JP2008539807A - Medical supplies - Google Patents

Abstract

A guide shaft of a medical article such as a guide wire, an embolization device, or a microcatheter includes a solid and / or non-expandable core member made of, for example, metal (such as tantalum), and an outer surface layer formed by electrospun nanofibers. ,including. The outer surface layer can include a pharmacologically active substance (such as a nitric oxide (NO) donor) for release in the biological vasculature or neurovascular system. NO donors can be incorporated into polymers such as linear poly (ethyleneimine) diazeniumdiolate.

Description

  The present invention relates to a medical article and a method for manufacturing the same, and more particularly to a guide wire or an embolization device.

  Medical supplies such as guidewires and embolic devices are often used in various diagnostic procedures and treatments. These medical supplies often include a drug that elutes into the surrounding tissue after placement to prevent side effects such as cell proliferation. In general, it is desirable for a medical article for insertion into a living vasculature to meet certain physical requirements. For example, the medical article must be able to follow a tortuous path to the treatment site while having sufficient rigidity to allow reliable insertion. Also, to facilitate insertion, the surface of the medical article must be hydrophilic and have low surface friction. The surface of the medical article may be coated with a polymer matrix containing nitric oxide. The matrix that releases nitric oxide can alleviate or prevent arterial spasm after the medical article is placed at the site of interest. Medical articles intended to release a medicament after being inserted into a living vasculature may be coated or coated with a suitable pharmaceutical compound. An inflatable stent may be placed on an angioplasty balloon catheter that is placed at the site of interest and then expanded to expand the stent. Alternatively, the stent can be formed of a resilient material such as a superelastic alloy such as Nitinol so that it automatically expands after being placed at the target site. Such self-expanding stents are often transmitted by a stretchable tube member where the outer member is removed by sliding over the inner member to which the stent is secured prior to expansion, for example. The

  The embolic device is used, for example, for blocking blood to a tumor region or treating an aneurysm.

  Various medical supplies including stents and catheters and methods for manufacturing the same have been proposed. U.S. Pat. No. 6,030,371 discloses a non-extrusion manufacturing method for catheters that can be used to manufacture catheters. A particulate preform of polymeric material is applied in layers on the outer surface of the core member.

  By forming a layer of particulate preform by application, the composition of the polymer material can be varied during application and the hardness can be varied over the length of the catheter. Fiber reinforcements having a constant or indefinite pitch and a constant or indefinite number and type of fibers can be used. U.S. Pat. No. 6,030,371 discloses using a plurality of mandrels arranged side by side to form a multilumen tube.

  Various nitric oxide (NO) donor compounds, pharmaceutical compositions containing nitric oxide donor compounds, and polymer compositions capable of releasing nitric oxide have been proposed. For example, European Patent No. 1220694 B1, corresponding to US Pat. No. 6,737,447 B1, describes a linear poly (ethyleneimine) diazenium diolate that forms a coating layer on a medical article. ) Of at least one nanofiber. This polymer is effective for supplying nitric oxide to the surrounding tissue of the medical article. EP 1220694 B1 refers to the possibility of depositing polymers in an electrospinning process.

  The object of a preferred embodiment of the present invention is a coated solid and / or non-expandable medical article (such as a guide wire or embolization device) that allows for precise control of manufacturing. Is to provide. Another object of a preferred embodiment is to provide a medical article coated with a material that can deliver an effective amount of a pharmacologically active substance to a treatment site and that can efficiently release the pharmacologically active substance at the treatment site. There is to do.

  In a first aspect, the present invention provides a medical article comprising a solid and / or non-expandable core member having an outer surface layer formed by electrospun nanofibers. The present invention also provides a method of manufacturing a medical article comprising a solid and / or non-intumescent core member having an outer surface layer, comprising forming the outer surface layer by electrospinning nanofibers. .

  The inventors have noted that solid and / or non-inflatable core members (eg, guide wires or embolic devices) such as wires or particles (especially metal or polymer wires or particles) are core members having a small diameter. Has also been found to be advantageously coated with electrospun nanofibers such as fibers that provide a large surface area. Accordingly, such a coating is useful as a storage material for a medicament that is released at a treatment site (such as the biological vascular system or neurovascular system). In addition, electrospinning has high accuracy, and a medical product with low surface friction can be obtained.

  The core member may consist essentially of a thread or helical coil member preferably made of a metal or a polymer such as a biodegradable polymer (such as polylactic acid). The helical coil member can form any curved trajectory in space. For example, the helical coil member can form a coil spring or a three-dimensional sphere in which the coil member obviously extends at random so as to coincide with the cavity at the use site in the living body. In an embodiment, another coil or a three-dimensional sphere may be wound around a coil spring-like first coil. Coil members are often used as embolization devices.

  Alternatively, the core member can include one or more particles (preferably metal particles such as tantalum or tungsten particles) in which a single fiber is applied by electrospinning. The particles may be provided on a film of plastic material supported during application by electrospinning, or may be coated with electrospun nanofibers in a fluidized bed. The fluidized bed may be provided using an air stream at a negative potential and the electrospinning source may be at a positive potential. Particles provided with an electrospun single fiber can be injected into a living body by a microcatheter, and the microcatheter is manufactured by nanofiber electrospinning. Particles coated with electrospun nano monofilaments are often used as embolic devices.

  For example, a fibrous surface or thrombogenic material provided on a coil member coated with nanospun fibers has been found to promote the formation of thrombi or emboli advantageous for the treatment of arterial disease in the vasculature. .

  The diameter of the nanofiber is usually 2 to 4000 nm, preferably 2 to 3000 nm, and a large number of nanofibers will be present on the outer surface of the medical article. Thus, the nanofibers on the outer surface of the medical article form a large cumulative area and the area relative to the weight of the medical article is greater than the area obtained by other surfaces that are not electrospun. Thus, compared to the weight of the coated medical article, the electrospun surface can constitute a fairly large reservoir of pharmacologically active substance. Nanofibers can also be made to have a diameter of 0.5 nm, which is close to the size of a single molecule.

  It has been found that the spinning of the nanofibers can be controlled more easily and accurately than the method of spraying the polymer only on the core. This has the advantage that the medical article can be formed with a smaller size than before (eg, with a smaller diameter). According to the present invention, compared with a medical article having a large diameter, a medical article having a relatively small diameter that facilitates introduction into the vascular system of a living body and reduces side effects that may occur as a result of the introduction of the medical article. Can be manufactured. Spinning nanofibers can produce an integral composite medical article in which two or more materials are combined on a small size molecular scale while maintaining sufficient mechanical stability. A cross-sectional area equivalent to a size of about 2-5 molecules of the spun material can be achieved. The size of the molecule obviously depends on the material used. The size of the polyurethane molecule is usually less than 3000 nm. Therefore, it is possible to manufacture a medical article having a very small diameter than before. For example, a conventional stent has a diameter of 2 mm or more.

  It has also been found that medical articles made by a preferred embodiment of the method according to the present invention have low surface friction. In embodiments of the present invention, low surface friction can be achieved by using a water-absorbing material as the fiber forming material for the electrospinning process. Thus, when introduced into the vascular system, the water-absorbing electrospun material absorbs body fluids and a hydrophilic low friction surface is obtained. For example, a water absorbing surface can be obtained using polyurethane or polyacrylic acid materials.

  The term “electrospinning” includes the process of applying particles to a substrate maintained at a certain potential (preferably a constant potential, preferably a negative potential). The particles are supplied from a source of another potential (preferably a positive potential). The positive potential and the negative potential can be balanced, for example, with reference to the potential of the surrounding environment (that is, the room where the process is performed). The potential of the substrate relative to the potential of the ambient environment is preferably -5 to -30 kV, and the positive potential of the source relative to the potential of the ambient environment is preferably +5 to +30 kV. The potential difference between is 10-60 kV.

  In recent years, nanofiber electrospinning technology has been greatly developed. US Pat. No. 6,382,526 discloses methods and apparatus for producing nanofibers, which are useful in the method according to the present invention. US Pat. No. 6,520,425 discloses a nozzle for forming nanofibers. Although the methods and apparatuses disclosed in these US patents can be applied to the method according to the present invention, the protection scope of the present invention is not limited to these methods and apparatuses.

  In the case of a long medical product such as a guide wire, a plurality of portions may be formed along the length. For example, the plurality of portions can have different characteristics (such as different hardnesses). Such different characteristics can be attributed to the use of different fiber forming materials in different parts and / or manufacturing parameters (electrode voltage in electrospinning process, distance between high and low voltage side electrodes, medical supplies ( Alternatively, it can be obtained by changing the rotation speed, electric field strength, corona discharge start voltage, corona discharge current, etc.) of the core wire around which the medical article is manufactured.

  The outer surface layer of the medical article can store a medicament. The electrospun portion of the outer surface layer constitutes a reservoir location for holding the drug, or the drug is sequestered in or attached to the molecular chain or constitutes a matrix polymer source surrounding the molecular chain can do. The medical article disclosed herein can carry a suitable medicine such as, but not limited to, a nitric oxide composition, heparin, a chemotherapeutic agent, and the like.

  For example, a guidewire coated with an electrospun material containing nitric oxide can be used when a guidewire is used to place another medical article (such as a balloon and / or stent or stent-graft) in a living vasculature. Useful for relaxing walls.

  The embolic device can be formed of or include a blood clotting material, such as, for example, a biodegradable blood clotting polymer. Biocompatible polyurethane and / or polylactic acid can be used.

  The outer surface layer of the medical article is preferably formed of an electrospun fiber containing at least one pharmacologically active substance. The electrospun fiber forms a polymer matrix of one or more polymers. The “outer surface layer formed of electrospun fibers (ie, polymer matrix)” need not be the outermost layer of the medical article, for example, hydrophilic polymers (eg, polyacrylic acid (and copolymers), polyethylene oxide, poly ( A layer of N-vinyl lactam such as polyvinylpyrrolidone)) may be provided as a coating on the outer surface layer (polymer matrix). Alternatively, a barrier layer can be provided as a coating on the outer surface layer (polymer matrix) to delay contact between the polymer matrix and blood until the medical article is placed at the target site. The barrier layer can be formed of a biodegradable polymer that dissolves or disintegrates.

  The term “polymer matrix” means a three-dimensional structure formed by electrospun fibers. Due to the nature of the electrospinning process, the polymer matrix is characterized by a very accessible surface allowing rapid release of the pharmacologically active substance. Polymers of the polymer matrix can be prepared from a variety of polymer-based materials, including polymer solutions and molten polymers, and composite matrices thereof. Polymers that can be used include, for example, polyamides such as nylon, polyurethanes, fluoropolymers, polyolefins, polyimides, polyimines, (meth) acrylic polymers, and polyesters, and suitable copolymers. Carbon can also be used as a fiber forming material.

  The polymer matrix is formed of one or more polymers and can contain other components such as salts, buffer components, microparticles in addition to the pharmacologically active substance.

  “Contains at least one pharmacologically active substance” means that the pharmacologically active substance is present in the polymer matrix as a separate molecule, or the pharmacologically active substance is bound to the matrix polymer by covalent bonds or ionic interactions. Means that In the latter case, it is usually necessary to release the pharmacologically active substance from the polymer molecule before the biological action occurs. The release of a pharmacologically active substance often occurs by contact with a physiological fluid (for example, blood) by hydrolysis, ion exchange or the like.

  In a preferred embodiment, the pharmacologically active agent is covalently attached to the polymer molecule.

  The pharmacologically active substance may be mixed with a liquid substance for producing the outer surface layer.

  In one interesting embodiment, the pharmacologically active substance is a nitric oxide donor. For certain types of treatment, it is desirable that nitric oxide be released into the living tissue in the gas phase immediately after the medical article is placed at the treatment site (or within 5 minutes after placement). When nitric oxide is released in the gas phase, little NO donor residue adheres to the tissue.

  In a preferred embodiment of the present invention, NONO'ate is used as the nitric oxide donor. NONO'ate decomposes to the parent amine and NO gas under acid catalysis according to the following formula (US Pat. No. 6,147,068, Larry K. Keefer: Methods Enzymol, (1996) 268,281-293). , Naunyn-Schmeideberg, Arch Pharmacol (1998) 358, 113-122).

[formula]

  In this embodiment, NO is released in the electrospun polymer matrix. Since the matrix is porous, water can enter the matrix. NO molecules can be transported from the matrix into the tissue by many methods and combinations thereof. Several scenarios are described below: NO dissolves in water within the matrix and is transported out of the matrix by diffusion or water flow; NO diffuses out of the matrix in gaseous form and into the water outside the matrix Dissolves; NO diffuses from the water into the tissue; NO diffuses from the matrix into the tissue in gaseous form.

  As shown in the above equation, the rate of NO release is highly dependent on the pH of the medium. Thus, the release rate of NO can be controlled by adding various amounts of acid to the matrix. For example, the half-life of NO release at pH 5.0 is about 20 minutes and the half-life of release at pH 7.4 is about 10 hours. For example, ascorbic acid can be used as an acidic agent to increase NO release.

  Also, various nitric oxide (NO) donor compounds and polymer compositions capable of releasing nitric oxide are disclosed, for example, in US Pat. No. 5,691,423, US Pat. No. 5,962,520, US Pat. US Pat. No. 5,958,427, US Pat. No. 6,147,068, US Pat. No. 6,737,447 B1 (corresponding to European Patent No. 1220694 B1), This reference is incorporated herein by reference.

  In preferred embodiments, the nanofibers are formed of a polymer having a nitric oxide donor (eg, diazeniumdiolate moieties) linked by covalent bonds.

  Polyimines represent a variety of polymers that can have diazeniumdiolate moieties linked by covalent bonds. Polyimines include poly (alkyleneimines) such as poly (ethyleneimine). For example, the polymer may be linear poly (ethyleneimine) diazeniumdiolate (NONO-PEI) as disclosed in US Pat. No. 6,737,447, the disclosure of which is It shall be made a part of this specification by reference. The addition amount of the nitric oxide donor to the linear poly (ethyleneimine) (PEI) is such that 5 to 80% (for example, 10 to 50% (for example, 33%)) of the amine group of PEI is a diazeniumdiolate site. It can be changed to carry. Depending on the conditions applied, linear NONO-PEI can release various proportions of nitric oxide out of the total amount of nitric oxide that can be released.

  Polyamines having a diazeniumdiolate moiety (especially poly (ethyleneimine) diazeniumdiolate) can be advantageously used as polymers for the electrospinning process. This is because such polymers usually have a suitable hydrophilicity and the addition of the diazeniumdiolate moiety (and thus the addition of NO molecules) can be varied over a wide range (see above). See NONO-PEI example).

  In another embodiment, the pharmacologically active agent is present in the polymer matrix as a separate molecule.

  In this embodiment, the pharmacologically active substance may be contained in fine particles such as microspheres and microcapsules. Such microparticles are particularly useful for the treatment of cancer. The microparticles may be biodegradable, including biodegradable polymers (polysaccharides, polyamino acids, poly (phosphate esters) biodegradable polymers, polymers or copolymers of glycolic acid and lactic acid, poly (dioxanone), poly (trioxane). Methylene carbonate) copolymer, poly (α-caprolactone) homopolymer or copolymer, etc.).

  Alternatively, the microparticles may be non-biodegradable materials such as amorphous silica, carbon, ceramic materials, metals, or non-biodegradable polymers.

  The microparticles may be in the form of microspheres that encapsulate pharmacologically active substances such as chemotherapeutic agents. Release of the pharmacologically active substance is preferably initiated after administration.

  The microspheres encapsulating the pharmacologically active substance can be treated so as to easily release the pharmacologically active substance by electromagnetic waves or ultrasonic shock waves.

  It is preferred to provide a hydrophilic layer on the outer surface layer in order for the guidewire or shaft according to the present invention to easily reach the treatment site, often through a tortuous path. The hydrophilic layer can be provided as a separate material layer. Alternatively, the outer surface layer itself may have hydrophilicity.

  The outer surface layer advantageously comprises an acidic agent (such as lactic acid or vitamin C) that acts as a catalyst for releasing pharmacologically active substances such as nitric oxide. Acidic agents can change the pH value at the treatment site, and the rate of nitric oxide release at the treatment site varies as a function of the local pH value. Thus, the presence of vitamin C can increase the release of nitric oxide, ie, lead to a rapid release of nitric oxide.

  In general, nitric oxide release is described in terms of “Prevention of intimate hyperplasty and / or stent insertion” or “How to mend a heart hen hen”. MD, Heart Radiology, University of Lund, Sweden, 2003.

  The pharmacologically active substance can be provided in the form of biodegradable beads dispersed between nanofibers, the beads can release the pharmacologically active substance, and in the case of biodegradable beads, after the release of the pharmacologically active substance Decompose. Such beads are described in detail in International Patent Application No. PCT / DK2004 / 000560, the disclosure of which is hereby incorporated by reference into the present disclosure, and the tissue at the treatment site. It can penetrate into and release pharmacologically active substances within the tissue. Alternatively, the beads may have a small size that can be transported away from the treatment site, eg, by blood flow.

  In one embodiment of the method of manufacturing a medical article, the outer surface layer is oxidized in a chamber containing nitric oxide pressurized at a pressure of, for example, 1-5 bar (or 1.5-5 bar, or 2-5 bar). Nitrogen oxide can be applied to the outer surface layer by exposure to nitrogen.

  The process of electrospinning nanofibers typically involves obtaining multiple strands of fiber-forming material from the distribution electrode by feeding the fiber-forming material through a dispensing electrode disposed away from the support member. Including. In one embodiment of the method of the present invention, the properties of the outer surface layer are controlled by controlling the flowability of the yarn as it reaches the support member, e.g., the distance between the distribution electrode and the support member. It is controlled by controlling. By controlling the fluidity of the jet, intersecting fibers can be formed as a multi-connected network that cannot be broken even if it is broken at only one point. Also, the fluidity allows the fiber with higher fluidity to closely follow the medical article or other support member where the fiber contacts the medical article or support member in the electrospinning process.

  In its broadest aspect, the present invention provides a medical article for insertion into a biological vasculature, a medical article for insertion into a biological vasculature (vascular insert, at least partially formed by electrospun nanofibers, Artificial blood vessels, stents, stent grafts, embolic devices or medical tubes such as catheters, etc.) comprising the steps of forming at least a portion of a medical article by electrospinning of nanofibers, wherein The nanofibers solidify to form a medical article (or at least a portion of the medical article). The electrospun portion of the medical article can be, for example, an outer surface layer that includes all features of the outer surface layer of the medical article according to the first aspect of the invention disclosed herein.

  Hereinafter, embodiments of the present invention will be described with reference to the drawings.

  The present invention will be further described with reference to the tube shown in FIGS. 1-6, the stent shown in FIG. 7, and the embolic device shown in FIGS. It should be understood that the following description is not limited to medical tubes, stents, and embolic devices. Therefore, other medical supplies for introduction into the vascular system of a living body can be manufactured as described below.

  In the embodiment shown in FIGS. 1-6, nanofibers are spun onto the outer surface of the core member. The core member includes a core wire (or mandrel) 100, a PTFE layer 102 provided on the outer surface of the core wire, a coating 104 of a thermoplastic material provided on the outer surface of the PTFE layer 102, and an outer side of the thermoplastic coating. And at least one reinforcing wire 106 provided on the surface, and electrospun nanofiber monofilament is provided as an outer layer 108 (ie, surrounding the reinforcing wire and thermoplastic coating). A hydrophilic layer 110 is optionally applied to the outer surface of the medical article (see FIG. 6).

  Preferably, the guide wire has a diameter of at least 0.1 mm (for example, 0.1 to 1.0 mm) or more. The thermoplastic coating, preferably a polyurethane (PU) coating, has a thickness of 5 μm to about 0.05 mm, preferably 0.01 mm ± 20%. The reinforcing wire has a diameter of 5 μm to about 0.05 mm, preferably 0.01 mm ± 20%.

  One core wire may be provided, or a plurality of core wires extending in parallel provided side by side may be provided. When a plurality of core wires are provided, the tube to be manufactured is a so-called multi-lumen tube, in which the core member is constituted by a plurality of core wires, and nanofibers are spun around the core member. The nanofibers and optionally the PTFE layer, the thermoplastic layer, and the reinforcing wire will surround the core wires. Multi-lumen tubes are useful for pressure measurements, such as measuring the pressure drop at a stenotic site. One or more passages of the multi-lumen tube can be used to transmit transmitted light (eg, light emitted through the blood), which can facilitate a diagnostic procedure.

  As described above, the PTFE layer 102 can be provided on the outer surface of the core member 100. At least a portion of the surface of the PTFE layer (such as a portion provided with nanofibers and / or a thermoplastic coating) can be modified to improve the adhesion of the material to the outer surface of the PTFE layer. Preferably, such modification includes etching, which can form a primed PTFE surface, eg, for covalent bonding or adhesion. Etching can be performed by applying flux acid or hydrofluoric acid to the surface of the PTFE layer. The PTFE layer can be covered with a core wire (a plurality of core wires in the case of a multi-lumen tube) or can be provided as a hose extending coaxially with the core wire.

  A coating of a thermoplastic material 104 such as polyurethane (PU) can be provided on the outer surface of the core member 100 (or the outer surface of the PTFE layer 102 if the PTFE layer 102 is provided). Following the step of providing the PTFE layer 102 and / or the step of providing the thermoplastic coating 104, one or more reinforcing wires 106 can be provided on the outer surface of the core member 100. In a preferred embodiment, one or more reinforcing wires 106 are provided on the outer surface of the polyurethane coating 104. The reinforcing wire can consist of one or more steel wires or / and wires made of yarns such as carbon monofilaments and can be provided by winding. Alternatively, the reinforcing wire can be provided by spinning nanofibers (preferably electrospinning as described above). The electrospun reinforcement wire can be formed from carbon or a polymer and can include a polymer solution and a molten polymer. Examples of the polymer that can be used include nylon, fluoropolymer, polyolefin, polyimide, and polyester.

  In order to disperse the nanofibers evenly around the outer surface of the core member, preferably in the core member 100, when forming the medical article, or at least when forming the portion of the medical article formed by electrospinning. Rotate.

  In a preferred embodiment of the present invention, nanofibers 108 are now provided on the outer surface of the core member (ie, preferably the outer surface of the thermoplastic coating 104 that is reinforced by a reinforcing wire as needed). Electrospinning has already been described in detail.

  Next, a solvent such as tetrahydrofuran (THF) or isopropanol (IPA) can be applied to the outer surface of the core member, and the outer surface can be formed by the electrospun portion (layer) 108 of the medical article. As a result, the thermoplastic coating 104 is at least partially dissolved in the solvent and the reinforcing wire 106 is adhered to the thermoplastic coating 104. As a result, the reinforcing wire 106 is embedded in the thermoplastic coating 104. It has been clarified that the step of supplying the solvent results in a surface with low surface friction and very high density, which means that when the solvent is applied, the stretched molecules of the electrospun nanofibers become wrinkled. This is thought to be due to shrinkage.

  A stent graft can be obtained by omitting the step of applying a solvent.

  The core wire 100 (or mandrel) is removed after the step of applying the solvent or before the step of applying the solvent, and after the step of applying the single fiber of the electrospun nanofiber 108.

  FIG. 7 shows a zigzag corrugated stent 109 with electrospun nanofibers 111 applied to the surface.

  The embolic device shown in FIG. 8 includes a wire wound in a coil and covered with electrospun nanofibers. The device shown in FIG. 9 is a coil formed by a wound coil as shown by the cross section of FIG.

  FIG. 12 shows an embolization device having the form of a three-dimensional sphere manufactured by the method according to the present invention. As shown in the cross-section of FIG. 11, electrospun nanomonofilament is applied to a substrate 112 that is substantially composed of yarn or coil members.

  FIG. 13 shows an embolization device having the form of tantalum particles 114 coated with electrospun single fibers 116.

Drawing 1 is an explanatory view in order of each process of one embodiment of a manufacturing method of medical supplies. Drawing 2 is an explanatory view in order of each process of one embodiment of a manufacturing method of medical supplies. Drawing 3 is an explanatory view in order of each process of one embodiment of a manufacturing method of medical supplies. Drawing 4 is an explanatory view in order of each process of one embodiment of a manufacturing method of medical supplies. Drawing 5 is an explanatory view in order of each process of one embodiment of a manufacturing method of medical supplies. Drawing 6 is an explanatory view in order of each process of one embodiment of a manufacturing method of medical supplies. FIG. 7 is a longitudinal side view of a stent partially coated with nanospun fibers. FIG. 8 shows two embodiments of a coiled embolization device. FIG. 9 shows two embodiments of a coiled embolization device. FIG. 10 shows two embodiments of a coiled embolization device. FIG. 11 shows the embolic device in the form of a three-dimensional sphere. FIG. 12 shows the embolic device in the form of a three-dimensional sphere. FIG. 13 shows an embolization device in a particulate form in which a single fiber is applied by electrospinning.

Claims (28)

  A medical article comprising a solid and / or non-expandable core member having an outer surface layer formed by electrospun nanofibers. In claim 1,
A medical article selected from the group consisting of a guide wire for introducing a medical article within a tubular structure of a living body, an embolic device, and a guide shaft of a microcatheter. In claim 1 or 2,
The medical article, wherein the outer surface layer contains a pharmacologically active substance. In claim 3,
The pharmacologically active substance includes nitric oxide,
The medical article, wherein the outer surface layer further comprises an acid agent. In claim 3,
A medical article wherein the pharmacologically active substance comprises a chemotherapeutic agent. In any of claims 3 to 5,
The medical article, wherein the outer surface layer is substantially formed of a polymer matrix, the polymer matrix comprising a molecule capable of releasing at least one of the pharmacologically active substances. In claim 6,
The outer surface layer is a medical article substantially formed of linear poly (ethyleneimine) diazeniumdiolate. In any of claims 3 to 7,
The medical article, wherein the pharmacologically active substance is provided in the form of biodegradable beads dispersed between the nanofibers. In any of claims 2 to 8,
The medical article is an embolic device;
The embolic device has a substantially spherical outer shape, and comprises one or more coil members;
The medical article, wherein the outer surface layer is provided on the coil member or on each coil member. In any of claims 2 to 8,
The medical article is an embolic device;
The core member is a particle,
The medical article, wherein the outer surface layer is formed on the particles. In any of claims 2 to 8,
The medical article is an embolic device;
The said core member is a medical article formed with the blood coagulation biodegradable polymer. In claim 11,
The medical article, wherein the biodegradable polymer comprises collagen. In claim 11 or 12,
The biodegradable polymer is a medical article containing polylactic acid. In any one of claims 11 to 13,
The medical article, wherein the biodegradable polymer includes urethane.   A method of manufacturing a medical article comprising a solid and / or non-expandable core member having an outer surface layer, comprising forming the outer surface layer by electrospinning nanofibers. In claim 15,
The method wherein the outer surface layer comprises a pharmacologically active substance. In claim 16,
The method wherein the pharmacologically active substance comprises nitric oxide. In claim 17,
The method wherein the outer surface layer further comprises an acid agent. In claim 16,
The method wherein the pharmacologically active agent comprises a chemotherapeutic agent. In any of claims 15 to 19,
The method wherein the outer surface layer is substantially formed of a polymer matrix, the polymer matrix comprising molecules capable of releasing at least one of the pharmacologically active substances. In claim 20,
The method wherein the outer surface layer is substantially formed of linear poly (ethyleneimine) diazeniumdiolate. A device according to any one of claims 15 to 21.
Applying nitrogen oxide to the outer surface layer by exposing the outer surface layer to nitric oxide in a chamber containing pressurized nitric oxide. In claim 22,
Exposing the medical article to nitric oxide at a pressure of 1 to 5 bar in the chamber. 24. Any one of claims 15 to 23.
The step of electrospinning the nanofiber includes causing a plurality of twisted yarns of the fiber-forming material to emerge from the distribution electrode by supplying the fiber-forming material through a distribution electrode disposed away from the core member. ,
Controlling the properties of the outer surface layer by controlling the flowability of the yarn as it reaches the core member. In claim 24,
The method, wherein the fluidity of the twisted yarn as it reaches the core member is controlled by controlling the distance between the distribution electrode and the core member. In any of claims 15 to 25,
The core member is provided on a sheet-like support member,
Forming the outer surface layer by electrospinning nanofibers with the core member supported on the support member; In any one of claims 15 to 26,
A method of providing the outer surface layer on the core member in a fluidized bed.   A medical article for insertion into a vascular system of a living body, at least partially formed of electrospun nanofibers.