JPS6219870B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Technical Field of the Invention] The present invention relates to an artificial blood vessel having a compliance similar to that of a living 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 approximately 6 mm or more include Dobesky artificial blood vessels made of Dacron knitted fabric manufactured by USCI, and Gore-Tex made of expanded polytetrafluoroethylene manufactured by Gore, Inc. of the United States. Used clinically. However, these artificial blood vessels have drawbacks such as a compliance that is 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 pannus hyperplasia at the anastomotic site may occur after a long period of time after implantation in a living body. Occur. Furthermore, when these artificial blood vessels are used as artificial blood vessels for small-caliber arteries with an inner diameter of about 6 mm or less, patency is poor due to differences in compliance and poor blood compatibility, and they cannot be used clinically.
Therefore, autologous veins are used in revascularization surgeries for arteries below the knee, coronary arteries, and the like.

Special Publication No. 50-32554, No. 53-15556, No. 55-
Publications No. 4414 and No. 55-4415 describe artificial blood vessels in which hydrophilic monomers are graft-copolymerized to artificial blood vessels made of Dacron fibers, artificial blood vessels made of Teflon fibers, artificial blood vessels made of stretched polytetrafluoroethylene, etc. is disclosed. However, the compliance of these artificial blood vessels is significantly different from that of biological blood vessels. Furthermore, the graft copolymer layers of hydrophilic monomers 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 it is said that it is important to satisfy these requirements, the reality is that we have not found anything 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 that approximates 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 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. A thermoplastic elastomer that does not cause serious damage to physiological functions and has excellent antithrombotic properties. Examples of such elastomers include polystyrene elastomers, polyurethane elastomers, polyolefin elastomers, polyester elastomers, etc.
These elastomers may be blended with polymers other than elastomers within a range that maintains the properties of elastomers. These may be used alone or in combination of two or more. 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 referred to in this specification refers to a network structure,
It means a sponge-like structure or a structure similar to these structures. For example, a network structure is about 1
Pores having a maximum diameter of about 100 μm exist in a network shape. A sponge-like structure is an aggregation of cellular voids that are spherical, ellipsoidal, or modified shapes of these, and have a maximum diameter of approximately 1 μm to approximately 3/5 of the thickness of the tube wall. It is.

A skin layer having a thickness of about 50 μm or less and having a denser structure than the porous structure may be present on the surface of the artificial blood vessel having a porous structure inside the tube wall. It is preferable that part or all of the artificial blood vessel is exposed on the surface, 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.

The artificial blood vessel of the present invention is made of an elastomer,
Since the porous structure is provided inside the tube wall, the elastomer density of the tube wall becomes sparse, resulting in a soft structure and increased compliance. Therefore, by adjusting the elastomer density of the tube wall, the porous structure, the strength of the elastomer, etc., the compliance of the artificial blood vessel can be approximated to 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 unconditionally. However, it is preferably 0.05 to 0.35 g/cm ³ , more preferably 0.1 to 0.3 g/cm ³ , and particularly preferably 0.125 to 0.25 g/cm ³ .

The compliance referred to in this specification is expressed by the formula (1): C=ΔV/Vo・ΔP×100 (1) (where C is compliance and Vo is the internal pressure of 50 mm.
The internal volume of the measured blood vessel when Hg is measured, ΔP is the internal pressure 50 mm
100mmHg from Hg to internal pressure 150mmHg, ΔV is internal pressure
It is defined as the internal volume of the measured blood vessel that increases from 50 mmHg to 150 mmHg. Actual measurement involves, for example, inserting a measurement blood vessel into a closed circuit, injecting liquid into this circuit using a micrometer metering pump, measuring the amount of injected liquid and the change in pressure within the circuit, and calculating compliance from equation (1). can be calculated.

The preferred compliance for artificial blood vessels is
It varies depending on the thickness of the artificial blood vessel, the site of use, etc., and cannot be determined unconditionally, but the compliance of the living blood vessel used for normal revascularization surgery is 0.1 to 0.8.
Therefore, it is thought that it is preferable to set it within such a 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 to 0.8 can be manufactured. Artificial blood vessels with a compliance of 0.1 to 0.8 are suitable for applications such as artificial blood vessels for arteries, depending on their thickness, and those with an inner diameter of 1 to 6 mm and a compliance of 0.1 to 0.5 are suitable for use in small-caliber arteries. It can be suitably used as an 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 compared to layers graft copolymerized with other monomers such as methyl methacrylate, ethyl methacrylate, methyl acrylate, ethyl acrylate, vinyl acetate, 2-hydroxyethyl methacrylate, and styrene. It has excellent blood compatibility. In addition, monomers such as acrylic acid and acrylic ester are added to the acrylamide to be graft copolymerized.
It may be added as long as the graft copolymer layer to be formed has sufficient hydrophilicity.

The artificial blood vessel of the present invention is reinforced by providing mesh netting, non-woven fabric, etc. on the outside of the artificial blood vessel or inside the vessel wall in order to withstand abnormal increases in blood pressure during surgery and maintain durability for a long period of time. You may.

The artificial blood vessel of the present invention having the above structure has a compliance similar to that of a biological blood vessel, and
In addition to the property that the blood contact surface is excellent in blood compatibility, it also has the following useful properties.

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 penetrability and suturing with living blood vessels is easy, and even if the sutured part is pulled, the sutured part will not fray or the suture thread will come off. Never.
Moreover, since the tube wall is made of elastomer, the hole through which the suture needle is inserted 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.

The artificial blood vessel of the present invention, as explained below,
The first step is to obtain a tubular material made of elastomer and has a porous structure inside the tube wall;
It can be manufactured by a step of graft copolymerizing acrylamide onto the tubular material.

[First step] An elastomer solution having a cloud point is extruded from an annular nozzle together with an internal coagulating liquid while maintaining the temperature above the cloud point, and is immersed in an external coagulating liquid immediately or after a dry distance. 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 tube having a porous structure, for example a network structure, in which pores are present throughout the thickness from the inside to the outside of the tube wall is obtained.

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 elastomer. Examples of the good solvent include N.N.-dimethylacetamide, N.N.-dimethylformamide, dimethyl sulfoxide, 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 phagocytic 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 is not particularly limited as long as it can extrude the elastomer solution into a tubular shape and inject the internal coagulation liquid into the annular nozzle.
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 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] As a method for graft copolymerizing acrylamide onto the tubular material produced in the first step, gamma rays, x
There are various methods such as a method of irradiating with radiation such as a beam or an electron beam, a method using corona discharge or glow discharge, a method of irradiating with ultraviolet rays, and a method of using a catalyst such as cerium ion. Any method 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, such as a network structure, in which pores exist throughout the thickness from the inside to the outside of the tube wall, and at least the inside surface has a hydrophilic monomer. A graft copolymerized layer is present and has porosity.

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

Compliance approximates that of biological blood vessels.

Excellent blood compatibility on blood contact surfaces.

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

Pores that help organize the Γ artificial blood vessel can be formed as necessary.

The Γ suture needle has good penetration and suturing is easy.

ΓThe cut end will not fray even when cut to any length.
Moreover, the suture thread does not become frayed from the sutured portion.

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

Nodules are difficult to form under high Γ 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 patch material, etc. in revascularization surgery of living blood vessels, and can also be used for blood access, etc. be able to. Furthermore, the artificial blood vessel of the present invention has
It can be used as an arterial artificial blood vessel with a compliance of 0.1 to 0.8. In particular, because the compliance is close to that of biological blood vessels and the blood contact surface is excellent in blood compatibility, artificial blood vessels with a compliance of 0.1 to 0.5 and an inner diameter of approximately 1 to 6 mm, which currently do not exist in clinical use, are suitable. It can also be used as an artificial blood vessel for small diameter arteries. Therefore, it can be suitably used for revascularization of an artery below the knee or as an artificial blood vessel for bypassing the aorta and coronary artery. 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 having 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 4,4'-diphenylmethane diisocyanate 2
17.5 g of segmented polyurethaneurea, which is obtained by chain-extending a prepolymer consisting of 1 mole of polytetramethylene glycol with a molecular weight of 2000 and 1 mole of ethylenediamine, was dissolved in a mixed solvent of 47.5 ml of N·N-dimethylacetamide and 35 ml of propylene glycol. . The cloud point of the resulting solution was approximately 50°C. While maintaining this solution at 70° C., it was extruded at about 40 cm/min using a gear pump through an annular nozzle with solution outlet dimensions of 3 mm in inner diameter and 4.5 mm in outer diameter. 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 elastomer 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 10 ⁵ R), then immersed in a 20% by volume aqueous solution of degassed acrylamide, and heated for 50 minutes under shaking.
It was heated at ℃ for 15 minutes to graft copolymerize acrylamide. After the reaction was completed, purification was carried out by repeated washing with water and boiling to obtain the artificial blood vessel of the present invention. The grafting rate of acrylamide was 24%, as determined from the increase in weight of the obtained artificial blood vessel after washing it with methanol and drying it.

The resulting artificial blood vessel has an inner diameter of 3 mm and an outer diameter of approximately 4.5 mm.
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 with a network of pores with a diameter of approximately 5 to 50 μm throughout the thickness of the wall. was. 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 cm, pre-clotted with bovine blood, inserted into a closed circuit, and compliance was measured using the method shown below.
It was 0.4.

Next, the artificial blood vessel with a length of 17 mm was inserted into the jugular vein of a mongrel dog weighing 15 kg, and after 4 hours, it was removed and the blood contact surface was observed with the naked eye and with a scanning electron microscope. It was found that there was very little adhesion of components and that it had excellent blood compatibility.

(Compliance measurement method) A metering pump that delivers 0.05ml per stroke is used to
ACD blood is sent through this closed circuit, the change in internal pressure is measured, and it is calculated using formula (1) from the number of strokes of the metering pump and the change in internal pressure.

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.