JPH0228337B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an artificial blood vessel having porosity and compliance similar to that of a biological blood vessel. In recent years, along with advances in vascular surgery, research into artificial blood vessels has progressed, and many 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 holes that communicate from the inside to the outside of the blood vessel, and after being implanted in a living body, they are immediately covered with pseudoendothelium, allowing tissue to enter from the living tissue side through these holes. , 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 biological blood vessels, and therefore, after a long period of time after implantation in a living body, various problems related to incompatibility such as hyperplasia of pannus occur at the anastomotic site. Also, the inner diameter is approximately 6mm
When used as the following small-caliber arterial artificial blood vessels, the difference in compliance is noticeable and the patency is poor, making it impossible to use clinically. Therefore, autologous veins are used in revascularization surgeries for arteries below the knee, coronary arteries, and the like. Based on the above, when developing artificial blood vessels, especially small-caliber arterial artificial blood vessels, in addition to ensuring that the artificial blood vessels have porosity and improving the blood compatibility of the artificial blood vessel materials, it is important to improve compliance. It is said that it is important to approximate biological 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】

[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 such compliance discrepancies, US Pat.
A method for producing an artificial blood vessel having a porous wall and compliance similar to that of a living blood vessel has been disclosed. However, with this artificial blood vessel, the mandrel is immersed in an elastomer solution, the mandrel is taken out, the solution is coated on the mandrel, and this is immersed in a poor solvent (water) to precipitate the elastomer. There are no holes communicating from the contact surface to the living tissue contact surface, and the cross section of the wall of the manufactured artificial blood vessel has only very small holes, resulting in a relatively dense structure. Although the compliance of the artificial blood vessel manufactured in this manner is greater than that of conventional artificial blood vessels, it is still lower than that of biological blood vessels. As mentioned above, it has been proposed that it is important for artificial blood vessels, especially for small-caliber arteries, to have porosity and compliance that approximates that of biological blood vessels. Despite efforts being made to achieve this goal, the reality is that no artificial blood vessel with the necessary compliance has been developed. As a result of extensive research in order to obtain an artificial blood vessel with porosity and compliance similar to that of biological blood vessels, the present inventor extruded an elastomer solution containing a pore-forming agent into a tubular shape from an annular nozzle. By immersing the inside and outside in a coagulation liquid, it is possible to obtain a tubular article having a skin layer on at least the inside of the tube wall cross section and a spongy structure inside;
We have discovered that by removing the pore-forming agent from this, it is possible to obtain an artificial blood vessel that is porous and has compliance similar to that of a biological blood vessel, and has thus arrived at the present invention. That is, the present invention is a structure made of an elastomer, having a skin layer on at least the inner side of the tube wall cross section, and a sponge-like structure inside, and in which the skin layer and the partition wall forming the sponge-like structure have 1 to 1.
50μm pores exist, compliance is 0.1~
The present invention relates to an artificial blood vessel characterized in that it is 0.8. 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 cause acute toxicity, inflammation, hemolysis, exothermic reactions, etc. A thermoplastic elastomer that does not cause damage and has excellent antithrombotic properties. Examples of such elastomers include polystyrene elastomers, polyurethane elastomers, polyolefin elastomers, polyester elastomers, etc.
These elastomers may be blended with polymers other than elastomers within a range that maintains the properties of elastomers. These may be used alone or in combination of two or more. Among these, polyurethane elastomers are more preferred from the viewpoint of strength, durability, antithrombotic properties, etc. Specific examples of polyurethane elastomers include polyurethane, polyurethane urea, and blends of these with 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 segmented polyurethaneurea containing fluorine,
Examples include polyurethane or polyurethane urea containing polydimethylsiloxane in the main chain as disclosed in JP-A-57-211358.
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 part contains -(
CH ₂ CH ₂ CH ₂ CH ₂ O−) or

Examples include polyurethane or polyurethane urea. The cross-section of the tube wall of the artificial blood vessel of the present invention has at least a skin layer on the inside and a sponge-like structure inside. The skin layer is a layer made of elastomer that is more uniform and dense than the inside of the tube wall, and its thickness is preferably 50 μm or less, and 0.5 μm or less.
It is more preferable that it is ~20μm, and it is 1~15μm.
It is particularly preferable that it is m. When the thickness of the skin layer exceeds 50 μm, it is difficult to form communicating holes, and the compliance tends to be too small.
Conversely, if the thickness of the skin layer is less than 0.5 μm, there is a risk of rupture due to blood pressure. The maximum diameter of the communicating pores present on the surface of the skin layer formed at least inside the artificial blood vessel is preferably 1 to 50 μm, more preferably 10 to 40 μm,
A thickness of 11 to 30 μm is particularly preferred. If the maximum diameter of the communicating hole is larger than 50 μm, the strength will be too weak, blood flow will be squeezed out, and the antithrombotic property will tend to decrease. Maximum diameter of communication hole is 1μ
When it is smaller than m, organization of the artificial blood vessel tends to be delayed. The sponge-like structure in the present invention is a structure in which cell-like voids made of a sphere, an ellipsoid, or a modified form thereof are present with partition walls made of an elastomer interposed therebetween. The partition wall made of this elastomer has communication holes with a maximum diameter of 1 to 50 μm. This diameter is preferably the same as the diameter of the pores on the surface of the skin layer. This spongy structure part is
It has a very sparse structure compared to the skin layer. A more preferable sponge-like structure is one in which cellular voids of uniform size are present. The maximum diameter of the cellular voids is preferably 1 to 100 μm, and 5 to 75 μm.
It is more preferable that it is, and it is especially preferable that it is 10-40 micrometers. The partition wall made of an elastomer forming the skin layer or sponge-like structure is
It is preferable to include a large number of minute holes and holes in addition to the communicating holes. The maximum diameter of the micropores and holes is approximately 1μ.
m or less, more preferably 0.5 μm,
Particularly preferred is 0.1 μm or less. Since the artificial blood vessel of the present invention has a hole that communicates from the inside to the outside of the vessel wall, when implanted in a living body,
Organization progresses rapidly and stable organization is achieved. The compliance referred to in this specification is expressed by the formula (1): C=△V/V ₀・△P×100 (1) (where C is compliance and V ₀ is the internal pressure of 50 mm
The internal volume of the measured blood vessel when Hg is measured, △P is the internal pressure 50 mm
100 mmHg from Hg to internal pressure 150 mmHg, ΔV is the internal volume of the measurement blood vessel that increases between internal pressure 50 mmHg and internal pressure 150 mmHg). The actual measurement involves inserting a measurement blood vessel (approximately 6 to 10 cm in length) into a closed circuit, injecting liquid into this circuit using a micrometer metering pump, and measuring the amount of injected liquid and changes in pressure within the circuit. Compliance can be calculated from equation (1). In the artificial blood vessel of the present invention, the constituent material is an elastomer, and the density of the elastomer occupying the vessel wall is sparse, so that compliance is increased.
Furthermore, the compliance of a living blood vessel can be approximated by adjusting the elastomer density, porosity, elastomer strength, and thickness of the tube wall. The preferred compliance for artificial blood vessels is
It varies depending on the thickness of the artificial blood vessel, the site of use, etc., and cannot be determined unconditionally, but the compliance of the living blood vessel used for normal revascularization surgery is 0.1 to 0.8.
Therefore, it is thought that it is preferable to set it within such a range. The compliance of the artificial blood vessel according to the present invention can be adjusted as described above, and any compliance within the range of 0.1 to 0.8 can be manufactured. Artificial blood vessels with a compliance of 0.1 to 0.8 are suitable for applications such as arterial blood vessels, depending on their thickness, and those with an inner diameter of 1 to 6 mm and a compliance of 0.1 to 0.5 are used as small-caliber arterial blood vessels. It can be suitably used. The optimal density of the vessel wall elastomer cannot be determined unconditionally because it varies depending on the porosity, the strength of the elastomer, and the thickness of the vessel wall, and the required compliance differs depending on the location of the biological blood vessel. , preferably 0.05-0.35g/ ^cm3 , 0.1-0.3
g/cm ³ is more preferred, and 0.125 to 0.25 g/cm ³ is particularly preferred. The strength of an elastomer cannot be determined unconditionally due to the influence of the elastomer density of the tube wall, etc., but the tensile strength when broken is 100 to 700 kg/cm ² , and the elongation when broken is 100 to 700 kg/cm 2.
It is preferably 100-1500%. The thickness of the tube wall may be adjusted to that of a living blood vessel. By adjusting these factors, the compliance of the artificial blood vessel of the present invention can be made to approximate that of a biological blood vessel. The inside of the artificial blood vessel of the present invention, that is, the blood contact surface, is a skin layer made of an elastomer with excellent blood compatibility. For the purpose of improving the quality, the surface may be coated with albumin, gelatin, chondroitin sulfate, heparinized material, etc. Further, the outside of the artificial blood vessel of the present invention may be reinforced with a net-like net, a nonwoven fabric, or the like in order to withstand an abnormal increase in blood pressure during surgery or the like or to maintain durability for a long period of time. The artificial blood vessel of the present invention having the structure described above 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 the following characteristics. 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, in addition to the structure in which the cross section of the tube wall has a low elastomer density, the skin layer and the partition wall itself, which is made of elastomer, has a sparse structure with minute pores and holes inside. It is easy to suture the blood vessel, and even if the sutured portion is pulled, the sutured portion will not fray or the suture thread will 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. Another surprising property is that the artificial blood vessel of the present invention does not form knots when blood flows inside it and blood pressure is applied. This is thought to be due to the fact that the compliance is similar to that of living blood vessels. Next, one embodiment of the method for manufacturing an artificial blood vessel of the present invention will be described. In the artificial blood vessel of the present invention, an elastomer solution containing a pore-forming agent is extruded from an annular nozzle together with an internal coagulating liquid, and the entire body is immersed in an external coagulating liquid immediately or after a certain dry distance, and the elastomer is precipitated into a tubular shape. , and then removing the pore-forming agent. The annular nozzle is capable of extruding the elastomer solution into a tubular shape and injecting the internal coagulating liquid into the annular nozzle. The annular nozzle will be explained using drawings. FIG. 1 shows the extrusion port of the annular nozzle 3 for extruding the elastomer solution. 1 is an outlet for the elastomer solution, and the inner and outer diameters of 1 may be determined according to the inner and outer diameters of the intended artificial blood vessel. 2 is an outlet for the internal coagulating liquid. The pore-forming agent may be used without particular limitation as long as it is insoluble in a good solvent for the elastomer used and can be removed during or after molding of the artificial blood vessel. When considering use in artificial blood vessels implanted in living bodies, it is desirable to use a pore-forming agent that is sufficiently safe for living bodies. Therefore, safe inorganic substances such as common salt, water-soluble saccharides such as glucose or starch, and proteins are preferable. Among these pore-forming agents, proteins are preferred from the viewpoint of handling. When protein is used as a pore-forming agent, stable pore-forming is possible without causing secondary aggregation due to moisture in the air even if the particle size is fine. Moreover, from molded products as artificial blood vessels,
It can be easily dissolved and removed with an alkaline solution, an acid solution, a solution containing enzymes, etc. Specific examples of proteins preferable as pore-forming agents include casein, collagen, gelatin, and albumin. The particle size of the pore-forming agent may be determined mainly according to the maximum diameter of the pores formed on the inner surface of the artificial blood vessel.
Amount of pore-forming agent (% of amount of pore-forming agent/amount of elastomer
(expressed as ) varies depending on the required porosity and the particle size of the pore-forming agent, so it cannot be determined unconditionally, but it is preferably 1 to 250%, more preferably 20 to 200%, Particularly preferably 50 to 150%. If the amount of the pore-forming agent exceeds 250%, there will be a tendency for the compliance to become too large, the durability against blood pressure to be poor, and the viscosity of the elastomer solution to become high, making it difficult to operate. On the other hand, if the amount of the pore-forming agent is less than 1%, it tends to be impossible to obtain the necessary porosity. The best good solvent for use in the present invention varies depending on the type of elastomer, so it cannot be determined unconditionally, but usually N,N-dimethylacetamide, N,N-dimethylformamide,
Examples include dimethyl sulfoxide, N-methyl-2-pyrrolidone, dioxane, and tetrahydrofuran, and these may be used alone or in combination. For the purpose of adjusting the structure and shape of the inner or outer surface of the artificial blood vessel wall, a solvent that does not dissolve the elastomer but is miscible with a good solvent (hereinafter referred to as a poor solvent) may be added to the elastomer solution. Examples of the poor solvent include water, lower alcohols, ethylene glycol, propylene glycol, 1,4-
Butanediol, glycerin, etc. are preferred. The elastomer concentration in the solution is preferably 5 to 35% (weight %: hereinafter the same), more preferably 10 to 30%, and particularly preferably 12.5 to 25%. When the elastomer concentration is less than 5%, the compliance tends to become too large and the precipitates in the coagulation liquid tend to be difficult to form into a tubular shape. On the other hand, when the elastomer concentration exceeds 35%, the compliance becomes too small and the solution viscosity becomes too high, making it difficult to extrude the elastomer solution into a tubular shape from the annular nozzle. The coagulating liquid used in the present invention includes poor solvents that do not dissolve the elastomer but are miscible with good solvents, such as water, lower alcohols, ethylene glycol, propylene glycol,
It is preferable to use at least one of 4-butanediol, glycerin, and the like. The internal coagulating liquid and external coagulating liquid may have the same or different compositions. The artificial blood vessel obtained in this way has a skin layer on at least the inside of the cross section of the tube wall, and has a sponge-like structure inside, and the skin layer and the partition wall forming the sponge-like structure have a thickness of 1 to 50 μm. pores exist, and the compliance is similar to that of biological blood vessels. FIG. 2 is an explanatory view of one embodiment of the cross section of the artificial blood vessel obtained as described above, FIG. 3 is a partially enlarged explanatory view of the cross section shown in FIG. 2, and the inner surface of the artificial blood vessel is shown in FIG. An explanatory diagram for explanation is shown in FIG. As shown in FIGS. 2 and 3, there are skin layers 4 and 5 on the inside and outside of the tube wall, and between the skin layers 4 and 5 there are cells 6 separated by partition walls 8. exist. Further, the skin layers 4 and 5 have a large number of holes 9 that open toward the outside (not shown in FIG. 2), and the partition wall 8 has a large number of holes 7. There are holes communicating up to layer 5. The holes that communicate with each other and reach the surface of the skin layer communicate with the outside as holes 9 shown in FIG. 4 on the inner surface 4a. The artificial blood vessel of the present invention having the above structure has the following features. (1) It has porosity that helps organize the artificial blood vessel. (2) Compliance approximates that of biological blood vessels. (3) The blood contact surface has excellent blood compatibility. (4) Suture needles penetrate well and suturing is easy. (5) No fraying will occur at the cut end even when cut to any length. Moreover, the suture thread does not become frayed from the sutured portion. (6) The through hole of the suture needle self-occludes. (7) Nodules are unlikely to form under actual conditions of use where blood pressure is high. Therefore, the artificial blood vessel of the present invention can be used as an artificial blood vessel, a bypass artificial blood vessel,
It can be used as a material for patches, and can also be used for blind access. More preferably, it can be used as an arterial artificial blood vessel having a compliance of 0.1 to 0.8. Particularly preferably, there are no artificial blood vessels currently used in clinical practice, since the compliance is similar to that of biological blood vessels and the blood contact surface has excellent blood compatibility.
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-caliber artificial blood vessel. In particular, it can be suitably used for revascularization of arteries below the knee and as an artificial blood vessel for aorta-coronary artery bypass. Furthermore, the artificial blood vessel of the present invention can be used as a venous artificial blood vessel by covering the outside with a net with low compliance, and can also be used as a substitute for a soft tubular body such as a ureter. Next, the artificial blood vessel of the present invention will be explained using Examples. Example 1 In 80 ml of N,N-dimethylacetamide, the particle size was
20 g of casein with a diameter of 30 to 50 μm was added and dispersed by stirring with a homogenizer. 20 g of the polyurethane described in Example 1 of JP-A-58-188458 was added and dissolved in this casein dispersion. After thoroughly degassing this solution under reduced pressure, it was heated using a gear pump while maintaining the solution at 60°C.
mm, outer diameter 4.5 mm) at approximately 40 cm/min. At the same time, defoamed water was injected into the inside of the tube at a rate of 1.2 times the internal volume of the extruded elastomer solution.
The extruded tubular solution was immediately immersed in water to precipitate the elastomer into a tubular shape. Wash thoroughly with water,
After removing the solvent, it was cut into required dimensions. The tubing was immersed in an aqueous solution of sodium hydroxide at a pH of approximately 13. The casein was eluted by stirring occasionally. The aqueous solution of sodium hydroxide was exchanged five times to completely remove casein, followed by washing with water to wash and remove the sodium hydroxide, and an artificial blood vessel was obtained. The resulting artificial blood vessel has an inner diameter of approximately 3 mm and an outer diameter of approximately 4.5 mm.
The inner diameter surface and outer diameter surface have a maximum diameter of 20 to 30 μm.
The skin layer had uniform pores. The cross section of the wall of the artificial blood vessel had a spongy structure, and the partition wall forming the spongy structure also had similar holes. An explanatory diagram for explaining the image obtained when the cross section of the wall of this artificial blood vessel is observed with a scanning electron microscope is shown in Fig. 2, and a partially enlarged explanatory diagram is shown in Fig. 3. FIG. 4 shows an explanatory diagram for explaining the image obtained when the inner surface of the wafer is observed with a scanning electron microscope. Even if this artificial blood vessel was cut at any point, the cut surface did not fray. Furthermore, suturing with a biological blood vessel was very easy, and the sutured portion did not become frayed even when the sutured portion was pulled. Furthermore, the through hole of the suture needle self-occluded when the needle was removed. Before removing the casein, this artificial blood vessel was cut into a length of 8 cm, inserted into the occlusion circuit, and the compliance was measured using the method shown below.
It was 0.5. The method of measuring compliance is to first send cow ACD blood to this closed circuit using a metering pump that pumps 0.05ml per stroke, measure the change in internal pressure, and measure the number of strokes of the metering pump and the change in internal pressure. It was calculated from equation (1). Furthermore, even when this artificial blood vessel was bent under an internal pressure of 50 to 150 mmHg, no knots were formed. From the above, it can be seen that this artificial blood vessel is excellent as an artificial blood vessel for small-caliber arteries.

[Brief explanation of drawings]

Fig. 1 is an explanatory diagram showing the extrusion port of the elastomer solution of the annular nozzle, and Fig. 2 is a cross-section of the wall of the artificial blood vessel of the present invention manufactured in Example 1, which was obtained by observing with a scanning electron microscope. An explanatory diagram for explaining the images, Fig. 3 is a partially enlarged explanatory diagram of Fig. 2, and Fig. 4 shows the inner surface of the artificial blood vessel obtained in Example 1 observed with a scanning electron microscope. FIG. 2 is an explanatory diagram for explaining the obtained video.

Claims (1)

[Claims] 1 It is made of an elastomer, has a skin layer on at least the inside of the tube wall cross section, and has a sponge-like structure inside, and pores of 1 to 50 μm are present in the skin layer and the partition wall forming the sponge-like structure, An artificial blood vessel characterized by a compliance of 0.1 to 0.8.