JPH0228979B2 - - Google Patents

Description

[Detailed description of the invention]

[Technical Field of the Invention] The present invention relates to a method for manufacturing an artificial blood vessel having porosity and compliance similar to that of a biological blood vessel. [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 are available in the United States, for example.
Dobesky artificial blood vessels made of Dacron knitted fabric manufactured by USCI and Gore-Tex made of expanded polytetrafluoroethylene (hereinafter referred to as EPTFE) manufactured by Gore, Inc. in the United States are used clinically. These artificial blood vessels have a hole that communicates from the inside to the outside of the blood vessel, and after being implanted in a living body, they are immediately covered with pseudoendothelium, and tissue enters from the living tissue side through this hole, making it stable. organized into
It fulfills its mission as an artificial blood vessel. Having communicating pores that are useful for organizing the artificial blood vessel in this way is hereinafter referred to as having porosity. However, the compliance of these artificial blood vessels is significantly different from that of biological blood vessels, so if a long period of time has passed after implantation in a living body,
Various incompatibility problems occur, such as hyperplasia of the pannus at the anastomosis. Furthermore, when used as a small-caliber arterial artificial blood vessel with an inner diameter of about 6 mm or less, there is a noticeable difference in compliance and poor patency, making it impossible to use clinically. Therefore, autologous arteries are used in revascularization surgeries for arteries below the knee, coronary arteries, and the like. Based on the above, when developing artificial blood vessels for arteries, especially artificial blood vessels for small diameter arteries, it is necessary to improve the porosity of the artificial blood vessels and the blood compatibility of the material of the artificial blood vessels. It is said that it is important to approximate compliance to that of living blood vessels. However, the compliance of currently developed artificial blood vessels is limited by the reports of Sasashima et al. (Artificial Organs 12(1),
179-182, 1983), as shown in Table 1.

【table】

[Structure of the invention]

In view of the above-mentioned circumstances, the inventor of the present invention has conducted intensive research into a manufacturing method for an artificial blood vessel that is porous and has a compliance similar to that of a biological blood vessel, and has found that the phase change of the elastomer solution and the coagulation solution The present invention was completed based on the discovery that the above object can be achieved by combining the precipitation of an elastomer in the elastomer. That is, the present invention relates to a method for manufacturing an artificial blood vessel, which comprises maintaining an elastomer solution having a cloud point at a temperature above the cloud point, coating the mandrel, and then immersing the mandrel in a coagulating liquid at a temperature below the cloud point. [Embodiments of the Invention] The cloud point is the temperature at which a polymer precipitates from a dissolved state into a colloid, that is, undergoes a phase change. The cloud point can be confirmed by a change in the viscosity of the polymer solution or by the phenomenon of cloudiness. In the present invention, the elastomer solution having a cloud point is maintained at a temperature exceeding the cloud point,
After coating the mandrel, the mandrel is immersed at a temperature below the cloud point temperature, either immediately or after a phase change has occurred, to cause a phase change of the coating layer and precipitation in the coagulation liquid, either simultaneously or sequentially. It causes it to occur. The artificial blood vessel manufactured by this method has holes that communicate from the inside of the tube to the outside. Further, in order to control the number and size of these communicating pores, it is more advantageous to include a pore-forming agent in the elastomer solution. The elastomer used in the present invention is a thermoplastic elastomer with excellent blood compatibility, that is, it does not contain low-molecular eluates that can cause acute toxicity, inflammation, hemolysis, exothermic reactions, etc., and does not cause serious damage to blood physiological functions. It is a thermoplastic elastomer with excellent antithrombotic properties. Examples of such elastomers include polystyrene elastomers, polyurethane elastomers, polyolefin elastomers, and polyester elastomers, and these may be used alone or two or more of them may be mixed. The elastomer used in the present invention only needs to have properties as an elastomer when molded into an artificial blood vessel, so a composition of the above-mentioned elastomer (resin) and a resin that does not have properties as an elastomer may be used. However, if the final molded product has properties as an elastomer, it can be used as an elastomer for the present invention. Among these elastomers, polyurethane elastomers are more preferred from the viewpoint of strength, durability, and antithrombotic properties. Specific examples of polyurethane elastomers include polyurethane, polyurethane urea, and blends of these and silicone polymers. Among the above-mentioned polyurethanes and polyurethane ureas, polyether types are more preferable than polyester types from the viewpoint of durability in vivo, and even more preferable are segmented polyurethanes, segmented polyurethane ureas, hard segments, or soft segments. Segmented polyurethane or polyurethane urea containing fluorine, polyurethane or polyurethane urea containing polydimethylsiloxane in the main chain disclosed in JP-A-57-211358, and the like. Particularly preferred are polydimethylsiloxanes of the formula: (In the formula, R ₁ to _{R 6} are alkylene groups having 1 or more carbon atoms,
Preferably, an alkylene group having 2 to 6 carbon atoms such as ethylene, propylene, butylene, hexamethylene, etc., a and e are integers of 0 to 30, b and d are 0 or 1, and c is an integer of 2 or more). The polyether moiety is (-CH ₂ CH ₂ CH ₂ CH ₂ O) - _{26 to 30} or

Examples include polyurethane or polyurethane urea. The solvent for preparing the elastomer solution used in the present invention includes a solvent that dissolves the elastomer well (hereinafter referred to as a good solvent), and a solvent that is miscible with the good solvent but does not dissolve the elastomer (hereinafter referred to as a poor solvent). Consisting of The good solvent used is
Solvents such as N,N-dimethylacetamide, N,N-formamide, N-methyl-2-pyrrolidone, dioxane, and tetrahydrofuran may be used, although it cannot be determined unambiguously because they vary depending on the type of elastomer. may be used alone or as a mixed solvent. The poor solvent to be used also varies depending on the type of elastomer, so it cannot be determined unconditionally, but examples include water, lower alcohols, ethylene glycol, propylene glycol, 1,4-butanediol, and glycerin. At least one of these is used. The elastomer solution used in the present invention contains an elastomer, a good solvent, and a poor solvent as essential components, and optionally contains a pore-forming agent. The antisolvent is included to ensure that the elastomer solution has a cloud point. The pore-forming agent used as necessary in the present invention is insoluble in the solvent in which the elastomer is dissolved, can be removed during or after molding of the artificial blood vessel, and forms pores and pores. Since it is used for an artificial blood vessel to be implanted in a living body, it is preferable to use a pore-forming agent that is sufficiently safe for the living body. Therefore, it is preferable to use safe substances such as inorganic salts such as common salt, and water-soluble sugar proteins such as glucose and starch. However, inorganic salts and water-soluble sugars are inherently hygroscopic, so if they are made into fine particles, their surface area increases and they tend to cause secondary aggregation due to moisture in the air, so they must be handled with great care. need to pay. Therefore, proteins are particularly preferred as pore-forming agents.
Even though the protein has a small particle size, it does not cause secondary aggregation due to moisture in the air, and it can be easily dissolved and removed from molded articles for artificial blood vessels with alkaline solution, acid solution, or solution containing enzymes. It is possible to form stable holes. Preferred proteins include casein, collagen, gelatin, and albumin, with casein being particularly preferred.
The particle size of the pore-forming agent is preferably 1 to 100 μm, and 10 to 100 μm.
More preferably 74 μm, 20 to 50 μm
It is particularly preferable that This particle size represents the length of one side of the mesh of the sieve, and refers to the particles classified by these sieves. The amount of pore-forming agent (in volume % of amount of pore-forming agent/amount of elastomer in the elastomer solution) varies depending on the desired porosity, the particle size of the pore-forming agent, and the composition of the elastomer solution. So,
Although it cannot be determined unconditionally, it is preferably 1 to 250%, more preferably 20 to 200%, and particularly preferably 50 to 150%. If the amount of the pore-forming agent exceeds 250%, too many pores are formed, resulting in excessive compliance, poor durability against blood pressure, and high viscosity of the elastomer solution, making it difficult to operate. They tend to get used to each other. The concentration of elastomer in the elastomer solution is
5 to 35% (weight%, the same applies hereinafter), preferably 10
-30% is more preferable, and 12.5-25% is particularly preferable. When the elastomer concentration is lower than 5%, uniform molding tends to be difficult. Furthermore, if the elastomer concentration exceeds 35%, the viscosity of the solution increases, which tends to make uniform coating difficult. The coagulating liquid used in the present invention may be substantially a poor solvent for the elastomer. Examples include water, lower alcohols, ethylene glycol, propylene glycol, 1,4-butanediol, and glycerin, which may be used alone or in combination of two or more. Preferred is water, ethylene glycol, propylene glycol, or a poor solvent containing these as main components, and more preferred is a mixed solvent in which 1 to 50 volume % of a good solvent is added to 99 to 50 volume % of the poor solvent. Porosity can be easily obtained by adding a good solvent to the coagulation solution. This is considered to be due to the slow coagulation rate of the elastomer solution in the coagulation solution. The mandrel used in the present invention is not particularly limited as long as it is not dissolved in the elastomer solution. For example, a glass rod, a Teflon rod, or a stainless steel rod with a smooth surface is suitable. It is also possible to use a mold of any shape instead of the mandrel, and by using such a mold, various medical molded objects other than tubular molded products can be manufactured by the method of the present invention. can. For example, if a flat plate is used as a mold, a film-like molded product is obtained, which can be used for artificial skin and the like. Next, the method for manufacturing an artificial blood vessel of the present invention will be explained based on one embodiment. An elastomer solution with a cloud point is prepared and maintained at a temperature above the cloud point. By immersing the mandrel in this solution and then taking it out, the mandrel is coated uniformly. Immediately or after causing a phase change in the coating layer, the mandrel is immersed in a coagulating liquid at a temperature below the cloud point to precipitate the elastomer.
Repeat this operation as necessary to obtain the desired thickness. After sufficient solvent removal, the mandrel is removed, and if a pore-forming agent is used, the pore-forming agent is removed to obtain the desired artificial blood vessel. The inside of the artificial blood vessel of the present invention manufactured in this way, that is, the blood contact surface, is composed of an elastomer with excellent blood compatibility, and although the blood compatibility is good, the initial The inner surface may be coated with albumin, gelatin, chondroitin sulfate, heparinized material, etc. in order to further improve the antithrombotic properties. Further, in order to withstand abnormal increases in blood pressure during surgery, etc., and to maintain durability over a long period of time, mesh nets, non-woven fabrics, etc. may be inserted outside the artificial blood vessel of the present invention or between the coating layers for reinforcement. . The artificial blood vessel manufactured by the method of the present invention described above has a network structure in which the tube wall is partially or completely exposed on the inner and outer surfaces. The elastomer phase forming the network structure has pores and pores associated with the removal of fine particles. Therefore, by changing the cloud point, type of poor solvent, amount of pore-forming agent, particle size, etc., any desired porosity can be achieved. and,
The pores thus formed promote the formation of pseudointima and help stabilize the formed pseudointima.
Further, the artificial blood vessel manufactured by the method of the present invention can be made to have a compliance that matches that of the artery when the inner diameter of the tube and the thickness of the tube wall are matched to that of the artery. This is achieved because the constituent material is an elastomer and the elastomer occupying the tube wall has a sparse density structure. The compliance referred to in this specification is expressed by the formula (1): C=ΔV/Vo・ΔP×100 (1) (where C is the 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. For specific measurements, a measurement blood vessel is inserted into a closed circuit, a liquid is injected into this circuit using a micrometer metering pump, and the amount of injected liquid and the change in pressure within the circuit are measured.
Compliance can be found from equation (1). The artificial blood vessel manufactured by the method of the present invention is porous, has a compliance similar to that of a biological blood vessel, and has a blood contact surface with excellent blood compatibility. In addition, it also has the following useful properties: have. That is, since the tube wall is substantially a continuous structure of elastomer, the cut end will not fray even if it is cut to an arbitrary length. In addition, because the cross section of the tube wall has a structure with low elastomer density, the suture needle penetrates very well, making it easy to suture with living blood vessels.
Moreover, even if the sutured portion is pulled, the sutured portion will not fray and the suture thread will not come off. Since the tube wall is made of elastomer, the hole penetrated by the suture needle also self-closes when the needle is no longer present, and no blood leaks. A further surprising property is that the artificial blood vessel according to the present invention does not form knots when blood flows inside it and pressure is applied. This is considered to be due to the fact that the compliance is similar to that of living blood vessels. As described above, the method for manufacturing an artificial blood vessel of the present invention has the following characteristics. A porous artificial blood vessel can be manufactured. An artificial blood vessel with compliance similar to that of a biological blood vessel can be manufactured. It is possible to manufacture an artificial blood vessel that satisfies the basic properties of an artificial blood vessel as shown below. Γ Blood contact surface has excellent blood compatibility. The Γ suture needle has good penetration and suturing is easy. ΓNo fraying occurs at the cut end even when cut to any length. The suture thread does not come undone from the Γ suture. 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 manufactured by the method of the present invention can be used as an artificial blood vessel, a bypass artificial blood vessel, a patch material, etc. in revascularization surgery, and can also be used for blood vessel access, etc. can do. Furthermore, it can be used as an arterial artificial blood vessel having 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 has excellent blood compatibility, there are currently no artificial blood vessels for clinical use.
It has a compliance of 0.1 to 0.5, and the inner diameter is approximately 1 to 1.
It can also be used as a 6mm small diameter artery artificial blood vessel. In particular, it can be suitably used for revascularization of arteries below the knee and for aorta-coronary artery bypass vessels. Furthermore, the artificial blood vessel according to the present invention can be used as an arterial artificial blood vessel by covering the outside with a net with low compliance, and can also be used as a substitute for soft tubular objects in living bodies such as ureters. be. Next, the method for manufacturing the artificial blood vessel of the present invention will be explained using Examples. Example 1 15 g of the polyurethane described in Example 1 of JP-A-58-188458 was mixed with 55 g of N,N-dimethylacetamide.
70 ml to a mixed solvent of 30 ml of propylene glycol
The mixture was stirred and dissolved at ℃. The cloud point of this solution was approximately 40°C. A glass rod with a diameter of 3 mm was immersed in this solution kept at 70°C and then taken out, and the solution was uniformly coated on the glass rod. After the coating layer was left in the air until it became cloudy, the glass rod was immersed in water at 15°C, and the mixed solvent was thoroughly stirred with water. Thereafter, this operation was repeated once again, and after thorough washing with water, the glass rod was removed and an artificial blood vessel was obtained. The obtained artificial blood vessel has an inner diameter of approximately 3 mm and an outer diameter of approximately 4.5 mm.
It was warm in mm. When the inner surface, outer surface, and cross section of the tube wall of this artificial blood vessel were observed using a scanning electron microscope, pores with a maximum diameter of about 10 μm were almost uniformly present on the inner surface, the tube wall surface had a network structure, and the outer surface There were pores with a smaller maximum diameter than the inner surface. When water was passed through the artificial blood vessel at a pressure of 50 to 150 mmHg, water became wet on the outside of the artificial blood vessel. Next, this artificial blood vessel was pre-clotted with bovine blood, cut into pieces of 8 cm in length, inserted into a closed circuit, and fed bovine ACD blood into the closed circuit using a metering pump that pumped 0.05 ml per stroke. Changes in internal pressure were measured. Compliance was measured using equation (1) from the stroke number of the metering pump and changes in internal pressure, and was found to be 0.3. Furthermore, even if this artificial blood vessel was cut at any arbitrary location, the cut portion did not fray, and the suturing properties were excellent. Furthermore, the through hole of the suture needle self-occluded when the needle was removed, and no knots were formed in the presence of an internal pressure of 50 to 150 mmHg. From the above, it can be seen that the obtained artificial blood vessel is excellent as an artificial blood vessel for small-caliber arteries. Comparative Example 1 15g of the polyurethane used in Example 1 was mixed with N,N-
The mixture was stirred and dissolved in 85 ml of dimethylacetamide. This solution had no cloud point. The following operations were performed in the same manner as in Example 1 to obtain an artificial blood vessel. However, the glass rod uniformly coated with the solution was left in the air for the same time as in Example 1. The obtained artificial blood vessel had no porosity, as observed by scanning electron microscopy and when water was passed through it at a pressure of 50 to 150 mmHg. Example 2 Passed through a sieve of 30μm (sieve mesh size), 20μm
Casein that does not pass through a sieve of m (sieve mesh size)
22.5g, propylene glycol 45ml, dioxane 57.8ml, N,N-dimethylacetamide 24.8ml
was stirred and dispersed in a mixed solvent using a homogenizer. This dispersion was added to 22.5 g of the polyurethane used in Example 1, and the polyurethane was dissolved at 80°C. The cloud point of the resulting solution was approximately 45°C.
A glass rod with a diameter of 3 mm was immersed in this solution kept at 80°C and then taken out, and the solution was uniformly coated on the glass rod. The glass rod was then immersed in water at 18°C, and the mixed solvent was sufficiently replaced with water.
Thereafter, this operation was repeated once again, the glass rod was thoroughly washed with water, and the glass rod was extracted to obtain a tubular object. This tubular article was immersed in an aqueous sodium hydroxide solution with a pH of about 13.5, casein was sufficiently extracted and removed, and finally thoroughly washed with water to obtain an artificial blood vessel according to the present invention. The resulting artificial blood vessel has an inner diameter of approximately 3 mm and an outer diameter of approximately 4.5 mm.
It was hot. When the inner surface, outer surface, and cross section of the tube wall of this artificial blood vessel were observed using a scanning electron microscope, pores of about 5 to 10 μm were uniformly present on the inner and outer surfaces, and the cross section of the tube wall had a network structure. When water was passed through this artificial blood vessel at an internal pressure of 50 to 150 mmHg, water leaked to the outside. When the compliance of this artificial blood vessel was measured in the same manner as in Example 1, it was 0.35. In addition, even if this artificial blood vessel was cut at an arbitrary location, the cut surface did not fray, and the sutureability was excellent, and the through hole of the suture needle self-occluded when the needle was removed. No nodules were formed when the internal pressure was 50 to 150 mmHg.

Claims (1)

[Claims] 1. After maintaining an elastomer solution having a cloud point at a temperature exceeding the cloud point and coating it on the mandrel,
A method for manufacturing an artificial blood vessel, which comprises immersing the mandrel in a coagulating liquid at a temperature below the cloud point. 2. The method according to claim 1, wherein the elastomer solution contains a pore-forming agent in an amount of 1 to 250% by volume based on the elastomer.