JPS60242857A - Artificial blood vessel - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an artificial blood vessel having a compliance similar to that of a biological blood vessel and a blood contact surface having excellent blood compatibility.

[Prior Art] In recent years, along with advances in vascular surgery, research on artificial blood vessels has progressed, and a large number of artificial blood vessels have been developed. Currently, artificial blood vessels for medium or large diameter arteries with an inner diameter of about 61 lllIl or more include the Dobesky artificial blood vessel made of Dacron knitted fabric made by USC1, and the Voretex made of expanded polytetrafluoroethylene made by Boa Co., Ltd. of the United States. is used clinically. However, these artificial blood vessels
They have drawbacks such as compliance being significantly different from that of biological blood vessels and poor blood compatibility at the blood contact surface.

Therefore, when these artificial blood vessels are used as medium-diameter or large-diameter arterial artificial blood vessels, problems related to various incompatibilities such as hyperplasia of pannus at the anastomotic site occur after a long period of time after implantation. do. Furthermore, when these artificial blood vessels are used as artificial blood vessels for small-caliber arteries with an inner diameter of about 5 mm or less, they have poor patency due to differences in compliance and poor blood compatibility, and cannot be used clinically.

Therefore, autologous veins are used in revascularization surgeries for arteries below the knee, coronary arteries, and the like.

In each of the Japanese Patent Publications No. 50-32554, No. 53-15556, No. 55-4414, and No. 55-4445,
Artificial blood vessels have been disclosed in which a hydrophilic epithelium is graft-copolymerized onto an artificial blood vessel made of Dacron fiber, an artificial blood vessel made of Teflon 111I, an artificial blood vessel made of expanded polytetrafluoroethylene, or the like. However, the compliance of these artificial blood vessels is significantly different from that of biological blood vessels. Furthermore, the hydrophilic graft copolymer layers disclosed in these publications are still unsatisfactory in terms of blood compatibility.

As described above, when developing artificial blood vessels, especially artificial blood vessels for small-caliber arteries, it is important to simultaneously approximate compliance to that of biological blood vessels and improve blood compatibility at the blood contact surface. Although they are said to be important, the reality is that nothing has been changed that satisfies both of these requirements at the same time.

[Summary of the Invention] In view of the above-mentioned circumstances, the present inventors have conducted extensive research with the aim of creating an artificial blood vessel that has a compliance similar to that of a biological blood vessel and has excellent blood compatibility at the blood contact surface. As a result, the present invention was completed.

That is, the present invention relates to an artificial blood vessel that is made of an elastomer, has a porous structure inside the tube wall, and has an acrylamide graft copolymer layer on at least the inner surface of the tube wall.

[Embodiments of the invention] The elastomer 7 used in the present invention is a thermoplastic elastomer with excellent blood compatibility, that is, it does not contain low molecular weight eluates that cause acute toxicity, inflammation, hemolysis, exothermic reactions, etc. It is a thermoplastic elastomer with excellent antithrombotic properties that does not cause serious damage to the physiological functions of the body. Examples of such elastomers include polystyrene elastomers,
Examples include polyurethane elastomers, polyolefin elastomers, polyester elastomers, etc., and blends of these elastomers with polymers other than elastomers within a range that maintains the properties of elastomers. These may be used alone (or two or more may be used in combination. Among these, polyurethane elastomers are more preferred.

This is because it has excellent mechanical properties, durability, blood compatibility, etc.

Polyurethane-based elastomers are broadly classified into polyether-type polyurethanes (which also contain polyurethane urea, the same applies hereinafter) and polyester-type polyurethanes, but polyether-type elastomers are preferred from the standpoint of in-vivo durability.

Particularly preferred are polyether type segmented polyurethanes and segmented polyurethanes containing polydimethylsiloxane or fluorine components in the main chain.

The artificial blood vessel of the present invention has a porous structure inside the vessel wall.

The porous structure as used herein means a network structure, a sponge-like structure, or a structure similar to these structures. For example, the network structure is one in which pores having a maximum diameter of about 1 to 100 ρ exist in a network shape. A sponge-like structure is an aggregation of cellular voids that are spherical, ellipsoidal, or modified shapes thereof, and have a maximum diameter of about 111 m to about 315 m, which is the thickness of the tube wall. .

On the surface of an artificial blood vessel having a porous structure inside the vessel wall, there may be a skin layer having a thickness of about 50 mm or less and having a denser structure than the porous structure. It is preferable that part or all of the surface is exposed, and it is particularly preferable that the artificial blood vessel has a porous structure from the inside to the outside and has communicating pores. The porous structure and communicating pores exposed on the inner surface promote the formation of pseudointima,
It is useful for stabilizing the formed pseudointima and is important for preventing the artificial blood vessel from being occluded by thrombus.

Since the artificial blood vessel of the present invention is made of an elastomer and has the porous structure inside the tube wall, the elastomer density of the tube wall is sparse, resulting in a soft structure and increased compliance. Therefore, the elastomer density of the tube wall,
By adjusting the porous structure, the strength of the elastomer, etc., the compliance of the artificial blood vessel can be made to approximate that of a biological blood vessel.

The optimal elastomer density for the tube wall varies depending on the porous structure inside the tube wall, the strength of the elastomer, etc., and the required compliance varies depending on the location of the biological blood vessel, so it cannot be determined generally. ,0.
05~0, preferably 35g/Cm3, 0
．． It is more preferably 1 to 0.3 g 7 cm3, and particularly preferably 0.125 to 0.25 a/cRls.

The compliance referred to in this specification is expressed by the formula (1): (where C is the compliance, ■0 is the internal volume of the measured blood vessel when the internal pressure is 50 mmHg, and ΔP is the internal volume from the internal pressure 50 mmH ( ) to the internal pressure 150 mm H (l). 100mm H(]
, ΔV is internal pressure 50 + nmH (from l to internal pressure 150 mm H
! +) is the internal volume of the measured blood vessel that increases during Actual measurement involves, for example, inserting a measurement blood vessel into a closed circuit, injecting liquid into this circuit using a micrometer metering pump, and measuring the amount of injected liquid and the change in pressure within the circuit. can be calculated.

The preferred compliance for an artificial blood vessel varies depending on the thickness of the artificial blood vessel, the site of use, etc. - Although it cannot be determined generally, the compliance of a living blood vessel in which normal revascularization surgery is performed is about 0.1 to 0.8. Therefore, it is considered preferable to set it within this range. The compliance of the artificial blood vessel of the present invention can be adjusted as described above, and any compliance within the range of 0.1.-0.8 can be manufactured. Compliance is 0.1
Artificial blood vessels with an inner diameter of 1 to 6+am and a compliance of 0.1 to 0.5 are suitable for applications such as arterial artificial blood vessels, depending on their thickness etc. It can be suitably used as a caliber artery artificial blood vessel.

The artificial blood vessel of the present invention has an acrylamide graft copolymer layer on at least the inner surface (blood contact surface) of the vessel wall. This layer is a layer in which acrylamide is graft copolymerized onto the surface of a tube wall made of an elastomer, and by graft copolymerizing acrylamide, the tube wall surface becomes highly hydrophilic and exhibits excellent blood compatibility.

This acrylamide graft copolymer layer is a layer obtained by graft copolymerizing other seven polymers such as methyl methacrylate, ethyl methacrylate, methyl acrylate, ethyl acrylate, vinyl acetate, 2-hydroxyethyl methacrylate, and styrene. In comparison, it has excellent blood compatibility. Note that a monomer such as acrylic acid or acrylic ester may be added to the acrylamide to be graft copolymerized to the extent that the resulting graft copolymer layer has sufficient hydrophilicity.

In order for the artificial blood vessel of the present invention to withstand abnormal increases in internal pressure such as during surgery and maintain durability for a long period of time,
A mesh net, nonwoven fabric, or the like may be provided on the outside of the artificial blood vessel or inside the vessel wall for reinforcement.

The artificial blood vessel of the present invention having the above-mentioned structure has the following properties in addition to the following properties: the conjugate approximates that of a biological blood vessel, and the blood contact surface has excellent blood compatibility. have.

That is, since the artificial blood vessel of the present invention has a substantially continuous elastomer wall, the cut end will not fray even if it is cut to an arbitrary length. In addition, since the tube wall has a structure with low elastomer density, the suture needle has good penetration and suturing with biological blood vessels is easy, and even if the sutured part is pulled, the sutured part will not fray or the suture will come off. Never. Moreover, since the tube wall is made of an elastomer, the hole through which the suture needle is passed will self-close when the needle is no longer present, and no blood will leak.

Another surprising property is that nodules are difficult to form under high blood pressure. This is thought to be due to the fact that the compliance is similar to that of biological blood vessels.

Next, a method for manufacturing an artificial blood vessel according to the present invention will be explained based on one embodiment.

As explained below, the artificial blood vessel of the present invention includes a first step of forming a tubular object made of an elastomer and having a porous structure inside the tube wall, and a second step of forming an acrylamide into the tubular object. It can be manufactured by a graft copolymerization process.

[First step] Extruding an elastomer solution having a cloud point from an annular nozzle together with an internal coagulating liquid while maintaining the temperature above the cloud point,
Immediately or after maintaining a dry distance, immerse in external coagulation fluid. At this time, at least one of the internal coagulating liquid, the external coagulating liquid, and the air within the dry distance is maintained at a temperature below the cloud point temperature. In this way, a tubular body having a porous structure, for example a network structure, is obtained in which pores are present throughout the thickness from the inside to the outside of the tube wall.

An elastomer solution having a cloud point consists of an elastomer, a good solvent that dissolves the elastomer, and a poor solvent that is miscible with the good solvent but difficult to dissolve the extomer. Examples of the good solvent include N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, dioxane, and tetrahydrofuran, and these may be used alone or as a mixture. It may also be used as

Examples of the poor solvent include water, lower alcohol, ethylene glycol, propylene glycol, 1,4-butanediol, glycerin, etc., and these may be used alone or in combination.

The annular nozzle can extrude the elastomer solution into a tubular shape and inject the internal coagulation liquid into the annular nozzle.
It is not particularly limited. By adjusting the inner diameter and outer diameter of the annular nozzle that extrudes the elastomer solution into a tubular shape, the diameter and wall thickness of the artificial blood vessel can be adjusted as desired.

As the internal coagulating liquid or the external coagulating liquid, the poor solvent or a mixed solvent of the poor solvent and a good solvent may be used. The internal coagulation liquid and the external coagulation liquid may be the same solvent or may be different solvents.

[Second Step] Methods for graft copolymerizing acrylamide onto the tubular material produced in the first step include methods of irradiating with radiation such as gamma rays, X-rays, and electron beams, methods using corona discharge or glow discharge, and methods using ultraviolet rays. There are various methods such as a method of irradiating with ion and a method of using a catalyst such as cerium ion, and any of these methods may be used.

For example, acrylamide can be graft copolymerized onto the surface of the tubular material by irradiating the dried tubular material with gamma rays in argon gas, then immersing it in a degassed aqueous acrylamide solution and heating it. By performing graft copolymerization and then purifying this tubular material, the artificial blood vessel of the present invention can be obtained.

The artificial blood vessel obtained as described above has a porous structure in which pores are present throughout the entire thickness from the inside to the outside of the vessel wall, such as a network structure, and at least the inner surface has hydrophilic septa. There is a graft copolymerized layer,
Porous.

The artificial blood vessel of the present invention thus obtained has the following excellent properties.

■Compliance approximates that of biological blood vessels.

■Excellent compatibility with white liquid on blood contact surfaces.

■It has the necessary properties as an artificial blood vessel as shown below.

0 Porosity can be formed as needed to help organize the artificial blood vessel.

0 suture needle has good penetration and suturing is easy.

0 The cut end will not fray even if it is cut to any length. Furthermore, there is no possibility that the suture thread will become frayed from the sutured portion.

The through hole of the 0 suture needle self-closes.

Nodules are less likely to form under zero blood pressure.

Therefore, the artificial blood vessel of the present invention can be used as an artificial blood vessel, a bypass artificial blood vessel, a batch material, etc. in revascularization surgery of living blood vessels, and can also be used for blood access. Furthermore, the artificial blood vessel of the present invention can be used as an arterial artificial blood vessel having a compliance of 0.1 to 0.8.

In particular, the compliance is close to that of biological blood vessels, and the blood contact surface has excellent blood compatibility. It can also be used as an artificial blood vessel for small diameter arteries of 1 to 6 III. Therefore, it can be suitably used for revascularization of arteries below the knee or as an artificial blood vessel for aorta-coronary artery bypass.

Furthermore, the artificial blood vessel of the present invention can be used as a venous artificial blood vessel by covering the outside with a net with low compliance, and can also be used as a substitute for a soft tubular body such as a ureter.

Next, the artificial blood vessel of the present invention will be explained based on Examples.

Example 1 17.5 g of a segmented polyurethaneurea obtained by chain-extending a prepolymer consisting of 2 moles of 4'-diphenylmethane diisocyanate and 1 mole of polytetramethylene glycol having a molecular weight of 2000 with 1 mole of ethylenediamine was mixed with N,N-dimethylacetamide. 47.5m and propylene glycol 35Id. The cloud point of the resulting solution was approximately 50°C. While keeping this solution at 70°C, use a gear pump to adjust the solution outlet size to 3
1III11 from an annular nozzle with an outer diameter of 4.51111 approx.
It was extruded at 0C111/min. At the same time, degassed water at 20°C was injected into the inside of the tube. The extruded tubular solution was immediately immersed in water at 20°C to precipitate the nidradomer into a tubular shape. After washing with water, it was cut to the required length and dried to obtain a tubular product.

The obtained tubular material was irradiated with gamma rays in argon gas (total dose: 3.6 x 105 R), then immersed in a 20% by volume aqueous solution of degassed acrylamide, heated at 50°C for 15 minutes under shaking, Acrylamide was graft copolymerized. After the reaction is completed, purification is carried out by repeated washing with water and boiling.
The artificial blood vessel of the present invention was obtained. The grafting rate of acrylamide was determined to be 24% when the obtained artificial blood vessel was washed with methanol and then dried, based on the increase in layer thickness.

The obtained artificial blood vessel has an inner diameter of 3Il1m1 and an outer diameter of about 4.51cm.
The inner and outer surfaces were highly hydrophilic. Further, even if the artificial blood vessel was cut at any point, the cut surface did not fray, and suturing was easy, and the through hole of the suture needle closed itself when the needle was removed.

When the cross-section of the wall of the obtained artificial blood vessel was observed using a scanning electron microscope, it was found that the wall had a network structure in which pores with a diameter of approximately 5 to 50 ρ existed throughout the thickness of the wall. . Furthermore, when water was poured into the artificial blood vessel and water pressure was applied, water leaked through the wall of the artificial blood vessel. This shows that the artificial blood vessel has porosity.

The artificial blood vessel was cut into a length of 8 cWl, pre-clotted with bovine blood, inserted into a closed circuit, and the compliance was measured using the method described below and found to be 0.4.

Next, the artificial blood vessel having a length of 17 IN was inserted into the jugular vein of a mongrel dog weighing 15 to 9, and removed after 4 hours.

When the blood-contact surface was observed with the naked eye and with a scanning electron microscope, it was found that there was no thrombus formation and only a small amount of blood cell components were attached, indicating that the material had excellent blood compatibility.

(Compliance measurement method) A metering pump that delivers liquid at 0.05 d per stroke
CD blood is sent through this closed circuit, the change in internal pressure is measured, and formula (1) is calculated from the number of strokes of the metering pump and the change in internal pressure.
Calculated from.

Patent applicant: Director of the Agency of Industrial Science and Technology, Haka 1 person

Claims (1)

[Scope of Claims] 1. An artificial blood vessel characterized by being made of an elastomer, having a porous structure inside the tube wall, and having an acrylamide graft copolymer layer on at least the inner surface of the tube wall. 2. The artificial blood vessel according to claim 1, wherein the artificial blood vessel is an arterial artificial blood vessel having a compliance of 0.1 to 0.8.