined based on fluid analysis using a vascular model. For example, when the opening occupancy of the fine through-holes is large, blood flowing into the aneurysm from downstream of the aneurysm swirls upstream along the inner wall of the aneurysm and flows out upstream of the aneurysm opening. Conversely, when the opening occupancy of the through-holes is small, blood flowing into the aneurysm from upstream of the aneurysm swirls downstream along the inner wall of the aneurysm and flows out downstream of the aneurysm opening. Based on the analysis results of these reversals in blood flow patterns within the aneurysm, an opening occupancy of 25% to 50% is determined as the range in which blood flow within the aneurysm essentially stops.

[0013] On the other hand, intravascular stents used in arterial therapy are recognized as foreign bodies by biological tissue materials such as vascular endothelial cells. To prevent these foreign bodies from being recognized within the blood vessel, intimalization is achieved by covering them with connective tissue generated by vascular endothelial cells. In the analysis of the working fluid using a vascular model, intimalization was not considered; factors such as (i) intimalization at the aneurysm orifice and (ii) intimalization at the branch orifices were not taken into account. As a result, there is still room for improvement in using intravascular stents for the surgical treatment of aneurysms, particularly in achieving a state where blood flow into the branch vessels is ensured and there is virtually no blood flow within the aneurysm.

[0014] Furthermore, as explained in the above discussion of endometrialization, a larger opening in the perforation facilitates the intrusion of biological tissue material, which is conducive to endometrialization, into the medial side of the indwelling stent. Factors contributing to endometrialization include not only (iii) the ease of passage of biological tissue material through the opening of the perforation, but also (iv) the ease with which the biological tissue material generates its self-defense function. While the ease of passage of biological tissue material, as a primary factor in endometrialization, is taken into consideration when determining the opening occupancy rate of the perforation per unit area, it cannot be said that it also reflects the ease with which (iv) the self-defense function is generated.

[0015] The purpose of this invention is to provide an intravascular stent that can balance the preservation of blood flow in branch vessels and the embolization of the aneurysm site.

[0016] Methods for solving problems

[0017] The intravascular stent for solving the above-mentioned problems is an intravascular stent placed within a blood vessel. The intravascular stent comprises a tubular stent body capable of expansion and a polymer membrane covering the stent body. The polymer membrane has a plurality of through holes with opening sizes of 0.02 mm to 0.2 mm, communicating between the inside and outside of the tube of the intravascular stent. The proportion of the opening area of ​​all the through holes per unit area of ​​the outer surface of the polymer membrane is called the opening occupancy rate. The proportion of the length of the opening edges of all the through holes per unit area of ​​the outer surface of the polymer membrane is called the areal density. Furthermore, the opening occupancy rate is 25% to 41%, and the areal density is 9.5 / mm to 30 / mm.

[0018] The inventors of this invention have conducted in-depth research on the process of intravascular stents being covered by biomaterials. During this process, they discovered that the formation of connective tissue covering the intravascular stent begins at the opening edge of the perforation. Specifically, they discovered that the foreign body recognition and encapsulation reaction, caused by the contact between the biomaterial and the artificial material, occurs from the opening edge of the perforation. In other words, they discovered that collagen production begins at the opening edge of the perforation, and the connective tissue extends from the opening edge towards the surface of the polymer membrane. Furthermore, they discovered that the connective tissue forming from the opening edge of the perforation grows to the surface of the polymer membrane surrounding and defining the perforation, thereby endomembraneating the polymer membrane and forming a neointima.

[0019] (A) In the aforementioned endometrialization process, the length of the opening edge of the perforation and the areal density obtained by standardizing the length of the opening edge of the perforation per unit area represent the width of the part where endometrialization begins per unit area, i.e., the width of the starting point. In other words, the areal density functions as an indicator of the ease with which (iv) the self-defense function of biological tissue materials is generated, and also functions as an indicator of the ease with which (i) endometrialization is carried out at the tumor opening and (ii) the endometrialization is carried out at the branch opening.

[0020] (B) The area occupied by the openings of the perforations during the aforementioned endometrialization process, and the opening occupancy rate obtained by standardizing the opening area of ​​the perforations per unit area, are indicators of the area that connective tissue must cover before endometrialization is completed with the polymer membrane. In other words, the opening occupancy rate functions as an indicator of the surface area of ​​the endometrialized object, i.e., the polymer membrane, and also as an indicator of the ease with which biological tissue material passes through the openings of the perforations (iii).

[0021] (C) In the polymer membrane constituting the outer surface of an intravascular stent, the portion directly in contact with the vascular intima and the portion near the vascular intima located at the aneurysm opening where blood flow is obstructed are areas where cells and other components of the biological tissue material are prone to movement, and are therefore more likely to undergo endometrialization. On the other hand, the portion of the polymer membrane located at the branch opening where blood flow is continuous is an area where cells of the biological tissue material are less likely to adhere, and is therefore less likely to undergo endometrialization.

[0022] While increasing the orifice occupancy rate to facilitate blood flow is effective in achieving both non-closure of branch vessels and intimalization at those locations, this alone is insufficient. Intimalization of the polymer membrane is required even under conditions of continuous blood flow. Specifically, the areal density must be determined according to the aforementioned technical viewpoints (A) to (C) to promote collagen production even in environments where cells contained in biological tissue materials do not readily adhere to the surface of the artificial material. In this regard, the aforementioned intravascular stent, with an orifice occupancy rate of 25% or higher and an areal density of 9.5 / mm or higher, facilitates both non-closure of branch vessels and intimalization at those locations.

[0023] In achieving both aneurysm embolization and intimalization at the site, reducing the occlusion rate to impede blood flow is effective, but further preventing the closure of branch vessels is excessive. Ideally, aneurysm embolization should be achieved after intimalization of the polymer membrane. Specifically, the areal density should be determined according to the aforementioned technical viewpoints (A) to (C) to ensure that, in an environment where cells contained in the biological tissue material can easily move to the surface of the artificial material, the perforation is embolized after intimalization. Regarding this, according to the aforementioned intravascular stent, since the occlusion rate is 41% or less and the areal density is 9.5 / mm or more and 30 / mm or less, it is easy to preserve blood flow in branch vessels while simultaneously achieving embolization of the aneurysm ostium.

[0024] Thus, the above-mentioned intravascular stent, with an opening size of 0.02 mm to 0.2 mm, an opening occupancy rate of 25% to 41%, and a division area density of 9.5 / mm to 30 / mm, can improve the blood flow preservation of branch vessels and the embolization of the aneurysm orifice.

[0025] Preferably, in the above-mentioned intravascular stent, the plurality of through holes include through holes with different opening sizes.

[0026] Intravascular stents require both strength to support the vessel wall and flexibility to adapt to the vessel's curvature. Furthermore, they require stress to push the vessel wall outwards with uniform pressure. Thus, limiting the orifice occupancy and areal density within specific ranges in intravascular stents, which demand various mechanical properties, significantly restricts structural freedom. On the other hand, if, as in the aforementioned intravascular stents, a configuration includes multiple through-holes with varying opening sizes, smaller opening sizes can be used in areas requiring vessel wall strength, while larger opening sizes can be used in areas requiring flexibility. Moreover, since the opening sizes of each through-hole in an intravascular stent that allows for diameter reduction change to various sizes after diameter expansion, this aspect also increases design freedom in intravascular stents.

[0027] Preferably, in the above-mentioned intravascular stent, the thickness of the polymer membrane is more than 1 μm and less than 100 μm.

[0028] Based on the aforementioned intravascular stent, the surface area of ​​the polymer membrane, which is the target for intimalization, is further specifically defined due to the specific thickness of the polymer membrane. This improves the preservation of blood flow in branch vessels and the embolization of the aneurysm site, thereby enhancing the effectiveness of the aforementioned effects. Furthermore, if the polymer membrane thickness is 1 μm or more, membrane breakage can be suppressed during membrane formation, reducing the time required for membrane formation. Moreover, if the polymer membrane thickness is 100 μm or less, the depth of the perforation, i.e., the migration distance of cells contained in the biological tissue material, can be suppressed, facilitating the formation of connective tissue necessary for intimalization of the intravascular stent on its inner side.

[0029] Preferably, in the above-mentioned intravascular stent, the stent body is constructed in such a way that the annular filaments are arranged along the extension direction of the intravascular stent, the annular filaments are repeatedly bent in a corrugated manner along the circumference of the intravascular stent, and the through holes are arranged in such a way that they fill the gaps between the adjacent annular filaments.

[0030] According to the above-described endovascular stent, the opening edges of the perforations, which serve as the starting point for intimalization, can be arranged approximately uniformly throughout the stent body. As a result, it is also possible to suppress variations in the progression of intimalization that may arise due to the misalignment of the perforations. This improves blood flow preservation in branch vessels and embolization at the aneurysm orifice, and these effects also suppress deviations caused by the placement of the endovascular stent within the vessel.

[0031] Preferably, in the above-mentioned intravascular stent, the opening size of the through hole is 0.06 mm or more and 0.12 mm or less, the opening occupancy rate is 30% or more and 35% or less, and the surface density is 14 / mm or more and 20 / mm or less.

[0032] The aforementioned intravascular stent placement can improve the preservation of blood flow in branch vessels and the embolization of the aneurysm orifice, and also enhance the effectiveness of such effects.

[0033] The effects of the invention

[0034] The intravascular stent of the present invention can improve the preservation of blood flow in branch vessels and the embolization of the aneurysm orifice. Attached Figure Description

[0035] Figure 1 This is a side view showing the side structure of the catheter during installation in an intravascular stent.

[0036] Figure 2 This is a side view showing the enlarged lateral structure of an intravascular stent.

[0037] Figure 3 It is a magnified side view of a portion of an intravascular stent after it has been enlarged.

[0038] Figure 4 This is a schematic diagram illustrating the formation process of connective tissue in pores formed in artificial materials.

[0039] Figure 5 This is a schematic diagram illustrating the formation process of connective tissue in macropores formed in artificial materials.

[0040] Figure 6 This is a schematic diagram illustrating the formation process of connective tissue in the macropores located at the apex of the nodule.

[0041] Figure 7 This is a schematic diagram illustrating the formation process of connective tissue in the small opening at the apex of the tumor.

[0042] Figure 8 This is a schematic diagram illustrating the formation process of connective tissue in the small openings of branching blood vessels.

[0043] Figure 9 This is a top view used to illustrate the definition of the density of the dividing surface.

[0044] Figure 10 This is a schematic diagram showing the state in which collagen is generated at the opening edge of the through-hole.

[0045] Figure 11 This is a cross-sectional view showing the cross-sectional structure of the connective tissue testing apparatus used in the test example.

[0046] Figure 12 This is a top view showing an example of a through hole used in the test case.

[0047] Figure 13 It is a graph showing the relationship between the state of connective tissue and the opening occupancy and the density of the dividing surface. Detailed Implementation

[0048] Reference Figures 1 to 13 One embodiment of an intravascular stent is described. Figure 1 This is a side view showing an intravascular stent before dilation. Figure 2 This is a side view showing an intravascular stent placed after being installed in a catheter. Figure 3 It is a side view obtained by magnifying a portion of the side of the indwelling stent after dilation.

[0049] [Intravascular stent placement]

[0050] Intravascular stents are used, for example, in cerebral vessels and large arteries as covered stents. Intravascular stents are configured to cover the opening of an aneurysm that has formed within the artery, and are used to thrombotic the aneurysm.

[0051] like Figure 1 As shown, the intravascular stent includes a strut 11, which is a cylindrical stent body that can be expanded within an artery, and a cylindrical polymer membrane 21 held in place by the strut 11.

[0052] The support column 11 is a structure made of metal with a mesh-like structure capable of diameter expansion. The length of the support column 11 in the extending direction before diameter expansion is, for example, 10 mm to 300 mm. The diameter of the support column 11 before diameter expansion is, for example, 0.3 mm or more. After diameter expansion, the diameter of the support column 11 is expanded to approximately 2 to 5 times its original size. The radial thickness of the support column 11 is 20 μm to 500 μm.

[0053] The structure of the support column 11 is a shape formed by repeatedly bending (bending) zigzag-shaped loops of wire along its circumference, connected to each other by chains. That is, the support column 11 has a structure comprising unit structures 13 arranged circumferentially along its length (see reference). Figure 3 ), and the link 12 that connects one of the adjacent unit structures 13 to the other along the extension direction of the pillar 11 (see reference). Figure 2 The shape of the link support. The number of links is, for example, more than 2 and less than 24 in the circumference of the support 11.

[0054] The repeating unit structures 13, excluding the links, in the structure of the pillar 11 are hexagonal and arranged along the circumference and extension direction of the pillar 11. In the extension direction of the pillar 11, one of the adjacent unit structures 13 is connected to the other at the vertices of the hexagon via links.

[0055] Furthermore, the structure of the support column 11 can have the following shape: zigzag loop filaments that are repeatedly corrugated or bent along the circumference of the support column 11 are arranged in the extending direction of the support column 11 and connected to each other by laser welding or spraying. That is, the structure of the support column 11 does not include chains and can be a form in which the loop filaments are supported by a polymer film 21.

[0056] Furthermore, the structure of the support 11 can be a coil type obtained by processing the annular filament into a coil shape. The coil type has low bending stiffness in the extension direction of the support 11, and excellent conformity to the shape of the bend in the blood vessel.

[0057] Furthermore, the structure of the support column 11 can be a tubular shape obtained by laser processing of a metal tube. The tubular shape has higher radial rigidity than the coil shape, which is superior in supporting the blood vessel wall. In addition, the structure of the support column 11 can also include a component that extends through the interior of the support column 11 along its extension direction.

[0058] The metallic materials constituting the strut 11 are, for example, biocompatible stainless steel, titanium, tantalum, aluminum, tungsten, nickel-titanium alloys, cobalt-chromium alloys, platinum-chromium alloys, and cobalt-chromium-nickel-iron alloys. The metallic materials constituting the strut 11 are the same materials used for balloon dilation of indwelling stents for intravascular placement. Biocompatible metallic materials are those that do not degrade or disappear within the body and do not cause allergic or inflammatory reactions.

[0059] Furthermore, the metal material constituting the strut 11 can be a shape memory material that has been heat-treated to have self-expanding properties for use as an intravascular stent. Alternatively, the strut 11 can be a laminated structure consisting of a core layer located at the center of the cross-section of the strut 11 and a covering layer that covers the entire outer surface of the core. In this case, the core layer and the covering layer are made of different metal materials, and the covering layer is formed by spraying metal particles onto the core layer, or by other methods.

[0060] The polymer membrane 21 covers the entire support 11, including both the inner and outer sides of the support 11. The polymer membrane 21 covering the outer side of the support 11 facilitates the movement of the intravascular stent within the blood vessel. Furthermore, to further facilitate the movement of the intravascular stent, the polymer membrane 21 covering the outer side of the support 11 can be coated with a lubricating substance. Such lubricating substances include, for example, hydrophilic low-molecular-weight substances like glycerin, biocompatible substances like hyaluronic acid or gelatin, and lipid components present in biological organisms.

[0061] The thickness of the polymer membrane 21 is, for example, 1 μm to 100 μm. When the thickness of the polymer membrane 21 is 1 μm or more, the breakage of the polymer membrane during its formation can be suppressed, thereby reducing the time required for its formation. When the thickness of the polymer membrane 21 is 100 μm or less, the migration distance of cells contained in the biological tissue material can be suppressed, thereby facilitating the formation of connective tissue required for the intimalization of the endovascular stent on the inner side of the stent.

[0062] The material constituting the polymer membrane 21 is a biocompatible and flexible polymeric elastomer that follows the expansion of the support column 11. Examples of polymeric elastomers include urethane polymers, polyolefin polymers, polystyrene polymers, polyester polymers, polyamide polymers, silicone polymers, fluoropolymers, natural rubber polymers, and copolymers or polymer alloys thereof.

[0063] The material constituting the polymer membrane 21 is, for example, a segmented urethane polymer. The segmented urethane polymer comprises a soft polyether segment as a soft segment and a segment containing aromatic rings and urethane bonds as a hard segment, exhibiting a fine structure in which the soft and hard segments are phase-separated. Compared to other materials, segmented urethane polymers can impart excellent antithrombotic properties, as well as high strength and elongation to the polymer membrane 21.

[0064] The polymer membrane 21 can have a single-layer structure or a multilayer structure. The surface of the polymer membrane 21 can be covered, for example, with a biodegradable polymer that degrades in vivo and whose decomposition products do not exhibit toxicity. Examples of biodegradable polymers include polylactic acid, polyglycolic acid, poly(p-dioxanone), and poly(β-hydroxybutyric acid). The polymer membrane 21 with a biodegradable polymer on its surface can facilitate early recovery of vascular tissue from chronic inflammation induced by the polymer membrane 21.

[0065] like Figure 2 , Figure 3 As shown, a large number of through holes 22 are formed in the polymer membrane 21 to communicate between the inner and outer sides of the intravascular stent. The through holes 22 formed in the polymer membrane 21 are, for example, generally hexagonal in shape. The through holes 22 formed in the polymer membrane 21 are located in the gaps defined by the unit structure 13 of the strut 11, and are arranged to fill the gaps between adjacent annular filaments in the extending direction of the intravascular stent. That is, the polymer membrane 21 prevents the strut 11 from being exposed to the outside, and ensures that the inside and outside of the intravascular stent are substantially uniformly connected throughout the entire intravascular stent.

[0066] The opening shape of the through hole 22 can also be changed to an irregular shape other than a circle, ellipse, triangle, quadrilateral, or pentagon. The location of the through hole 22 can be, for example, a grid point on a rhombic lattice, hexagonal lattice, square lattice, rectangular lattice, parallelogram lattice, or other geometric lattices. The opening size of the through hole 22 is the diameter of the largest circle inscribed in the opening by two or more points.

[0067] Furthermore, when the support 11 is a coil type or has a chain structure, the through hole 22 formed in the polymer membrane 21 prevents the support 11 from being exposed to the outside and allows communication between the inside and outside of the stent in the intravascular placement. That is, the through hole 22 formed in the polymer membrane 21 is located between the gaps of adjacent annular filaments in the extension direction of the support 11, or is a gap defined by adjacent annular filaments and chains in the extension direction of the support 11.

[0068] The polymer membrane 21 may also contain a drug soluble in the blood within a range sufficient to maintain the size of the perforation 22. The drug contained in the polymer membrane 21 may include, for example, a drug that promotes the embolization of aneurysms, a drug that promotes the organic transformation of aneurysms, a drug that prevents delayed stent thrombosis, or an immunosuppressant. Other examples of drugs contained in the polymer membrane 21 may include heparin derivatives, antithrombin drugs, platelet membrane receptor antibodies, recombinant hirudin, angiotensin-converting enzyme inhibitors, vascular endothelial growth factor, fibroblast growth factor antagonists, steroids, serotonin inhibitors, and histamine.

[0069] In a method for manufacturing an intravascular stent, for example, a cylindrical mandrel is immersed in a solution of a polymer used to form a polymer membrane 21, and a polymer membrane is formed on the outer peripheral surface of the mandrel. This forms an inner membrane covering the inner side of the strut 11 within the polymer membrane 21. Next, the strut 11 is brought into close contact with the outer side of the inner membrane formed on the outer peripheral surface of the mandrel, thereby attaching the inner membrane to the inner side of the strut 11.

[0070] Next, the mandrel, which has an inner membrane and a support body, is immersed again in a polymer solution for forming the polymer membrane 21, and a polymer membrane is formed on the outside of the support 11 in a manner that integrates with the inner membrane. Thus, a polymer membrane 21 covering the entire support 11 is formed.

[0071] Next, the polymer membrane 21 covering the inner and outer sides of the support 11 and the support 11 are pulled out from the mandrel, and a through hole 22 is formed in the polymer membrane 21 covering the support 11 by laser processing. Thus, the entire support 11 is covered by the polymer membrane 21 with the through hole 22, and an intravascular stent is manufactured.

[0072] Alternatively, laser processing can be performed before the stent is removed from the mandrel. In this case, the polymer membrane 21 and the strut 11 are removed from the mandrel after laser processing, thereby creating an intravascular stent.

[0073] In stent delivery methods using intravascular stents, for example, the intravascular stent is reduced in diameter from its initial shape and inserted into the lumen of a blood vessel using a catheter. When the intravascular stent is balloon-type, its diameter is increased by using a balloon, causing the stent to press against the inner circumferential surface of the blood vessel. Then, by removing the delivery catheter from the intravascular stent, the increased-diameter stent remains in the lumen of the blood vessel. When the intravascular stent is self-expanding, its diameter automatically increases when released from the delivery catheter.

[0074] Furthermore, the expanded shape of the intravascular stent can be either the initial shape or a different shape. If the expanded shape is the same as the initial shape, the expanded shape can be stabilized within the lumen, and strain or residual stress in the expanded shape can be suppressed.

[0075] Alternatively, the polymer film 21 can be configured to be located only on the inside of the support column 11 or only on the outside of the support column 11. Furthermore, the polymer film 21 can also be manufactured by rolling it onto or around the support column 11.

[0076] Alternatively, the through-hole 22 formed in the polymer membrane 21 can be modified so that a portion of the support 11 is exposed to the outside. In this case, in the portion of the polymer membrane located in the blood vessel wall, the through-hole 22 exposes a portion of the support 11.

[0077] [Through Hole 22]

[0078] Next refer to Figures 4 to 12 The structure of the perforation 22 will be explained. First, the environmental conditions around the artificial material such as the intravascular stent after it is placed in the blood vessel will be explained. Then, the factors contributing to intimalization by the perforation 22 will be explained. Finally, the various conditions satisfied by the perforation 22 will be explained.

[0079] and, Figure 4 An example of an intravascular stent with a few through holes 22 of small opening size is shown, namely (A) an intravascular stent with a few small holes is placed in a blood vessel.

[0080] Figure 5 , Figure 6 An example of (B) a macroporous intravascular stent placed in a blood vessel is shown. This macroporous intravascular stent is either an intravascular stent with a plurality of large-sized through holes 22 or an intravascular stent with a few large-sized through holes 22.

[0081] Figure 7 , Figure 8 An example of (C) a multi-hole type intravascular stent placed in a blood vessel is shown. The multi-hole type intravascular stent is an intravascular stent with a multi-hole type of small-sized through-hole 22.

[0082] Typically, if an artificial material is left in a blood vessel, platelets and other blood cells immediately adhere to or aggregate on the surface of the artificial material, forming a thrombus. To inhibit thrombus formation caused by the artificial material's presence in the blood vessel, anticoagulants such as heparin and antiplatelet drugs, which prevent blood clotting caused by thrombin, are usually used when the artificial material is left in place. The administration period of these anticoagulants and antiplatelet drugs is longer than the period required for the artificial material to undergo intimalization within the blood vessel. This period may be six months to one year if the surface area of ​​the artificial material is small, and even longer, possibly lifelong, if the surface area of ​​the artificial material is large.

[0083] like Figure 4 As shown, if an intravascular stent is placed in the blood vessel, it helps the endometrial cells move from the intima 31 of the blood vessel through the perforation 22 to the surface of the polymer membrane 21. This helps the endometrial cells form connective tissue on the inner surface of the perforation 22 in the polymer membrane 21 and on the surface exposed in the blood vessel, thus ending the endometrialization process.

[0084] (A) A few small-hole intravascular stents

[0085] The larger the surface area of ​​the polymer membrane 21, the longer the period during which the connective tissue 32 covers the polymer membrane 21, i.e., the longer the period until the end of endometrialization. In addition, the longer the period until the end of endometrialization, the more slowly the opening of the through-hole 22 is blocked by the connective tissue. Therefore, even after the endometrialization of the inner surface of the through-hole 22 is completed, there are still parts on the surface of the polymer membrane 21 that are not covered by connective tissue.

[0086] That is, needless to say, even if the perforation 22 is completely blocked by the connective tissue 32, if the surface of the polymer membrane 21 is too wide, there will still be areas on the inner surface of the blood vessel within the polymer membrane 21 that are not covered by the connective tissue 32, and blood can easily adhere to these areas. As a result, it becomes necessary to administer anticoagulants or antiplatelet drugs continuously for a long period to prevent thrombus 33 formation on the surface of the polymer membrane 21. Consequently, in some small-pore type intravascular stents, the administration period for anticoagulants and antiplatelet drugs becomes longer due to the excessively wide surface of the polymer membrane 21.

[0087] (B) Macropore type intravascular stent

[0088] like Figure 5As shown, the larger the opening size of the perforation 22, the shorter the period during which the connective tissue 32 covers the polymer membrane 21, i.e., the period until endembraneation is completed. Furthermore, even if the opening of the perforation 22 is slowly blocked by the connective tissue 32, when the endembraneation of the inner surface of the perforation 22 is completed, the surface of the polymer membrane 21 is also completely covered by the connective tissue 32, and the endembraneation of the entire intravascular stent is completed.

[0089] The more numerous the perforations 22 of an intravascular stent, i.e., the smaller the surface area of ​​the polymer membrane 21, the higher the accuracy of the tendency for good intimalization. However, even if the perforations 22 are few, the same applies to macroporous intravascular stents. As a result, macroporous intravascular stents can accelerate the intimalization of the polymer membrane 21 and further inhibit neointimal thickening. Furthermore, macroporous intravascular stents can inhibit long-term continuous administration of anticoagulants or antiplatelet drugs.

[0090] Among them, such as Figure 6 As shown, when a macroporous endovascular stent is placed at the ostium of aneurysm 34, the opening of the perforation 22 remains open even after the endonucleation of the polymer membrane 21 is complete, resulting in insufficient embolization at the ostium. Consequently, although macroporous endovascular stents can accelerate endonucleation, the excessively large opening size of the perforation 22 makes it difficult to achieve embolization at the ostium.

[0091] (C) Most small-hole intravascular stents

[0092] like Figure 7 As shown, if it is a multi-pore type intravascular stent, then although the opening size of the perforation 22 is small, similar to (A) a few-pore type intravascular stent, the area of ​​the surface to be covered by connective tissue 32 is also reduced by a corresponding amount corresponding to the increase in the number of perforations 22. Moreover, it can accelerate intimalization in the same way as (B) a macropore type intravascular stent. In addition, as the opening of the perforation 22 is slowly blocked by the connective tissue 32, and the intimalization of the inner circumferential surface of the perforation 22 is completed, the entire surface of the polymer membrane 21 is covered by connective tissue 32.

[0093] The results show that, with multi-pore endovascular stents, the intimalization of the polymer membrane 21 is accelerated, similar to that of macroporous endovascular stents, while further inhibiting neointimal thickening and suppressing long-term continuous administration of anticoagulants or antiplatelet drugs. Furthermore, after the intimalization of the polymer membrane 21 is complete, a portion of the perforation 22 is blocked by connective tissue 32 to the point of obstructing blood flow within the aneurysm, thus embolizing the aneurysm orifice. Therefore, multi-pore endovascular stents can accelerate intimalization while simultaneously achieving embolization of the aneurysm orifice.

[0094] On the other hand, such as Figure 8 As shown, cases where aneurysms arise from the branches of the internal carotid artery and the posterior communicating artery, as described above, often involve branch vessels 35 branching from the aneurysm body 34. Even in the case of numerous small-hole endovascular stents that achieve embolization of the aneurysm orifice while accelerating intimalization, it is further required that the branch orifice of the branch vessel 35 not be embolized. That is, the configuration of the through-hole 22 is required to achieve both accelerated intimalization and embolization of the aneurysm orifice, while also preserving blood flow in the branch vessel 35.

[0095] (D) Opening occupancy rate

[0096] As described above, the area of ​​the openings per unit area, i.e., the opening occupancy rate, is an indicator of the size of the area that connective tissue must cover before endometrialization is complete. In other words, the opening occupancy rate of the through-hole 22 functions as an indicator of the size of the surface area of ​​the endometrialized object, i.e., the polymer membrane 21, and also as an indicator of the ease with which biological tissue material can pass through the openings of (iii) the through-hole 22.

[0097] Among these, the reactions directly involving intravascular stents made of artificial materials and biological tissue materials are important in the initial stage when biological tissue materials recognize the intravascular stents as foreign bodies. After the intravascular stent comes into contact with biological tissue materials, the initial reactions include protein adsorption, adsorption displacement, and cell attachment, but are not determined solely by the ease of passage of proteins or cells.

[0098] That is, the opening occupancy rate does not significantly contribute to (iv) the ease with which the self-defense function of the biological tissue material is generated. Therefore, in a configuration of the through-hole 22 determined solely by the ease with which the biological tissue material passes through it—in other words, in a configuration of the through-hole 22 determined solely by the opening occupancy rate—a significant deviation may occur between the passage of the tumor opening after placement and its intended passage. Similarly, a significant deviation may also occur between the passage of the branch opening after placement and its intended passage.

[0099] Furthermore, there are significant differences in the time required for cells to migrate to the surface of the artificial material between the aneurysm opening where blood flow is easily obstructed and the branch opening of the branch vessel 35 where blood flow is continuous. In the configuration of the perforation 22 determined based on considering (i) endometrialization factors of the aneurysm opening and (ii) endometrialization factors of the branch opening to the same degree, a significant deviation may further occur between the actual passage of the aneurysm opening after placement and its intended passage. Similarly, a significant deviation may further occur between the actual passage of the branch opening after placement and its intended passage.

[0100] (E) Division of surface density

[0101] In their in-depth research on the process of covering intravascular stents with biomaterials, the inventors discovered that the formation of connective tissue covering the intravascular stent begins at the opening edge of the perforation 22. That is, it was found that the foreign body recognition reaction and encapsulation reaction caused by the contact between the biomaterial and the artificial material proceed from the opening edge of the perforation 22. In other words, it was found that collagen production begins at the opening edge of the perforation 22, and the connective tissue extends from the opening edge of the perforation 22 towards the surface of the polymer membrane. Furthermore, it was found that the connective tissue forming from the opening edge of the perforation 22 grows to the surface of the polymer membrane 21 that defines the perforation 22, thereby endometrializing the polymer membrane 21.

[0102] During the aforementioned endometrialization process, the length of the opening edge of the perforation 22 and the areal density obtained by standardizing the length of the opening edge of the perforation 22 per unit area refer to the width of the starting point for endometrialization formation per unit area. In other words, the areal density of the perforation 22 functions as an indicator of (iv) the ease with which self-defense functions arise due to biological tissue materials, and also as an indicator of the ease with which endometrialization proceeds at (i) the tumor opening and (ii) the branch opening.

[0103] Figure 9 This is a top view used to illustrate the opening size, opening occupancy, and division surface density. It shows an example of a square opening, which serves as an example of an opening for a through hole 22, with the center of each grid point on the square grid arranged in 2 rows × 2 columns.

[0104] like Figure 9As shown, the opening of the through hole 22 is a square-shaped area, configured such that the center of the opening roughly coincides with the grid points of the square grid. The length of each opening in the extension direction of the support 11 is the length of one side of the opening, i.e., the opening size 2L. The direction orthogonal to the extension direction of the support 11 is the circumferential direction of the support 11. The length of each opening in the circumferential direction of the support 11 is the length of the other side of the opening, i.e., the opening size 2W.

[0105] Each opening is arranged with an opening spacing dimension 2LP between it in the extending direction of the support column 11. The opening spacing dimension 2LP is an example of the length between adjacent through holes 22, and is the shortest distance between adjacent openings in the extending direction of the support column 11. Each opening is arranged with an opening spacing dimension 2WP between it in the circumferential direction of the support column 11. The opening spacing dimension 2WP is also an example of the length between adjacent through holes 22, and is the shortest distance between adjacent openings in the circumferential direction of the support column 11.

[0106] Furthermore, the center-to-center distance of the through hole 22 is the sum of the opening size 2L and the opening gap size 2LP, and the sum of the opening size 2W and the opening gap size 2WP.

[0107] On the outer surface of the support column 11, the area per unit region is the unit area of ​​the support column 11. The total area of ​​the openings occupied within the unit region is the opening area defined by the openings. The ratio of the opening area to the unit area of ​​the support column 11 is the opening occupancy rate (%). The total length of the dividing lines 22L existing within the unit region is the areal density of the openings. The areal density of the openings divided by the unit area of ​​the support column 11 yields the dividing areal density ( / mm).

[0108] The unit area of ​​the outer surface of the support column 11 is, for example, the area occupied by the repeating unit of the outer surface, namely the unit structure 13. Moreover, the unit area of ​​the outer surface of the support column 11 can be an area including an opening that is connected and the area around it, or it can be a pre-defined rectangular area. When the unit area is a defined area that is repeated regardless of the opening, the opening occupancy rate and the division surface density mentioned above are the average of the opening occupancy rate of all unit areas and the average of the division surface density of all unit areas.

[0109] As described above, (D) opening occupancy rate functions as an indicator of the ease with which biological tissue material passes through the openings of the perforations 22. On the other hand, (E) areal density functions as an indicator of the ease with which the biological tissue material generates a self-defense function. Both (D) opening occupancy rate and (E) areal density factors that deeply participate in the endometrialization process. If the configuration of these determined perforations 22 is based on these factors, it is possible to reduce the deviation that may occur between the post-placement process and the intended process.

[0110] Among them, such as Figure 10 As shown, the time required for cells to migrate to the opening edge of the perforation 22 differs considerably between the aneurysm 34, where blood flow is easily obstructed, and the branch opening of the branch vessel 35, where blood flow is continuous. Furthermore, the time required for collagen 32A to begin formation from the opening edge of the perforation 22 also varies.

[0111] That is, since the environment conducive to endometrialization at the tumor orifice differs from that conducive to endometrialization at the branch orifice, the contribution of factors (i) to endometrialization at the tumor orifice and (ii) to endometrialization at the branch orifice also differs. Therefore, it is difficult to determine the configuration of the through-hole 22 that achieves both embolism at the tumor orifice and blood flow preservation of the branch vessel 35 solely based on factors (i) to endometrialization at the tumor orifice or solely based on factors (ii) to endometrialization at the branch orifice.

[0112] For example, in ensuring that the branch vessel 35 remains open while simultaneously undergoing endometrialization, increasing the orifice occupancy rate to facilitate blood flow is effective, but this alone is insufficient. It is required that the polymer membrane 21 can be endometrialized even in an environment of continuous blood flow. That is, the areal density must be determined in a manner that ensures endometrialization to the extent that collagen production progresses and blood flow is guaranteed, even in an environment where cells contained in biological tissue materials do not readily adhere to the surface of the artificial material.

[0113] For example, in achieving both embolization and intimalization of the aneurysm 34, reducing the occupancy of the opening to impede blood flow is effective, but further allowing the branch vessels 35 to remain open is excessive. Embolization of the aneurysm 34 is preferably achieved by partially occluding the polymer membrane 21 after intimalization. That is, the areal density should be determined by embolizing the aneurysm 34 by partially occluding the intimalized perforation 22 in an environment where cells contained in the biological tissue material can easily move to the surface of the artificial material.

[0114] Thus, in the polymer membrane 21 constituting the outer surface of the endovascular stent, the portion directly in contact with the vascular intima and the portion near the vascular intima located at the aneurysm opening where blood flow is obstructed are areas where cells contained in the biological tissue material are easily mobile, and thus endometrialization is relatively easy to achieve in the polymer membrane 21. On the other hand, the portion of the polymer membrane 21 located at the branch opening where blood flow is continuous is a portion where cells contained in the biological tissue material are not easily attached, and thus the portion of the polymer membrane 21 is less likely to undergo endometrialization.

[0115] The inventors classified (i) the aneurysm 34 orifice into types that are easier to intimatize, and (ii) the branch orifice of the branch vessel 35 into types that are less difficult to intimatize. Based on experiments in each type, the conditions that can balance the embolism of the aneurysm orifice and the preservation of blood flow at the branch orifice were determined as follows.

[0116] (Condition 1) The opening size during diameter expansion is between 0.02mm and 0.2mm.

[0117] (Condition 2) The opening occupancy rate during diameter expansion is more than 25% and less than 41%.

[0118] (Condition 3) The surface density during diameter expansion is above 9.5 / mm and below 30 / mm.

[0119] The minimum opening size that biological tissue materials used to form connective tissue can pass through is about 0.01 mm. Therefore, if the opening size is 0.02 mm or larger, the biological tissue materials used to form connective tissue can pass through the through hole 22 sufficiently.

[0120] If the opening size is 0.02 mm or more, the opening occupancy rate is 25% or more, and the division area density is 9.5 / mm or more and 30 / mm or less, then by specifying the division area density, it is possible to suppress the situation where it is difficult to achieve (i) thrombosis of the aneurysm 34 due to the increase in opening size and opening occupancy rate. In addition, if the opening size is 0.02 mm or more, the opening occupancy rate is 25% or more, and the division area density is 9.5 / mm or more and 30 / mm or less, then by specifying the opening occupancy rate, it is possible to suppress the situation where it is difficult to achieve (ii) blood flow preservation of the branch opening of the branch vessel 35 due to the decrease in division area density.

[0121] If the opening size is 0.02 mm or more, the opening occupancy rate is 41% or less, and the division surface density is 9.5 / mm or more and 30 / mm or less, then by specifying the opening occupancy rate and the division surface density, it is possible to suppress the situation where it is difficult to obtain the occlusion of the aneurysm opening due to the increase in opening size.

[0122] If the opening size is 0.2 mm or less, the opening occupancy rate is 25% or more, and the division area density is 9.5 / mm or more, the specificity of the opening size and division area density can suppress the situation where it is difficult to achieve (i) thrombosis of the aneurysm 34 due to an increased opening occupancy rate. Furthermore, if the opening size is 0.2 mm or less, the opening occupancy rate is 25% or more, and the division area density is 9.5 / mm or more, the specificity of the opening occupancy rate can suppress the situation where it is difficult to achieve (ii) blood flow preservation of the branch opening of the branch vessel 35 due to a decreased opening size and an increased division area density.

[0123] If the opening size is less than 0.2 mm, the opening occupancy rate is less than 41%, and the division surface density is more than 9.5 / mm, then by the specific division surface density, it is possible to suppress the situation where it is difficult to obtain the blood flow preservation of the branch opening of (ii) branch vessel 35 due to the reduction of opening size and the reduction of opening occupancy rate.

[0124] Thus, the endovascular stent that meets the above conditions 1, 2, and 3 can improve the blood flow preservation of branch vessels and the embolization of the aneurysm site because the opening size is 0.02 mm to 0.2 mm, the opening occupancy rate is 25% to 41%, and the cleavage density is 9.5 / mm to 30 / mm.

[0125] Furthermore, intravascular stents require strength to support the vessel wall and flexibility to adapt to the vessel's curvature. Additionally, they require stress to push the vessel wall outwards under uniform pressure. Thus, determining the occlusion ratio (D) and the areal density (E) of intravascular stents to satisfy conditions 1, 2, and 3 significantly restricts the structural freedom of intravascular stents in meeting these various mechanical requirements.

[0126] Therefore, by including through holes 22 with different opening sizes in multiple through holes 22, it is possible to set a small opening size in areas requiring strength such as support for the blood vessel wall, and a large opening size in areas requiring flexibility. Furthermore, since the opening size of each through hole 22 in the intravascular stent becomes various sizes after expansion when the diameter is allowed to be reduced, this also increases the design freedom of the intravascular stent.

[0127] [Experimental Example A]

[0128] Reference Figure 11 and Figure 12 The experimental examples conducted to determine conditions 1, 2, and 3 above will be explained. Figure 11 This is a cross-sectional view showing the cross-sectional structure of the connective tissue testing apparatus used in the test example. Figure 12 This is a graph showing the relationship between the state of connective tissue and the opening occupancy and the areal density in each test example.

[0129] like Figure 11 As shown, the connective tissue testing apparatus 41 includes an outer cylinder 42 made of resin and an inner cylinder 43 made of resin.

[0130] The outer cylinder 42 is a cylindrical body. The inner diameter of the outer cylinder 42 is 5 mm, and the thickness of the outer cylinder 42 is 0.5 mm. Multiple through holes 34H are formed in the outer cylinder 42, each having an opening on its outer circumferential surface 34S. The through holes 34H penetrate both the exterior and interior of the outer cylinder 42. One example of the through holes 34H is located at each grid point on a square grid defined along the outer circumferential surface 34S. The through holes 34H may be quadrilateral holes with square openings or circular openings. Other examples of the through holes 34H are located at each grid point on a rhomboid grid defined along the outer circumferential surface 34S, with hexagonal openings or circular openings. Other examples of the through hole 34H in the outer cylinder are large square holes located at each lattice point on a square lattice defined along the outer peripheral surface 34S, and small square holes located at each lattice point on a square lattice with a smaller lattice constant than the aforementioned square lattice, in a manner that fills the spaces between adjacent large holes.

[0131] The inner cylinder 43 is a cylindrical body. A portion of the outer circumferential surface of the inner cylinder 43 is fixed to the inner circumferential surface of the outer cylinder 42 via a cross-linking portion 44. That is, the inner cylinder 43 is fixed to the outer cylinder 42 in such a way that a gap of a specified width is formed between the outer circumferential surface of the inner cylinder 43 and the inner circumferential surface of the outer cylinder 42, and this gap is open at both ends of the connective tissue testing apparatus 41. The inner diameter of the inner cylinder 43 is 2 mm, and the thickness of the inner cylinder 43 is 0.5 mm. The inner cylinder 43 is fixed to the inner circumferential surface of the outer cylinder 42 in such a way that the radial width of the gap between the outer circumferential surface 35S of the inner cylinder 43 and the inner circumferential surface of the outer cylinder 42 is 1 mm.

[0132] A plurality of through holes 35H are formed in the inner cylinder 43, each having an opening on its outer peripheral surface 35S. The through holes 35H penetrate both the exterior and interior of the inner cylinder 43. One example of the through holes 35H is located at each lattice point on a square lattice defined along the outer peripheral surface 35S. The through holes 35H may be quadrilateral holes with square openings or circular openings. Other examples of the through holes 35H are hexagonal holes with regular hexagonal openings or circular openings located at each lattice point on a rhomboid lattice defined along the outer peripheral surface 35S. Furthermore, other examples of the through holes 35H are large square holes located at each lattice point on a square lattice defined along the outer peripheral surface 35S, and small square holes located at each lattice point on a square lattice with a smaller lattice constant than the aforementioned square lattice, filling the spaces between adjacent large holes.

[0133] The connective tissue testing device 41 is implanted in a subcutaneous sac in the abdomen of a dog, which serves as the environment for the biological tissue material. To form the subcutaneous sac, a minimal incision is performed on the organism under adequate anesthesia. Next, a guide rod with a convex curved tip is inserted into the organism through an insertion port on the surface of the organism. While sliding the outer circumferential surface of the guide rod, a cylindrical insertion tube is inserted into the organism through the insertion port. Then, after withdrawing the guide rod from the inside of the insertion tube, the connective tissue testing device is inserted to the front end of the insertion tube while sliding the inner circumferential surface of the insertion tube. Next, a pusher is inserted into the inside of the insertion tube. While maintaining the position of the connective tissue testing device, the insertion tube is withdrawn from the insertion port, and the pusher is further withdrawn, thereby leaving the connective tissue testing device in the organism. The insertion port, which serves as a wound, is then sutured.

[0134] The connective tissue testing device 41, embedded in the environment of biological tissue material, is removed from the environment after a predetermined embedding period, which is the period for connective tissue formation. When removing the connective tissue testing device 41 from the organism, a minimal incision is first performed on the organism under adequate anesthesia. Afterwards, the wound is sutured following the removal of the connective tissue testing device 41.

[0135] In the connective tissue testing device 41 embedded in a biological body, the outer peripheral surface of the outer cylinder 42, its two end faces, and the two end faces of the inner cylinder 43 are in direct contact with the biological tissue material. In the connective tissue testing device 41, cells CE are first moved directly from the biological tissue material into the through-hole 34H of the outer cylinder. Through the through-hole 34H, connective tissue is formed on the inner peripheral surface of the outer cylinder 42. The biological tissue material invades between the inner peripheral surface of the outer cylinder 42 and the outer peripheral surface 35S of the inner cylinder 43 through the through-hole 34H. Additionally, cells CE move from the end face of the inner cylinder 43, which is in direct contact with the biological tissue material, toward the outer peripheral surface 35S, the inner peripheral surface, and the interior of the through-hole 35H. Then, connective tissue bodies are formed on the inner peripheral surface and the outer peripheral surface 35S of the inner cylinder 43. At this time, the outer cylinder 42 is recognized as a foreign body, and collagen is produced from the opening edge 34E of the through-hole 34H. Next, cells that move to the outer circumferential surface 35S or the inner circumferential surface of the inner cylinder 43 recognize the opening edge 35E of the inner cylinder through hole 35H as foreign matter, and collagen is also produced by the opening edge 35E of the inner cylinder through hole 35H.

[0136] At the branching opening of the branch vessel 35, cells CE move from around the branching opening and reach the opening edge of the through-hole 22 to form connective tissue. The formation of connective tissue that requires cells to move from the end of the inner cylinder 43, which is in direct contact with the biological tissue material, towards the opening edge 35E of the inner cylinder through-hole 35H, is simulated in the through-hole 22 located at the branching opening of the branch vessel 35.

[0137] That is, as an experiment simulating an environment where intimalization is relatively easy, such as the aneurysm orifice of (i) aneurysm 34, an outer tube through-hole 34H is first prepared. Next, as an experiment simulating an environment where intimalization is relatively difficult, such as the branch orifice of (ii) branch vessel 35, an outer tube 42 with a large outer tube through-hole 34H and an inner tube through-hole 35H located inside the outer tube 42 are prepared.

[0138] Then, using the connective tissue testing device 41 taken from the organism, the connective tissue formed in and around the through hole 34H of the outer cylinder and the connective tissue formed in and around the through hole 35H of the inner cylinder were observed.

[0139] In the observation of connective tissue, the connective tissue was repeatedly impregnated with ethanol and xylene, covering the inner surface of the outer cylinder 42 and the inner surface of the through hole 34H of the outer cylinder. Then, it was embedded in paraffin wax to replace water, forming a paraffin-embedded block of connective tissue. Next, sections were cut from the paraffin-embedded block, including the connective tissue around the through hole 34H of the outer cylinder. The sections were stained with Masson's trichrome and then mounted on glass using a sealing agent.

[0140] Next, the sections sealed with an encapsulating agent were photographed at 10x magnification, and the blue portion was extracted using an H filter in HSV space as the collagen portion. The collagen portion is a newly formed inner membrane generated through endometrialization. The collagen portion indicates that endometrialization has ended; it is not a layer where fibrous collagen is aggregated into bundles and oriented, but rather a layer where collagen is randomly oriented from the surface of connective tissue. Subsequently, the following evaluations 1 and 2 were performed based on the observation of the extracted collagen portion. Moreover, in evaluation 2, the embolization state refers to: the outer cylinder through-hole 34H being completely filled with collagen portion, or the gap formed by the collagen portion of the outer cylinder through-hole 34H being less than 0.01 mm.

[0141] (Evaluation 1) Whether the endometrialization of the entire outer cylinder 42 based on connective tissue has ended.

[0142] (Evaluation 2) Whether the through hole 34H of the outer cylinder is blocked by connective tissue.

[0143] Similarly, in the observation of connective tissue, the connective tissue was repeatedly impregnated with ethanol and xylene, covering the inner surface of the inner cylinder 43 and the inner surface of the through hole 35H. This was followed by paraffin embedding to replace water with paraffin, forming a paraffin-embedded block of connective tissue. Next, sections were cut from the paraffin-embedded block, including the connective tissue around the through hole 35H of the inner cylinder. The sections were stained with Masson's trichrome and then mounted on glass using a sealing agent.

[0144] Next, the section sealed with an encapsulating agent was photographed at 10x magnification, and the blue portion was extracted using an H filter in HSV space as the inner membrane collagen portion. Then, the following evaluations 3 and 4 were performed based on the observation of the extracted collagen portion. Moreover, in evaluation 4, the unclosed state refers to the formation of a gap with a width of 0.1 mm or more in the collagen portion of the inner cylinder through-hole 35H.

[0145] (Evaluation 3) Whether the endometrialization of the entire inner cylinder 43 based on connective tissue has ended.

[0146] (Evaluation 4) Whether the inner cylinder through hole 35H is not closed after the inner membrane is formed.

[0147] Furthermore, as an experiment simulating an environment where endometrialization is relatively easy, multiple connective tissue testing apparatuses 41 are prepared to vary the opening size, opening occupancy, and dividing surface density of the outer cylinder through hole 34H within the following ranges.

[0148] In addition, as a test to simulate an environment where endothelialization is relatively difficult in (ii), multiple connective tissue test apparatuses 41 are prepared to change the opening size, opening occupancy and dividing surface density of the inner cylinder through hole 35H within the following ranges, and to make the opening size of the outer cylinder through hole 34H 0.3 mm and the opening occupancy 60%.

[0149] • Opening size: 0.01mm to 0.3mm

[0150] • Distance between the centers of the openings: 0.03mm to 0.7mm

[0151] • Opening occupancy rate: 15% to 60%

[0152] • Surface density: 2.5 / mm² to 120 / mm²

[0153] • Installation period: 1 month

[0154] The combination of the opening size, the distance between the opening centers, the opening occupancy rate, and the division surface density of the through holes 22 in the square and rhomboid grids used in the test example is denoted as [opening size, distance between the opening centers, opening occupancy rate, division surface density], as shown below.

[0155] [0.3mm, 0.84mm, 20%, 2.7 / mm]

[0156] [0.3mm, 0.68mm, 31%, 4.1 / mm]

[0157] [0.3mm, 0.59mm, 41%, 5.4 / mm]

[0158] [0.2mm,0.56mm,20%,4.0 / mm]

[0159] [0.2mm,0.50mm,25%,5.0 / mm]

[0160] [0.2mm,0.45mm,31%,6.1 / mm]

[0161] [0.2mm,0.42mm,36%,7.1 / mm]

[0162] [0.2mm,0.39mm,41%,8.1 / mm]

[0163] [0.2mm,0.35mm,50%,10.0 / mm]

[0164] [0.15mm,0.42mm,20%,5.3 / mm]

[0165] [0.15mm,0.38mm,25%,6.7 / mm]

[0166] [0.15mm,0.34mm,31%,8.1 / mm]

[0167] [0.15mm,0.32mm,36%,9.5 / mm]

[0168] [0.15mm,0.30mm,41%,10.8 / mm]

[0169] [0.15mm,0.27mm,50%,13.4 / mm]

[0170] [0.12mm,0.34mm,20%,6.7 / mm]

[0171] [0.12mm,0.30mm,25%,8.4 / mm]

[0172] [0.12mm,0.27mm,31%,10.2 / mm]

[0173] [0.12mm,0.25mm,36%,11.9 / mm]

[0174] [0.12mm,0.24mm,41%,13.5 / mm]

[0175] [0.12mm,0.21mm,50%,16.7 / mm]

[0176] [0.10mm,0.28mm,20%,8.0 / mm]

[0177] [0.10 mm, 0.25 mm, 25%, 10.0 / mm]

[0178] [0.10 mm, 0.20 mm, 41%, 16.2 / mm]

[0179] [0.10 mm, 0.18 mm, 50%, 20.0 / mm]

[0180] [0.06 mm, 0.17 mm, 20%, 13.4 / mm]

[0181] [0.06 mm, 0.15 mm, 25%, 16.7 / mm]

[0182] [0.06 mm, 0.12 mm, 41%, 27.0 / mm]

[0183] [0.06 mm, 0.11 mm, 50%, 33.4 / mm]

[0184] [0.04 mm, 0.11 mm, 20%, 20.0 / mm]

[0185] [0.04 mm, 0.10 mm, 25%, 25.1 / mm]

[0186] [0.04 mm, 0.09 mm, 26%, 29.6 / mm]

[0187] [0.04 mm, 0.09 mm, 31%, 30.5 / mm]

[0188] [0.04 mm, 0.08 mm, 36%, 35.6 / mm]

[0189] [0.02 mm, 0.06 mm, 20%, 40.1 / mm]

[0190] [0.02 mm, 0.05 mm, 31%, 60.9 / mm]

[0191] [0.02 mm, 0.05 mm, 25%, 50.2 / mm]

[0192] [0.02 mm, 0.04 mm, 21%, 41.3 / mm]

[0193] [0.02 mm, 0.04 mm, 41%, 80.9 / mm]

[0194] In addition, such as Figure 12As shown, a connective tissue testing apparatus 41 is prepared, wherein the outer cylinder through-hole 34H and the inner cylinder through-hole 35H are each composed of holes of two sizes: a first through-hole 22A as a large hole and a second through-hole 22B as a small hole, which fills the space between adjacent first through-holes 22A. The opening size of the first through-hole 22A is the first opening size. The opening size of the second through-hole 22B is the second opening size. The distance between the opening edges of the first through-hole 22A is the first edge distance. The distance between the opening edges of the second through-hole 22B is the second edge distance. A portion of the combination of the first opening size, the second opening size, the first edge distance, the second edge distance, the opening occupancy rate, and the dividing surface density is denoted as [first opening size, second opening size, first edge distance, second edge distance, opening occupancy rate, dividing surface density], as shown below.

[0195] [0.2mm, 0.02mm, 0.2mm, 0.08mm, 28%, 11.0 / mm]

[0196] [0.2mm, 0.02mm, 0.2mm, 0.03mm, 37%, 29.0 / mm]

[0197] [0.3mm, 0.02mm, 0.3mm, 0.08mm, 28%, 9.3 / mm]

[0198] Figure 13 The hollow circle indicates that the entire outer cylinder 42 has been internally membraned (evaluation 1 is good), the outer cylinder through hole 34H is plugged (evaluation 2 is good), the entire inner cylinder 43 has been internally membraned (evaluation 3 is good), and the inner cylinder through hole 35H is not closed (evaluation 4 is good).

[0199] Figure 13 A solid square mark indicates that the inner lining of a portion of the inner circumferential surface of the outer cylinder 42 has not been completed (evaluation 1 is poor) or the through hole 34H of the outer cylinder has not been plugged (evaluation 2 is poor).

[0200] Figure 13 A solid triangle mark indicates that the inner circumferential surface of the inner cylinder 43 has not been completely laminated (evaluation 3 is defective), or the inner cylinder through hole 35H is not closed (evaluation 4 is defective).

[0201] like Figure 13 As shown, when the opening size is greater than 0.2 mm but less than 0.3 mm, the opening occupancy rate is less than 25%, and the surface density is less than 5 / mm, a defect is identified in either Evaluation 1 or Evaluation 2, similar to the non-closure of the outer cylinder through hole 34H. That is, a defect is identified in either Evaluation 1 or Evaluation 2 when conditions 1, 2, and 3 are not met.

[0202] Furthermore, when the opening size is 0.01 mm or more but less than 0.2 mm, the opening occupancy rate is less than 25%, and the surface density is 5 / mm or more, a defect is identified in evaluation 3 or evaluation 4, similar to the plug of the inner cylinder through hole 35H. That is, even if conditions 1 and 3 are met but condition 2 is not met, a defect is identified in evaluation 3 or evaluation 4.

[0203] Furthermore, when the opening size is between 0.01 mm and 0.3 mm, the opening occupancy rate is between 42% and 50%, and the surface density is 7 / mm or higher, a defect is identified in Evaluation 1 or Evaluation 2, such as the non-closure of the outer cylinder through hole 34H. That is, even if conditions 1 and 3 are met but condition 2 is not met, a defect is identified in Evaluation 1 or Evaluation 2.

[0204] Furthermore, when the opening size is less than 0.02 mm, the opening occupancy rate is 20% to 50%, and the surface density is 42 / mm or higher, a defect is identified in evaluation 3 or evaluation 4, similar to the plug of the inner cylinder through hole 35H. That is, even if condition 2 is met but conditions 1 and 3 are not met, a defect is identified in evaluation 3 or evaluation 4.

[0205] On the other hand, when the opening size is 0.02 mm to 0.2 mm, the opening occupancy rate is 25% to 41%, and the segmentation density is 9.5 / mm to 30 / mm, evaluations 1, 2, 3, and 4 are deemed good. That is, by satisfying conditions 1, 2, and 3, the specific segmentation density can suppress the situation where (i) the occlusion of the aneurysm 34 is difficult to achieve due to an increase in opening size and opening occupancy rate. In addition, by specifying the opening occupancy rate, the specific segmentation density can suppress the situation where (ii) the blood flow preservation of the branch opening of the branch vessel 35 is difficult to achieve due to a decrease in segmentation density.

[0206] [Experimental Example B]

[0207] Internal carotid artery (ICA) aneurysms with a diameter of 4.2 mm, a maximum length of 35 mm, and a neck length of 9.6 mm were selected as treatment subjects. Intravascular stents meeting conditions 1, 2, and 3 above were used in the treatment of these subjects. Furthermore, angiography was performed to confirm blood flow before stent placement, immediately after placement, and 6 months after placement.

[0208] At this time, a polyurethane membrane with a thickness of 0.02 mm is used as the polymer membrane 21. Furthermore, a hexagonal hole with an opening size of 0.1 mm is used as the through hole 22. The opening occupancy rate is set to 30%, and the areal density is set to 16 / mm.

[0209] The aforementioned patient presented with an exceptionally large cerebral aneurysm, with an unusually long aneurysm opening, classifying it as a refractory unruptured aneurysm. Furthermore, the patient's internal carotid artery (ICA) contained a branch vessel opposite the aneurysm opening. Such cases have been difficult to completely cure even with conventional treatments such as surgical clamping of the artery or endovascular embolization of the aneurysm using a coil.

[0210] On the other hand, the results of using an intravascular stent that meets conditions 1, 2, and 3 above are as follows: blood flow within the aneurysm confirmed in the angiography images immediately before placement was confirmed as blockage in the angiography images immediately after placement. Furthermore, blood flow in the branch vessels confirmed in the angiography images immediately before placement was still confirmed in the angiography images immediately after placement. Moreover, thrombosis of the aneurysm and blood flow in the branch vessels were confirmed in angiography images 6 months after placement.

[0211] As described above, the following effects can be obtained according to the above embodiments.

[0212] (1) If the endovascular stent meets conditions 1, 2, and 3, then: (i) after intimalization in an environment where cells contained in the biological tissue material can easily migrate to the surface of the artificial material, the perforation 22 is embolized; on the other hand, (ii) even in an environment where cells contained in the biological tissue material have difficulty attaching to the surface of the artificial material, intimalization progresses to the point of ensuring blood flow. As a result, since the opening size is 0.04 mm to 0.15 mm, the opening occupancy rate is 25% to 41%, and the areal density is 9.5 / mm to 30 / mm, the blood flow preservation of the branch vessels and the embolization of the aneurysm opening can be improved.

[0213] (2) When multiple through holes 22 include through holes 22 with different opening sizes, it is possible to set a small opening size in areas where strength such as supporting the blood vessel wall is required, and a large opening size in areas where flexibility is required. Limiting the opening occupancy rate and the division surface density in intravascular stents to a specific range also greatly restricts the structural freedom of intravascular stents. Therefore, having various opening sizes is particularly preferred from the perspective of improving design freedom.

[0214] (3) When the thickness of the polymer film is 1 μm or more, the breakage of the polymer film 21 can be suppressed during the formation of the polymer film 21, and the time required for the formation of the polymer film 21 can be reduced.

[0215] (4) When the thickness of the polymer membrane is less than 100 μm, the depth of the through hole 22, that is, the migration distance of the cells contained in the biological tissue material, can be suppressed, and the connective tissue required for the intimalization of the endovascular stent can be easily formed on the inner side of the endovascular stent.

[0216] (5) When the through holes 22 are arranged in such a way that they fill the gaps between adjacent annular filaments, the opening edges of the through holes 22, which serve as the starting point for intimalization, can be arranged approximately uniformly throughout the stent body. As a result, it is also possible to suppress differences in the progression of intimalization that may occur due to the misalignment of the through holes 22. Thus, based on the effect described in (1) above, it is also possible to suppress deviations caused by the placement of intravascular stents within the blood vessel.

[0217] (6) When the opening size of the through hole 22 is 0.06 mm or more and 0.12 mm or less, the opening occupancy rate is 30% or more and 35% or less, and the dividing surface density is 14 / mm or more and 20 / mm or less, the blood flow preservation of the branch vessel 35 and the embolism of the aneurysm opening can be improved, and the effectiveness of the above-mentioned effects can also be improved.

[0218] Furthermore, the above implementation method can also be modified as follows.

[0219] The through-holes 22 formed in the polymer film 21 can also be continuous members consisting of multiple through-holes 22. For example, six through-holes 22 with hexagonal openings are arranged at the grid points constituting a hexagonal lattice, and these six through-holes 22 constitute a hole group. Furthermore, the polymer film 21 can also have through-holes 22 arranged at each grid point on a square lattice. Moreover, the distance between one hole group consisting of multiple through-holes 22 and other hole groups consisting of multiple through-holes 22 can be greater than or less than the distance between the centers of the openings within a single hole group.

[0220] Explanation of reference numerals in the attached figures

[0221] 2L, 2W... opening sizes

[0222] 11…Pillars

[0223] 12…link

[0224] 13…Unit Structure

[0225] 21…polymer film

[0226] 22… Through hole

[0227] 31…Endometrium

[0228] 32… connective tissue

[0229] 33…thrombosis

[0230] 34…Aneurysm

[0231] 34E, 35E… Opening edge

[0232] 35…branch vessels

[0233] 41… Connective Tissue Testing Apparatus

Claims

1. An intravascular stent, which is placed in a blood vessel and comprises: It has a tubular support body capable of expansion; and The polymer film covering the main body of the scaffold, The polymer membrane has multiple through holes that connect the inside and outside of the stent for intravascular placement. The opening size during expansion is between 0.02 mm and 0.2 mm. The proportion of the total opening area of ​​all the through holes contained within a unit area of ​​the outer surface of the polymer film is called the opening occupancy rate. The ratio of the lengths of the opening edges of all the through holes contained within a unit area of ​​the outer surface of the polymer film to the unit area of ​​that area is called the areal density. The opening occupancy rate during diameter expansion is between 25% and 41%. The surface density of the dividing surface during diameter expansion is above 9.5 / mm and below 30 / mm.

2. The intravascular stent according to claim 1, wherein, The plurality of through holes include through holes with different opening sizes when the diameter is expanded.

3. The intravascular stent according to claim 1 or 2, wherein, The thickness of the polymer film is between 1 μm and 100 μm.

4. The intravascular stent according to claim 1 or 2, wherein, The stent body is constructed with annular filaments arranged along the extension direction of the intravascular stent, and the annular filaments are repeatedly bent in a corrugated manner along the circumference of the intravascular stent. The through holes are arranged to fill the gaps between the adjacent annular filaments.

5. The intravascular stent according to claim 3, wherein, The stent body is constructed with annular filaments arranged along the extension direction of the intravascular stent, and the annular filaments are repeatedly bent in a corrugated manner along the circumference of the intravascular stent. The through holes are arranged to fill the gaps between the adjacent annular filaments.

6. The intravascular stent according to claim 1 or 2, wherein, The opening size of the through hole during enlargement is between 0.06 mm and 0.12 mm. The opening occupancy rate during diameter expansion is between 30% and 35%. The surface density of the dividing surface during diameter expansion is above 14 / mm and below 20 / mm.

7. The intravascular stent according to claim 3, wherein, The opening size of the through hole during enlargement is between 0.06 mm and 0.12 mm. The opening occupancy rate during diameter expansion is between 30% and 35%. The surface density of the dividing surface during diameter expansion is above 14 / mm and below 20 / mm.

8. The intravascular stent according to claim 4, wherein, The opening size of the through hole during enlargement is between 0.06 mm and 0.12 mm, and the opening occupancy rate during enlargement is between 30% and 35%. The surface density of the dividing surface during diameter expansion is above 14 / mm and below 20 / mm.

9. The intravascular stent according to claim 5, wherein, The opening size of the through hole during enlargement is between 0.06 mm and 0.12 mm, and the opening occupancy rate during enlargement is between 30% and 35%. The surface density of the dividing surface during diameter expansion is above 14 / mm and below 20 / mm.

Images