JPH0254101B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an artificial blood vessel having a 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, large-diameter arterial artificial blood vessels with an inner diameter of approximately 6 mm or more include, for example, Dobesky artificial blood vessels made of Dacron knitted fabric manufactured by the US patent USCI, and expanded polytetrafluoroethylene (hereinafter referred to as EPTFE) manufactured by Gore, Inc. BIOGRAFT using Goretex and human umbilical veins
(manufactured by Meedokus Medical Co., Ltd.) and others are used clinically. However, since the compliance of these artificial blood vessels is significantly different from that of living blood vessels, they have the disadvantage that various problems of incompatibility may occur at the anastomosis after a long period of time after implantation in a living body. Furthermore, when used as a small-caliber arterial artificial blood vessel with an inner diameter of about 6 mm or less, the difference in compliance is noticeable and the patency is poor, making it impossible to use clinically. Therefore, autologous veins are used in surgeries for revascularization of arteries below the knee, coronary arteries, and the like. Based on the above, when developing artificial blood vessels, especially artificial blood vessels for small-caliber arteries, it is important to not only improve the blood compatibility of the material of the artificial blood vessel, but also to make the compliance similar to that of biological blood vessels. It is said that. However, the compliance of currently developed artificial blood vessels is limited by the report by Sasashima et al. (Artificial Organs 12(1), 179
-182, 1983), as shown in Table 1.

【table】

[Table] As shown in Table 1, the compliance of current artificial blood vessels is very small compared to that of living arteries, and 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, this artificial blood vessel is manufactured by dipping the mandrel in an elastomer solution, then taking it out, coating the solution on the mandrel, and dipping it in a poor solvent (water) to precipitate the elastomer. There are only very small pores in the cross-section of the wall of the artificial blood vessel, resulting in a relatively dense structure. Although the compliance is certainly greater than that of conventional artificial blood vessels, it is still smaller than that of biological blood vessels and is not fully satisfactory. Another drawback is that it is difficult to uniformly coat the mandrel with the elastomer solution, making it difficult to obtain an artificial blood vessel with uniform performance. JP-A-57-150954 discloses an arterial graft prosthesis consisting of at least two zones: a porous elastomer zone and a solid elastomer zone. Among the artificial blood vessels described in this patent, the present inventor has manufactured the artificial blood vessels whose tube wall cross section consists of a solid elastomer zone, a porous elastomer zone, and a solid elastomer zone by the method disclosed in the patent. However, due to the two solid elastomer zones, the pore-forming agent in the porous elastomer zone could not be eluted, and the desired artificial blood vessel could not be manufactured. As mentioned above, it is said that it is important for artificial blood vessels to have compliance that approximates that of living blood vessels, especially as the artificial blood vessels become smaller in diameter. However, the reality is that no artificial blood vessel has been developed that has the compliance that is considered necessary. As a result of extensive research aimed at creating an artificial blood vessel with compliance similar to that of a biological blood vessel, the present inventor discovered that by extruding an elastomer solution into a tube shape from an annular nozzle and immersing the inside and outside of the tube in a coagulating liquid, The inventors have discovered that it is possible to obtain a tubular object that includes an asymmetric structure in the cross section of the tube wall, and that the compliance of this tubular object can be made to approximate that of a biological blood vessel, and the present invention has been achieved. That is, the present invention is made of an elastomer, includes a structure corresponding to an asymmetric structure in which the cross section of the tube wall has a skin layer at least on the inside of the tube wall, and a sponge structure layer inside the tube wall, and has a low compliance.
The present invention relates to an artificial blood vessel characterized in that the ratio is 0.1 to 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 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, polyester elastomers, and blends of these elastomers with polymers other than elastomers within the range that maintains the properties of elastomers. can give. 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, and the like. 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, bird segment, and soft segment. Examples include segmented polyurethane urea containing fluorine in the main chain, and polyurethane or polyurethane urea containing polydimethylsiloxane in the main chain as disclosed in JP-A-57-211358. Particularly preferred are polydimethylsiloxane formulas: (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 cross-section of the tube wall of the artificial blood vessel of the present invention includes an asymmetric structure in which at least a skin layer is present inside the tube and a sponge structure layer is formed inside the tube wall, and the sponge structure layer has a double-cell structure. It is preferable to have a layer consisting of: The skin layer is a layer made of an elastomer that is more uniform and dense than the inside of the tube wall, and its thickness is preferably 0.5 to 20 μm, more preferably 1 to 15 μm. The thickness of the skin layer
If it exceeds 20 μm, the compliance tends to become too small, and if it becomes less than 0.5 μm, the strength of the blood vessel tends to decrease. Unlike cast films or molded products manufactured from a molten state, which have very dense elastomer molecules and have a transparent or clear appearance, the skin layer has minute pores and holes inside. It has a sparse structure compared to the above films and molded products, and is an opaque layer when observed with the naked eye. The maximum diameter of the minute pores or holes present in the skin layer is preferably about 1 μm or less, more preferably 0.5 μm or less, and particularly preferably 0.1 μm or less. However, holes with a maximum diameter of about 1 to 10 μm may exist on the surface of the skin layer. When the skin layer exists at least inside the tube and has the structure described above, an artificial blood vessel that does not disrupt blood flow and has appropriate compliance and strength can be obtained. A sponge structure layer is a structure in which cellular voids are assembled in a spherical, ellipsoidal, or modified shape with a maximum diameter of about 1 μm to about 3/5 of the thickness of the tube wall. say. This sponge structure layer portion has a very sparse structure compared to the skin layer. However, it is preferable that the partition walls themselves forming the pores having a sponge structure contain many minute pores and pores, similarly to the skin layer. A more preferable sponge structure layer is a layer having a structure in which cells of uniform size exist in a sponge-like manner. The maximum diameter of the cell at this time is 1 to 100 μm
is preferable, more preferably 5 to 75 μm, and particularly preferably 10 to 40 μm.
A particularly preferred sponge structure is a double cell structure in which two cells are arranged between the inner skin layer and the outer side of the tube. The maximum diameter of this cell is preferably about 1/5 to 3/5 of the thickness of the tube wall, more preferably about 1/3 to 1/2 of the thickness of the tube wall. However, a cell smaller than this cell may exist in the portion where this cell and the skin layer are in contact. If there is no skin layer on the outside of the tube, the outside may have the shape of cut sponge or a mesh shape. 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
Differential pressure 100 mmHg from Hg to internal pressure 150 mmHg, ΔV represents the internal volume of the measuring vessel increasing between ΔP)
It is defined by In actual measurement, a measurement blood vessel is inserted into a closed circuit, and a micrometer metering pump is used to measure the amount of injected fluid and changes in the pressure inside the circuit, and compliance can be determined from the above equation. Since the tube wall of the artificial blood vessel of the present invention includes an asymmetric structure, the density of the elastomer in the tube wall is sparse. Therefore, the compliance of the artificial blood vessel of the present invention is increased, and it can be approximated to a living blood vessel. Adjustment of compliance is possible by adjusting the elastomer density of the tube wall, the strength of the elastomer, the thickness of the tube wall, etc. 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 of 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 tube wall elastomer varies depending on the strength of the elastomer and the thickness of the tube wall, and the required compliance varies depending on the location of the biological blood vessel, so it cannot be determined unconditionally, but it is preferably 0.05 ~0.35g/cm ³ , more preferably 0.1~
0.3 g/cm ³ , particularly preferably 0.125 to 0.25 g/cm ³
It is. The strength of the elastomer cannot be absolutely determined due to the influence of the elastomer density of the tube wall, etc., but preferably the tensile strength at break is 100 to 700 Kg/cm ² and the elongation at break is 100 to 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 further improvement, 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. Further, when a skin layer is formed on the outside of the artificial blood vessel, holes with a diameter and depth of approximately 1 to 30 μm may be provided for the purpose of improving the bonding property with living tissue. The artificial blood vessel of the present invention having the above-described structure has a compliance similar to that of a biological blood vessel, and a blood contact surface that has excellent blood compatibility.
It also has the following useful properties: 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 to having a structure with a low elastomer density that includes an asymmetric structure in the cross section of the pipe wall, the partition wall itself that forms the skin layer and the pocket-like voids of the sponge structure has a sparse structure with minute holes inside. Therefore, the penetrating property of the suture needle is very good, and suturing with a living blood vessel is easy, and even if the sutured portion is pulled, the sutured portion will not fray or 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. 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 considered to be due to the fact that the compliance is similar to that of living blood vessels. The artificial blood vessel of the present invention, which has such excellent performance, extrudes the elastomer solution from the annular nozzle together with the internal coagulating liquid, and immerses the entire body in the external coagulating liquid.
It can be manufactured by depositing an elastomer into a tubular shape. The annular nozzle is capable of extruding the elastomer solution into a tubular shape and injecting an internal coagulating liquid into the annular nozzle. The annular nozzle will be explained using drawings. FIG. 1 shows the surface of the annular nozzle 3 having an extrusion port for 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. Next, one embodiment of the method for manufacturing an artificial blood vessel of the present invention will be shown and explained. An elastomer solution can be obtained by dissolving the elastomer in a good solvent that dissolves the elastomer well.
After extruding this solution into a tube from an annular nozzle,
Immediately or after maintaining a certain dry distance,
Immerse in coagulation solution. At the same time, a fixed amount of coagulating liquid is injected into the tube according to the extrusion speed from the nozzle. The elastomer solution extruded into a tubular shape is replaced with a good solvent and a coagulating solution, whereby the elastomer is precipitated and an artificial blood vessel, which is a tubular structure made of the elastomer, is obtained. Good solvents vary depending on the type of elastomer, so they cannot be determined unconditionally, but they are usually N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, and N-methyl-2.
- Solvents such as pyrrolidone, dioxane, and tetrahydrofuran may be used alone or in combination of two or more. The coagulating liquid may be one that does not dissolve the elastomer and is miscible with a good solvent. Usually water,
Lower alcohols, ethylene glycol, propylene glycol, 1,4-butanediol, glycerin, etc. may be used alone or in combination of two or more. The selection of the elastomer concentration in the solution is important because it has a strong influence on the compliance and viscosity of the solution. Usually 5~
35% (weight%, same below) is preferable, 10-30%
is more preferable, and 12.5 to 25% is particularly preferable. When the elastomer concentration is lower than 5%, the compliance tends to be too large and the precipitates in the coagulation liquid tend to be difficult to form into a tubular shape. Elastomer concentration
If it exceeds 35%, the compliance will be too small or the solution viscosity will be too high, making it difficult to extrude the elastomer solution into a tubular shape from the annular nozzle. For the purpose of adjusting the sponge structure inside the tube wall, the thickness of the skin layer, and the appearance and shape of the artificial blood vessel, a poor solvent that is miscible with a good solvent but does not dissolve the elastomer may be added to the elastomer solution. Furthermore, for the same purpose, a water-soluble inorganic salt or a good solvent may be added to the coagulation solution to adjust the coagulation rate of the elastomer solution. Of course, it is not necessary that the coagulating liquid passed into the tube and the coagulating liquid outside the tube be the same, and may be adjusted so as to obtain a desired artificial blood vessel. The artificial blood vessel thus obtained includes an asymmetric structure in the cross section of the vessel wall, and has a compliance similar to that of a living blood vessel. An explanatory diagram of one embodiment of the cross section of the artificial blood vessel obtained as described above is shown in FIG. 2, and a partially enlarged explanatory diagram thereof is shown in FIG. As shown in FIG. 2, skin layers 4 and 7 exist on the inside and outside of the tube wall, and the skin layer 4 and the skin layer 7
A cell 6 partitioned by a diaphragm 5 is formed so as to have a substantially double cell structure, and the cross section of the tube wall includes an asymmetric structure. The artificial blood vessel of the present invention having the above structure has the following features. Compliance approximates that of biological blood vessels. The blood contact surface has excellent blood compatibility. The suture needle has good penetrability and suturing is easy. No fraying occurs at the cut end even when cut to any length. Further, the suture thread does not become frayed from the sutured portion. The suture needle's through hole self-closes. 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, a patch material, and can also be used for blood access, etc. in revascularization surgery. Furthermore, it can be used as an arterial artificial blood vessel with a compliance of 0.1 to 0.8. In particular, the compliance is close to that of biological blood vessels, and the blood contact surface has excellent blood compatibility, so it has a compliance of 0.1 to 0.5, which is currently not available in clinically used artificial blood vessels, and an inner diameter of approximately 1.
It can be used as an artificial blood vessel for small diameter arteries of ~6 mm. 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 object of a living body such as a ureter. . Next, the artificial blood vessel of the present invention will be explained with reference to Examples. Example 1 20 g of the polyurethane described in Example 1 of JP-A-58-188458 was mixed with 80 g of N,N-dimethylacetamide.
Dissolved in ml. After thoroughly degassing this solution under reduced pressure, a gear pump is used to pump it through an annular nozzle (solution outlet dimensions are 3 mm in inner diameter and 4.5 mm in outer diameter) at a constant speed (40 mm in diameter).
cm/min). At the same time, water was injected inside the tube at the same rate as the extrusion rate. The extruded tubular solution was immediately immersed in water to precipitate the elastomer into a tubular shape. After thoroughly washing with water to remove the solvent, it was cut to the required size to obtain an artificial blood vessel. The resulting artificial blood vessel has an inner diameter of 3 mm and an outer diameter of approximately 4.5 mm.
It was hot. An explanatory view for explaining the image obtained when a 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 view is shown in FIG. Next, this artificial blood vessel was cut and the cut part was sutured 1 mm from the end, and the penetrability of the suture needle was as follows.
Similar to biological blood vessels, there was no fraying at the cut section, and the tube did not tear even when the sutured section was pulled. Moreover, the through hole of the suture needle self-occluded when the needle was removed. The obtained artificial blood vessel was cut to a length of 8 cm and inserted into a closed circuit. Then, using a metering pump that pumps 0.05 ml per stroke, bovine ACD blood was pumped into this closed circuit, and 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 0.35. 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 was found that this artificial blood vessel is excellent as an artificial blood vessel for small-caliber arteries. Example 2 4,4'-diphenylmethane diisocyanate 2
17.5 g of segmented polyurethaneurea, which is a prepolymer prepared from 1 mole of polytetramethylene glycol with a molecular weight of 2000 and chain-extended with 1 mole of ethylenediamine, is dissolved in a mixed solvent of 37.5 ml of N,N-dimethylacetamide and 25 ml of propylene glycol. did. After this solution was sufficiently degassed under reduced pressure, it was injected at a constant rate into an annular nozzle (solution outlet dimensions: inner diameter 3 mm, outer diameter 4.1 mm) using a gear pump, and extruded into a tubular shape. At the same time, defoamed water was injected into the inside of the tube at a rate 1.2 times the extrusion rate. The extruded tubular solution was immediately immersed in water to precipitate the elastomer into a tubular shape. After thoroughly washing with water to remove the solvent, it was cut to the required size to obtain an artificial blood vessel. The obtained artificial blood vessel has an inner diameter of approximately 3 mm and an outer diameter of approximately 4.1 mm.
It was warm in mm. The cross section of the tube wall had a sponge-like structure, and compliance was measured in the same manner as in Example 1 and was found to be 0.4. This artificial blood vessel could be cut at any location without fraying at the cut end. In addition, suturing with living blood vessels was very easy, and even when the sutured portion was pulled, it did not tear, and the through hole of the suture needle self-occluded.

[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 an image obtained when observing a cross section of the wall of the artificial blood vessel of the present invention manufactured in Example 1 with a scanning electron microscope. FIG. 3 is a partially enlarged explanatory diagram of FIG. 2.

Claims (1)

[Claims] 1. It is made of an elastomer, has a skin layer on the inside of the pipe wall at least on the cross section of the pipe wall, has a sponge structure layer on the inside of the pipe wall, and has an asymmetric structure, and has a compliance of 0.1 to 0.8. An artificial blood vessel characterized by: 2. The artificial blood vessel according to claim 1, wherein the elastomer is a thermoplastic elastomer with excellent blood compatibility. 3. The artificial blood vessel according to claim 1, wherein the sponge structure layer has a double cell structure. 4. The artificial blood vessel according to claim 1, wherein the artificial blood vessel is a small-caliber arterial artificial blood vessel having an inner diameter of 1 to 6 mm and a compliance of 0.1 to 0.5. 5. The artificial blood vessel according to claim 1, wherein the artificial blood vessel is an artificial blood vessel for aorta-coronary artery bypass.