JPS62167560A - Production of 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 (Field of Industrial Application) The present invention relates to an artificial blood vessel. More specifically, the present invention relates to an artificial blood vessel whose inner surface has particularly excellent antithrombotic properties and which can be used even in areas with a small diameter, and a method for manufacturing the same.

(Prior Art) Much research has been carried out on artificial blood vessels since the beginning of this century), and as a result, tubular woven and knitted fabrics of polyester fibers and porous tubes of expanded polytetrafluoroethylene have been put into practical use.

However, the application of these artificial blood vessels at the practical stage is limited to relatively large arteries with an inner diameter of 6 mm or more.
Sufficient clinical results have not yet been achieved for smaller arteries and veins. The reason for this is that small arteries have a small diameter, which makes them more likely to become occluded if blood clots form, and because blood flow is slow in small arteries and veins, blood clots grow quickly and become occluded. . In addition, all of the artificial blood vessels currently in practical use are ultimately made of living organisms, so they acquire antithrombotic properties and are stabilized by intimal formation, but in this case, endothelial hyperplasia This can cause narrowing of the vascular lumen, which can lead to occlusion. This is also thought to occur when the structure of the artificial blood vessel, for example, the ability to retain neoendothelium is low.

In recent years, many attempts have been made to overcome the above-mentioned problems and to develop artificial blood vessels with excellent performance. Among these, many proposals have been made that use elastomers as materials for artificial blood vessels, and in some cases, use polyurethane among elastomers. They can be roughly divided into those that use elastomers in the form of fibers and those that use them as porous bodies.

Among these, those used in the form of fibers include a conduit obtained by electrostatically spinning a liquid composition containing a fiber-forming polymer such as polyurethane into fibers and collecting the fibers on a shaped molding tool. Prosthetic material and its manufacturing method
-110977), a manufacturing method that improves the above molding method (
JP-A-54-151,675 @), artificial blood vessels whose mechanical properties are the same as those of living blood vessels, and their manufacturing method (JP-A-59-11,864), and electrostatic spinning (fibrous vessels). A structure in which the fiber-forming polymer composition is changed on one side and the opposite side, and its manufacturing method
-190947).

Still another method is to roll the fibrous material onto a mandrel while rotating the mandrel to form a porous tube (Japanese Patent Application Laid-Open No. 157465/1982), or by spraying a polymer solution through a nozzle. A method of forming a single fiber into a tubular artificial blood vessel by winding it around a mandrel (
JP-A-59-181149).

I would also like to add about the polymers that make them porous (Japanese Patent Application Laid-Open No. 57-150954, Japanese Patent Application Laid-open No. 59-22505).
8, Japanese Patent Application Laid-open No. 60-2254, etc.),
All of these methods start from a polymer solution, and the porosity formation method involves mixing a pore-forming agent such as an inorganic salt or other water-soluble substance with the polymer solution, and then dissolving and removing the inorganic salt after shaping. By replacing the polymer with a good solvent and a poor solvent, micropores are generated and the polymer is made porous.

(Problems to be Solved by the Invention) The main purpose of the above proposal is to prevent thrombus formation by using a material with excellent antithrombotic properties and to approximate mechanical properties to biological blood vessels, and to prevent the formation of porous blood vessels. This is intended to improve the invasion and retention of new tissue.

However, most of the above proposals use the polymer as an organic solution, so when making an artificial blood vessel, it is essential to completely remove the solvent, and this solvent removal is difficult and the process becomes complicated. be. Electrostatic spinning requires high voltage, which is dangerous, and has the disadvantage that the equipment is complicated. Furthermore, regarding the porous method, it is said that the method of creating a sponge-like porous material with many closed cells not only reduces the mechanical strength of the blood vessel, but also makes it difficult to make the mechanical properties of the entire tube uniform. It has a kasu point. Furthermore, if the entire tube is made of an antithrombotic material and has excellent antithrombotic properties, if there are communicating holes in the tube wall, blood leakage from the communicating holes becomes a problem.

The purpose of the present invention is to solve the above-mentioned problems, and has an inner surface with excellent antithrombotic properties, easy tissue penetration through the outer surface, excellent healing stability, and excellent mechanical properties. An object of the present invention is to provide a method for manufacturing an artificial blood vessel that can be applied to a small-diameter artificial blood vessel at low cost and efficiently by a completely dry process without using a cutting solvent.

(Means for Solving the Problems) The method of the present invention involves melt-spinning a thermosetting polyurethane elastomer, then thinning it by entraining it in high-speed high-temperature gas, and forming substantially continuous filaments into a sheet. The polyurethane elastic fiber nonwoven fabric obtained by lamination is wrapped around a core frame, heated and molded to form a porous tubular body, and then at least the inner surface of the tubular body is subjected to low-temperature gas plasma treatment with a fluorine compound. do.

The polyurethane elastomer applied to the method of the present invention is a known thermoplastic polyurethane elastomer with a molecular weight of 500 to 600.
0 polyol, such as dihydroxy polyether, dihydroxy polyester, dihydroxy silicone, and block copolymers thereof, and an organic diisocyanate having a molecular weight of 500 or less, such as I) t p'-diphenylmethane diisocyanate, tolylene diisocyanate, hexamethylene diisocyanate, etc. and a chain extender such as water, hydrazine, diamine, glycol, etc. Particularly good among these polymers are those using polytetramethylene glycol or a flock copolymer of polytetramethylene glycol and silicone as the polyol. It is also used as an organic diincyanate.
'-Diphenylmethane diisocyanate is preferred.

In addition, glycol is suitable as a chain extender, and 1,4-
Butanediol is particularly preferred.

The polyurethane nonwoven fabric used in the method of the present invention can be produced, for example, by the following method. The above-mentioned thermoplastic polyurethane elastic body is melted, and using a spinning apparatus described in, for example, Jiko Sho 41-7888, the filaments are thinned by hot gas flows discharged from a spinneret and ejected from both ends of a nozzle. urge The atomized fissures are separated from the gas stream on a collection device, such as a moving conveyor net, and stacked on the net without being substantially bundled. The laminated filaments are bonded to each other by their own heat. They may be bonded by heating and pressing using a roller or the like before or after being laminated on the collection device and cooled and solidified.

In either method, the nonwoven fabric is made by bonding polyurethane elastic fibers themselves, and solvents, adhesives, etc. are not used. Therefore, a nonwoven fabric containing extremely few impurities, eluates, etc. can be obtained.

In the method of the present invention, the average diameter of the polyurethane elastic fibers constituting the nonwoven fabric is determined by the amount of polyurethane discharged, the spinning speed,
Although the tensile speed etc. can be selected arbitrarily, the average diameter is preferably 30 microns or less for use in artificial blood vessels. More preferably, it is 20 microns or less. As the diameter of the fibers increases, a blood clot with a rougher inner wall of the artificial blood vessel is more likely to form.

The polyurethane elasticity thus obtained
It is preferable to use unrecognized cloth with a date of 10 y/m2 to 50 y/m. If the basis weight is small, it will be difficult to handle, and if it is large, the ends wound around the core frame will easily tear.

The core frame used when molding the tubular body is preferably made of a material that does not easily stick to polyurethane fibers in order to pull out the tubular body after heating and molding, and suitable materials include iron rods coated with fluororesin and fluororesin round bars. used for. The reason why it is possible to pull out the core frame after hot molding is because the porous tubular body of the present invention, which is made of polyurethane elastic fibers, has stretchability), which is almost impossible with non-stretchable material tubes.

The heating temperature and time used for molding are preferably 70 to 200°C in order to bond the polyurethane nonwoven fabrics together and integrate them.1. 100-1300C is suitable for +1 temple. The porous tubular body obtained in this way is made up of nonwoven fabrics of polyurethane elastic fibers that are firmly bonded to each other by heat and integrated, and the diameter and wall thickness of the inner cavity of the tubular body are the same as those of the core frame. It is possible to change the dimensions of the formwork.

From the perspective of an artificial blood vessel, the diameter of the lumen of the tubular body is 2.
~40 mm, but in order to exhibit the features of the present invention,
~20 mm, more preferably 8 to 15 mm. The wall thickness of the tubular body is 0.1 to 5 mm, preferably 0.2 to 3 mm. Furthermore, the porosity of the artificial blood vessel of the present invention can be arbitrarily adjusted by adjusting the amount of nonwoven fabric used in the tubular body having a certain wall thickness.

Porosity can generally be expressed by pore size distribution and porosity, but in the case of artificial blood vessels, it is common and practical to express it by water permeability. In particular, when it is a fibrous structure like the porous tubular body of the present invention, it is preferable to express it in terms of water permeability. Water permeability refers to the amount of water (ml) that passes through 1 cm2 of the wall of an artificial blood vessel under a pressure of 120 mmHH. In the present invention, this water permeability is 3000 m#/min or less, preferably 1500 trJ/min or less, and more preferably 500 ml/min or less.

The low-temperature gas plasma of the present invention can be generated in a conventional manner. Although the high voltage can be either direct current or alternating current, it is preferable to use a high frequency of 18.56 MHz from the viewpoint of ease of plasma generation, plasma stability, and uniformity of processing effect. There are two types of electrodes for applying high-frequency voltage: an internal electrode type inside the plasma reactor, and an external electrode type installed outside the plasma reactor.Also, for each type, there are capacitively coupled electrodes and inductively coupled electrodes, but both can be used. can.

In low-temperature gas plasma treatment of the inner surface of a tubular body, the inner surface can be selectively plasma-treated by placing the tubular body in a vacuum container, introducing a monomer into the inside of the tubular body, and generating plasma. Preferably, the outside of the tubular body is covered with a non-metallic tube such as plastic, glass, or ceramic having an inner diameter that closely fits the tubular body, one side of the tubular body is evacuated, and monomer is introduced into the other (the other side) to form the tubular body. Monomer plasma is generated only inside the tubular body, and only the inner surface of the tubular body is selectively treated with plasma. More preferably, in the above method, if the electrode to which the high frequency voltage is applied is moved at a constant speed in the length direction of the tubular body, more uniform plasma treatment becomes possible.

The formation of a polymer film of a fluorine compound by low-temperature gas plasma and the state of surface treatment depend on so-called plasma parameters such as the degree of vacuum, power, time, and monomer flow rate. Generally, the amount of polymerized film formed increases as the monomer flow rate increases, the vacuum level decreases, and the polymerization time increases.

The fluorine compound is introduced into the plasma reactor in gaseous form.

For compounds with high boiling points, heat them using an appropriate heating device.
Vaporize and introduce. The amount of monomer introduced greatly affects the state of plasma generation and the properties of O/products), and is usually 10-4 to 10 Torr s, preferably 1
0-3 to 10° Torrs, more preferably 5×10
˜5×10 Torr.

If the pressure of the fluorine compound is less than 10' Torr, plasma generation is not sufficient, and formation of a plasma polymerized film on the surface of the nonwoven fabric or surface modification is not sufficient. Also, 1
Exceeding 0 Torr is not preferable because plasma generation is unstable, the properties of the polymer are not sufficient, or the treatment is non-uniform. It is also possible to use a gas that activates the monomer simultaneously with the introduction of the monomer, such as nitrogen, argon, helium, or the like. However, it is preferable that the pressure of the monomer and these gases is in the range of 10-4 to 10 Torr.

The output of the plasma is usually at most 3 W/unit area of the electrode.
Cm2, preferably at most 2 W/cm2, more preferably from 0.05 to I W/cm2. 8W/cm2
In the above case, the degree of crosslinking of the plasma polymerized film is large, the strength of the film is decreased, the film is colored, or the nonwoven fabric as the base material is damaged. The longer the plasma polymerization time, the better the formation of a polymer film and the surface fluorination treatment, but on the other hand, the increase in cross-linking density of the polymer film and the denaturation and deterioration caused by etching, etc.
3600 seconds, preferably 30 to 1300 seconds.

By low-temperature gas plasma treatment of the fluorine compound, a plasma polymerized film of the fluorine compound or a fluorinated surface is formed on the surface of the nonwoven fabric or the polyurethane fibers constituting the nonwoven fabric. The plasma polymerized film is usually formed in a thickness of 50^ to 100^ or more on the surface of a nonwoven fabric or a polyurethane fiber. This is confirmed by surface electron microscopic contact angle measurements and spectroscopic measurements such as IR'PE5CA.

The major difference in plasma polymerization/treatment method is 50A to 10
Even ultra-thin films such as 0^ can be applied uniformly.

The fluorine compound used in the present invention is not particularly limited as long as it has a carbon skeleton and a fluorine atom in the molecule. Molecules containing functional groups such as benzene rings, OH groups, CO groups, double bonds, triple bonds, etc. have problems with contact angles, coloration, etc., and are difficult to form a good plasma polymerized film. Furthermore, the higher the fluorine content in the fluorine compound, the better, and preferably 50% or more.

Although the composition and structure of plasma-polymerized films of fluorine-based compounds are not necessarily certain, it is important that the polymerized film has no solvent solubility and that the contact angle with water is 100° or more, preferably 105° or more (the contact angle is small). and C-F characterized by the introduction of fluorine
A characteristic feature is that the absorption of is observed by IR or ESCA.

The thickness of the plasma polymerized film is preferably 50A or more, more preferably 100A. According to electron microscopy, it forms a uniform film with a thickness of at most 10 μm.
It can be seen that in the nonwoven fabric of the present invention, the surfaces of these constituent fibers are covered with a thin film.

It is unclear why the plasma-treated product of the fluorine compound of the present invention has good antithrombotic properties, but it is speculated that the fluorine surface has low surface energy and low platelet stickiness, and that the plasma-polymerized and treated surface Possible causes include the extremely homogeneous and smooth surface.

One way to evaluate the antithrombotic properties of the present invention is the Imai-Nose method (Artificial Organs, 2,95 ('7B)) described below.
This was done in accordance with.

Place the sample tightly on the watch glass and place it in a constant temperature bath at 87°C. On top of this, add 0.26 ml of 8.18% sodium citrate-added dog blood (an adult mongrel dog was used), and then add 0.025 ml of 0.1M calcium chloride.
After shaking the sample a little by hand to mix it with the blood, pour a small amount of water around the sample to compensate for evaporation and cover the watch glass with a glass plate. Water is added at appropriate time intervals to stop the clotting reaction. Remove the clot with a spatula, leave in water for 5 minutes, then transfer to a test tube containing approximately 8 ml of 87% formalin and leave for 5 minutes. It is then stored in distilled water until weighed. The fixed blood clot is sandwiched between F paper to absorb excess moisture, and then weighed. The thrombus production rate is calculated based on the weight of the final clot formed on the glass surface as 100%. The inventors conducted an evaluation focusing particularly on the thrombus formation rate after 15 minutes.

As a second evaluation of antithrombotic properties, platelet adhesion and morphology were observed.

PRP prepared from fresh blood of an adult mongrel dog is dropped onto the sample rinsed with physiological saline. 1 After removing PRP and washing with physiological saline, fixing at room temperature with glutaraldehyde, dehydrating with alcohol, and drying at critical point, the number of attached platelets was observed using a scanning electron microscope. The morphological changes of platelets were observed. Morphological changes were classified into the following eight categories.

Type I: The normal disc shape has become spherical and has 3 to 4 pseudopods, and the adhesion to the material surface is relatively weak. Type I: The pseudopods have a long length with several or more pseudopods extended. Type: Thin foam spread over half of the length of the pseudopod and strongly adherent; Type: Thin foam spread over half the length of the pseudopod; and completely sticky.

(Example) EXAMPLES Hereinafter, the present invention will be explained in more detail by showing examples.

Example 1 5825 parts of dehydrated polytetramethylene glycol having a hydroxyl value of 102 (hereinafter, all parts mean heavy slope parts).
and 220 parts of 1,4-butanediol were placed in a jacketed kneader and thoroughly dissolved with stirring, then 8 parts of 1,4-butanediol were added.
The temperature was maintained at 5° C., and 1985 parts of p+p-diphenylmethane diisocyanate was added thereto for reaction.

When stirring was continued, powdered polyurethane was obtained in about 30 minutes, which was molded into pellets using an extruder and had a concentration of 1y/100mA as measured at 25°C in dimethylformamide!
A polyurethane elastomer having a relative viscosity of 2.25 was obtained.

Using the polyurethane elastic pellets obtained in this way as a raw material, a melt blow spinning device having slits for jetting heated gas on both sides of nozzles with a diameter of 0.8 mm arranged in a row was used to spin the polyurethane elastic material at a melting temperature of 288°C. o, i per minute
The polymer was discharged at a rate of 5 y, and air heated to 200° C. was injected from the slit at a pressure of 8.5 kg/cm 2 to atomize the polymer. The thinned filament was placed 25 cm below the nozzle, collected on a conveyor made of a 930-mesh wire mesh, and sandwiched between rollers to obtain a taken-off shin woven fabric. This nonwoven fabric was made up of opened and laminated monofilaments of polyurethane elastic fibers, and the intertwining points between the filaments were joined together by fusion. The property value of this nonwoven fabric was as follows.

Weight 1 5 9'/
m2 Tensile strength: 0.12 kg/am Breaking elongation: 520% Bending resistance: 10 mm Filament diameter: 5 microns Next, this nonwoven fabric was wrapped around a core frame coated with fluororesin with a diameter of 5 mm, and then rolled into a cylindrical shape with an inner diameter of 7 mm. It was placed in a mold and heated and molded at 150°C for 30 minutes. The core frame was pulled out to obtain a porous polyurethane tubular body. This tubular body had an integrated structure in which nonwoven fabrics were firmly bonded to each other.

Subsequently, CF4 monomer gas was flowed inward of the tubular body, and argon gas was flowed to the outside so that the pressure was slightly higher than that of the inner surface. The pressure of argon gas was 1 mbar. 18.
Apply a high frequency of 56MHz with an output of 30W for 5 minutes,
The inner surface of the cylindrical body was treated with a low-temperature gas plasma using a fluorine compound. The contact angle of the inner surface with water was 117.6°, indicating good water repellency.

The water permeability of this tubular body was measured and was 830 m11 min. Furthermore, Table 1 shows the results of evaluating antithrombotic properties using the method described in this specification. As shown in Table 1, the antithrombotic properties of the inner surface of the membrane were very good, making it ideal for use as an artificial blood vessel.

Furthermore, the mechanical properties of the material did not change before and after plasma treatment.

Table 1 Thrombus formation rate is the thrombus formation rate after 15 minutes when the glass surface is taken as 100.

(Effects of the Invention) Since the polyurethane elastic fibers of the present invention are porous tubular bodies bonded to each other, it is possible to utilize the good properties of polyurethane as a biomedical material, including its elasticity, and to prevent the infiltration of living tissues. It has the advantage that it is advantageous in that it is easy to maintain the living image style. Furthermore, since at least the blood-contacting surface is given high antithrombotic properties by low-temperature plasma treatment with a fluorine compound, the inner surface also has high antithrombotic properties, and it has the feature that it can be used as a small-diameter artificial blood vessel. In addition, in order to form a fluorine compound plasma polymerized film on mechanically good elastic polyurethane fibers, we have taken advantage of the mechanical advantages of the material and changed only the surface properties of the material to antithrombotic properties. It is a material that improves on the drawbacks of conventional materials, such as poor moldability, low mechanical strength, low durability, and changes in antithrombotic properties.

In addition, since the method of the present invention is a completely dry process that does not use any solvent, there is no need to consider the danger of residual solvent to the human body, and it is completely safe.
It has great advantages, such as being able to be manufactured at an extremely low cost since it does not require any processes or conditions. Furthermore, in addition to straight artificial blood vessels, one with a single taper, one with branches, etc. can be easily manufactured by using molding tools suitable for each type of artificial blood vessel.

Kanebo Kaisen Co., Ltd.

Claims (4)

[Claims] (1) After melt-spinning a thermoplastic polyurethane elastomer, it is entrained in high-speed high-temperature gas to be thinned, and the resulting substantially continuous filaments are laminated into a sheet shape. A polyurethane elastic fiber nonwoven fabric is then wrapped around a core rod. A method for producing an artificial blood vessel, which comprises heating and molding the tubular body to form a porous tubular body, and then subjecting at least the inner surface of the tubular body to a low-temperature gas plasma treatment using a fluorine compound. (2) The manufacturing method according to claim 1, wherein the heating molding temperature is 70-200°C. (3) The manufacturing method according to claim 1, wherein the polyurethane elastic fibers have an average diameter of 30 microns or less. (4) The manufacturing method according to claim 1, wherein the inner surface has a contact angle with water of 100° or more.