Stents and methods for relieving respiratory obstructions to allow airflow

Abstract

A respiratory stent having an inner surface and an outer surface, the stent comprising a substrate and a hydrophilic polymer layer, the hydrophilic polymer layer comprising a hydrophilic polymer having hydroxyl and amide groups, at least a portion of the inner surface and / or at least a portion of the outer surface comprising the hydrophilic polymer layer.

Description

[Technical field]

[0001] The present disclosure relates to a stent having excellent biocompatibility that can inhibit mucus adhesion and inhibit cilia loss and goblet cell hyperproliferation, and a method for using the stent to relieve respiratory tract obstruction and ensure airflow. [Background technology]

[0002] Stents are implanted medical devices that can be placed inside the body, some of which are radially expandable, and are placed inside various body cavities or vessels (e.g., the vascular system, esophagus, gastrointestinal tract, large and small intestines, bile duct, pancreatic duct, lung duct, ureter, nasal cavity and airway, trachea, bronchi, etc.) When a body cavity or vessel is narrowed, a stent is placed in the narrowed portion to secure the lumen.

[0003] Such stents include those that are left in the body lumen or vessel for a long period of time, and those that maintain the patency of the lumen for only a predetermined period of time and then are removed from the body. For example, Non-Patent Document 1 discloses an airway stent that is placed at the narrowed site to ensure breathing when the airway or bronchi are blocked by lung cancer or the like.

[0004] However, complications such as loss of cilia and goblet cell hyperproliferation due to mucus adhesion and poor biocompatibility are serious problems. Therefore, there is a clinical need for a stent that can be used for a long time while suppressing complications by suppressing mucus adhesion and improving biocompatibility.

[0005] In response to such needs, airway stents coated with hydrophilic polymers or superhydrophobic polymers have been developed (Patent Document 1 and Non-Patent Document 1). In addition, Patent Document 2 discloses a device with a hydrophilized surface and a method for easily producing the same. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] US Patent Application Publication No. 2017 / 0340782 [Patent Document 2] International Publication No. 2017 / 146102 [Non-patent literature]

[0007] [Non-Patent Document 1] Hans J. Lee, et al., Journal of Thoracic Disease 2017;9(11):4651-4659. Summary of the Invention [Problem to be solved by the invention]

[0008] However, the performance of stents in the conventional technology is insufficient, and many problems remain to be overcome. Therefore, an object of the present disclosure is to provide a respiratory stent that can suppress mucus adhesion and the occurrence of complications and has excellent biocompatibility. [Means for solving the problem]

[0009] In order to solve the above problems, exemplary aspects of the present disclosure are as follows. [1] A respiratory stent having an inner surface and an outer surface, the stent having a substrate and a hydrophilic polymer layer, the hydrophilic polymer layer comprising a hydrophilic polymer having hydroxyl groups and amide groups, the hydrophilic polymer layer being disposed on at least a portion of the inner surface. [2] A respiratory stent having an inner surface and an outer surface, the stent having a substrate and a hydrophilic polymer layer, the hydrophilic polymer layer comprising a hydrophilic polymer having hydroxyl groups and amide groups, the hydrophilic polymer layer being disposed on at least a portion of the outer surface. [3] The stent according to claim 1 or 2, wherein the substrate comprises a silicone resin. [4] The stent according to any one of [1] to [3], further comprising a mixed layer of a component of the substrate and a component of the hydrophilic polymer layer, the mixed layer being provided between the substrate and the hydrophilic polymer layer. [5] The stent according to any one of [1] to [4], wherein a ratio X:Y of a thickness X of the layer containing a hydrophilic polymer to a thickness Y of the base material is within a range of 1:400 to 1:120,000. [6] The stent according to any one of [1] to [5], comprising a tubular structural portion. [7] The stent according to [6], wherein the tubular structure portion has an outer diameter of 4 mm or more and 24 mm or less, and a thickness of 0.2 mm or more and 2 mm or less. [8] The stent described in any one of [1] to [7], having a plurality of protrusions or irregularities on the outer surface. [9] The stent according to any one of [1] to [8], wherein the respiratory organs are the airways, bronchi, or lungs.

[10] The stent according to any one of [1] to [9], wherein the hydrophilic polymer having a hydroxyl group and an amide group is at least one polymer selected from the group consisting of polyamides having a carboxyl group, and copolymers of a monomer having a hydroxyl group and a monomer having an amide group.

[11] The stent according to

[10] , wherein the monomer having a hydroxyl group is at least one monomer selected from the group consisting of methacrylic acid, acrylic acid, vinylbenzoic acid, thiophene-3-acetic acid, 4-styrenesulfonic acid, vinylsulfonic acid, 2-acrylamido-2-methylpropanesulfonic acid, and salts thereof.

[12] The stent according to

[10] or

[11] , wherein the monomer having an amide group is at least one monomer selected from the group consisting of N-vinylpyrrolidone, N-vinylacetamide, N,N-dimethylacrylamide, N,N-diethylacrylamide, N-isopropylacrylamide, N-(2-hydroxyethyl)acrylamide and acrylamide.

[13] 1. A method of relieving respiratory obstructions and ensuring airflow using a respiratory stent having an inner surface and an outer surface, the stent having a base material and a hydrophilic polymer layer, the hydrophilic polymer layer comprising a hydrophilic polymer having hydroxyl groups and amide groups, the hydrophilic polymer layer being located on at least a portion of the inner surface.

[14] 1. A method of relieving respiratory obstructions and ensuring airflow using a respiratory stent having an inner surface and an outer surface, the stent having a base material and a hydrophilic polymer layer, the hydrophilic polymer layer comprising a hydrophilic polymer having hydroxyl groups and amide groups, and at least a portion of the outer surface having the hydrophilic polymer layer.

[0010] According to an exemplary embodiment of the present disclosure, a respiratory stent can be provided that can suppress mucus adhesion, has excellent biocompatibility, and suppresses the occurrence of complications. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 is a schematic diagram of a specific stent according to one embodiment. [Diagram 2] FIG. 2 is a cross-sectional view taken along line AA of the stent according to one embodiment shown in FIG. [Diagram 3] FIG. 3 is a schematic diagram of another exemplary stent according to one embodiment. [Figure 4] FIG. 4 is a schematic diagram of a further exemplary stent, according to one embodiment. [Diagram 5]FIG. 5 is a schematic diagram of a stent used in an embodiment of the present disclosure. [Figure 6] FIG. 6 is a schematic diagram of a further exemplary stent, according to one embodiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] A stent according to one embodiment (first embodiment) is a respiratory stent having an inner surface and an outer surface, the stent having a base material and a hydrophilic polymer layer, the hydrophilic polymer layer including a hydrophilic polymer having a hydroxyl group and an amide group, and the hydrophilic polymer layer is disposed on at least a portion of the inner surface.

[0013] A stent according to another embodiment (second embodiment) is a respiratory stent having an inner surface and an outer surface, the stent having a base material and a hydrophilic polymer layer, the hydrophilic polymer layer including a hydrophilic polymer having a hydroxyl group and an amide group, and the hydrophilic polymer layer is disposed on at least a portion of the outer surface.

[0014] In the present disclosure, the term "respiratory system" is a general term for organs related to breathing, and examples thereof include the airway, oral cavity, nasal cavity, larynx, trachea, bronchi, bronchioles, lungs, etc. The stent according to the present embodiment is a stent for the respiratory system, and is preferably a stent for the airway, trachea, bronchi, or lungs. By placing the stent according to this embodiment in the narrowed respiratory tract, the obstruction in the respiratory tract can be relieved and airflow can be ensured. The stent according to this embodiment can be applied not only to a narrowed respiratory tract but also to a clogged respiratory tract.

[0015] In the stent according to the present embodiment, the "inner surface" refers to the surface through which respiratory air passes, and the "outer surface" refers to the surface other than the inner surface, that is, the surface that comes into contact with the respiratory system when the stent is applied to a living body. Fig. 1 is a schematic diagram of a stent 10 according to one embodiment. As shown in Fig. 1, the stent 10 according to this embodiment may include a tubular structural portion. In the stent 10 shown in Fig. 1, the inside of the tubular structural portion is an inner surface 11, and the surface other than the inner surface is an outer surface 12. In addition, the tubular structural portion may be expandable in the radial direction.

[0016] <Base material> The stent according to the present embodiment has a base material. The material forming the base material (stent base material) of the stent is not particularly limited, and may include metal or resin. Examples of metals include stainless steel, cobalt alloys, titanium alloys, nickel-titanium alloys (nitinol), and the like. Examples of the resin include polyurethane, polyester, PTFE (polytetrafluoroethylene), and silicone resin, with silicone resin being preferred from the standpoints of biocompatibility, mechanical properties, processability, and the like. That is, in the stent according to this embodiment, the base material preferably contains a silicone resin. The substrate may be made of one type of material, or may be made of two or more types of materials.

[0017] <Hydrophilic polymer layer> In this embodiment, the hydrophilic polymer layer on the surface of the stent is a hydrophilic polymer formed as a layer on the surface of a substrate.

[0018] The stent according to this embodiment preferably includes a mixed layer of a component of the substrate and a component of the hydrophilic polymer layer between the substrate and the hydrophilic polymer layer. In this specification, a hydrophilic polymer layer formed solely from a hydrophilic polymer and a mixed layer may be collectively referred to as a layer containing a hydrophilic polymer. FIG. 2 is a cross-sectional view taken along line AA of the stent 10 according to the present embodiment shown in FIG. For example, as shown in FIG. 2, the stent 10 of this embodiment preferably includes a mixed layer 22 between the substrate 21 and the hydrophilic polymer layer 23, in which components of the substrate 21 and components of the hydrophilic polymer layer 23 are mixed.

[0019] The mixed layer between the substrate and the hydrophilic polymer layer may be a layer in which a part of the hydrophilic polymer constituting the hydrophilic polymer layer is embedded in the substrate. The mixed layer may be a layer in which a part of the substrate is embedded in the hydrophilic polymer layer. When the stent according to the present embodiment includes a mixed layer, the layer containing the hydrophilic polymer has a laminated structure of two or more layers including the hydrophilic polymer layer and the mixed layer.

[0020] The stent according to this embodiment (first embodiment) must have a hydrophilic polymer layer on at least a part of the inner surface, and may have a hydrophilic polymer layer on the entire inner surface. The stent according to this embodiment may have a hydrophilic polymer layer on a part of the outer surface in addition to the inner surface. In this case, the stent may have a hydrophilic polymer layer on the entire outer surface in addition to the inner surface. A stent according to another embodiment (second embodiment) must have a hydrophilic polymer layer on at least a part of the outer surface, and may have a hydrophilic polymer layer on the entire outer surface. The stent according to this embodiment may have a hydrophilic polymer layer on a part of the inner surface in addition to the outer surface. In this case, a hydrophilic polymer layer may be present on the entire inner surface in addition to the outer surface. That is, the hydrophilic polymer layer must be provided on at least a part of the inner surface and / or at least a part of the outer surface. From the viewpoint of biocompatibility, the stent according to this embodiment preferably has a hydrophilic polymer layer on the entire inner and outer surfaces, i.e., on the entire surface of the stent. In the following description, the first embodiment will be described in detail. However, the description of the first embodiment can be applied to the second embodiment, except for the position of the hydrophilic polymer layer.

[0021] In this embodiment, the presence of a hydrophilic polymer layer on the surface of the stent imparts hydrophilicity to at least a portion of the surface of the stent. The material of the hydrophilic polymer layer is usually a material different from that of the substrate. However, the material of the hydrophilic polymer layer may be the same as that of the substrate as long as a desired effect is obtained.

[0022] The polymer forming the hydrophilic polymer layer is composed of a material having hydrophilicity (e.g., a hydrophilic polymer, etc.). However, additives other than the above materials may be included as long as the hydrophilicity is not impaired. Here, the hydrophilic material is a material that is soluble in 100 parts by mass of water at room temperature (20 to 23°C) at 0.0001 parts by mass or more, and the hydrophilic material is preferably soluble in 100 parts by mass of water at 0.01 parts by mass or more, more preferably soluble in 0.1 parts by mass or more, and particularly preferably soluble in 1 part by mass or more.

[0023] As the hydrophilic polymer, it is preferable to use a hydrophilic polymer having a hydroxyl group. The use of a hydrophilic polymer having a hydroxyl group is preferable because it can form a surface that is not only excellent in water wettability but also excellent in antifouling properties against body fluids and the like. As the hydrophilic polymer having a hydroxyl group, a polymer having an acidic hydroxyl group is preferable. Specifically, the hydrophilic polymer having a hydroxyl group is preferably a polymer having a group selected from a carboxyl group and a sulfonic acid group, and a polymer having a carboxyl group is most preferable. The carboxyl group or the sulfonic acid group may be in the form of a salt.

[0024] Examples of the hydrophilic polymer having a hydroxyl group include polymethacrylic acid, polyacrylic acid, poly(vinylbenzoic acid), poly(thiophene-3-acetic acid), poly(4-styrenesulfonic acid), polyvinylsulfonic acid, poly(2-acrylamido-2-methylpropanesulfonic acid), and salts thereof. The above are examples of homopolymers, but copolymers of hydrophilic monomers constituting the hydrophilic polymer, or copolymers of the hydrophilic monomers and other monomers, can also be suitably used.

[0025] When the hydrophilic polymer having a hydroxyl group is a copolymer, the hydrophilic monomer constituting the copolymer is preferably a monomer having a group selected from an allyl group, a vinyl group, and a (meth)acryloyl group, and most preferably a monomer having a (meth)acryloyl group. Suitable examples of such monomers include (meth)acrylic acid, vinylbenzoic acid, styrenesulfonic acid, vinylsulfonic acid, 2-acrylamido-2-methylpropanesulfonic acid, and salts thereof. Among these, a monomer selected from (meth)acrylic acid, 2-acrylamido-2-methylpropanesulfonic acid, and salts thereof is more preferred, and most preferred is a monomer selected from (meth)acrylic acid and its salts.

[0026] The above-mentioned hydrophilic polymer having a hydroxyl group is preferably one having an amide group in addition to a hydroxyl group, because such a hydrophilic polymer is not only excellent in water wettability, but also capable of forming a surface that can suppress mucus adhesion and suppress cilia loss and goblet cell hyperproliferation. In addition, such a hydrophilic polymer is preferable because it has excellent body compatibility, since it can suppress mucus adhesion, cilia loss and goblet cell hyperproliferation. Examples of acidic hydrophilic polymers having a hydroxyl group and an amide group include polyamides having a carboxyl group, and copolymers of a monomer having a hydroxyl group and a monomer having an amide group.

[0027] Suitable examples of polyamides having a carboxyl group include polyamino acids such as polyaspartic acid and polyglutamic acid, and polypeptides. As the monomer having a hydroxyl group, a monomer selected from methacrylic acid, acrylic acid, vinylbenzoic acid, thiophene-3-acetic acid, 4-styrenesulfonic acid, vinylsulfonic acid, 2-acrylamido-2-methylpropanesulfonic acid, and salts thereof can be suitably used.

[0028] As the monomer having an amide group, it is preferable to use a monomer selected from a monomer having a (meth)acrylamide group and an N-vinyl carboxylic acid amide (including cyclic ones) in terms of ease of polymerization. Suitable examples of such monomers include N-vinylpyrrolidone, N-vinylcaprolactam, N-vinylacetamide, N-methyl-N-vinylacetamide, N-vinylformamide, N,N-dimethylacrylamide, N,N-diethylacrylamide, N-isopropylacrylamide, N-(2-hydroxyethyl)acrylamide, acryloylmorpholine, and acrylamide. Among these, N-vinylpyrrolidone and N,N-dimethylacrylamide are preferable in terms of suppressing mucus adhesion, cilia loss, and hyperproliferation of goblet cells, and N,N-dimethylacrylamide is the most preferable.

[0029] Preferred examples of hydrophilic polymer copolymers having amide groups in addition to hydroxyl groups are (meth)acrylic acid / N-vinylpyrrolidone copolymer, (meth)acrylic acid / N,N-dimethylacrylamide copolymer, 2-acrylamido-2-methylpropanesulfonic acid / N-vinylpyrrolidone copolymer, and 2-acrylamido-2-methylpropanesulfonic acid / N,N-dimethylacrylamide copolymer, and most preferably (meth)acrylic acid / N,N-dimethylacrylamide copolymer.

[0030] When a copolymer of a monomer having a hydroxyl group and a monomer having an amide group is used, the copolymerization ratio [mass of monomer having a hydroxyl group] / [mass of monomer having an amide group] is preferably within the range of 1 / 99 to 99 / 1. In the copolymerization, the ratio of the monomer having a hydroxyl group is more preferably 2% by mass or more, more preferably 5% by mass or more, and even more preferably 10% by mass or more. In addition, in the copolymerization, the ratio of the monomer having a hydroxyl group is more preferably 90% by mass or less, more preferably 80% by mass or less, and even more preferably 70% by mass or less. In the copolymerization, the ratio of the monomer having an amide group is more preferably 10% by mass or more, more preferably 20% by mass or more, and even more preferably 30% by mass or more. In addition, in the copolymerization, the ratio of the monomer having an amide group is more preferably 98% by mass or less, more preferably 95% by mass or less, and even more preferably 90% by mass or less. When the copolymerization ratio is within this range, the function of inhibiting mucus adhesion and the function of inhibiting cilia loss and goblet cell hyperproliferation are easily exhibited.

[0031] It is also possible to copolymerize the above-mentioned monomer having a hydroxyl group and monomer having an amide group with one or more monomers selected from monomers having different hydroxyl groups or amide groups or monomers having no hydroxyl group or amide group.

[0032] In addition, suitable examples of monomers other than those mentioned above include hydroxyethyl (meth)acrylate, hydroxypropyl (meth)acrylate, hydroxybutyl (meth)acrylate, hydroxyethyl (meth)acrylamide, glycerol (meth)acrylate, caprolactone-modified 2-hydroxyethyl (meth)acrylate, N-(4-hydroxyphenyl)maleimide, hydroxystyrene, and vinyl alcohol (with vinyl carboxylate as precursor). Among these monomers, the use of a monomer having a (meth)acryloyl group is preferred in terms of ease of polymerization, and a (meth)acrylic acid ester monomer is more preferred. Among these monomers, the most preferred from the viewpoint of suppressing mucus adhesion, cilia loss, and goblet cell hyperproliferation is the use of hydroxyethyl (meth)acrylate, hydroxypropyl (meth)acrylate, or glycerol (meth)acrylate, and among these, hydroxyethyl (meth)acrylate is the most preferred. It is also possible to use monomers having characteristics such as hydrophilicity, antibacterial properties, and antifouling properties. In addition, additives other than the above materials may be included in the hydrophilic polymer layer as long as they do not impair the properties required for the stent. Furthermore, the hydrophilic polymer layer may contain one or more other hydrophilic polymers in addition to the hydrophilic polymer having a hydroxyl group, however, since the manufacturing method tends to be complicated, it is preferable that the hydrophilic polymer layer is composed of only one type of hydrophilic polymer having a hydroxyl group.

[0033] Here, "one type of polymer" means a polymer or a group of polymers (isomers, complexes, etc.) produced by one synthesis reaction. When a copolymer is produced using multiple monomers, even if the constituent monomers are the same, polymers synthesized by changing the compounding ratio are not considered to be the same polymer.

[0034] Furthermore, "the hydrophilic polymer layer consists only of a hydrophilic polymer having one type of hydroxyl group" means that the hydrophilic polymer layer does not contain any polymer other than the hydrophilic polymer having a hydroxyl group, or even if it contains other polymers, the content of the other polymers per 100 parts by mass of the hydrophilic polymer having a hydroxyl group is more preferably 0.1 part by mass or less, and even more preferably 0.0001 part by mass or less.

[0035] In particular, when the other polymer is a basic polymer, if the content is greater than the above range, problems with transparency occur. In the prior art, an acidic polymer and a basic polymer are used in combination to laminate a hydrophilic polymer on the surface of a substrate in a stent by utilizing electrostatic adsorption, but according to an exemplary embodiment of the present disclosure, a hydrophilic polymer layer consisting of only one type of polymer can be formed and fixed on the surface of a substrate in a stent.

[0036] In this embodiment, "a hydrophilic polymer layer having hydroxyl groups is fixed to at least a part of the surface of the substrate of the stent" means that the hydrophilic polymer layer is fixed to the surface of the substrate of the stent by chemical bonds such as hydrogen bonds, ionic bonds, van der Waals bonds, hydrophobic bonds, complex formation, etc. The hydrophilic polymer layer may be bonded to the substrate by a covalent bond, but this makes it difficult to manufacture the substrate in a simple process, so it is preferable that there is no covalent bond between the hydrophilic polymer layer and the substrate.

[0037] In this embodiment (first embodiment), in order to suppress mucus adhesion to the inner surface of a respiratory stent having an inner surface and an outer surface, it is necessary to have a hydrophilic polymer layer on at least a part of the inner surface, and it is preferable to have a hydrophilic polymer layer on the entire inner surface. In another embodiment (second embodiment), in order to suppress cilia loss and goblet cell hyperproliferation, it is necessary to have a hydrophilic polymer layer on at least a part of the outer surface of the stent, and it is preferable to have a hydrophilic polymer layer on the entire outer surface. It is more preferable to have a hydrophilic polymer layer on the inner and outer surfaces of the stent, and even more preferable to have a hydrophilic polymer layer on the entire surface of the stent.

[0038] In addition, since this allows for easy manufacturing, it is preferable that there is no covalent bond between the substrate and the hydrophilic polymer layer. The absence of a covalent bond is determined by the absence of a chemically reactive group. Specific examples of chemically reactive groups include, but are not limited to, an azetidinium group, an epoxy group, an isocyanate group, an aziridine group, an azlactone group, and combinations thereof.

[0039] The thickness of the layer containing a hydrophilic polymer is preferably 1 nm or more and less than 1000 nm when the cross section of the stent frozen in a water-containing state (hereinafter, frozen state) is observed using a scanning transmission electron microscope. This is because if the thickness is within this range, the function of suppressing mucus adhesion and the function of suppressing cilia loss and goblet cell hyperproliferation are easily exhibited. The thickness of the layer containing a hydrophilic polymer in the frozen stent is more preferably 10 nm or more, even more preferably 20 nm or more, and most preferably 30 nm or more. The thickness of the layer containing a hydrophilic polymer in the frozen stent is more preferably 900 nm or less, even more preferably 800 nm or less, and most preferably 700 nm or less. The thickness of the layer containing a hydrophilic polymer in the frozen stent can be measured by observation using a scanning transmission electron microscope and a cryotransfer holder.

[0040] The thickness of the layer containing a hydrophilic polymer in the stent in a dry state is preferably within the range of 1 to 1000 nm. This is because a thickness within this range makes it easier to exhibit the function of suppressing mucus adhesion and the function of suppressing cilia loss and goblet cell hyperproliferation. The thickness of the layer containing a hydrophilic polymer in the stent in a dry state is more preferably 10 nm or more, and even more preferably 20 nm or more. In addition, the thickness of the layer containing a hydrophilic polymer in the stent in a dry state is more preferably 900 nm or less, even more preferably 800 nm or less, and most preferably 700 nm or less.

[0041] As described above, the layer containing the hydrophilic polymer is preferably in a state separated into two or more layers or two or more phases.

[0042] Here, the state in which the layer containing a hydrophilic polymer is separated into two or more layers refers to a state in which a multilayer structure of two or more layers is observed in the layer containing a hydrophilic polymer when the cross section of the stent is observed using a transmission electron microscope. If it is difficult to determine the separation of layers only by observation using a transmission electron microscope, the cross section of the stent is determined by analyzing the elements and composition of the cross section using a means capable of elemental analysis and composition analysis such as scanning transmission electron microscopy, electron energy loss spectroscopy, energy dispersive X-ray spectroscopy, and time-of-flight secondary ion mass spectrometry.

[0043] The state where the layer containing the hydrophilic polymer is separated into two or more phases means a state where phase separation into two or more phases is observed in the layer containing the hydrophilic polymer when the cross section of the stent is observed using a transmission electron microscope. When it is difficult to judge the phase separation only by observation using a transmission electron microscope, the same method as above is used to judge.

[0044] Conventionally, two or more types of polymers were required to form two or more layers or two or more phases of a polymer layer on a substrate surface. However, in an exemplary embodiment of the present disclosure, it has been found that even when only one type of polymer is present, a layer containing a hydrophilic polymer separated into two or more layers or two or more phases can be formed on a substrate surface.

[0045] As described above, the stent according to the present embodiment preferably includes a mixed layer between the substrate and the hydrophilic polymer layer, in which the substrate component and the hydrophilic polymer layer component are mixed. When the stent according to the present embodiment includes a mixed layer, the layer including the hydrophobic polymer has a laminated structure of two or more layers including the hydrophilic polymer layer and the mixed layer.

[0046] When the layer containing the hydrophobic polymer has a multilayer structure of two or more layers, the layer containing the hydrophobic polymer becomes sufficiently thick, and the function of suppressing mucus adhesion and the function of suppressing cilia loss and goblet cell hyperproliferation are improved. In addition, when the layer containing the hydrophobic polymer has a state of being separated into two or more phases, it is easy to distinguish it from foreign matter such as dirt and dust when observing the cross section of the stent using a transmission electron microscope, so that it is easy to confirm the formation of a polymer layer on the surface of the base material in the stent, which is efficient in terms of quality inspection.

[0047] In addition, the state in which the components of the hydrophilic polymer layer are mixed with the components of the substrate can be confirmed by detecting elements derived from the substrate in the mixed layer when the cross section of the stent is observed with an observation means capable of performing elemental analysis or compositional analysis such as scanning transmission electron microscopy, electron energy loss spectroscopy, energy dispersive X-ray spectroscopy, time-of-flight secondary ion mass spectrometry, etc. By mixing the components of the hydrophilic polymer layer with the components of the substrate, the hydrophilic polymer layer can be more firmly fixed to the substrate.

[0048] When the stent has a mixed layer in which the components of the hydrophilic polymer layer and the components of the base material are mixed, it is preferable that a two-layer structure of the hydrophilic polymer layer and the mixed layer is observed. The thickness of the mixed layer is preferably 3% or more, more preferably 5% or more, and even more preferably 10% or more, based on the total thickness of the mixed layer and the hydrophilic polymer layer. The thickness of the mixed layer is preferably 98% or less, more preferably 95% or less, even more preferably 90% or less, and most preferably 80% or less, based on the total thickness of the mixed layer and the hydrophilic polymer layer. If the thickness ratio of the mixed layer is too small, the mixture of the hydrophilic polymer and the base material is not sufficient, which is not preferable. If the thickness ratio of the mixed layer is too large, the properties of the hydrophilic polymer may not be fully expressed, which is not preferable.

[0049] The number of layers or phases containing a hydrophilic polymer is preferably 2 to 3 layers or phases, more preferably 2 layers or phases, in terms of excellent transparency of the stent.

[0050] The mucus adhesion inhibitory ability of the exemplary embodiments of the present disclosure can be evaluated by a mucin adhesion test using mucin extracted from human saliva. The lower the amount of mucin adhesion in these evaluations, the higher the mucus adhesion inhibitory effect, the better the biocompatibility, and the lower the risk of stent infection or migration, which is preferable. The amount of mucin attached is preferably 50% or less, more preferably 40% or less, and most preferably 30% or less, relative to the silicone base material. The measurement method will be described in detail later.

[0051] <Stent manufacturing method> Next, a method for producing the stent according to this embodiment will be described. The stent according to this embodiment (first embodiment) can be manufactured by forming a hydrophilic polymer layer on at least a part of the inner surface of a substrate. The stent according to another embodiment (second embodiment) can be manufactured by forming a hydrophilic polymer layer on at least a part of the outer surface of a substrate. In the first embodiment, it is preferable to form a hydrophilic polymer layer on the entire inner surface of the substrate. Furthermore, a hydrophilic polymer layer may be formed on at least a portion of the outer surface of the substrate. In the second embodiment, it is preferable to form a hydrophilic polymer layer on the entire outer surface of the substrate. Furthermore, a hydrophilic polymer layer may be formed on at least a portion of the inner surface of the substrate. It is more preferable to form a hydrophilic polymer layer on the inner and outer surfaces of the substrate, and it is even more preferable to form a hydrophilic polymer layer on the entire surface of the substrate. In the following description, the manufacturing method of the stent according to the first embodiment will be described in detail. However, the description of the first embodiment is applicable to the second embodiment, except for the position of the hydrophilic polymer layer.

[0052] The stent according to the present embodiment can be manufactured by coating at least a part of the inner surface of the substrate with a solution containing a hydrophilic polymer. The coating method is not particularly limited, and includes conventionally known methods such as dipping, spraying, coating, printing, etc. Among them, it is preferable to obtain the hydrophilic polymer layer by a method of immersing the substrate in a solution containing a hydrophilic polymer having a hydroxyl group and heating the solution. Alternatively, the hydrophilic polymer layer can be formed on a part of the substrate surface by spraying or applying the polymer solution on the substrate surface or a part of it. Furthermore, the hydrophilic polymer layer can be formed on a part of the substrate surface by heating the solution in a state where only the inner surface or only the outer surface is in contact with the polymer solution. From the viewpoint of the manufacturing process, it is preferable to form a hydrophilic polymer layer on at least a part of the inner surface of a substrate that has been preformed into a desired shape. In order to prevent migration after placement, for example, a substrate may be used that is shaped to a size and shape appropriate for the shape of the respiratory tract of the patient to which it is to be applied, using 3D printing technology based on anatomical analysis and highly accurate anatomical data created based on 3D CT.

[0053] Here, the present inventors have found that by a very simple method of adjusting the initial pH of the solution containing the hydrophilic polymer having hydroxyl groups to 2.0 or more and 6.0 or less, placing a stent base material in the solution, and heating the solution in this state, the hydrophilic polymer having hydroxyl groups can be fixed onto the surface of a stent base material without using a special method known in the art, such as a method utilizing electrostatic adsorption using an acidic polymer and a basic polymer in combination, and that the stent exhibits a function of suppressing mucus adhesion and a function of suppressing cilia loss and goblet cell hyperproliferation. This is of great industrial significance from the viewpoint of shortening the manufacturing process.

[0054] When a polymer layer is formed on the surface of a stent substrate using only a hydrophilic polymer having one type of hydroxyl group, conventional technology has the problem that the thickness of the layer is insufficient, making it difficult to impart to the stent the function of sufficiently suppressing mucus adhesion or the function of suppressing cilia loss and goblet cell hyperproliferation. Here, when the molecular weight of the hydrophilic polymer is increased, the thickness of the obtained polymer layer generally increases. However, when the molecular weight is too large, the viscosity may increase, which may make it more difficult to handle the hydrophilic polymer during production, so there is an upper limit to the thickness of the obtained polymer layer. Also, when the concentration of the hydrophilic polymer in the solution during production is increased, the thickness of the obtained polymer layer generally increases. However, when the concentration of the hydrophilic polymer is too high, the viscosity may increase, which may make it more difficult to handle the hydrophilic polymer during production, so the concentration of the hydrophilic polymer is limited in the same way as when the molecular weight is too large. However, when the stent according to the present embodiment includes a mixed layer, the layer including the hydrophilic polymer has a laminated structure of two or more layers including a hydrophilic polymer layer and a mixed layer, even though only one type of hydrophilic polymer having a hydroxyl group is used. As a result, even if a hydrophilic polymer having a molecular weight in the following range is used and even if the concentration of the hydrophilic polymer in the solution during production is set to the following range, it is possible to increase the thickness of the layer including the hydrophilic polymer, and it is easy to obtain a sufficient function of suppressing mucus adhesion and a sufficient function of suppressing cilia loss and goblet cell hyperproliferation.

[0055] The hydrophilic polymer having a hydroxyl group used in the present disclosure preferably has a molecular weight of 2000 to 1500000. The molecular weight of the hydrophilic polymer having a hydroxyl group is more preferably 5000 or more, and even more preferably 10000 or more. The molecular weight of the hydrophilic polymer having a hydroxyl group is more preferably 1200000 or less, and even more preferably 1000000 or less. Here, the molecular weight is the weight average molecular weight in terms of polyethylene glycol measured by gel permeation chromatography (aqueous solvent).

[0056] In addition, when the concentration of the hydrophilic polymer in the solution during production is increased, the thickness of the obtained hydrophilic polymer layer generally increases. However, if the concentration of the hydrophilic polymer is too high, the viscosity increases, which may increase the difficulty of handling during production, so the concentration of the hydrophilic polymer having a hydroxyl group is preferably in the range of 0.0001 to 30% by mass. The concentration of the hydrophilic polymer having a hydroxyl group is more preferably 0.001% by mass or more, and even more preferably 0.005% by mass or more. The concentration of the hydrophilic polymer having a hydroxyl group is more preferably 20% by mass or less, and even more preferably 15% by mass or less.

[0057] In the above steps, the initial pH of the solution containing the hydrophilic polymer is preferably in the range of 2.0 to 6.0, since the solution does not become turbid and a stent with good transparency can be obtained. The initial pH is more preferably 2.2 or more, more preferably 2.4 or more, even more preferably 2.5 or more, and most preferably 2.6 or more. The initial pH is preferably 5.0 or less, more preferably 4.5 or less, and most preferably 4.0 or less. When the initial pH is 2.0 or more, the solution is less likely to become turbid. If the solution does not become turbid, it is preferable because biological tissue reactions tend to be discovered early during observation with an endoscope, etc. When the initial pH is more than 6.0, the hydrophilic polymer layer tends not to be separated into two or more layers or two or more phases, and the function of suppressing mucus adhesion and the function of suppressing cilia loss and goblet cell hyperproliferation are reduced, which is undesirable.

[0058] The pH of the above solution can be measured using a pH meter (e.g., Eutech pH2700, manufactured by Eutech Instruments). Here, the initial pH of the solution containing a hydrophilic polymer having a hydroxyl group refers to the pH value measured after adding all of the hydrophilic polymer to the solution, stirring the solution at room temperature (23 to 25°C) for 2 hours using a rotator to make the solution uniform, and before placing the substrate and heating it. In the present disclosure, the pH value is rounded off to one decimal place.

[0059] The pH of the solution may change due to the heating operation. The pH of the solution after the heating operation is preferably 2.0 to 6.5. The pH of the solution after heating is more preferably 2.2 or more, more preferably 2.3 or more, and most preferably 2.4 or more. The pH of the solution after heating is more preferably 5.9 or less, more preferably 5.5 or less, even more preferably 5.0 or less, and most preferably 4.5 or less. By setting the pH of the solution after the heating operation within the above range, the pH condition can be kept appropriate during the heating operation, and the physical properties of the resulting stent are favorable. Note that, after the heating operation according to the present disclosure is performed to modify the stent surface, the pH can be adjusted by neutralization or by adding water, but the pH of the solution after the heating operation referred to here is the pH of the solution before such a pH adjustment treatment is performed.

[0060] The solvent of the solution containing the hydrophilic polymer having a hydroxyl group is preferably water. The pH of the solution containing the hydrophilic polymer can be adjusted by adding an acidic substance such as acetic acid, citric acid, formic acid, ascorbic acid, trifluoromethanesulfonic acid, methanesulfonic acid, nitric acid, sulfuric acid, phosphoric acid, or hydrochloric acid to the solution. Among these acidic substances, citric acid, ascorbic acid, and sulfuric acid are preferred from the viewpoints of low volatility and high safety to living organisms. In addition, it is also preferred to add a buffer to the solution in order to facilitate fine adjustment of the pH.

[0061] As the buffer, any known physiologically compatible buffer can be used. Buffers that can be appropriately used in the present disclosure are known to those skilled in the art, and include, for example, boric acid, borates (e.g., sodium borate), citric acid, citric acid salts (e.g., potassium citrate), bicarbonates (e.g., sodium bicarbonate), phosphate buffer (e.g., Na 2 HPO 4 , NaH 2 PO 4 and K.H. 2 PO 4 ), TRIS (tris(hydroxymethyl)aminomethane), 2-bis(2-hydroxyethyl)amino-2-(hydroxymethyl)-1,3-propanediol, bis-aminopolyols, triethanolamine, ACES (N-(2-acetamido)-2-aminoethanesulfonic acid), BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid), HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), MOPS (3-[N-morpholino]-propanesulfonic acid), Examples of the buffering agent include piperazine-N,N'-bis(2-ethanesulfonic acid), PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid), TES (N-[tris(hydroxymethyl)methyl]-2-aminoethanesulfonic acid), and salts thereof. Each buffering agent is used in an amount necessary to be effective in achieving the desired pH, and typically, these buffering agents are present in the above solution in an amount of 0.001% by mass to 2% by mass, preferably 0.01% by mass to 1% by mass, and more preferably 0.05% by mass to 0.30% by mass. Each buffering agent may be present in a range that combines any of the above upper and lower limits.

[0062] The heating method includes high-pressure steam sterilization, electromagnetic wave (gamma rays, microwaves, etc.) irradiation, dry heat method, flame method, etc. High-pressure steam sterilization is most preferable from the viewpoint of suppressing mucus adhesion, suppressing cilia loss and goblet cell overgrowth, and shortening the manufacturing process. An autoclave is preferably used as the apparatus.

[0063] The heating temperature is preferably within the range of 60° C. to 200° C., from the viewpoint of obtaining a stent having a good function of suppressing mucus adhesion and a good function of suppressing cilia loss and goblet cell hyperproliferation, and having little effect on the strength of the stent itself. The heating temperature is more preferably 80° C. or higher, even more preferably 100° C. or higher, even more preferably 101° C. or higher, and most preferably 110° C. or higher. The heating temperature is more preferably 180° C. or lower, even more preferably 170° C. or lower, and most preferably 150° C. or lower.

[0064] If the heating time is too short, a stent having good functions of suppressing mucus adhesion and suppressing cilia loss and goblet cell hyperproliferation cannot be obtained, and if the heating time is too long, the strength of the stent itself is affected, so the heating time is preferably within the range of 5 to 600 minutes. The heating time is preferably 10 minutes or more, more preferably 15 minutes or more. The heating time is preferably 400 minutes or less, more preferably 300 minutes or less.

[0065] After the above heat treatment, the obtained stent may be subjected to other treatments. Examples of other treatments include a method of performing the same heat treatment again in a solution containing a hydrophilic polymer having a hydroxyl group, a method of replacing the solution with one not containing a hydrophilic polymer and performing the same heat treatment, a method of performing the same heat treatment again in a solution not containing a polymer, a method of irradiating radiation, a method of performing an LbL treatment (Layer by Layer treatment) in which a polymer material having an opposite charge is alternately coated layer by layer on a substrate, a method of performing a crosslinking treatment with metal ions, a method of performing a chemical crosslinking treatment, and the like. However, in light of the idea of ​​the present disclosure that the stent surface can be hydrophilized by a simple method, it is preferable to perform the treatment within a range that does not make the manufacturing process too complicated.

[0066] The radiation used in the above-mentioned radiation irradiation is preferably various ion beams, electron beams, positron beams, X-rays, gamma rays, or neutron beams, more preferably electron beams and gamma rays, and most preferably gamma rays.

[0067] As the LbL treatment, for example, a treatment using an acidic polymer and a basic polymer as described in WO 2013 / 024800 may be used.

[0068] As the metal ion used in the above-mentioned crosslinking treatment with metal ions, various metal ions are preferable, more preferably monovalent and divalent metal ions, and most preferably divalent metal ions. Chelate complexes may also be used.

[0069] As the above-mentioned chemical crosslinking treatment, for example, a reaction between an epoxide group and a carboxyl group as described in JP 2014-533381 A (WO 2013 / 074535 A) or a known crosslinking treatment formed with an acidic hydrophilic polymer having a suitable hydroxyl group may be used. In the method of replacing the above solution with a solution not containing a hydrophilic polymer and carrying out the same heat treatment, the solution not containing a hydrophilic polymer is not particularly limited, but it is preferable to use a buffer solution. The buffer may be any of the above.

[0070] The pH of the buffer solution is preferably in the physiologically acceptable range of 6.3 to 7.8. The pH of the buffer solution is preferably 6.5 or higher, more preferably 6.8 or higher. The pH of the buffer solution is preferably 7.6 or lower, more preferably 7.4 or lower.

[0071] In order to exhibit the function of suppressing mucus adhesion and the function of suppressing cilia loss and goblet cell hyperproliferation while functioning as a respiratory stent, the ratio X:Y of the thickness X of the layer containing the hydrophilic polymer to the thickness Y of the base material in a dry state is preferably within the range of 1:400 to 1:120000, more preferably 1:800 to 1:100000, even more preferably 1:1200 to 1:80000, and particularly preferably 1:1500 to 1:60000.

[0072] The shape of the stent according to this embodiment will be described. 1, 3 and 4 are diagrams illustrating a stent according to the present embodiment. The shape of the stent according to this embodiment is not particularly limited, but the stent may include a tubular structural portion as shown in Fig. 1. The stent according to this embodiment may be branched as shown in Fig. 4. It is preferable that the stent according to this embodiment is one that matches the shape of the respiratory tract to which it is applied. The size of the stent according to the present embodiment is not particularly limited, but in order to function as a respiratory stent, the outer diameter of the tubular structure is preferably 4 mm or more and 24 mm or less, and the thickness of the stent is preferably 0.2 mm or more and 2 mm or less. The outer diameter of the tubular structure is preferably 6 mm or more and 20 mm or less, and the thickness of the stent is preferably 0.25 mm or more and 1.5 mm or less. The "outer diameter" used herein is defined to include protrusions or irregularities formed on the outer peripheral surface. If no protrusions or irregularities are formed on the outer peripheral surface, the "outer diameter" is defined as the casting not including the protrusions or irregularities, and it is sufficient that the part of the stent has an outer diameter within the above range.

[0073] As described above, the shape of the stent according to the present embodiment is not particularly limited, but in order to prevent the stent from moving after placement, it is preferable that the outer surface of the stent has projections or irregularities formed thereon. It is preferable that a plurality of projections or irregularities are formed. The multiple protrusions may be arranged regularly or randomly. When protrusions are formed on the outer surface of the stent, the plurality of protrusions 40A may be arranged in a regular or random manner, for example as shown in FIGS. The protrusions or irregularities may be locally located on the outer surface, may be located over the entire outer surface, or may be scattered over the outer surface.

[0074] The shape of the protrusions 40A is not particularly limited, and may be hemispherical, cylindrical, conical, columnar, polygonal pyramidal, hook-shaped, etc. More specifically, for example, each protrusion 40A may be hemispherical as shown in Fig. 1 or cylindrical as shown in Fig. 3. The shape of the projections and recesses is not particularly limited and may be pleated, embossed, patterned (lines, waves, stars), etc. More specifically, for example, the projections and recesses may be pleated as shown in Fig. 5, or a linear pattern such as the projections 40B of the stent shown in Fig. 6. When protrusions or irregularities are arranged on the outer surface of the stent, the size of the protrusions is not particularly limited. From the viewpoint of suppressing irritation to tissues, the size of the protrusions is preferably 4 mm or less, more preferably 3 mm or less, and even more preferably 2 mm or less. In order to exert the function of inhibiting migration of the stent after placement, the size of the projections is preferably 0.1 mm or more, and more preferably 0.2 mm or more.

[0075] In order to prevent the stent from moving after placement, for example, highly accurate anatomical data based on 3DCT can be created, and a stent of a size and shape suitable for the shape of the respiratory system of the patient to which it is applied can be created using 3D printing technology based on anatomical analysis. In addition, the difference between the lumen diameter of the respiratory system in which the stent is placed and the outer diameter of the stent is preferably 10% or less, more preferably 8% or less, even more preferably 6% or less, and particularly preferably 5% or less.

[0076] <How to relieve respiratory obstruction and ensure airflow> The method of this embodiment for relieving respiratory obstruction and ensuring airflow is a method for relieving respiratory obstruction and ensuring airflow using a respiratory stent having an inner surface and an outer surface, the stent having a base material and a hydrophilic polymer layer, the hydrophilic polymer layer including a hydrophilic polymer having a hydroxyl group and an amide group, and the hydrophilic polymer layer is disposed on at least a portion of the inner surface.

[0077] The method of this embodiment for relieving respiratory obstruction and ensuring airflow uses the above-mentioned stent, which can suppress mucus adhesion, is a method with excellent biocompatibility, and can suppress the occurrence of complications. In the method for relieving obstruction in the respiratory tract and ensuring airflow according to this embodiment, the above description can be applied to the stent as is. [Industrial Applicability]

[0078] The stent according to the present embodiment is a stent for the respiratory system, and can be applied to, for example, the airway, oral cavity, nasal cavity, larynx, trachea, bronchi, bronchioles, lungs, etc. The stent according to the present embodiment can also be applied to applications in which the stent is transplanted into narrowed sites of various body cavities or vessels other than the respiratory system (e.g., the vascular system, esophagus, gastrointestinal tract, large intestine and small intestine, bile duct, pancreatic duct, pulmonary duct, ureter, nasal cavity and airway, trachea, bronchi, etc.) to secure the lumen. EXAMPLES

[0079] Hereinafter, illustrative aspects of the present disclosure will be described in detail with reference to examples and comparative examples, but the present disclosure is not limited thereto.

[0080] (Measurement example 1: Water wettability (liquid film retention time)) The stent was lightly washed in 100 mL of phosphate buffer in a beaker at room temperature (23°C to 25°C), and then immersed in 100 mL of fresh phosphate buffer for 24 hours or more. The stent was removed from the phosphate buffer and held in the air, and the time the liquid film on the surface was maintained was visually observed, and the average time of three measurements was evaluated according to the following criteria.

[0081] A: The liquid film on the surface is maintained for more than 60 seconds. B: The liquid film on the surface disappears in 30 to 60 seconds. C: The liquid film on the surface disappears in 5 to 30 seconds. D: The liquid film on the surface disappears in less than 5 seconds.

[0082] (Measurement example 2: Weight average molecular weight measurement) The weight average molecular weight of the hydrophilic polymer used was measured under the conditions shown below.

[0083] (GPC measurement conditions) Equipment: Shimadzu Corporation "Prominence GPC System" Pump: LC-20AD Autosampler: SIL-20AHT Column oven: CTO-20A Detector: RID-10A Column: Tosoh GMPWXL (inner diameter 7.8 mm x 30 cm, particle size 13 μm) Solvent: Water / methanol = 1 / 1 (0.1N lithium nitrate added) Flow rate: 0.5mL / min Measurement time: 30 minutes Sample concentration: 0.1% by mass Injection volume: 100μL Standard sample: Agilent polyethylene oxide standard sample (0.1 kD to 1258 kD)

[0084] (Measurement example 3: Initial pH measurement method) The pH of the solution was measured using a pH meter "Eutech pH2700" manufactured by Eutech Instruments. In the table, the initial pH of the solution containing a hydrophilic polymer having a hydroxyl group is the pH measured after adding all of the hydrophilic polymer to the solution described in each Example, stirring the solution with a rotator at room temperature (23 to 25°C) for 2 hours to make the solution uniform.

[0085] (Measurement Example 4: Determination of separation of layer containing hydrophilic polymer) Whether or not the layer containing the hydrophilic polymer was separated into two or more layers was judged by observing the cross section of the stent using a transmission electron microscope. Equipment: Transmission electron microscope, Hitachi "H-7100FA" Accelerating voltage: 100kV Sample preparation: Silicone-based substrate (RuO 4 Stained ultrathin section method) Hydrogel-based substrate (OsO 4Stained ultrathin sectioning or RuO 4 Stained ultrathin section method)

[0086] (Measurement Example 5: Elemental composition analysis of layer containing hydrophilic polymer) The elemental composition of the layer containing the hydrophilic polymer was analyzed by analyzing a cross section of the stent frozen in a hydrated state using a cryotransfer holder by scanning transmission electron microscopy and electron energy loss spectroscopy. Equipment: Field emission electron microscope (JEOL "JEM-2100F") Accelerating voltage: 200kV Measurement temperature: about -100℃ Electron Energy Loss Spectroscopy: GATAN GIF Tridiem Image acquisition: Digital Micrograph Sample preparation: RuO 4 Stained frozen ultrathin section method

[0087] (Measurement Example 6: Film Thickness of Layer Containing Hydrophilic Polymer) The thickness of the layer containing the hydrophilic polymer in a dry state was measured by observing the cross section of the stent in a dry state using a transmission electron microscope. Measurements were performed under the conditions described above in (Measurement Example 4: Determination of Separation of the Layer Containing a Hydrophilic Polymer). The thickness was measured at 5 locations in each field of view at 7 different locations, for a total of 35 locations. The average thicknesses measured are shown in Table 1. The thickness of the layer containing the hydrophilic polymer in a frozen state was measured by observing the cross section of the stent frozen in a water-containing state using a cryotransfer holder with a transmission scanning electron microscope. Measurements were performed under the conditions described above (Measurement Example 5: Elemental composition analysis of the layer containing the hydrophilic polymer). The thickness was measured at 5 locations in each field of view at 7 different locations, for a total of 35 locations. The average thicknesses of the measured thicknesses are shown in Table 1.

[0088] (Measurement Example 7: In vitro mucus adhesion test) Mucin was purified from saliva and a mucin solution with a concentration of 100 μg / mL was prepared. Stents were punched into disk shapes with a diameter of 4 mm and placed in 48 wells of a microtiter plate. 600 μL of mucin solution with a concentration of 100 μg / mL was added to each well and incubated at 37 °C for 20 to 24 hours. As a control, PBS was added instead of the mucin solution and incubated at 37 °C for 20 to 24 hours. After washing three times with PBS, blocking buffer (ThermoFisher Scientific 37570) was added and incubated at room temperature (23 °C to 25 °C) for 1 hour. After washing three times with PBS, WGA (Biotinylated Wheat Germ Agglutinin (WGA) [Vector Laboratories B-1025-5], diluted 500 times with PBS) was added and incubated at room temperature for 1 hour. After washing three times with PBS, horseradish peroxidase (HRP)-labeled streptavidin (HRP-Streptavidin [Sigma-Aldrich RABHRP3-600UL]) was added and incubated at room temperature for 1 hour. After washing three times with PBS, 250 μL of TMB (3,3′,5,5′-Tetramethylbenzidine (TMB) substrate [Thermo Scientific PI34028]) solution was added and incubated at room temperature for 15 to 30 minutes. After removing the sample, 250 μL of 2 M sulfuric acid was added, and the absorbance at 450 nm was measured with a microplate spectrophotometer to calculate the amount of mucus (mucin) attached, as shown in the following formula (1).

[0089] (Mucus adhesion amount (%)) = (As-Asb) × 100 / (Ac-Acb) (1) As: absorbance of sample Asb: Absorbance of the blank solution of the sample (incubated overnight in PBS instead of mucin solution) Ac: Absorbance of silicone stent (Dumon stent) Acb: Absorbance of a blank solution of a silicone stent (Dumon stent) (incubated overnight in PBS instead of mucin solution)

[0090] (Measurement Example 8: Evaluation of biocompatibility by airway stent implantation test into porcine bronchus) Based on the literature by HS Jung et al. (Scientific Reports 11, 7958, 2021), airway stents were placed in the pig bronchi to a depth of approximately 1 cm, and the surface of the placed airway stent was periodically observed using a bronchoscope. Two airway stents were placed per pig (one in the left bronchus and one in the right bronchus). Four weeks after placement, mucus was collected from and around each airway stent, and the mucus mass was measured. Four weeks after placement, the airway stents were removed and HE-stained (hematoxylin and eosin stained) and PAS-stained (periodic acid-Schiff stained) specimens were prepared. The specimens were observed under a microscope and the degree of cilia loss and the number of goblet cells were scored according to the following criteria.

[0091] Cilia disappearance (HE staining): None:0 Low:1 Medium: 2 High: 3

[0092] Goblet cells (PAS staining): 0~20%:0 More than 20% to less than 60%: 1 Over 60% ~ 80% or less: 2 Over 80% ~ 90% or less: 3 Over 90%~100%: 4

[0093] [Phosphate buffer] The compositions of the phosphate buffer solutions used in the processes of the following Examples and Comparative Examples and in the above-mentioned measurements are as follows. KCl: 0.2g / L KH 2 PO 4 : 0.2g / L NaCl: 8.0g / L Na2 HPO 4 (anhydrous): 1.15g / L EDTA: 0.25g / L

[0094] [Reference example 1] Using liquid silicone rubber for 3D printers (SILASTIC(R) 3D 3335 LSR, manufactured by Dow) and a 3D printer "L320" manufactured by German RepRap, a silicone stent substrate with an outer diameter of 14 mm, a thickness of 1 mm, and a length of 4 cm was fabricated (Figure 5).

[0095] [Example 1] The silicone stent substrate of Reference Example 1 was placed in a solution of 0.2% by mass of acrylic acid / N,N-dimethylacrylamide copolymer (molar ratio in copolymerization 1 / 9, Mw: 800000, manufactured by Osaka Organic Chemical Industry Co., Ltd.) in pure water, adjusted to pH 2.8 with citric acid, and the solution was heated in an autoclave at 121° C. for 30 minutes. The resulting stent was washed with a phosphate buffer solution, naturally dried, and then evaluated by the above-mentioned method. The results are shown in Table 1. As a result of performing elemental composition analysis of the layers containing the hydrophilic polymer in the above Measurement Example 5, one layer was a mixed layer of the components of the substrate and the components of the hydrophilic polymer layer, and the other layer was a layer of the hydrophilic polymer alone.

[0096] [Example 2] The silicone stent substrate of Reference Example 1 was placed in a solution containing 0.2 mass% of acrylic acid / N,N-dimethylacrylamide copolymer (molar ratio in copolymerization 1 / 9, Mw: 700,000, manufactured by Osaka Organic Chemical Industry Co., Ltd.) in a phosphate buffer solution adjusted to pH 2.6 with citric acid, and the solution was heated in an autoclave at 121° C. for 30 minutes. The obtained stent was washed with a phosphate buffer solution, naturally dried, and then evaluated by the above-mentioned method. The results are shown in Table 1.

[0097] [Example 3] The silicone stent substrate of Reference Example 1 was placed in a solution of 0.2% by mass of acrylic acid / N,N-dimethylacrylamide copolymer (molar ratio in copolymerization 1 / 9, Mw: 800000, manufactured by Osaka Organic Chemical Industry Co., Ltd.) in pure water, adjusted to pH 2.5 with citric acid, and the solution was heated in an autoclave at 121° C. for 30 minutes. The resulting stent was washed with a phosphate buffer solution, naturally dried, and then evaluated by the above-mentioned method. The results are shown in Table 1.

[0098] [Example 4] The silicone stent substrate of Reference Example 1 was placed in a solution containing 0.1% by mass of acrylic acid / vinylpyrrolidone copolymer (molar ratio in copolymerization 1 / 4, Mw: 500,000, manufactured by Osaka Organic Chemical Industry Co., Ltd.) in a phosphate buffer solution adjusted to pH 3.2 with citric acid, and the solution was heated in an autoclave at 121° C. for 30 minutes. The resulting stent was washed with a phosphate buffer solution, naturally dried, and then evaluated by the above-mentioned method. The results are shown in Table 1.

[0099] [Example 5] A silicone stent (Dumon stent) substrate was placed in a solution containing 0.2% by mass of acrylic acid / N,N-dimethylacrylamide copolymer (molar ratio in copolymerization 1 / 9, Mw: 800,000, manufactured by Osaka Organic Chemical Industry Co., Ltd.) in a phosphate buffer solution adjusted to pH 3.3 with citric acid, and the solution was heated in an autoclave at 121° C. for 30 minutes. The resulting stent was washed with a phosphate buffer solution, naturally dried, and then evaluated by the above method. The results are shown in Table 1.

[0100] [Example 6] A silicone stent (Dumon stent) substrate was placed in a solution containing 0.2% by mass of acrylic acid / N,N-dimethylacrylamide copolymer (molar ratio in copolymerization 1 / 9, Mw: 500,000, manufactured by Osaka Organic Chemical Industry Co., Ltd.) in a phosphate buffer solution adjusted to pH 3.0 with citric acid, and the solution was heated in an autoclave at 121° C. for 30 minutes. The resulting stent was washed with a phosphate buffer solution, naturally dried, and then evaluated by the above method. The results are shown in Table 1.

[0101] [Example 7] A silicone stent (Dumon stent) substrate was placed in a solution containing 0.2% by mass of acrylic acid / N,N-dimethylacrylamide copolymer (molar ratio in copolymerization 1 / 2, Mw: 700,000, manufactured by Osaka Organic Chemical Industry Co., Ltd.) in a phosphate buffer solution adjusted to pH 3.1 with citric acid, and the solution was heated in an autoclave at 121° C. for 30 minutes. The resulting stent was washed with a phosphate buffer solution, naturally dried, and then evaluated by the above method. The results are shown in Table 1.

[0102] [Example 8] A silicone stent (Dumon stent) substrate was placed in a solution containing 0.1% by mass of acrylic acid / vinylpyrrolidone copolymer (molar ratio in copolymerization 1 / 4, Mw: 800,000, manufactured by Osaka Organic Chemical Industry Co., Ltd.) in a phosphate buffer solution adjusted to pH 4.1 with citric acid, and the solution was heated in an autoclave at 121° C. for 30 minutes. The resulting stent was washed with a phosphate buffer solution, naturally dried, and then evaluated by the above method. The results are shown in Table 1.

[0103] [Example 9] A silicone stent (Dumon stent) substrate was placed in a solution containing 0.1% by mass of acrylic acid / vinylpyrrolidone copolymer (molar ratio in copolymerization 1 / 9, Mw: 400,000, manufactured by Osaka Organic Chemical Industry Co., Ltd.) in a phosphate buffer solution adjusted to pH 4.3 with citric acid, and the solution was heated in an autoclave at 121° C. for 30 minutes. The resulting stent was washed with a phosphate buffer solution, naturally dried, and then evaluated by the above method. The results are shown in Table 1.

[0104] [Example 10] A silicone stent (Dumon stent) substrate was placed in a solution containing 0.2% by mass of acrylic acid / N,N-dimethylacrylamide copolymer (molar ratio in copolymerization 1 / 9, Mw: 500,000, manufactured by Osaka Organic Chemical Industry Co., Ltd.) in a phosphate buffer solution adjusted to pH 2.7 with citric acid, and the solution was heated in an autoclave at 121° C. for 30 minutes. The resulting stent was washed with a phosphate buffer solution, naturally dried, and then evaluated by the above method. The results are shown in Table 1.

[0105] [Example 11] A silicone stent (Dumon stent) substrate was placed in a solution containing 0.2% by mass of acrylic acid / N,N-dimethylacrylamide copolymer (molar ratio in copolymerization 1 / 9, Mw: 800,000, manufactured by Osaka Organic Chemical Industry Co., Ltd.) in a phosphate buffer solution adjusted to pH 2.9 with citric acid, and the solution was heated in an autoclave at 121° C. for 30 minutes. The resulting stent was washed with a phosphate buffer solution, naturally dried, and then evaluated by the above method. The results are shown in Table 1.

[0106] [Comparative Example 1] A silicone stent (Dumon stent) substrate was washed with a phosphate buffer solution, naturally dried, and then evaluated using the above-mentioned method. The results are shown in Table 1.

[0107] [Comparative Example 2] The silicone stent substrate of Reference Example 1 was washed with a phosphate buffer solution, naturally dried, and then evaluated by the above-mentioned method. The results are shown in Table 1.

[0108] [Comparative Example 3] A silicone stent (Dumon stent) substrate was placed in a solution containing 0.03% by mass of acrylic acid / N,N-dimethylacrylamide copolymer (molar ratio in copolymerization 1 / 2, Mw: 500,000, manufactured by Osaka Organic Chemical Industry Co., Ltd.) in a phosphate buffer solution adjusted to pH 3.2 with citric acid, and the solution was heated in an autoclave at 121° C. for 30 minutes. The resulting stent was washed with a phosphate buffer solution, naturally dried, and then evaluated by the above method. The results are shown in Table 1.

[0109] [Comparative Example 4] The silicone stent substrate of Reference Example 1 was placed in a solution containing 0.03 mass% of acrylic acid / vinylpyrrolidone copolymer (molar ratio in copolymerization 1 / 4, Mw: 500,000, manufactured by Osaka Organic Chemical Industry Co., Ltd.) in a phosphate buffer solution adjusted to pH 4.5 with citric acid, and the solution was heated in an autoclave for 30 minutes at 121° C. The resulting stent was washed with a phosphate buffer solution, naturally dried, and then evaluated by the above-mentioned method. The results are shown in Table 1.

[0110] [Example 12] The stent obtained in Example 8 was evaluated by the method described in Measurement Example 8, and the results are shown in Table 2.

[0111] [Example 13] The stent obtained in Example 11 was evaluated by the method described in Measurement Example 8, and the results are shown in Table 2.

[0112] [Comparative Example 5] The stent obtained in Comparative Example 1 was evaluated by the method described in Measurement Example 8, and the results are shown in Table 2.

[0113] [Comparative Example 6] The stent obtained in Comparative Example 3 was evaluated by the method described in Measurement Example 8, and the results are shown in Table 2.

[0114] [Example 14] A silicone stent (Dumon stent) base material was placed in a solution containing 0.2 mass% of acrylic acid / N,N-dimethylacrylamide copolymer (molar ratio in copolymerization 1 / 9, Mw: 800000, manufactured by Osaka Organic Chemical Industry Co., Ltd.) in a phosphate buffer solution adjusted to pH 2.9 with citric acid, and the solution was heated in an autoclave at 121°C for 30 minutes. The obtained stent was washed with a phosphate buffer solution, naturally dried, and then heated again in a phosphate buffer solution at 121°C for 30 minutes in an autoclave. The obtained stent was washed with a phosphate buffer solution, naturally dried, and then evaluated by the above method. The results are shown in Table 1.

[0115] [Example 15] A solution containing 0.2% by mass of acrylic acid / N,N-dimethylacrylamide copolymer (molar ratio in copolymerization 1 / 9, Mw: 800000, manufactured by Osaka Organic Chemical Industry Co., Ltd.) in phosphate buffer was adjusted to pH 2.9 with citric acid to prepare a solution. A silicone stent (Dumon stent) base material was placed in the solution so that only the outside of the base material was in contact with the solution, and the solution was heated in an autoclave at 121°C for 30 minutes. The obtained stent was washed with phosphate buffer, naturally dried, and then evaluated by the above method. The results are shown in Table 1.

[0116] [Example 16] The stent obtained in Example 14 was evaluated by the method described in Measurement Example 8, and the results are shown in Table 2.

[0117] [Example 17] The stent obtained in Example 15 was evaluated by the method described in Measurement Example 8, and the results are shown in Table 2.

[0118] For each of the stents obtained in Examples 1 to 11, 14, and 15 and Comparative Examples 3 and 4, elemental composition analysis of the layer containing the hydrophilic polymer was performed using Measurement Example 5 above. As a result, it was found that one layer was a mixed layer of a component of the base material and a component of the hydrophilic polymer layer, and the other layer was a layer of hydrophilic polymer alone.

[0119] [Table 1]

[0120] [Table 2]

[0121] [Table 3] [Explanation of symbols]

[0122] 10 Stents 11 Inner surface 12 Outer surface 21 Substrate 22 Mixed layer 23 Hydrophilic polymer layer 40A Protrusion 40B Protrusion

Claims

1. 1. A respiratory stent having an inner surface and an outer surface, The stent has a substrate and a hydrophilic polymer layer; the hydrophilic polymer layer contains a hydrophilic polymer having a hydroxyl group and an amide group, A stent having the hydrophilic polymer layer on at least a portion of the inner surface.

2. 1. A respiratory stent having an inner surface and an outer surface, The stent has a substrate and a hydrophilic polymer layer; the hydrophilic polymer layer contains a hydrophilic polymer having a hydroxyl group and an amide group, A stent having the hydrophilic polymer layer on at least a portion of the outer surface.

3. The stent of claim 1 or 2, wherein the substrate comprises a silicone resin.

4. The stent according to claim 1 or 2, further comprising a mixed layer of a component of the base material and a component of the hydrophilic polymer layer, the mixed layer being provided between the base material and the hydrophilic polymer layer.

5. 3. The stent according to claim 1, wherein a ratio X:Y of a thickness X of the layer containing the hydrophilic polymer to a thickness Y of the substrate is within a range of 1:400 to 1:120000.

6. 3. The stent of claim 1 or 2, comprising a tubular structural portion.

7. The stent according to claim 6, wherein the tubular structural portion has an outer diameter of 4 mm or more and 24 mm or less, and a thickness of 0.2 mm or more and 2 mm or less.

8. The stent according to claim 1 or 2, wherein the outer surface has a plurality of protrusions or irregularities.

9. 3. The stent of claim 1 or 2, wherein the respiratory tract is an airway, a bronchus, or a lung.

10. 3. The stent according to claim 1, wherein the hydrophilic polymer having a hydroxyl group and an amide group is at least one polymer selected from the group consisting of polyamides having a carboxyl group and copolymers of a monomer having a hydroxyl group and a monomer having an amide group.

11. The stent according to claim 10, wherein the monomer having a hydroxyl group is at least one monomer selected from the group consisting of methacrylic acid, acrylic acid, vinylbenzoic acid, thiophene-3-acetic acid, 4-styrenesulfonic acid, vinylsulfonic acid, 2-acrylamido-2-methylpropanesulfonic acid, and salts thereof.

12. The monomer having an amide group is N-vinylpyrrolidone, N-vinylacetamide, N,N-dimethylacrylamide, N,N-diethylacrylamide, N-isopropylacrylamide, 11. The stent according to claim 10, wherein the monomer is at least one monomer selected from the group consisting of acrylamide, N-(2-hydroxyethyl)acrylamide, and acrylamide.

13. 1. A method for relieving respiratory obstruction and ensuring airflow using a respiratory stent having an inner surface and an outer surface, comprising: The stent has a substrate and a hydrophilic polymer layer; the hydrophilic polymer layer contains a hydrophilic polymer having a hydroxyl group and an amide group, A method of relieving obstruction and allowing airflow in the respiratory system, comprising the hydrophilic polymer layer on at least a portion of the inner surface.

14. 1. A method for relieving respiratory obstruction and ensuring airflow using a respiratory stent having an inner surface and an outer surface, comprising: The stent has a substrate and a hydrophilic polymer layer; the hydrophilic polymer layer contains a hydrophilic polymer having a hydroxyl group and an amide group, A method of relieving obstruction and allowing airflow in the respiratory system, comprising the hydrophilic polymer layer on at least a portion of the outer surface.

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