JPS62186864A - 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) Many studies on artificial blood vessels have been conducted since the beginning of this century, and as a result, tubular woven or knitted fabrics of polyester fibers and porous tubes of expanded polytetrafluoroethylene have been put into practical use.

However, these artificial blood vessels at the practical stage are only applicable 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 reasons for this include the exposure of small arteries, their small diameter, which makes them easy to block if a blood clot occurs, and the slow blood flow in small arteries and veins, which causes blood clots to grow quickly and become blocked. It will be done. Also.

All of the artificial blood vessels that are currently in practical use ultimately acquire antithrombotic properties and are stabilized by the formation of pseudointima by the living body, but in this case, the vascular lumen is reduced due to endothelial hyperplasia. A narrowing occurs.

This may cause a blockage. It is also thought that this occurs when the structure 1 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 1jfi' and XA points and to develop artificial blood vessels with excellent performance. Among these, many proposals have been made for artificial blood vessels using elastomers as materials, and in particular, among elastomers, polyurethane is used. 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.

Conduit M binding material obtained by electrostatically spinning a liquid composition containing a fiber-forming polymer made of polyurethane into fibers and collecting the fibers directly above the shaped molding, and its manufacturing method -110977 Publication), a manufacturing method by improving the above-mentioned molding tool (Japanese Patent Application Laid-Open No. 151675-1982), and a method for making the artificial blood vessel whose mechanical properties are the same as those of biological blood vessels (Japanese Patent Application Laid-open No. 11864-1986). There is also a fiber structure obtained by electrostatic spinning, in which the fiber-forming polymer composition is changed on one side and the opposite side, and a method for producing the same (Japanese Patent Application Laid-Open No. 190947/1983).

Another method is to extrude the fibrous material onto a mandrel while rotating the mandrel to form a porous tube (Japanese Patent Application Laid-open No. 157465/1989), or by spraying a polymer solution through a nozzle. A method of making a single fiber and winding it around a mandrel to make a tubular artificial blood vessel (
Japanese Unexamined Patent Publication No. 59-181149 Jij).

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).
3, JP-A No. 60-2254, etc.), but
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. The porous υ is made porous by generating p micropores by replacing a good solvent and a poor solvent in the polymer.

In addition, as a method for imparting antithrombotic properties to the material itself, 1, for example, a method of making the surface charge negative (Japanese Patent Laid-Open No. 58-1
49915, etc.) 1. A method of creating a microdomain structure with differences in surface energy (Japanese Patent Publication No. 57-8134)
Publication No. 7, etc.).

A method of lowering surface energy using fluororesin or silicone resin (Japanese Patent Publication No. 51-18991), a method of increasing surface energy using water-absorbing gel, etc.
-1744, etc.), heparin immobilization (Special Publication No. 1744, etc.), heparin immobilization (Special Publication
9-15122, Japanese Patent Publication No. 59-15121, etc.), immobilization of urokinase (Japanese Patent Publication No. 58-5302, etc.)
immobilization of albumin (JP-A-57-198)
703, etc.). Among them, heparin, urokinase, a! By immobilizing repmin etc. on the surface of the material, it shows good platelet adhesion and can be used as an excellent antithrombotic material. Nothing is coming out.

(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 by approximating mechanical properties to biological blood vessels. The aim is to improve the invasion and retention of new tissue by making it more sensitive.

However, most of the above proposals use the polymer as an organic solution, so when making one artificial blood vessel, it is impossible to completely remove the solvent, and this solvent removal is difficult and the process becomes complicated. It is. Electrostatic spinning requires high voltage, which is dangerous, and has the disadvantage that the equipment is complicated. Furthermore, regarding the porous method, the method of creating a sponge-like porous material with many closed cells does not only reduce the mechanical strength of the blood vessel, but also makes it difficult to equalize the mechanical properties of the entire tube. There is a problem with this. (9) If the entire tube is made of an antithrombotic material and has excellent antithrombotic properties, if there are communicating holes in the tube wall, 7111 blood from the communicating holes will become a problem.

The purpose of the present invention is to solve the above-mentioned problems, to have an inner surface with excellent antithrombotic properties, excellent stabilization of tissue invasion from the outer surface, and excellent mechanical properties. It is an object of the present invention 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 that does not use a cutting solvent.

(Means for Solving the Problems) The method of this J et al. involves melt-spinning a thermoplastic polyurethane elastomer and then thinning it by entraining it in a high-speed high-temperature gas to form virtually continuous filaments into a sheet. The polyurethane elastic fiber nonwoven fabric obtained by lamination is wrapped around a core body and 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 to adsorb albumin. characterized by things.

The polyurethane elastomer applied to the method of the present invention is a known thermoplastic polyurethane elastomer, and has a molecular weight of 500 to 600.
0 polyols, such as dihydroxy polyethers, dihydroxy polyesters.

Dihydroxy silicone and block copolymers thereof, organic diisocyanate with a molecule of 1 soo or less,
For example, ps p'-diphenylmethane diisocyanate, tolylene diisocyanate, hexamethylene diisocyanate, etc., and a chain extender.

For example, it consists of a polymer obtained by reaction with water, hydrazine, diamine, glycol, etc. Particularly good among these polymers are those using polytetramethylene glycol or a block copolymer of polytetramethylene glycol and silicone as the polyol. In addition, as organic diisocyanates, p, p'
-diphenylmethane diisocyanate is preferred. Further, as the chain extender, glycol is suitable, and 1,4-butanediol and bishydroxyethoxybenzene are particularly suitable.

The polyurethane nonwoven fabric used in the method of the present invention is.

For example, it can be manufactured by the following method. The thermoplastic polyurethane elastomer described above is melted and prepared as follows:
Using the spinning equipment described in Japanese Patent No. 883, filaments are thinned by a high-temperature gas flow discharged from a spinneret and ejected from both ends of a nozzle. The attenuated filaments are separated from the gas stream on a collecting device, such as a moving conveyor net, and are deposited on the net without being substantially focused. The stacked 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 is made using a solvent.

Do not use dressings, etc. Therefore, a nonwoven fabric containing extremely few impurities, eluates, etc. can be obtained.

The average diameter of the polyurethane elastic fibers used to create the nonwoven fabric in the method of the present invention can be arbitrarily selected depending on the polyurethane discharge vessel, spinning degree, tensile speed, etc.
For artificial blood vessels, the average diameter is preferably 30 microns or less, more preferably 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 be formed.

The thus obtained polyurethane elastic fiber nonwoven fabric preferably has a basis weight of 10 g/m2 to 50 g/m2. If the weight is small, it will be difficult to handle, and if it is large, the end wrapped around the core will easily break.

The tubular body is molded by wrapping polyurethane elastic fiber nonwoven fabric around a core, and the core used during molding is used to pull out the tubular body after heating and molding.

It is desirable to use a material that does not easily adhere to polyurethane fibers, and fluororesin-coated iron rods, fluororesin round rods, and the like are preferably used. It should be noted that the reason why it is possible to pull out the core after hot molding is because the porous tubular body of the present invention made of polyurethane elastic fibers has stretchability, and it is almost impossible to pull out the core body with a non-stretchable material tube.

The heating temperature and time used for molding are 70 to 200' in order to bond the polyurethane nonwoven fabrics together and integrate them.
C is preferred, more preferably 90 to 180°C,
Particularly suitable is 100 to 150'C. The porous tubular body thus obtained is.

The non-woven fabric of polyurethane elastic fibers is firmly bonded to each other by heat and integrated, and the diameter and wall thickness of the inner cavity of the tubular body can be changed depending on the dimensions of the mandrel and the formwork.

From the perspective of an artificial blood vessel, the diameter of the lumen of the tubular body is 2.
~40 mm, but 1.2 to exhibit the features of the present invention.
-20 mm, more preferably 3-15 mm. The wall thickness of the tubular body is 0.1 to 5 mm, preferably 0.1 to 5 mm.
It is 2-3 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 generally expressed by water permeability9. And it's also practical. In particular, when it is made of a fiber 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 that passes per 1 cm2 of the wall of an artificial blood vessel in 1 minute under a pressure of 120 mmHH.

In the present invention, this water permeability is 3000 mff/min or less, preferably xsoome/min or less, more preferably 500 me/min or less.

The low temperature gas plasma of the present invention can be generated by a conventional method. For example, it is usually 10-4 to 10 Torr.

It is generated by applying a high voltage at a vacuum degree of preferably 10-3 to 10' Torr, more preferably 5X10-2 to 5X10' Torr. High voltage can be either direct current or alternating current, but from the viewpoint of ease of plasma generation, plasma stability, and uniformity of processing effect,
Preference is given to using a high frequency of 6 kHz.

There are two types of electrodes for applying high-frequency voltage: an internal electrode type located inside the plasma reactor, and an external ``T4. Also available.

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, and one side of the tubular body is evacuated.

A monomer is introduced from the other side to generate monomer plasma only inside the tubular body, and only the inner surface of the tubular body is selectively subjected to plasma treatment. More preferably.

In the above method, if the electrode for applying the high frequency voltage is moved at a constant speed in the length direction of the tubular body, more uniform plasma treatment becomes possible.

Formation of a polymer film using low-temperature gas plasma of a fluorine compound and treatment of - and A-sides under vacuum degree and output for 1 hour.

It depends on so-called plasma parameters such as monomer flow rate. In general, the formation of a polymeric film increases as the flow rate increases, the degree of vacuum decreases, and the temperature increases.

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

Compounds at the commercial IP point are heated and vaporized using an appropriate HA heating device before being introduced. The amount of hexamer to be introduced greatly affects the state of plasma generation and the properties of the product, and is usually 10-4 to 10'I'orr, preferably 1
0-3 to 10"I'orr, more preferably 5X
10-2 to 5 x 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.
If it exceeds 0 T'orr, plasma generation may be unstable, the properties of the polymer may be insufficient, or the treatment may become non-uniform, which is undesirable. A gas that activates the monomer at the same time as the introduction of the 7-mer.

For example, it is also possible to use gases such as nitrogen, argon, and helium. However, if the pressure of seven gases and these gases is 10
It is preferable that the pressure is in the range of −4 to 10 Torr.

The output power of the plasma is υ1 per unit area of the electrode, usually at most 3 W.
/cm2. Preferably at most 2 W/cm2. More preferably, it is 0.05 to IW/cm2. 3
When W/crn2 or more, the degree of crosslinking of the plasma polymerized film increases.

There may be a decrease in film strength, discoloration, or damage to the nonwoven fabric that is the base material. The longer the plasma time, the better the formation of a polymeric film and the surface fluorination treatment, but on the other hand, the increase in the crosslinking density of the Eio film and the denaturation and deterioration due to etching, etc., so the plasma time is normally 1 to 3,600 seconds, preferably 1. is 30 to 1800 seconds.

By low-temperature gas plasma treatment of fluorine compounds.

A plasma polymerized film of a fluorine compound or a fluorinated surface is formed on the surface of the nonwoven fabric or the polyurethane fibers constituting the nonwoven fabric. Plasma polymerized membranes usually have 501 to 10
01 or more are formed. This is an electron microscopy contact angle measurement of 5 surfaces.

This is confirmed by spectroscopic measurements such as L and E80A.

The major feature of the plasma polymerization/processing method is that SOf~100
^This means that even an extremely thin round string film can be applied uniformly.

The fluorine compound used in the present invention only needs to have a carbon skeleton and a fluorine atom in the molecule, and is not particularly limited to a benzene ring or an Ofi group in one molecule.

Those containing functional groups such as CO groups, double bonds, triple bonds, etc.
It is difficult to form a good plasma polymerized film due to problems such as contact angle and coloration. Furthermore, the higher the fluorine content in the fluorine compound, the better, and preferably 50% or more. Suitable fluorine compounds include:

For example, CF4, C2Ii6, C3F8.04H1o,
Examples include perfluoroalkyl compounds such as C5Ht 2.0sHt4 and cyclic compounds comprising a perfluoroalkyl group.

Although the composition and structure of the plasma polymerized film of fluorine-based compounds are not necessarily certain, the single polymer film has no solvent solubility, the contact angle with water is 100'' or more, preferably 105' or more, and it is difficult to introduce fluorine. C-F well characterized
Absorption is IR or ESC! One of its characteristics is that it is recognized with an A grade.

The thickness of the plasma 1 composite film is preferably 50× or more, more preferably 100× or more.

According to electron microscopic observation, a uniform film with a thickness of at most 10 μm is formed, and 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.

A dry woven cloth treated with low-temperature gas plasma of a fluorine-based compound has excellent selective adsorption of albumin, and an albumin adsorption layer can be easily formed on its surface by simply immersing it in an albumin aqueous solution for a short time.

For example, usually o, ooi% or more, preferably 0.01%
As mentioned above, the adsorption can be completed by simply leaving the albumin in an aqueous solution of more preferably 0.05% or more for about 1 to 10 minutes. The adsorption temperature may be room temperature.

Although the albumin adsorption layer differs depending on the plasma conditions and albumin adsorption conditions, it is usually IXI per unit area of nonwoven fabric.
0-8g/cm2 or more, preferably 1x10'g
/cm2 or more, more preferably 1:10'ν'c
m2 or more. The amount of albumin adsorbed is 1 x 10'
If it is less than g/cm2, the antithrombotic effect and the effect on the adhesion and invasion of living cells and the prompt formation of pseudointima due to this are poor.

In general, it is known that materials that preferentially adsorb albumin exhibit excellent antithrombotic properties, while materials that strongly adsorb -mr-globulin and fibrinogen have poor antithrombotic properties. Also, if albumin is adsorbed onto the material in advance,
It is also known that the antithrombotic properties of the material are improved. The reason for this is presumed to be that albumin is a protein that does not contain sugar f4 at all, so it cannot bind to receptors on platelet membranes and is less likely to activate platelets.

In the present invention, since albumin is adsorbed after low-temperature gas plasma treatment with a fluorine compound, the amount of albumin adsorbed is significantly higher than when it is adsorbed to an untreated material, and the above-mentioned antithrombotic effect is improved. It seems that it will work. It is also presumed that the plasma-polymerized membrane of the fluorine compound (because the surface energy is low and the surface is smooth, platelet stickiness is low) also contributes to the antithrombotic effect.

Furthermore, since albumin is a material derived from a living body, when the artificial blood vessel according to the present invention is transplanted into the body.

It is expected that the adhesion and invasion of biological cells will be rapid and that pseudoendometrium formation will occur at an early stage.

The albumin wicking of the present invention appears to be different from the conventional albumin adsorption mechanism. That is, conventional methods for attaching and immobilizing albumin include chemical bonding, ionic bonding, and embedding in hydrogel; however, albumin is bonded by covalent or ionic bonding.

Albumin activity changes and antithrombotic properties decrease.

In the method of sealing albumin in the mesh of a polymer gel such as a hydrogel, albumin is water-soluble and an extremely small molecule, so it easily elutes to the outside and does not have a lasting effect. On the other hand, 1
Although the cause of the unique adsorption behavior of albumin in the fluorine compound plasma-treated product of the present invention is not clear, it is thought to be due to the hydrophobicity of the fluorine compound plasma-treated product and the hydrophobic-hydrophobic interaction between the hydrophobic groups of albumin. Advantages that differ from other attachment methods are that because specific chemical bonds and ionic bonds are not used to fix albumin, there is no change in the activity of albumin, and the adhesive strength is different from that of embedding and fixing in gel etc. It is a matter of sustainability.

In particular, because it is surface adsorbed, the amount of albumin used is much smaller than conventional methods, and because it is a hydrophobic-hydrophobic bond, denatured albumin falls off, and the surface always has new, undenatured albumin attached to it. Anti-thrombotic properties are always imparted to the skin.

Many methods for evaluating antithrombotic properties have been proposed.

In the present invention, the adhesion and morphology of platelets were observed.

PRf' prepared from fresh blood of an adult mongrel dog is dropped onto the sample rinsed with physiological saline. Remove 1 minute diameter PRP,
After washing with physiological saline, fixation at room temperature with glutaraldehyde, further alcohol dehydration, and critical point drying.
The number of adhered platelets is observed using a scanning electron microscope, and changes in the morphology of the adhered platelets are observed at the same time. The morphological changes are as follows:
Classify into.

Type 1: The normal disk shape becomes spherical with 3 to 4 pseudopods, and the adhesion to the material surface is relatively weak.

Type L: Strongly adhesive, with several or more pseudopods extended and thin, slender bodies spread out to half the length of the pseudopods.

Placement type: From a t-shaped body with a thin slender body spread out to more than half the length of the pseudopod, to a type with a thin slender body expanded completely to a nearly circular shape and completely adhesive.

In this case, it can be said that the less the morphological change is, that is, the more the type (■) is, the better the antithrombotic property is.

(Example) Hereinafter, the present invention will be explained in more detail by showing examples. The albumin concentration in the aqueous solution was determined from UV absorbance at 278 nm.

Example 1 Dehydrated polytetramethylene glyco with a hydroxyl value of 102
/I15325 parts (hereinafter) 1 part means parts by weight. ) and 220 parts of 1,4-butanedio-/l in a jacketed kneader, and after sufficiently dissolving with stirring, the temperature was kept at 85'C, and p,p'-diphenylmethane diisocyanate 1985 part was added and reacted.

When stirring was continued, a powdered polyurethane was obtained in about 30 minutes, which was molded into a pellet shape using an extruder and had a concentration of 1 g/100 rn measured at 25°C in dimethylformamide.
A polyurethane elastomer having a relative viscosity of 2,250 was obtained.

The thus obtained pellets of polyurethane elastomer were used as raw materials, and the melting temperature was 233°C using a melt-spinning device having slits for jetting heated gas on both sides of nozzles with a diameter of 0.8 mm arranged in a row. .

The polymer was discharged at a rate of 0.15 g/min per nozzle, and the air heated to 200 °C was heated to 3.5 kg/cm.
It was injected from the slit at a pressure of 2 to make it thin. The thinned filament was collected on a conveyor consisting of a 30-mesh wire mesh placed 25 cm below the nozzle.

Next, the shiné woven fabric is collected by sandwiching it between rollers. This nonwoven fabric was made by opening monofilaments of polyurethane elastic fibers and laminating them, and the intertwining points between the filaments were joined together by fusion. The physical properties of this nonwoven fabric were as follows.

Weight: 15 g
/ m2 Tensile strength: 0.12 kg/Cm Breaking elongation: 520% Bending strength: 10 mm Filament diameter: 5 microns Next, this nonwoven fabric was wound around a fluororesin-coated mandrel with a diameter of 5 mm, and then a cylindrical piece with an inner diameter of 7 mm was wrapped. It was placed in a mold and heated and molded at 150°C for 10 minutes. The mandrel was pulled out to obtain a porous polyurethane tubular body. This tubular body had a secondary structure in which the nonwoven fabrics were firmly joined to each other and integrated.

Subsequently, CF4 monomer gas was flowed on the inner surface of the tubular body, and argon gas was flowed on the outside so that the pressure was slightly higher than that of the inner surface. The pressure of argon gas was 1 mbar. 13.
A high frequency of 56 MHz was applied at an output of 30 W 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 contact.

Albumin adsorption was performed by immersing the sample in a 0.1% albumin aqueous solution and stirring the solution. The wicking capacity was determined from the albumin concentration of the residual solution.

3. The amount of adsorption is that of plasma-free. lX10'g
/cm2, whereas the plasma treated product is 1.2X
The water permeability of this tubular body was measured to be 380 me/min. Furthermore, Table 1 shows the results of evaluating antithrombotic properties using the method described in this specification. As shown in Table 1, M and tM were found to have very good antithrombotic properties on the inner surface and were used as artificial blood vessels.

(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 also to make use of the elastic properties of polyurethane as a biomedical material. It has the advantage of being favorable for invasion and of being easy to retain living tissue. In addition, the blood-contacting surface has been given high antithrombotic properties by low-temperature plasma treatment with fluorine compounds and albumin adsorption treatment, and the inner surface has high antithrombotic properties, making it suitable for use as a small-diameter artificial blood vessel. In addition, since a fluorine compound plasma polymerized film is formed on mechanically good elastic polyurethane fibers and albumin is further adsorbed, it takes advantage of the mechanical advantages of the material and Only the surface properties of the material have been changed to antithrombotic properties, and the drawbacks of conventional materials include poor formability, low mechanical strength, low durability, and changes in antithrombotic properties. This is a greatly improved version of the following.

In addition, the method of the present invention does not use any solvents, so there is no need to worry about harm to the human body due to residual bath additives, and it is completely safe.Furthermore, it does not require special materials, processes, or conditions. It has great advantages, such as being able to be manufactured at an extremely low cost.

Furthermore, in addition to straight-shaped 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.

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 low-temperature gas plasma treatment with a fluorine compound, and then adsorbing albumin. (2) The manufacturing method according to claim 1, wherein the polyurethane elastic fibers have an average diameter of 30 microns or less. (3) The manufacturing method according to claim 1, wherein the heating molding temperature is 70 to 200°C. (4) The manufacturing method according to claim 1, in which albumin is adsorbed by immersing the inner surface of a tubular body subjected to plasma treatment in an albumin aqueous solution.