JP2005034256A - Blood vessel wall restoration material - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a blood vessel wall restoration material having biocompatibility for restoring a blood vessel wall when the blood vessel of a small diameter is damaged. <P>SOLUTION: The blood vessel wall restoration material is constituted of a high polymer material containing carbon as a constitutive element and at least a part of a surface is reformed by an ion impact. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a vascular wall repair material that can be used for treatment of damaged blood vessels, and a method for producing the same.
[0002]
[Prior art]
A stent is a device that restores its function by knitting a metal wire into a mesh shape and expanding blocked blood vessels and non-vascular lumens. Representative stents reported to date include medical devices made of Ti—Zr alloys (Japanese Patent Application No. 11-375057 (Japanese Patent Laid-Open No. 2001-3126)). Although heparin is covalently bonded to the surface of this medical device alloy to prevent blood coagulation, heparin is gradually released over time, and there is a problem with maintaining long-term antithrombogenicity. It was.
[0003]
Since the stent has a mesh shape, there is a gap between the metal wires. In the case of a large-diameter endoluminal treatment such as the abdominal aorta or the digestive tract, the generation of an initial thrombus due to the reaction between metal and blood, and the invasion of tissue or cells from the lumen wall through the gap. However, generally, if the function of the stent to expand the occlusion site is sufficiently exerted, the subsequent healing is not greatly affected. However, in the case of small-diameter blood vessels such as coronary arteries, even if the function of expanding the occlusion site of the stent is sufficiently exerted, the formation of an initial thrombus due to the reaction between metal and blood and the tissue through the gap between the lumen wall and the stent In many cases, cells or cells invade, resulting in occlusion of autologous blood vessels with autologous tissue. Therefore, in the case of a small-diameter, it is indispensable to combine an artificial blood vessel with an anti-thrombogenic property to the stent itself and an excessive invasion of the self-tissue from the lumen wall together with a stent capable of expanding the occlusion site. It is. An artificial blood vessel combined with these stents is described in Japanese Patent Application No. 9-145042 (Japanese Patent Laid-Open No. 10-328214). However, even in the artificial blood vessel for stent described in this patent document, heparin has a problem in long-term antithrombogenicity, and there is a problem that the adhesion of the film layer cannot be maintained for a long time with respect to the film treatment such as collagen. As described above, antithrombogenicity is a very important problem regarding stents and stent grafts.
[0004]
Various approaches have been taken to date for the formation of antithrombotic surfaces. A typical method is as follows.
1. Chemical methods Chemical surface modification aimed at antithrombogenicity has been performed for a long time. In the past, various functional groups were introduced, and the ratio of polycation to polyanion was changed using electrostatic properties ⁾ . Other typical antithrombotic treatments include the following methods.
[0005]
(1) Use of hydrogel It was reported that water-soluble polymers such as poly-2-hydroxyethyl methacrylate and polyacrylamide were cross-linked and the hydrogel with high water content had blood compatibility.
(2) Utilization of excluded volume effect By grafting onto the surface of polyethylene glycol, polyvinyl alcohol or the like and introducing a mobile hydrophilic polymer onto the material surface, protein adsorption was reduced and blood coagulation was suppressed.
(3) Immobilization of physiologically active substance There is a method of immobilizing heparin or fibrinolytic enzyme urokinase as an anticoagulant on the surface of a material. In addition, a thrombomodulin immobilization material having a catalytic action of protein C having an inhibitory effect on a coagulation factor has been tried.
[0006]
2. Ultraviolet irradiation, glow discharge, plasma discharge, etc. were used for the purpose of changing the hydrophilicity and hydrophobicity of the physically treated surface. A typical example of antithrombogenicity is a plasma treatment method. Various materials surfaces were plasma treated with nitrogen, hydrogen, oxygen, helium, argon, carbon dioxide to improve blood compatibility. In particular, nitrogen plasma treatment has improved most materials.
[0007]
Regarding the antithrombogenic treatment of stents and stent grafts, a stent (Japanese Patent Application No. 2000-1255 (Japanese Patent Application Laid-Open No. 2001-190687) in which a polymer containing an antiplatelet agent and an antithrombin agent is coated on the outer peripheral surface and / or inner peripheral surface of a base material. Gazette)), a tubular film of tetrafluoroethylene resin porous material is disposed on the inner and outer surfaces of a tubular structure made of elastic wire, and the inner and outer tubular films are partially heat-fused. A stent manufacturing method (Japanese Patent Application No. 5-28549 (JP-A-7-24072)), an intravascular treatment material having an extracellular matrix containing a nitric oxide donor, and Endovascular treatment instrument comprising the endovascular treatment material and a holding body for holding the endovascular treatment material (Japanese Patent Application No. 2000-8777 (Japanese Patent Application Laid-Open No. 2001-198209)) A stent body that is formed in a substantially cylindrical shape and has a plurality of openings formed to communicate with the cylindrical outer surface and the inner surface; a thermoplastic resin layer that covers the stent body; and an outer periphery of the stent body. And / or a cylindrical cover that covers the inner periphery, closes the opening, and is fixed to the thermoplastic resin layer (Japanese Patent Application No. 6-315585 (JP-A-6-315585)). 8-141090 gazette)). However, these methods do not provide cell adhesion at the same time as antithrombogenicity, the antithrombotic treated surface only provides blood coagulation, and the cell adhesive treated surface only imparts cell adhesiveness.
[0008]
[Patent Document 1]
Japanese Patent Laid-Open No. 2001-3126 [Patent Document 2]
Japanese Patent Laid-Open No. 10-328214 [Patent Document 3]
JP 2001-190687 A [Patent Document 4]
JP-A-7-24072 [Patent Document 5]
JP 2001-198209 A [Patent Document 6]
Japanese Patent Laid-Open No. 8-141090
[Problems to be solved by the invention]
During cardiac surgery, vascular surgery or brain surgery, blood vessel walls are often damaged. When the damaged blood vessel has a small diameter, the blood vessel contracts together with the damage, and the blood flow path is inhibited. The problem to be solved by the present invention is to provide a vascular wall repair material having biocompatibility that repairs a vascular wall when a small-diameter blood vessel is damaged.
[0010]
[Means for Solving the Problems]
As a result of intensive studies to solve the above-mentioned problems, the inventors of the present invention have both antithrombogenicity and self-healing properties by modifying the surface of a polymer material containing carbon as a constituent element by ion bombardment. The present inventors have found that a blood vessel wall repair material can be provided, and have completed the present invention.
[0011]
That is, according to the present invention, there is provided a vascular wall repair material that is composed of a polymer material containing carbon as a constituent element and at least a part of the surface of which is modified by ion bombardment.
[0012]
Preferably, the polymer material containing carbon as a constituent element is expanded polytetrafluoroethylene (ePTFE), polyester, polylactic acid, or polyglactin.
Preferably, the surface of the polymer material containing carbon as a constituent element is coated with collagen.
Preferably, modification by ion bombardment is performed by performing ion implantation in a range where the dose amount φ is 1 × 10 ¹³ ≦ φ <1 × 10 ¹⁶ ions / cm ² .
[0013]
According to another aspect of the present invention, ions in a range where the dose amount φ is 1 × 10 ¹³ ≦ φ <1 × 10 ¹⁶ pieces / cm ^{2 on} at least a part of the surface of the polymer material containing carbon as a constituent element. There is provided a method of manufacturing a vascular wall repair material characterized by performing injection. Preferably, the polymer material containing carbon as a constituent element is expanded polytetrafluoroethylene (ePTFE), polyester, polylactic acid, or polyglactin.
[0014]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, embodiments of the present invention will be described in detail.
The present invention relates to a vascular wall repair material that can be used when a vascular wall or a blood vessel is damaged during an operation such as cardiac surgery, vascular surgery, or brain surgery. The outline of the present invention will be described with reference to FIGS.
[0015]
(1) Blood vessel wall repair method (Fig. 1)
If the blood vessel wall is damaged during surgery and bleeding occurs, a material for repairing the damaged part is required. In the case of a large-diameter blood vessel, since the blood flow velocity is high, thrombus formation or the like does not occur, so the antithrombogenicity of the repair material does not matter, but blood coagulation occurs for a small diameter of 3 mm or less. Thrombosis is a problem. The biocompatible polymer material according to the present invention can prevent bleeding by wrapping when a small-diameter blood vessel is damaged as shown in FIG. Fixation to the vessel wall can be performed with clips and fibrin glue.
[0016]
(2) Technology for imparting antithrombogenicity and self-healing properties to restoration materials (Figure 2)
The base material of the restoration material can be any material as long as it is a polymer material having plasticity. As an example of the present invention, type I collagen can be coated on the surface of the repair material as shown in FIG. The coated surface can be irradiated with an ion beam to impart antithrombogenicity and cell adhesion.
[0017]
Hereinafter, the implementation method of the present invention will be described more specifically.
The polymer material having carbon as a constituent element used in the present invention is not particularly limited as long as it is a material that is biocompatible and easy to operate, and any material can be used. Preferred polymer materials in the present invention include expanded polytetrafluoroethylene (ePTFE), polyester, or biodegradable polymer (for example, polylactic acid or polyglactin), and in particular, expanded polytetrafluoroethylene ( ePTFE) is preferred. Furthermore, in the present invention, it is preferable to coat the surface of a polymer material containing carbon as a constituent element as described above with collagen.
[0018]
At least a part of the surface of the polymer material of the vascular wall repair material of the present invention is modified by ion bombardment. Examples of ion species to be implanted include H ⁺ , He ⁺ , C ⁺ , N ⁺ , Ne ⁺ , Na ⁺ , N ⁺ , O ⁺ , Ar ⁺ , Kr ^{+, and the} like, but elution inhibits cell growth. If not, it is not particularly limited to these.
[0019]
The dose amount φ is preferably in the range of 1 × 10 ¹³ ≦ φ <1 × 10 ¹⁶ pieces / cm ² . When it is lower than 10 ¹³ pieces / cm ² , the remarkable improvement effect of cell adhesion is reduced, and when it is higher than 10 ¹⁶ pieces / cm ² , the polymer material is easily broken, which is not preferable. More preferably, the dose amount φ is in the range of 1 × 10 ¹³ ≦ φ <1 × 10 ¹⁵ pieces / cm ² .
[0020]
Regarding the ion acceleration energy, it is considered that the energy transfer mechanism varies depending on the height, but practically, the acceleration energy is in the range of several tens keV to several MeV, for example, in the range of 10 keV to 10 MeV. Yes, the lower limit value of acceleration energy can be, for example, 10 keV, 20 keV, 30 keV, 50 keV, or 100 keV, and the upper limit value of acceleration energy can be, for example, 10 MeV, 9 MeV, 8 MeV, 5 MeV, 3 MeV, 1 MeV, It can be within the range of any combination of the above lower limit value and upper limit value.
[0021]
The beam current density is preferably set in a range not exceeding about 0.5 μA / cm ² . This is because if the beam current density is excessive, the temperature of the target polymer material is excessively increased, the polymer material itself is deteriorated, and the cell adhesiveness may be decreased.
[0022]
In the present invention, ion implantation may be mentioned as a means for giving ion bombardment. In the ion implantation, the reaction itself is limited to the interaction between the ion beam and the material to be implanted (target material). In addition, by selecting the ion incident energy, ions can be embedded at an arbitrary depth from the surface, which is extremely excellent in controllability. This is a feature not found in plasma processing. Although the implanted ions have a mechanistic difference that the electron stopping power works at the early stage of diffusion for ions with relatively light mass, and the nuclear stopping power works for ions with relatively heavy mass from the beginning. It causes heating by lattice vibration to the polymer material (thermal non-equilibrium state), causing melting, amorphization and the like.
The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to the examples.
[0023]
【Example】
Example 1: Anti-thrombogenic and self-healing material of repair material ePTFE (Gore-Tex EPTFE Patch II: PSM-01200) was used as a repair substrate for animal experiments. After coating with collagen (Koken Collagen Acid Solution CELLGEN IAC-13), He ⁺ ion beam irradiation (1 × 10 ¹⁴ ions / cm ² ) was performed. The Japanese white rabbit carotid artery was exposed, artificially damaged (approximately 0.5 mm hole) in the blood vessel wall, wrapped with the above-mentioned collagen-coated ePTFE irradiated with an ion beam, then clipped and fibrinating Fixed with. Three months later, blood vessels were taken out and fixed with formalin, and then histological examination (HE staining) was performed. FIG. 3 shows a histological photograph at 3 months after vascular repair. Thrombus formation was not observed in the vascular injury part (blood vessel wall missing part). In addition, neointima formation was observed. In the evaluation by this animal experiment, patency of 3 cases for 1 week, 2 cases for 1 month, and 2 cases for 3 months was obtained.
[0024]
【The invention's effect】
According to the present invention, a blood vessel wall repair material having biocompatibility for repairing a blood vessel wall when a small-diameter blood vessel is damaged and a method for producing the same are provided. The vascular wall repair material of the present invention has both antithrombotic properties and self-repair properties, and is useful as a repair material for damaged blood vessels.
[Brief description of the drawings]
FIG. 1 shows a method for repairing damaged blood vessels.
FIG. 2 shows the provision of antithrombogenicity and cell adhesion to the surface of the repair material.
FIG. 3 shows a histological photograph at 3 months after vascular repair.

Claims (6)

A vascular wall repair material comprising a polymer material containing carbon as a constituent element, wherein at least a part of the surface is modified by ion bombardment. The vascular wall repair material according to claim 1, wherein the polymer material containing carbon as a constituent element is expanded polytetrafluoroethylene (ePTFE), polyester, polylactic acid, or polyglactin. The vascular wall repair material according to claim 1 or 2, wherein a surface of a polymer material containing carbon as a constituent element is coated with collagen. The blood vessel according to any one of claims 1 to 3, wherein the modification by ion bombardment is performed by performing ion implantation in a range where the dose amount φ is 1 × 10 ¹³ ≦ φ <1 × 10 ¹⁶ pieces / cm ^2. Wall repair material. Ion implantation is performed in a range where the dose amount φ is 1 × 10 ¹³ ≦ φ <1 × 10 ¹⁶ pieces / cm ^{2 on} at least a part of the surface of the polymer material containing carbon as a constituent element. Manufacturing method of wall repair material. The production method according to claim 5, wherein the polymer material containing carbon as a constituent element is expanded polytetrafluoroethylene (ePTFE), polyester, polylactic acid, or polyglactin.

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