JPH0254102B2 - - 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 a pseudoendothelium, and tissue enters from the living tissue side through this hole. It has been stably organized and is fulfilling 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 artificial blood vessels, and therefore, after a long period of time after being implanted in a living body, various problems related to incompatibility such as hyperplasia of pannus occur at the anastomotic site. Furthermore, when used as a small-caliber arterial artificial blood vessel with an inner diameter of approximately 6 mm or less, there is a noticeable difference in compliance.
It cannot be used clinically due to poor patency (difficulty in clogging blood vessels). 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. Therefore, 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] As described above, the compliance of current artificial blood vessels is extremely small compared to that of living arteries, and compared to arteries, they are considered rigid vessels. In order to resolve this compliance mismatch between biological blood vessels and artificial blood vessels, U.S. Patent No.
No. 4,173,689 discloses a method for producing an artificial blood vessel that uses an elastomer as a material constituting the artificial blood vessel, has a porous tube wall, and has a compliance similar to that of a biological blood vessel. However, this artificial blood vessel has no porosity. [Structure of the Invention] In view of the above-mentioned circumstances, the present inventor has conducted intensive research on a method for manufacturing an artificial blood vessel that has a compliance similar to that of a biological blood vessel and has porosity. The present invention was completed based on the discovery that the above object can be achieved by immersion in a coagulating liquid. That is, the present invention relates to a method for producing an artificial blood vessel, which comprises coating a mandrel with an elastomer solution in which fine particles are dispersed, and then immersing the mandrel in a coagulation solution. [Embodiments of the Invention] In the present invention, the elastomer precipitated in the coagulation liquid with fine particles as the nucleus has a network structure, and it is thought that porosity and compliance similar to that of biological blood vessels can be obtained. Furthermore, when the fine particles are extracted and removed after molding, they act as a pore-forming agent and ensure porosity. The fine particles used in the present invention are insoluble in the solvent in which the elastomer is dissolved (hereinafter referred to as a good solvent), and preferably can be removed after molding the artificial blood vessel. Considering use in artificial blood vessels implanted in living bodies, it is preferable to use particles that are safe for living bodies. Therefore, the fine particles are preferably inorganic salts such as common salt, water-soluble sugars such as glucose or starch, or proteins. However, since inorganic salts and water-soluble saccharides are inherently hygroscopic, when 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. On the other hand, even if proteins are made into fine particles, they do not cause secondary aggregation due to moisture in the air, and can be uniformly and stably dispersed. Therefore, proteins are particularly preferred as microparticles. Furthermore, when protein is used, the fine particles can be easily dissolved and removed from the molded artificial blood vessel using an alkaline solution, an acid solution, a solution containing an enzyme, or the like. Specific examples of such preferred proteins include casein, collagen, gelatin, and albumin, and among these, casein is particularly preferred. The particle size of the fine particles is preferably 1 to 100 μm, and 10 to 100 μm.
74 μm is more preferable, and 20 to 50 μm is particularly preferable. The particle size here refers to the length of one side of the mesh of the sieve, and refers to the particles classified by these sieves. When the particle size is smaller than 1 μm,
The precipitated elastomer tends not to form a network structure, and when it is larger than 100 μm, it tends to have poor pressure resistance. The amount of fine particles used in the present invention cannot be determined unconditionally because it varies depending on the required porosity, particle size of the fine particles, and composition of the elastomer solution, but is preferably 20 to 250%. (Amount of fine particles/% elastomer volume, the same applies hereinafter), more preferably 50 to 200%. The amount of fine particles is 250%
If it exceeds this, too many pores are formed, which tends to result in excessive compliance and poor durability against blood pressure. On the other hand, when the amount of fine particles is less than 20%, porosity tends to become poor. 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 in combination of two or more. Furthermore, since the elastomer used in the present invention only needs to have properties as an elastomer when molded into an artificial blood vessel, 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 polyurethane and polyurethane urea, polyether type is more preferable than polyester type from the viewpoint of durability in vivo, and more preferable are segmented polyurethane, segmented polyurethane urea, hard segment or soft segment. 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. A good solution for preparing the elastomer solution used in the present invention varies depending on the type of elastomer, so it cannot be determined unconditionally, but for example, N,
Examples include solvents such as N-dimethylacetamide, N,N-formamide, N-methyl-2-pyrrolidone, dioxane, and tetrahydrofuran.
These may be used alone or as a mixed solvent. The elastomer solution used in the present invention contains fine particles,
The elastomer and a good solvent are essential components, but if necessary, a solvent that does not dissolve the elastomer (hereinafter referred to as
(referred to as a "poor solvent") may be added to the extent that the elastomer does not undergo a phase change. By adding a poor solvent, the solidification rate, external shape, and shape of the elastomer solution can be changed.
Porosity etc. can be adjusted. Examples of such a poor solvent include water, lower alcohols, ethylene glycol, propylene glycol, 1,4-butanediol, and glycerin, and one or more of these can be used. The elastomer concentration in the elastomer solution is preferably 5 to 35% (weight %, hereinafter the same), more preferably 10 to 30%, and particularly preferably 12.5 to 25%. If the elastomer concentration is lower than 5%, uniform molding tends to be difficult. Also, the elastomer concentration is 35
%, the viscosity of the solution is so high that uniform coating tends to become difficult. The coagulating liquid used in the present invention may be substantially a poor solvent. For example, water, lower alcohols, ethylene glycol, propylene glycol, 1,4
-Butanediol, glycerin, etc.
These may be used alone or in combination of two or more. Preferred is water or a poor solvent containing water as a main component, 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 liquid. This is considered to be due to the slow coagulation rate of the elastomer solution in the coagulation liquid. 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 goes without saying that by using a mold of any shape in place of the mandrel, various medical molded objects other than tubular molded objects can be manufactured by the method of the present invention. For example, if a flat plate is used as a mold, a film-like molded product can be obtained.
This can be used for artificial skin, etc. Next, a method for manufacturing an artificial blood vessel according to the present invention will be explained based on one embodiment. After the mandrel is immersed in an elastomer solution in which fine particles are dispersed, the mandrel is taken out and the solution is coated on the mandrel. This mandrel is immersed in a coagulation liquid to precipitate the elastomer. Repeat this operation as necessary to obtain the desired thickness. After sufficient solvent removal, remove the mandrel and remove fine particles as necessary.
Obtain the desired artificial blood vessel. The inside of the artificial blood vessel according to the present invention manufactured in this way, that is, the blood contact surface, is made of an elastomer with excellent blood compatibility, and although the blood compatibility is good, In order to further improve thrombogenicity, the inner surface of the artificial blood vessel may be coated with albumin, gelatin, chondroitin sulfate, heparinized material, or the like. In order to withstand an abnormal increase in blood pressure during surgery or the like and to maintain durability over a long period of time, the artificial blood vessel according to the present invention may be reinforced with a mesh net, nonwoven fabric, etc. on the outside or between the coating layers. In the artificial blood vessel manufactured by the method of the present invention described above, the tube wall has a network structure, and a part or all of it is 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, any desired porosity can be obtained by changing the particle size and addition amount of the fine particles or the composition of the coagulating liquid. The pores created in this way promote pseudointima formation and help stabilize the formed pseudointima.
Further, the artificial blood vessel manufactured by the method of the present invention can 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 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 between 50 mmHg and 150 mmHg. For specific measurements, a measurement blood vessel is inserted into a closed circuit, and a liquid is injected into this circuit using a micrometer metering pump.
The amount of injected liquid and the change in pressure in the circuit are measured, and the compliance is determined 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 has the following useful properties. It also has characteristics. First, since the tube wall is essentially 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, suture needle penetration is very good, making it easy to suture with living blood vessels, and even if the suture is pulled, the suture will not fray or the suture will come off. Never. Moreover, since the tube wall is made of an elastomer, the suture through-hole also self-closes when the needle is no longer present, preventing blood from leaking. 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 features. 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. An artificial blood vessel that satisfies the following basic properties as an artificial blood vessel can be manufactured. Γ Blood contact surface has excellent blood compatibility. The penetration of the Γ suture needle is very good, making suturing easy. ΓEven when cut to any length, the cut end will not fray. The suture thread does not come undone from the Γ suture. The through hole of the Γ suture needle self-closes. Nodules are less likely to form under high Γ blood pressure. Therefore, the artificial blood vessel produced by the method of the present invention can be used as a material for artificial blood vessels, bypass artificial blood vessels, and patches 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 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 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 as an artificial blood vessel for revascularization of arteries below the knee or for aorta-coronary artery bypass. Furthermore, the artificial blood vessel according to the present invention can be used as a venous artificial blood vessel by covering the outside with a net with low compliance, and can also be used as a substitute for soft tubular objects in living bodies such as ureters. be. Next, the method for manufacturing an artificial blood vessel of the present invention will be explained using Examples. Example 1 Passed through a sieve of 30 μm (sieve mesh size), 20 μm
Casein 15 that does not pass through a sieve (size of sieve mesh)
g was added to a mixed solvent of 60 ml of dioxane and 26 ml of N,N-dimethylacetamide using a homogenizer and analyzed. To this dispersion, 15 g of the polyurethane described in Example 1 of JP-A-58-188458 was added and dissolved with stirring. A glass rod with a diameter of 3 mm was immersed in this solution and then taken out, and the solution was uniformly coated on the glass rod. Add 15% by volume of dioxane to this mandrel.
immersed in an aqueous solution containing After the elastomer had been thoroughly extracted, this operation was repeated once more.
After thorough washing with water, the glass rod was removed to obtain a tubular object. This tubular article was immersed in an aqueous sodium hydroxide solution of pH 13.5 to extract and remove casein, 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 this artificial blood vessel was observed using a scanning electron microscope, it was found that pores of approximately 4 to 10 μm were present almost uniformly on the inner and outer surfaces, and the cross section of the tube wall had a network structure, indicating that it was porous as a whole. Was. Next, this artificial blood vessel was pre-clotted with bovine blood, cut into 8 cm lengths, inserted into a closed circuit, and fed with bovine ACD blood into the closed circuit using a metering pump that pumps 0.05 ml per stroke. , changes in internal pressure were measured. Compliance was measured from equation (1) based on the stroke of the metering pump and changes in internal pressure, and was found to be 0.35. Furthermore, even if this artificial blood vessel was cut at any point, the cut portion did not fray, and the sutureability was excellent, and the through hole of the suture needle self-occluded when the needle was removed.
Furthermore, the artificial blood vessel did not form any knots in the presence of an internal pressure of 50 to 150 mmHg.

Claims (1)

[Scope of Claims] 1. A method for manufacturing an artificial blood vessel, which comprises coating a mandrel with an elastomer solution in which fine particles are dispersed, and then immersing the mandrel in a coagulation solution. 2. The manufacturing method according to claim 1, wherein the fine particles have a particle size of 1 to 100 μm. 3 The amount of the fine particles is 20 to 20% relative to the elastomer.
250% by volume of the manufacturing method according to claim 1. 4. The manufacturing method according to claim 1, wherein the fine particles are proteins. 5 The coagulation liquid is a poor solvent for elastomer 99-50
% by volume and a good solvent for the elastomer from 1 to 50% by volume.